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I study BTEC health and social care - it's the new syllabus so unit 4 is the external assessment. Part A is the research and Part B is the exam. There are two different articles. I chose the Dementia article
We are doing Part A now and if anyone has any good articles for secondary research it will be massively appreciated... I am dreading this exam
For this exam I haven't been taught any of the information, my teacher left two weeks ago as she is now off sick and nobody knows when she is coming back. Any help people would be able to give would be massively helpful
Thank you
I study BTEC health and social care - it's the new syllabus so unit 4 is the external assessment. Part A is the research and Part B is the exam. There are two different articles. I chose the Dementia article
We are doing Part A now and if anyone has any good articles for secondary research it will be massively appreciated... I am dreading this exam
For this exam I haven't been taught any of the information, my teacher left two weeks ago as she is now off sick and nobody knows when she is coming back. Any help people would be able to give would be massively helpful
Thank you

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#2
Hi,
There are a few chapters on dementia in a psychiatry volume I have; I will try and scan some pages for you t-rrow. They might be a little complex for you to understand, but if you are stuck on any sections, I am happy to go through them with you.
M
There are a few chapters on dementia in a psychiatry volume I have; I will try and scan some pages for you t-rrow. They might be a little complex for you to understand, but if you are stuck on any sections, I am happy to go through them with you.
M
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(Original post by macpatelgh)
Hi,
There are a few chapters on dementia in a psychiatry volume I have; I will try and scan some pages for you t-rrow. They might be a little complex for you to understand, but if you are stuck on any sections, I am happy to go through them with you.
M
Hi,
There are a few chapters on dementia in a psychiatry volume I have; I will try and scan some pages for you t-rrow. They might be a little complex for you to understand, but if you are stuck on any sections, I am happy to go through them with you.
M
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#4
Hi sorry about delay - TSR apparently has major issues with attaching files (see the error I have been getting in screenshot below)
As I could not attach the .pdf that I scanned for you (this is just the first one, so be prepared to put in some solid work reading through all I send you [some to follow] - tell your mum to cook some nutritious brain food for you next few days
)
In view of the probs attaching the .pdf, I have used OCR (Optical Character Recognition) software to try and paste the text below. Hold on tight to your table before looking below haha! (there might be some spelling errors because OCR is not perfect, but it might be better than attaching a pdf in one way - you can copy and paste small bits (I would not recommend it, but I know you spring chickens like doing that!!
, and it is editable - not easy for.pdf unless you have Adobe Acrobat [which costs a bit]. (I hope this does not crash TSR's server!!
Also, the formatting is altered by most OCR packages, so it will look like a massive chunk, just copy and paste whole thing to MS Word then change paragraph and line spacing under Home tab > Paragraph group > click on tiny icon with tiny arrow at bottom right. In the Paragragh dialog box that opens, change settings to your preference, the click OK.
4.1.3 DEMENTIA : ALZHEIMER'S DIS EASE Benzodiazepines are an alternative; they may be also be helpful in re-establishing the sleep- wake cycle, but often at the cost of increased daytime drowsiness. Therefore a short-acting agent should usually be chosen. Medicolegal issues Physical restraint can usually be avoided with adequate nursing care and medication. The psychiatrist should not become party to dubious practices in this area, such as the use of de facto restraint with tight blankets or deliberately induced parkinsonism with major tranquillizers. If continued physical restraint is necessary in rare cases, it should be as an explicit part of the treatment plan after medicolegal advice. Informed consent to treatment also involves important medicolegal issues.o6 ) Patients with delirium are often very ill, and frequently require surgery or other invasive procedures that they are incapable of understanding and consenting to. The legal position is complex, and will vary in different jurisdictions. However, legal capacity should certainly be assessed before seeking consent. It is almost always wise to involve relatives in decisions in these circumstances. It may be necessary to consult medicolegal advisers, including the hospital authorities. Prevention A variety of methods for delirium prevention in hospitalized patients have been subjected to controlled evaluations. Cole and coworkers identified ten studies, of which three were randomized, in a systematic review;(I 2) patients were middle-aged or elderly medical and surgical cases. Interventions included preintervention psychiatric assessment, and pre- and postoperative nursing assessments. Of these studies, only one showed a signifiqll1t reduction of delirium in the t reated group, but this was a non-randomized study. Therefore it appears that there is little evidence to support the introduction of special measures, over and above routine care, to prevent delirium. Good general medical and nursing care must be the key to prevention as well as to early recognition and effective treatment. Screening for alcohol dependence is important, for example with the CAGE questions. Elderly patients who are very unwell physically or who are having a major procedure, who have pre-existing cognitive problems, and who are receiving polypharmacy (especially psycho active drugs) are the most likely to develop delirium, and should be monitored clinically for this condition. Hypnotics are associated with an increased risk of delirium; routine use should be avoided, especially in such vulnerable patients. References 1. Berrios, G. and Porter, R. (1995). A history of clinical psychiatry. The origin and history of psychiatric disorders. Athlone, London. 2. Walzer, T., Herrmann, M., and Wallesch, CW. (1997). Neuropsychological disorders after coronary bypass surgery. Journal of Neurology, Neurosurgery and Psychiatry, 62, 644--8. 3. Dyer, CB., Ashton, C M., and Teasdale, T.A. (1995). Postoperative delirium. A rchives of Internal Medicine, 155, 461- 5. 4. Wise, M.G. and Trzepacz, P. (1994) . Delirium. In Textbook of consultation- liaison psychiatry (ed. J.R. Rundell and M.G. Wise) . American Psychiatric Press, Washington, DC 5. Treloar, A.J. and Macdonald, A.J. (199 7) . Outcome of delirium: Pa rt 1. Outcome of delirium di ag nosed by DSM-III-R, ICD-lO and CAMDEX and derivation of the Reversible Cognitive Dysfunction Scale among acute geriatric inpatients. International Journal of Geriatric Psychiatry, 12,609-13. 6. Newman, S. and Stygall, J. (2000). Changes in cognition following cardiac surgery (Editorial). Heart, in press. 7. Cole, M.G. and Primeau, F.J. (1993). Prognosis of delirium in elderly hospital patients. Canadian Medical Association Jou rnal, 149,41-6. 8. Trzepacz, PT. (1 994). A review of delirium assessment instruments. General Hospital~chiatry, 16, 397-405. 9. Hart, R.P., Best, A.M., Sessler, CN., and Levenson, J.L. (1997). Abbreviated cognitive test fo r delirium. Journal of Psychosomatic Research, 43, 417-23. 10. Hughes, J.R. (1996). A review of the usefuln ess of the standard EEG in psychiatry. Clinical Electroencephalography, 27, 35-9. 11. Cochrane Library, Issue 3 on CD-ROM. Update Software/BMJ Publishing, London. 12. Cole, M.G., Primeau, F., and McCusker, J. (1996). Effectiveness of interventions to prevent delirium in hospitalized patients: a systematic review. Canadian Medical Association Jo urnal, 155, 1263-8. 13. Breitbart, w., Marotta, R., PIa tt, M.M., et al. (1996) . A double-blind trial of haloperidol, chlorpromazine and lorazepam in the treatment of delirium in hospitalized AIDS patients. American Journal of Psychiatry, 153,231- 7. 14. Christensen, D.B. and Benfield, W.R. (1 998) . Alprazolam as an alternative to low-dose haloperidol in older, cognitively impaired nursing facility patients. Journal of the American Geriatrics Society, 46, 620- 5. 15. American Psychiatric Association (1999). Practice guidelines for the treatment of patients with delirium. American Journal of Psychiatry, 156, Supplement to Issue 5. 16. Auerswald, K. B., Charpentier, P.A., and Inouye, S.K. (1997) . The informed consent process in older patients who developed delirium: a clinical epidemiologic study. American JOllrnal of Medicine, 103,410-18. 4.1.3 Dementia: Alzheimer's disease Simon Lovestone Introduction Alzheimer's disease (AD) and other dementias incur huge costs to society, to the families of those affected, and to the individuals themselves. Costs to society include both direct costs to health and social services and indirect economic costs in terms of lost productivity, as carers are taken out of the workplace, and the economic costs to those families caring for or funding the care of their relative. Increasingly, as treatments become available, these costs are targets for change and are part of the cost- benefit analysis of new compounds, especially the largest single direct cost, that of the provision of nursing and other forms of continuing care. Apart from the financial cost to families there is the emotional impact resulting in distress and psychiatric morbidity. As the population ages, these costs pose substantial social and eco. nomic problems. Although lifespan itself has remained static, the 387 388 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY numbers of elderly in both developed and developing societies is increasing rapidly. In the developed world the sharpest projected growth is in the very elderly cohort- precisely the one that is at most risk of AD. Within the developing world the total number of elderly people is projected to rise substantially, reflecting to a large part better child health and nutrition. For countries in South America and Asia, with large and growing populations, the costs involved in caring for people with dementia in the future will become an increasing burden on health and social services budgets. In the absence of such services families will inevitably shoulder the main part of providing care, although the very process of development is associated with increasing urbanization and, to some degree, a diminution of the security provided by extended family structures. From discovery towards understanding In the early part of the twentieth century, Alois Alzheimer described his eponymous disorder in a middle-aged woman who suffered not only cognitive deterioration and functional decline but psychotic experiences, including delusions and auditory hallucinations. Neuropathology included gross atrophy and plaques and tangles on microscopy. Although all the important features of AD were described at this stage, two important developments came much later. First, in the 1960s with the studies of Roth and colleagues in Newcastle(l) and others elsewhere, it was appreciated that much dementia in the elderly has an identical neuropathological appearance to that of AD in younger people. The other development was the rediscovery that AD has a rich phenomenology. The non-cognitive symptomatology of AD is integral to the clinical manifestation of this disease, and is a major cause of carer burden and medical intervention. This second phase of research-the recognition that both the neuropathology and clinical phenomenology described by Alzheimer occur in what had previously been though of as senile dementia or, worse, just ageing, was accompanied by a growing understanding of the neurotransmitter deficits in AD. The cholinergic hypothesis provided the first glimpse of possible interventions, and remains the most important finding from this period of AD investigations. The third phase of AD research encompasses the use of molec ular approaches to understanding pathogenesis. The techniques of molecular biology have been applied to understanding the formation of plaques and tangles, to a growing understanding of the genetic aetiology of much of AD, and, through the use of transgenic approaches, to developing animal and cellular models of pathogenesis. Just as research can broadly be seen to h~ three phasesdiscovery, neuropathology, and IPolecul;u aspects-so too does the clinical response to AD. For many years cognitive impairment in the elderly was perceived as senility. As a process thought to be an inevitable consequence of ageing it was difficulty to establish medical-care models. Hence the needs of the elderly with AD were not seen as requiring speCialist intervention, carers needs were not realized, and public appreciation of the impact of dementia on the elderly themselves or on the family was negligible. The 'change in perception of AD from 'just ageing' to a disease was accompanied, and to some degree led, by the development of ' old age psychiatry' as a specialism on the one hand and by the rapid growth of the Alzheimer disease societies on the other. During this second phase of AD treatment, the goals have been to ensure that the care needs of patients are met, that families' . concerns are addressed, and that behavioural disturbance is minimized. The third phase of AD treatment began with the arrival of specifically designed interventions. Compounds have been introduced that were designed to ameliorate some of the deficits incurred by the disease process, and other approaches are being developed to treat those disease processes themselves. Clinical features Cognitive impairment Dementia is an acquired and progressive cognitive decline in multiple areas; AD is one cause of dementia and the core clinical symptom of AD is cognitive impairment. However, as noted above, AD is clinically heterogeneous and includes diverse non-cognitive symptoms and inevitable functional .impairment. Cognitive decline is manifested as amnesia, aphasia, agnosia, and apraxia (the 4As). Amnesia Memory loss in AD is early and inevitable. Characteristically, recent memories are lost before remote memories. However, there is considerable individual variation, with some patients able to recall specific and detailed events of childhood and others apparently having few distant memories accessible. With disease .progression, even remote and emotionally charged memories are lost. The discrepancy between recent and remote memory loss suggests that the primary problem is of acquisition or retrieval of memory rather than a destruction of memory, and this is confirmed in early AD,(2) although as the disease progresses it is likely that all memory processes are impaired. Retrieval ~f remote memory is assumed to be preserved for longer because of rehearsal over life. Aphasia Language problems are found in many patients at presentation, although the language deficits in AD are not as severe as those of the frontotemporal degenerations(3) and may only be apparent on detailed examination. Word-finding difficulties (nominal dysphasia) are the earliest phenomena observed and are accompanied by circumlocutions and other responses, for example repetitions and alternative wordings. As the disorder progresses, syntax is affected and speech becomes increasingly paraphasic. Although harder to assess, receptive aphasia, or comprehension of speech, is almost certainly affected. In the final stages of the disorder, speech is grossly deteriorated with decreased fluency, preservation, echolalia, and abnormal non-speech utterances. Agnosia Patients with AD may have difficulty in recognizing as well as naming objects. This can have implications for care needs and safety if the unrecognized objects are important for daily functioning. One particular agnosia encountered in AD is the loss of recognition of one's own face (autoprosopagnosia). This distressing symptom is the underlying cause of perhaps the only clinical sign in AD- the mirror sign. Patients exhibiting this will interpret the face in the mirror as some other individual and respond by talking to it or by apparent fearfulness. Autoprosopagnosia can present as an apparent hallucinatory experience, until it is realized that the 'hallucination' is fixed in both content and space, occurring only when self-reflection can be seen. 4.1.3 DEMENTIA: ALZHEIMER'S DISEASE Apraxia Difficulties with complex tasks that are not due to motor impairment become apparent in the moderate stages of AD. Typically, difficulties with dressing or tasks in the kitchen are noticed first, but these are inevitably preceded by loss of ability for more difficult tasks. Strategies . to avoid such tasks are often acquired as the disease progresses, and it is only when these fail that the dyspraxia becomes apparent. Other cognitive impairments There appear to be no cognitive functions that are truly preserved in AD. Visuospatial difficulties commonly occur in the middle stages of the disorder and may result in topographical disorientation, wandering, and becoming lost. Difficulties with calculation, attention, and cognitive planning all occur. Functional impairment Although the cognitive decline in AD is the core symptom, it is the functional deterioration that has the most impact on the person themselves and it is the functional loss that necessitates most of the care needs of patients with AD, including nursing-home residency.(4) Increasingly, abilities to function in ordinary life (activities of daily living (ADLs» are lost, starting with the most subtle and easily avoided and progressing to the most basic and essentiaL In general, functional abilities decline alongside cognitive abilities. However, the precise correlation between these functions is not perfect, suggesting that factors other than disease severity account for part of the variance between patients. (5 ) Functional abilities are related to gender; for example, cooking abilities are rehearsed more frequently in women, and home-improvement skills in men. However, the overall pattern shows some similarities between groups of patients with similar disease severity. This is exploited in the Functional Assessment Staging (FAST) scale;(6) in the original form, this is a seven-point scale of functional impairment, with stage 1 as no impairment and stage 7 as severe AD. A sequential decline is mapped by descriptions of the abilities that are lost: stage 2, difficulties with language and finding objects; stage 4, difficulties with finances; stage 6, incontinence and inability to dress or wash oneself. ADLs are divided into those that relate to self-care and those that concern instrumental activities. Instrumental ADLs, those related to the use of objects or the outside world, are lost first and can be subtle. (7) A change in the ability to use the telephone properly or to handle finances accurately may not be apparent. Self-care ADLs include dressing and personal hygiene and are also lost gradually; for example, untidiness in clothing progresses to difficulties in dressing. Personal hygiene becomes poor as dentures are not cleaned and baths taken less often, before finally assistance is required with all self-care tasks. Neuropsychiatric symptoms Mood The relationship between AD and depression is complex. Depression is a risk factor for AD, depression can be confused with dementia (pseudodementia), depression occurs as part of dementia, and cognitive impairments are found in depression. Depression occurring as a symptom of dementia will be considered here. Assessing the mood of a person with dementia is difficult for obvious reasoris. However, psychomotor ******ation, apathy, crying, poor appetite, disturbed sleep, and expressions of unhappiness all occur frequently. The rates of depression found in cohorts of patients with AD vary widely, reflecting changes in prevalence at different levels of severity and difficulties in the classification of symptoms suggestive of depression in those with cognitive loss. A major depressive episode is found in approximately 10 per cent of patients, minor depressive episode in 25 per cent, some features of depression in 50 per cent, and an assessment of depression by a carer in up to 85 per cent. (8- IQ) It is commonly believed that depression is more common in the early than in the later stages of AD, although this may reflect the difficulties of assessing depression in the more severely affected and least communicative patients. Indeed, severely affected patients in nursing homes may be particularly prone to depressio~: (I J) Ei; tion, disinhibition, and hypomania all occur in AD but are relatively infrequent, elevated mood being found in only 3.5 per cent of patients by Burns et al. (lO) The underlying cause of mood change in AD is not known. However, loss of serotonergic and noradrenergic markers accompanies cholinergic loss; some studies have found a greater loss of these markers at postmortem in AD patients with depression than in nondepressed patients. ( 12. 1 3 ) Psychosis Psychotic symptoms occur in many patients, although, as with depression, the difficulty in determining the presence of delusions or hallucinatory experiences in the moderately to severely demented gives rise to a very wide range of frequency rates. Few studies have been able to determine the rates of psychosis in community-dwelling, fully representative samples of patients with AD. However, of those known to, largely, psychiatric services, between 10 and 50 per cent suffer from delusions and between 10 and 25 per cent experience hallucinations.<' 4-16) Delusions are frequently paranoid and the most common delusion is one of theft. In the context of the confusion and amnesia of dementia, it is easy to appreciate how the experience of mislaying an object becomes translated into conviction of a theft. Other patients become convinced that someone, often a family member, is trying to harm them. Hallucinations are only somewhat less frequent than delusionsthe median of one series of studies being 28 per centY7) Visual hallucinations are reported more commonly than auditory ones, and other modalities are rareY6) Most studies of the non-cognitive symptomatology of AD precede the wide recognition and accepted criteria of dementia with Lewy bodies, one of the cardinal symptoms of which is visual hallucinations.<' S) It is probable that a large number of those AD patients experiencing visual hallucinations reported in the studies would now be classified as having dementia with Lewy bodies. Phenomena falling short of delusions or hallucinations, such as persecutory ideas or intrusive illusionary experiences, are common in AD as are misidentification syndromes. Cap gras' syndrome may occur, but frequently the symptom is less fully evolved with the patient mistaking one person for another. Failure to recognize one's own face may be due to visuospatial difficulties or to a true misidentification syndrome-distinguishing between the two is difficult. Various factors have been associated with psychosis in AD, but few have been substantiated in multiple studies. Burns et al. (16) found that more men than women suffered delusions of theft, although others find that psychosis occurs more often or earlier in women. An association with polymorphic variation in serotonin receptors has been 389 390 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY reported. (I9) Patients with psychotic symptoms show regional metabolic differences on functional neuroimaging. (20) The relationship between psychosis and dementia severity is not as clear cut as that between functional ability and dementia severity. Psychosis can occur at any stage of the disease process, although most studies find the maximal rate of psychosis in those with at least moderate dementiaY6.J7) Although the biological basis of psychosis within AD is not fully understood, it is probable that psychosis symptoms impact upon carers causing increased distress, (21) and that underlying psychosis accounts for much of the behavioural disturbance and aggression encountered in AD. (22) Personality Changes in personality are an almost inevitable concomitant of AD. Indeed, it is difficult to envisage how profound cognitive impairment resulting in the loss of recognition of loved ones, and an understanding of and ability to react with the outside world, could not result in a change in personality. Family members have described the loss of personality as a 'living bereavement'-the person remains, but the person once known has gone. Personality change is most frequently one of loss of awareness and normal responsiveness to the environment. Individuals may become more anxious or fearful, there is a flattening of affect, and a withdrawal from challenging situations. Catastrophic reactions are short-lived emotional reactions that occur when the patient is confronted, and cannot avoid, such a challenging situation. Less commonly, personality changes may be of disinhibition with inappropriate sexual behaviours or inappropriate affect. Aggressiveness is, as noted above, often accompanied by psychosis, but it may be part of a more general personality change. Other behavioural manifestations Behavioural complications in AD have become a target of therapy. However, the term encompasses a wide rage of behaviours, some of which include neuropsychiatric syndromes, some caused by neuropsychiatric syndromes, and some of which have little apparent relationship to mood or to thought content. Behavioural complication is itself a largely subjective term that relies to a great extent on informer evaluation: but a behaviour may be a complication in one context, although not in another. Behaviours exhibited in AD include wandering, changes in eating habit, altered sleep or circadian rhythms, and incontinence. These behaviours are closely linked to disease severity and occur to some extent in the majority of patients with AD. Wandering may be a manifestation of topographical confusion, a need for the toilet, or it may reflect hunger, boredom, or anxiety. Sleep is freqaently disturbed, with many patients exhibiting altered sleep- wake cycles and others experiencing increased confusion towards evening Csundowning'
.(23) A central defect in the regulation of circadian rhythms underlying these phenomena is postulated.(24) Excessive or inappropriate vocalizations (grunting and screaming) occur in the late stages. Classification AD is classified, as with all other disorders, by DSM-IV and by lCD-lO. In addition, it also has a specialized classification system resulting from the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). (25) This clinical diagnostic system is internationally accepted and widely observed. There are other classification systems for neuropathological diagnosis, most notably the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. (26) DSM-IV stipulates that a dementia syndrome is characterized by a decline in multiple cognitive deficits, including amnesia, resulting in impairment. A gradual onset and decline in the absence of other conditions sufficient to cause dementia indicates AD. lCD-IO shares with DSM-IV the definition of a dementia syndrome as a deterioration in more than one area of cognition, but including memory that is sufficient to impair function. Again an emphasis on insidious onset and slow decline in the absence of other disorders sufficient to cause dementia indicates AD. The NINCDS-ADRDA criteria defines possible, probable, and definite categories; the latter being restricted to neuropathological confirmation of a clinical diagnosis. (25) It is important to note that both clinical and neuropathological data are required-no single neuropathological lesion is pathognomonic of AD, and it is still uncertain how often or to what extent the neuropathologicallesions of AD also occur in normal ageing. Probable AD, according to NlNCDS-ADRDA, requires a dementia with progressive decline in memory and other cognitive areas, cognitive impairment established by formal testing, no disturbance of consciousness, and absence of other disorders sufficient to cause dementia. Supporting features include decline in function, change in behaviour, positive family history, and decline in specific cognitive areas including aphasia, apraxia, and agnosia. Non-specific change on electroencephalography (EEG) and progressive changes on CT are supporting, but not necessary, features. Possible AD should be diagnosed if there are variations in the clinical presentation, another disorder sufficient to cause a dementia (even if it is not thought to do so in this case), or a restricted cognitive decline. A number of studies have attempted to determine the accuracy of diagnostic criteria against postmortem diagnosis. One of the difficulties in these studies is that because AD is the most common dementia (by some way), such studies are very likely to find a high-positive predicative value. Kukull et al. (27) found the specificity of DSM-III to be higher than NINCDS-ADRDA (0.8 versus 0.65), but NINCDSADRDA had a higher sensitivity (0.92 versus 0.76); others find an even lower specificity.(28) Diagnosis AD is the most common of the dementias, occur"ring in some 60 to 70 per cent of cases. However, this oft-stated figure must be treated with some caution for two reasons. First, cases that come to postmortem represent a biased sample, and the proportion of pathologically confirmed AD in community-dwelling representative samples is unknown. Second, even at postmortem the distinction between different dementi as is not clear cut-many AD brains show the presence of Lewy bodies and others have considerable evidence of vascular damage. The proportion of mixed pathologies IS actually rather high, between 15 and 30 per cent of all dementias. History Making a clinical diagnosis of AD is a positive process and not one of exclusion. The most valuable diagnostic assessment is a careful . informant history, paying attention to the pattern and timing of onset Q- 5- a 4.1.3 DEMENTIA: ALZHEIMER'S DISEASE and progression. In the research context, a family history interview conducted by telephone provides a degree of accuracy compatible with a full clinical assessment. (29,30) Detailed semistructured family informant diagnostic schedules are available, such as CAMDEX.(31) A history should be taken for the presence of risk factors for AD (e.g. a positive family history) and vascular and other risk factors (e.g. hypertension 'and head injury). Taking a family history for late-onset disorders such as AD requires special attention. Because of attrition due to other illness, many elderly people have had too few relatives reach the age of onset of dementia to make a pedigree analysis informative. The ages at death of all relatives should be established, together with cause of death and the presence or absence of dementia or memory problems in late life. The term 'sporadic' dementia should be avoided, and is misleading when applied to an individual with a dementia where one parent died young and where no sibling reached the age of 65 to 70 years. The history should also screen for the presence of other illnesses sufficient to cause a dementia, and for systemic health in general. The presence of any significant physical illness, from chronic pain to delirium, may significantly alter cognitive abilities in the elderly, and especially so in those with AD. A careful history should also establish the presence of any behavioural disturbance that has occurred. The relationship of aggression, wandering, agitation, or other behaviours to care tasks and other recent changes in the provision of the care package should be established. As the mainstay of the management of behavioural disturbance in all dementias is behavioural, establishing the antecedents to behaviour is an absolute prerequisite to effective management. Examination In addition to an examination of the mental state to establish the presence of disorders of mood and thought content, the examination will establish the specific pattern of cognitive impairment and the degree of impairment. Screening tests used to establish the presence of cognitive impairments include the Mini Mental State Examination;(32) this is a 30-point scale routinely used in all clinical trials of drugs for the treatment of AD, which is also a useful proxy measure for severity. It should be accompanied, by other cognitive testing, including supplementary examination for aphasia and apraxias. Other cognitive and physical examinations will be necessary where the differential diagnosis is between a lobar dementia (e.g. frontotemporal dementia) or a subcortical dementia (e.g. that accompanying Huntington's disease). In addition to the cognitive examination, a physical examination should be conducted in all patients with AD, although this might not be most effectively and conveniently performed at the initial assess ment. Physical illness, including chronic pain, infection, cardiac insufficiency, or anaemia are all common in the elderly and can both complicate the diagnosis of AD and increase confusion in those known to have AD. Assessment of function Clinical assessment of function can be performed by informant history and by direct observation. The occupational therapist fulfils an invaluable role in establishing the detailed functional ability of those with AD, in addition to implementing changes in the home designed to maximize function. The FAST scale(6) is based on the premise that the pattern of decline in function is relatively uniform in AD, and hence establishes a staging of severity on function rather than cognition. As in most instances functional severity is of more relevance for the provision of services, there is much to recommend such an approach. Global assessment Driven largely by the United States Food and Drugs Administration, global assessment has become part of the assessment of all patients with AD in clinical trials and is finding its way into clinical practice. The underlying premise is that an assessment by a clinician, often supplemented by an informant history, provides information on severity that neither a cognitive assessment nor a functional assessment alone can provide. One scale, the Clinicians Interview of Change, has become widely used in this context and is an interesting attempt to se miformaliz~ ,the t9.1!tine clinical impression without operationalized criteria. Investigations At the initial assessment, patients with dementia should be investigated for other disorders that could complicate, exacerbate, or be confused with AD. A dementia screen might include routine biochemistry, thyroid function tests, vitamin Bl2 and folate estimations, and a full blood count; many would also include syphilis serology, although the frequency of abnormal findings is low. A CT brain scan is not necessary in many cases and is not a required investigation in the NINCDSADRDA classification, although worsening atrophy on CT is supportive evidence. Functional scanning (single-photon emission CT (SPECT) in particular) can be useful where regional dementias are suspected, and magnetic resonance imaging can provide supportive evidence where vascular dementia is a possibility. An EEG is nearly always non-specifically abnormal even in the early stages of AD, in contrast with frontotemporal degenerations where an EEG remains unaffected at a broadly equivalent severity. This can help to distinguish the conditions, particularly where there is neuroimaging evidence of regional insufficiency. Aetiology and molecular neurobiology AD is the most common dementia, affecting more than 20 per cent of the population over the age of 85 years. Epidemiological evidence has suggested risk factors and putative protective factors, but the greatest advances in understanding its pathogenesis have come from the combination of molecular and epidemiological approaches. Neuropathology At postmortem, the brain in AD is lighter than aged-unaffected controls with more prominent sulci and a larger ventricular volume. Microscopic examination reveals the most prominent lesions described by Alzheimer-the extracellular plaque and intracellular neurofibrillary tangleY6) No consensus has developed regarding which of these lesions is responsible for the cognitive impairment of AD. Plaques, or more precisely amyloid load, might correlate with the degree of cognitive impairment,(33) although a significant amyloid deposition is also found in normal, unimpaired, aged individualsY4) However, there is a high degree of correlation between dementia severity and neurofibrillary tangle formation, (35) although it is possible that some of the features of AD are more stable than others; for example, 391 392 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY extracellular neurofibrillary tangles persist after the neurone has died, whereas extracellular Lewy bodies are not found. The plaque consists of an amyloid core surrounded by dystrophic neurites, which are themselves filled with highly phosphorylated tau protein. Studies of Down syndrome brains have suggested a temporal course to plaque formation. First, peptides derived from the amyloid precursor protein (APP) are deposited in a diffuse plaque.(36) Over time this becomes organized as the amyloid pep tides become fibrillar and form the amyloid deposit, neuritic change then occurs, and the plaque becomes fully mature. Neurofibrillary tangles are composed of paired helical filaments, structures which are also found in the dystrophic neurites around mature plaques, and together with straight filaments, in neuropil threads. These filaments are themselves composed of the microtubuleassociated protein, tau, which is present in a stably and highly phosphorylated stateY7) Tau is a neuronal-specific protein, found predominantly in the axon, that functions to stabilize micro tubules, a property that is regulated by phosphorylation. Phosphorylated tau is less effective in promoting tubulin polymerization into microtubules, and in cells highly phosphorylated tau does not stabilize microtubules. (38) In normal adult brain a proportion of tau is highly phosphorylated, but this proportion is considerably greater in AD. Tau deposits are a feature of other disorders, such as progressive supranuclear palsy and some frontotemporal degenerations. Mutations have been found in frontotemporal degenerations with parkinsonism (FTDP-17), (39) and progressive supranuclear palsy has also been associated with changes in the tau gene(40) thereby emphasizing the importance of this molecule to neurodegeneration. Braak and Braak(41) studied large numbers of brains from individuals who died at various ages and at different stages of dementia severity, which has resulted in the wide acceptance of the neuropathological staging of AD. The very earliest stages, before the clinical manifestation of dementia, are characterized by the appearance of highly phosphorylated tau in the hippocampus. In later stages, neurofibrillary tangles appear in the same brain regions and then become more widely distributed. The cholinergic hypothesis The pathological changes in AD are localized both structurally and functionally. Plaques and tangles first occur in the hippocampus before spreading to involve other regions. Some areas of the brain are relatively preserved-the occipital lobe is affected relatively late and the cerebellum appears to be spared from neuritic change (neurofibrillary tangles and the fully matured plaques:"1l1thOligh diffuse amyloid deposits do occur). Functional localization was demonstrated by evidence of the relatively greater and earlier loss of cholinergic neurotransmission. At postmortem there is evidence of significantly greater neuronal loss in the cholinergic nucleus basalis of Meynert and loss of cholinergic markers. (42-44) These observations led to the cholinergic hypothesis, which stated that the cognitive impairment of AD was due to a disorder predominantly affecting cholinergic neurones. It was this hypothesis that led to the development of pharmacological strategies to rectify cholinergic loss and the introduction of the first compounds specifically designed for and efficacious in AD. However, the cholinergic hypothesis was something of a simplification as other neurotransmitter systems (e.g. serotonergic and noradrenergic) are also affected in AD. The amyloid cascade hypothesis In 1984, the protein deposited in blood vessels (congophilic angiopathy) in AD was shown to be a 4-kDa peptide known as ~-amyloid. (45 ) This peptide, which is identical to the amyloid in plaques, is derived from a larger peptide, APP, the gene for which is coded on chromosome 21. After a series of misleading linkage studies, mutations in the APP gene were found in a family with autosomal dominant early-onset AD.(46) These two discoveries- the identification of ~-amyloid and the discovery of mutations in the parent APP gene-led the way to the amyloid cascade hypothesis, which has remained the dominant molecular model of the disorder. (47) Many subsequent molecular observations have been consistent with this model, which posits the formation of ~-amyloid as the initiating, or at least early event, leading to all the other changes observed including tau aggregation and phosphorylation, neuronal loss, cholinergic deficits, and clinical symptoms. Perhaps the most convincing evidence that there is such a unidirectional cascade comes from the observation that mutations in the APP gene give rise to plaque formation and also to neurofibrillary tangle pathology, whereas mutations in the tau gene give rise to tangle formation but not to plaque formation in FTDP- 17. Much subsequent research has concentrated upon understanding the metabolism of APP and the formation of ~ -amyloid peptide.(48.49) APP is a ubiquitous single-pass cell-membrane protein expressed in many cell lines with a high degree of evolutionary conservation. At least three putative secretases cleave APP and the metabolic products can be detected in individuals unaffected by AD; the processing is not pathological in AD, but the balance between different metabolic routes may be shifted in the disease state. a-Secretase cleaves APP at the outer cell-membrane surface at a site within the ~-amyloid moiety itself. Clearly, a-secretase cannot therefore yield intact ~-amyloid, and this metabolic route, resulting in a secreted product, APPs, and other fragments, is termed non-amyloidogenic. a-Secretase activity is increased following stimulation of protein kinase C. (50) This might have some clinical relevance as certain neuronal receptors are coupled to protein kinase C and, indeed, muscarinic agonists do increase non-amyloidogenic metabolism. These studies predict that therapies designed to correct the cholinergic deficit in AD might have a disease modification effect. (51 ) Amyloidogenic metabolism is the result of ~-secretase cleaving APP beyond the amino terminus of ~-amyloid and of y-secretase cleaving the resulting peptides at the carboxy terminus in the cell. The ~ - amylo id products vary in length, with predominant species having a length of 40 or 43 amino acids. The longer pep tides are somewhat more prone to forming fibrils in vitro. It is probable that the proportion of ~-amyloid(4 2-43) pep tides relative to ~-amyloid ( 40) pep tides is critical in pathogenesis, (49) and that mutations in the APP gene increase these longer amyloid peptides. (52.53) Transgenic mice overexpressing the mutated APP gene also produce more ~-amyloid peptide and have amyloid deposits in brain.(54) Interestingly, these animals do not develop other aspects of AD pathology. The presenilin genes Mutations in presenilin-1 (PS-I) and presenilin-2 (PS-2), two very similar genes on chromosome 14 and chromosome 1 respectively, also cause early-onset autosomal dominant AD. (55) The function of these genes is not fully understood, but homology with genes in flies and 4.1.3 DEMENTIA: ALZHEIMER'S DISEASE worms suggests that the presenilins participate III NOTCH signalling-a complex signal-transduction cascade critical, amongst other things, in determining neuronal cell fate. Mutations in the presenilin genes, and hence their role in AD pathogenesis, may result in an interference with the normal functioning of the protein or may induce a gain in a novel pathogenic function. Whatever the mech. anism, it is clear that mutations in the presenilins result in an increase in the production of ~-amyloid. (49 ) Therefore the finding of mutations in these genes adds to, rather than detracting from, the amyloid cascade hypothesis although, as with any hypothesis, the complexity of an originally simple idea increases. Tangle formation and tau phosphorylation Tangles are composed of paired helical filaments, themselves composed of hyperphosphorylated tau. It is not fully determined whether tau phosphorylation precedes tau aggregation, but tau is highly phosphorylated in fetal brain and, albeit to a lesser extent, in normal adult brain. (37) However, neuropathological evidence suggests that highly phosphorylated tau does begin to accumulate in the brain before the formation of tangles, and before the clinical manifestation of AD.(S6) It seems as though, if not the only event in paired helical-filament formation, increased tau phosphorylation is at least an early event. Protein phosphorylation is a product of kinase and phosphatase activity. It is likely that many such enzymes may participate in the regulation of tau phosphorylation in the brain, but two have been shown to be predominant. In cells, and in vitro, glycogen synthase kinase-3 is the main tau-kinase and protein phosphatase 2A is the predominant tau phosphatase. (57.58) Molecular genetics Mutations in three genes have been found to cause early-onset familial AD, which is inherited in an autosomal dominant fashio n. (S9) Mutations in the APP gene (on chromosome 21) are the least common, only affecting perhaps 20 families worldwide. Mutations in PS-1 (on chromosome 14) are somewhat more frequent, although are still a rare cause of AD. Mutations in PS-2 (on chromosome 1) appear to be largely restricted to an ethnic German people residing in the United States, suggesting an individual founder effect. Mutations in these genes have not been identified in true late-onset AD. Individuals with Down's syndrome are at extremely high risk of AD, with neuropathological evidence being present in virtually all individuals living to middle age, probably because of trisomy APP. The genetic component oflate-onset AD has been demonstrated by epidemiological studies, showing that a family history of dementia is the largest single risk factor for AD.(60) However many, perhaps most, patients with AD do not have a positive family history, thus giving rise to the idea of , sporadic' AD with a separate aetiology to 'familial' AD. For late-onset AD this concept is outmoded and redundant. Many patients with AD do not have a family history because of attrition of family members due to death by other causes. For the cohort currently suffering from AD their parents were born in the latter part of the nineteenth century or early years of the twentieth, lived through two major world wars, and reached adulthood before the discovery of antibiotics. It is not surprising that few patients with late-onset AD have two parents and more than one sibling living to the age of onset of AD, and if one parent died young and there are no elderly siblings then the family history is non-informative. Well-designed studies examining the rate of AD in first-degree relatives by age find a cumulative incidence reaching 50 per cent or higher by the age of 90 years. (61.62) One gene has been unequivocally associated with late-onset AD, although even this gene accounts for only something like 50 per cent of the genetic variance.(63) The apolipoprotein E gene (APOE, gene; apoE, protein) on chromosome 19 has three common alleles, coding for three protein isoforms that differ by the substitution of an amino acid at just two positions. Of the three alleles £3 is the most frequent and £2 the least; following linkage to chromosome 18 it was demonstrated that the £4 allele confers risk, whilst the £2 may be protective.( M) This finding has been replicated in a huge number of studies and in many different populations, although there are some, as yet, unexplained differences as black African-Americans apparently do not show an increased risk with the £4 allele. (65) The mechanism-a1 action of the APOE gene in increasing the risk of AD is not known. As AFOE variation is a major genetic influence on serum cholesterol (people with the APOE £4/* genotype have higher serum cholesterol levels), it is possible that an altered lipid metabolism-either peripherally or locally-might affect the pathogenesis of AD.(66) Alternative theories arise from in vitro studies, which show a differential binding of APOE protein isoforms both to amyloid protein and to tau protein.(64) Certainly it does seem as though APOE isoforms affect neurones in culture in different ways, with apoE4 isoforms inducing shorter neurites and microtubule collapse.(67) Other genes have been associated with AD, but none have been replicated in as many studies as APOE. It is likely that a combination of linkage and association studies using large populations will identify the other genes that influence AD, either alone or in interactions with other genes or the environment. Treatment For many conditions the goals of treatment or intervention are selfevident- cure, prevention of relapse, and resolution of symptoms. For AD, however, the goals of treatment can be less obvious and differ between patients and for individual patients over time. Ultimately, the quality oflife of the patient should be improved, but assessing quality of life is difficult in those with dementia, and given the early loss of insight who is to judge such issues?(68) Quality of life may appear poor- patients may have diminished emotional repertoires, few pleasurable activities, and considerable handicap-but they may share none of the negative cognitions experienced by others with a similarly questionable quality of life induced by different illnesses. Other patients may appear content or happy, despite the loss of the autonomy and self-awareness normally considered an essential component of a good quality life. Equally, the treatment unit in AD includes carers, and there are times when the patient's quality of life is in conflict with the quality of life for other members of the family. Resolving such conflicts of interest and other moral and ethical issues is part of the treatment process in AD. With the arrival of specific treatments for AD and the prospect of disease-modifying therapies, an even harder question arises regarding prolonging life for those with dementia: if quality oflife appears poor to observers, is it right to prolong the process, can quality of life in those with dementia truly be assessed, or should carers and families be allowed to assess for themselves the benefits and costs of treatment?(69) 393 394 4 CLINICAL SYNDRO MES OF ADULT PSYCHIATRY There is no single model of management of patients with AD. In many countries management is the role of the gerontologist or neurologist. In others, as in the United Kingdom, the old-age psychiatry team provide the core specialist services. Many, perhaps even the majority, of those with AD are managed within primary care with the support of social services. Referral from primary care to specialist services will be according to local agreements, but most would concur that behavioural disturbance or the use of specific drugs to treat AD warrant referral to secondary care. Interventions for AD, whether provided in primary or secondary care, can be thought of as directed towards the patient, the patient's family, and the patient's environment . Guidelines on the identification and management of patients with dementia have been produced and may be a constructive approach to ensuring best clinical practice. (70-72) Managing the patient Management of the patient with dementia is discussed in greater detail in Chapter 4.1.14. Management starts with the assessment and diagnosis, and perhaps the difficult dilemma is how much of the diagnosis and prognosis to discuss with the patient. (73) Most practitioners do not discuss the diagnosis with the patient themselves, although especially in the early stages a frank cons'ultation can be beneficial. For most patients, however, cognitive impairment renders an appreciation of the diagnosis and prognosis difficult. A large part of managing the patient is directed towards managing mood and behavioural disturbance. Accurate assessment of the disturbance is critical, and includes determining the antecedents and responses to the behaviour as well as a full description of the behaviour and any associated abnormalities in the mental state. Treatments of behavioural disturbance in AD are most often behavioural and sometimes restricted to giving information to careers. However, pharmacological interventions are an important part of the management of behavioural disturbance, even though caution regarding the use of psychotropic medications in those with dementia is necessary. Specific treatments for AD have been developed, concentrating in clinical trials on ameliorating the core symptom of cognitive impairment. The cholinomimetic approaches are the most advanced, but other therapies are receiving extensive evaluation. Although designed for the large part as strategies to enhance cognition, these compounds also favourably appear to affect function and may reduce behavioural disturbance. Further evaluation is being conducted to determine whether there are disease-modifying effects. Drug treatments for AD are described in Chapter 6.2.7. Managing the family -- Although patients may not appreciate or be able to follow a detailed discussion of the diagnosis and prognosis, their relatives, spouses, and other carers will. This is an important part of the treatment process; as the carer provides the main interventions for much of the period of the disease process, care should be taken to ensure that appropriate and sufficiently complete information is given. Caring for a patient with AD can be difficult and stressful and some carers suffer accordinglyY4) The characteristics of both carers and patients influence the impact that this 'burden' of caring has on the carers themselves. Men in general, and husbands in particular, seem to be less vulnerable to the adverse effects of caring, possibly because of the response seen in many male carers of rapidly and effectively recruiting outside helpYS) Women may be socialized into accepting more caring roles themselves and therefore seek less help. Non-white carers appear to suffer from less adverse consequences of caring, perhaps because of cultural differences in the perception of family bonds. (76) Patient characteristics that increase the burden of caring include behavioural disturbances, (77.78) depression, (79 ) and unawareness of cognitive impairment,(80) but not the cognitive impairment itself. Although the core outcome variable in clinical trials of AD drugs is the severity of cognitive impairment, it is not the variable that induces most stress in relatives nor is it the variable that predicts entry to residential care. Other variables are almost certainly protective, and caring for a loved one with dementia is not a universally negative experience. Much caring is done willingly, effectively, with love, and without complaint. Carer support groups offer much to a person with a relative afflicted by AD. Through support groups, and especially through the national AD societies and the umbrella group-Alzheimer's Disease International-carers can obtain up-to-date and useful information regarding all aspects of AD. A support group can help individuals practically and emotionally through difficult times. Many carers talk of the support group as a life-line, although little empirical evidence exists as to the impact on carer well being. One particular intervention for the family is that of genetic counselling. Many relatives are worried about inheriting AD. This concern might arise from two sources-the frequent discussion of genes 'for' AD in the media and the observation of familial occurrence of AD in many individual families. For families with clinically apparent familial AD, advice, information, and where appropriate, genetic testing can be arranged through a genetics centre. Where predictive testing is contemplated for genes causing autosomal dominant, early-onset AD this will adhere to guidelines established for Huntington's disease. It is unlikely that true predictive testing will become available for late-onset AD.(sl) Managing the environment The mainstay of interventions for AD are provided by social services. The goal of the provision of social care in people with AD is 'to provide an environment that is comfortable, stimulating, and, above all, safe. For most patients, and for all patients in the early stages, this means care at home, perhaps with the support of home-meal delivery and home-helps to provide shopping and cleaning assistance. Further home care may become necessary as the patient requires assistance with basic self-care tasks such as washing and dressing. The carer may require a sitting service, either for periods during the day to allow them time to themselves or in the evening to allow them to attend a carers group or for socializing. Safety issues are especially important for those with dementia living alone. There are inherent risks to the patient themselves if they wander out of the home and risks to others if the gas can be left on or fires started. Day care is appropriate for many patients, ideally in a specialist unit. In a generic facility for elderly people those with early dementia can receive little input and those with moderate or advanced dementia can necessitate too much input from the day-centre staff. A good dementia specialist day-care facility will provide the staffing ratio appropriate to patients with a range of seventies, in addition to providing a varied programme of group and recreational facilities to maintain interest and stimulation. Day centres, where patients are 4.1.3 DEMENTIA: ALZHEIMER'S DISEASE arrayed around the edge of the room with a television as a focal point, are, or should be, consigned to history. Day care provides essential respite to many carers, and longer periods of occasional or regular respite can prolong the period a patient can remain in their own home. The multidisciplinary team consisting of care workers, social ser- . vices, community psychiatric nurse occupational therapist, and psychologist can maintain patients at home more effectively and for longer periods than can clinicians alone. However, long-term care becomes a necessity for many patients at some point. The costs of providing nursing- home care are 'huge and far outweigh the costs of providing relatively intensive community care or relatively costly drugs. If treatments were shown to reduce the total length of stay in nursing homes then this would affect the cost-benefit ratio of these compounds considerably. Preventing AD and future treatments A number of factors such as non-steroidal anti-inflammatory drugs, hormone replacement therapy, and the antioxidant vitamin E, might be of some use in strategies to prevent AD. Prevention could be primary before any signs of the disease or secondary after some manifestation of the process. Primary preventive measures would have to be directed at either the entire population or to groups at risk (identified by family history or genotype, for example), and therefore would have to be entirely benign and almost cost-free to be acceptable. Secondary prevention, possibly in those with memory impairments not amounting to dementia (minimal cognitive impairment), is a more realistic prospect rendering the determination of the very earliest signs of disease or evidence of a prodromal state a high priority. A biological marker for AD would have immense uti lity in both clinical practice and in clinical trials. Markers suggested have included platelet membrane fluidity and measurement of amyloid, apoE, and tau in cerebrospinal fluid, as well as genetic markers. (82) Of these only cerebrospinal fluid tau appears to have any possible value as a biomarker. Tertiary prevention or disease modification refers to treatments to arrest or slow down the disease process after it has become clinically evident. Some evidence exists that drugs already available might have a disease-modifying effect, and other compounds designed to reduce amyloid formation or aggregation or tau phosphorylation are in development. Other approaches have been developed to reduce the inflammatory component of pathogenesis, or to enhance function and provide support for the remaining neurones using nerve growth factor. This latter promising approach is made problematic by the fact that oral or parenteral administration of a peptide would result in its rapid degradation. Given that AD is a chronically deteriorating condition, determining efficacy of disease modification is diffic ult. Two approaches have been suggested. (83) The randomized start trial assigns patients to drug or placebo at random, and at some predetermined point those on placebo are switched to treatment. If the treatment is symptomatic only it would be expected that on switching to treatment these individuals would 'catch-up' with those treated from the outset. However, if the treatment has slowed the disease, those treated fro.m the outset would ' remain relatively improved compared to the switched group. The randomized withdrawal trial is a reverse of this, with patients withdrawn from active treatment failing to fall to the placebo group results if the compound had affected the disease process. Conclusions For the foreseeable future, AD will remain a disorder afflicting a large proportion of the world's elderly. The impact on developing countries especially will be considerable. 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Joumal of Neuropathology and ExperimentalNeurology, 53, 438-47. 49. Hardy, J. (1997). Amyloid, the presenilins and Alzheimer's disease. Trends in Neuroscience, 20, 154-9. 50. Hung, A.Y., Haass, C, Nitsch, R.M., et al. (1993). Activation of protein kinase C inhibits cellular production of the amyloid ~-protein . Joumal of Biological Chemistry, 268, 22 959-62. 51. Lovestone, S. (1997). Muscarinic therapies in Alzheimer's disease: from palliative therapies to disease modification. Intemational Journal of Psychiatry in Clinical Practice, 1, 15-20. 52. Kosaka, T, Imagawa, M., Seki, K., et al. (1997). The ~APP717 Alzheimer mutation increases the percentage of plasma amyloid-~ protein ending at A ~42 (43 ) . Neurology, 48,741-5. 53. Citron, M., Vigo-Pelfrey, c., Teplow, D.B., et al. (1994) . Excessive production of amyloid ~-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proceedings of the National Academy of Sciences of the United States of America, 91, 11993-7. 54. Price, D.L. and Sisodia, S.S. (1994). Cellular and molecular biology of Alzheimer's disease and animal models. Annual Review of Medicine, 45, 435-46. 55. Da Silva, H.A.R. and Patel, A.J. (1997). Presenilins and early-onset familial Alzheimer's disease. Neuroreport, 8, 1-12. 56. Braak, E., Braak, H., and Mandelkow, E.-M. (1994). A sequence of cytoskeleton changes related to the formation of neurofibril lary tangles and neuropil threads. Acta Neuropathologica (Berlin), 87, 554-67. 57.
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As I could not attach the .pdf that I scanned for you (this is just the first one, so be prepared to put in some solid work reading through all I send you [some to follow] - tell your mum to cook some nutritious brain food for you next few days

In view of the probs attaching the .pdf, I have used OCR (Optical Character Recognition) software to try and paste the text below. Hold on tight to your table before looking below haha! (there might be some spelling errors because OCR is not perfect, but it might be better than attaching a pdf in one way - you can copy and paste small bits (I would not recommend it, but I know you spring chickens like doing that!!

Also, the formatting is altered by most OCR packages, so it will look like a massive chunk, just copy and paste whole thing to MS Word then change paragraph and line spacing under Home tab > Paragraph group > click on tiny icon with tiny arrow at bottom right. In the Paragragh dialog box that opens, change settings to your preference, the click OK.
4.1.3 DEMENTIA : ALZHEIMER'S DIS EASE Benzodiazepines are an alternative; they may be also be helpful in re-establishing the sleep- wake cycle, but often at the cost of increased daytime drowsiness. Therefore a short-acting agent should usually be chosen. Medicolegal issues Physical restraint can usually be avoided with adequate nursing care and medication. The psychiatrist should not become party to dubious practices in this area, such as the use of de facto restraint with tight blankets or deliberately induced parkinsonism with major tranquillizers. If continued physical restraint is necessary in rare cases, it should be as an explicit part of the treatment plan after medicolegal advice. Informed consent to treatment also involves important medicolegal issues.o6 ) Patients with delirium are often very ill, and frequently require surgery or other invasive procedures that they are incapable of understanding and consenting to. The legal position is complex, and will vary in different jurisdictions. However, legal capacity should certainly be assessed before seeking consent. It is almost always wise to involve relatives in decisions in these circumstances. It may be necessary to consult medicolegal advisers, including the hospital authorities. Prevention A variety of methods for delirium prevention in hospitalized patients have been subjected to controlled evaluations. Cole and coworkers identified ten studies, of which three were randomized, in a systematic review;(I 2) patients were middle-aged or elderly medical and surgical cases. Interventions included preintervention psychiatric assessment, and pre- and postoperative nursing assessments. Of these studies, only one showed a signifiqll1t reduction of delirium in the t reated group, but this was a non-randomized study. Therefore it appears that there is little evidence to support the introduction of special measures, over and above routine care, to prevent delirium. Good general medical and nursing care must be the key to prevention as well as to early recognition and effective treatment. Screening for alcohol dependence is important, for example with the CAGE questions. Elderly patients who are very unwell physically or who are having a major procedure, who have pre-existing cognitive problems, and who are receiving polypharmacy (especially psycho active drugs) are the most likely to develop delirium, and should be monitored clinically for this condition. Hypnotics are associated with an increased risk of delirium; routine use should be avoided, especially in such vulnerable patients. References 1. Berrios, G. and Porter, R. (1995). A history of clinical psychiatry. The origin and history of psychiatric disorders. Athlone, London. 2. Walzer, T., Herrmann, M., and Wallesch, CW. (1997). Neuropsychological disorders after coronary bypass surgery. Journal of Neurology, Neurosurgery and Psychiatry, 62, 644--8. 3. Dyer, CB., Ashton, C M., and Teasdale, T.A. (1995). Postoperative delirium. A rchives of Internal Medicine, 155, 461- 5. 4. Wise, M.G. and Trzepacz, P. (1994) . Delirium. In Textbook of consultation- liaison psychiatry (ed. J.R. Rundell and M.G. Wise) . American Psychiatric Press, Washington, DC 5. Treloar, A.J. and Macdonald, A.J. (199 7) . Outcome of delirium: Pa rt 1. Outcome of delirium di ag nosed by DSM-III-R, ICD-lO and CAMDEX and derivation of the Reversible Cognitive Dysfunction Scale among acute geriatric inpatients. International Journal of Geriatric Psychiatry, 12,609-13. 6. Newman, S. and Stygall, J. (2000). Changes in cognition following cardiac surgery (Editorial). Heart, in press. 7. Cole, M.G. and Primeau, F.J. (1993). Prognosis of delirium in elderly hospital patients. Canadian Medical Association Jou rnal, 149,41-6. 8. Trzepacz, PT. (1 994). A review of delirium assessment instruments. General Hospital~chiatry, 16, 397-405. 9. Hart, R.P., Best, A.M., Sessler, CN., and Levenson, J.L. (1997). Abbreviated cognitive test fo r delirium. Journal of Psychosomatic Research, 43, 417-23. 10. Hughes, J.R. (1996). A review of the usefuln ess of the standard EEG in psychiatry. Clinical Electroencephalography, 27, 35-9. 11. Cochrane Library, Issue 3 on CD-ROM. Update Software/BMJ Publishing, London. 12. Cole, M.G., Primeau, F., and McCusker, J. (1996). Effectiveness of interventions to prevent delirium in hospitalized patients: a systematic review. Canadian Medical Association Jo urnal, 155, 1263-8. 13. Breitbart, w., Marotta, R., PIa tt, M.M., et al. (1996) . A double-blind trial of haloperidol, chlorpromazine and lorazepam in the treatment of delirium in hospitalized AIDS patients. American Journal of Psychiatry, 153,231- 7. 14. Christensen, D.B. and Benfield, W.R. (1 998) . Alprazolam as an alternative to low-dose haloperidol in older, cognitively impaired nursing facility patients. Journal of the American Geriatrics Society, 46, 620- 5. 15. American Psychiatric Association (1999). Practice guidelines for the treatment of patients with delirium. American Journal of Psychiatry, 156, Supplement to Issue 5. 16. Auerswald, K. B., Charpentier, P.A., and Inouye, S.K. (1997) . The informed consent process in older patients who developed delirium: a clinical epidemiologic study. American JOllrnal of Medicine, 103,410-18. 4.1.3 Dementia: Alzheimer's disease Simon Lovestone Introduction Alzheimer's disease (AD) and other dementias incur huge costs to society, to the families of those affected, and to the individuals themselves. Costs to society include both direct costs to health and social services and indirect economic costs in terms of lost productivity, as carers are taken out of the workplace, and the economic costs to those families caring for or funding the care of their relative. Increasingly, as treatments become available, these costs are targets for change and are part of the cost- benefit analysis of new compounds, especially the largest single direct cost, that of the provision of nursing and other forms of continuing care. Apart from the financial cost to families there is the emotional impact resulting in distress and psychiatric morbidity. As the population ages, these costs pose substantial social and eco. nomic problems. Although lifespan itself has remained static, the 387 388 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY numbers of elderly in both developed and developing societies is increasing rapidly. In the developed world the sharpest projected growth is in the very elderly cohort- precisely the one that is at most risk of AD. Within the developing world the total number of elderly people is projected to rise substantially, reflecting to a large part better child health and nutrition. For countries in South America and Asia, with large and growing populations, the costs involved in caring for people with dementia in the future will become an increasing burden on health and social services budgets. In the absence of such services families will inevitably shoulder the main part of providing care, although the very process of development is associated with increasing urbanization and, to some degree, a diminution of the security provided by extended family structures. From discovery towards understanding In the early part of the twentieth century, Alois Alzheimer described his eponymous disorder in a middle-aged woman who suffered not only cognitive deterioration and functional decline but psychotic experiences, including delusions and auditory hallucinations. Neuropathology included gross atrophy and plaques and tangles on microscopy. Although all the important features of AD were described at this stage, two important developments came much later. First, in the 1960s with the studies of Roth and colleagues in Newcastle(l) and others elsewhere, it was appreciated that much dementia in the elderly has an identical neuropathological appearance to that of AD in younger people. The other development was the rediscovery that AD has a rich phenomenology. The non-cognitive symptomatology of AD is integral to the clinical manifestation of this disease, and is a major cause of carer burden and medical intervention. This second phase of research-the recognition that both the neuropathology and clinical phenomenology described by Alzheimer occur in what had previously been though of as senile dementia or, worse, just ageing, was accompanied by a growing understanding of the neurotransmitter deficits in AD. The cholinergic hypothesis provided the first glimpse of possible interventions, and remains the most important finding from this period of AD investigations. The third phase of AD research encompasses the use of molec ular approaches to understanding pathogenesis. The techniques of molecular biology have been applied to understanding the formation of plaques and tangles, to a growing understanding of the genetic aetiology of much of AD, and, through the use of transgenic approaches, to developing animal and cellular models of pathogenesis. Just as research can broadly be seen to h~ three phasesdiscovery, neuropathology, and IPolecul;u aspects-so too does the clinical response to AD. For many years cognitive impairment in the elderly was perceived as senility. As a process thought to be an inevitable consequence of ageing it was difficulty to establish medical-care models. Hence the needs of the elderly with AD were not seen as requiring speCialist intervention, carers needs were not realized, and public appreciation of the impact of dementia on the elderly themselves or on the family was negligible. The 'change in perception of AD from 'just ageing' to a disease was accompanied, and to some degree led, by the development of ' old age psychiatry' as a specialism on the one hand and by the rapid growth of the Alzheimer disease societies on the other. During this second phase of AD treatment, the goals have been to ensure that the care needs of patients are met, that families' . concerns are addressed, and that behavioural disturbance is minimized. The third phase of AD treatment began with the arrival of specifically designed interventions. Compounds have been introduced that were designed to ameliorate some of the deficits incurred by the disease process, and other approaches are being developed to treat those disease processes themselves. Clinical features Cognitive impairment Dementia is an acquired and progressive cognitive decline in multiple areas; AD is one cause of dementia and the core clinical symptom of AD is cognitive impairment. However, as noted above, AD is clinically heterogeneous and includes diverse non-cognitive symptoms and inevitable functional .impairment. Cognitive decline is manifested as amnesia, aphasia, agnosia, and apraxia (the 4As). Amnesia Memory loss in AD is early and inevitable. Characteristically, recent memories are lost before remote memories. However, there is considerable individual variation, with some patients able to recall specific and detailed events of childhood and others apparently having few distant memories accessible. With disease .progression, even remote and emotionally charged memories are lost. The discrepancy between recent and remote memory loss suggests that the primary problem is of acquisition or retrieval of memory rather than a destruction of memory, and this is confirmed in early AD,(2) although as the disease progresses it is likely that all memory processes are impaired. Retrieval ~f remote memory is assumed to be preserved for longer because of rehearsal over life. Aphasia Language problems are found in many patients at presentation, although the language deficits in AD are not as severe as those of the frontotemporal degenerations(3) and may only be apparent on detailed examination. Word-finding difficulties (nominal dysphasia) are the earliest phenomena observed and are accompanied by circumlocutions and other responses, for example repetitions and alternative wordings. As the disorder progresses, syntax is affected and speech becomes increasingly paraphasic. Although harder to assess, receptive aphasia, or comprehension of speech, is almost certainly affected. In the final stages of the disorder, speech is grossly deteriorated with decreased fluency, preservation, echolalia, and abnormal non-speech utterances. Agnosia Patients with AD may have difficulty in recognizing as well as naming objects. This can have implications for care needs and safety if the unrecognized objects are important for daily functioning. One particular agnosia encountered in AD is the loss of recognition of one's own face (autoprosopagnosia). This distressing symptom is the underlying cause of perhaps the only clinical sign in AD- the mirror sign. Patients exhibiting this will interpret the face in the mirror as some other individual and respond by talking to it or by apparent fearfulness. Autoprosopagnosia can present as an apparent hallucinatory experience, until it is realized that the 'hallucination' is fixed in both content and space, occurring only when self-reflection can be seen. 4.1.3 DEMENTIA: ALZHEIMER'S DISEASE Apraxia Difficulties with complex tasks that are not due to motor impairment become apparent in the moderate stages of AD. Typically, difficulties with dressing or tasks in the kitchen are noticed first, but these are inevitably preceded by loss of ability for more difficult tasks. Strategies . to avoid such tasks are often acquired as the disease progresses, and it is only when these fail that the dyspraxia becomes apparent. Other cognitive impairments There appear to be no cognitive functions that are truly preserved in AD. Visuospatial difficulties commonly occur in the middle stages of the disorder and may result in topographical disorientation, wandering, and becoming lost. Difficulties with calculation, attention, and cognitive planning all occur. Functional impairment Although the cognitive decline in AD is the core symptom, it is the functional deterioration that has the most impact on the person themselves and it is the functional loss that necessitates most of the care needs of patients with AD, including nursing-home residency.(4) Increasingly, abilities to function in ordinary life (activities of daily living (ADLs» are lost, starting with the most subtle and easily avoided and progressing to the most basic and essentiaL In general, functional abilities decline alongside cognitive abilities. However, the precise correlation between these functions is not perfect, suggesting that factors other than disease severity account for part of the variance between patients. (5 ) Functional abilities are related to gender; for example, cooking abilities are rehearsed more frequently in women, and home-improvement skills in men. However, the overall pattern shows some similarities between groups of patients with similar disease severity. This is exploited in the Functional Assessment Staging (FAST) scale;(6) in the original form, this is a seven-point scale of functional impairment, with stage 1 as no impairment and stage 7 as severe AD. A sequential decline is mapped by descriptions of the abilities that are lost: stage 2, difficulties with language and finding objects; stage 4, difficulties with finances; stage 6, incontinence and inability to dress or wash oneself. ADLs are divided into those that relate to self-care and those that concern instrumental activities. Instrumental ADLs, those related to the use of objects or the outside world, are lost first and can be subtle. (7) A change in the ability to use the telephone properly or to handle finances accurately may not be apparent. Self-care ADLs include dressing and personal hygiene and are also lost gradually; for example, untidiness in clothing progresses to difficulties in dressing. Personal hygiene becomes poor as dentures are not cleaned and baths taken less often, before finally assistance is required with all self-care tasks. Neuropsychiatric symptoms Mood The relationship between AD and depression is complex. Depression is a risk factor for AD, depression can be confused with dementia (pseudodementia), depression occurs as part of dementia, and cognitive impairments are found in depression. Depression occurring as a symptom of dementia will be considered here. Assessing the mood of a person with dementia is difficult for obvious reasoris. However, psychomotor ******ation, apathy, crying, poor appetite, disturbed sleep, and expressions of unhappiness all occur frequently. The rates of depression found in cohorts of patients with AD vary widely, reflecting changes in prevalence at different levels of severity and difficulties in the classification of symptoms suggestive of depression in those with cognitive loss. A major depressive episode is found in approximately 10 per cent of patients, minor depressive episode in 25 per cent, some features of depression in 50 per cent, and an assessment of depression by a carer in up to 85 per cent. (8- IQ) It is commonly believed that depression is more common in the early than in the later stages of AD, although this may reflect the difficulties of assessing depression in the more severely affected and least communicative patients. Indeed, severely affected patients in nursing homes may be particularly prone to depressio~: (I J) Ei; tion, disinhibition, and hypomania all occur in AD but are relatively infrequent, elevated mood being found in only 3.5 per cent of patients by Burns et al. (lO) The underlying cause of mood change in AD is not known. However, loss of serotonergic and noradrenergic markers accompanies cholinergic loss; some studies have found a greater loss of these markers at postmortem in AD patients with depression than in nondepressed patients. ( 12. 1 3 ) Psychosis Psychotic symptoms occur in many patients, although, as with depression, the difficulty in determining the presence of delusions or hallucinatory experiences in the moderately to severely demented gives rise to a very wide range of frequency rates. Few studies have been able to determine the rates of psychosis in community-dwelling, fully representative samples of patients with AD. However, of those known to, largely, psychiatric services, between 10 and 50 per cent suffer from delusions and between 10 and 25 per cent experience hallucinations.<' 4-16) Delusions are frequently paranoid and the most common delusion is one of theft. In the context of the confusion and amnesia of dementia, it is easy to appreciate how the experience of mislaying an object becomes translated into conviction of a theft. Other patients become convinced that someone, often a family member, is trying to harm them. Hallucinations are only somewhat less frequent than delusionsthe median of one series of studies being 28 per centY7) Visual hallucinations are reported more commonly than auditory ones, and other modalities are rareY6) Most studies of the non-cognitive symptomatology of AD precede the wide recognition and accepted criteria of dementia with Lewy bodies, one of the cardinal symptoms of which is visual hallucinations.<' S) It is probable that a large number of those AD patients experiencing visual hallucinations reported in the studies would now be classified as having dementia with Lewy bodies. Phenomena falling short of delusions or hallucinations, such as persecutory ideas or intrusive illusionary experiences, are common in AD as are misidentification syndromes. Cap gras' syndrome may occur, but frequently the symptom is less fully evolved with the patient mistaking one person for another. Failure to recognize one's own face may be due to visuospatial difficulties or to a true misidentification syndrome-distinguishing between the two is difficult. Various factors have been associated with psychosis in AD, but few have been substantiated in multiple studies. Burns et al. (16) found that more men than women suffered delusions of theft, although others find that psychosis occurs more often or earlier in women. An association with polymorphic variation in serotonin receptors has been 389 390 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY reported. (I9) Patients with psychotic symptoms show regional metabolic differences on functional neuroimaging. (20) The relationship between psychosis and dementia severity is not as clear cut as that between functional ability and dementia severity. Psychosis can occur at any stage of the disease process, although most studies find the maximal rate of psychosis in those with at least moderate dementiaY6.J7) Although the biological basis of psychosis within AD is not fully understood, it is probable that psychosis symptoms impact upon carers causing increased distress, (21) and that underlying psychosis accounts for much of the behavioural disturbance and aggression encountered in AD. (22) Personality Changes in personality are an almost inevitable concomitant of AD. Indeed, it is difficult to envisage how profound cognitive impairment resulting in the loss of recognition of loved ones, and an understanding of and ability to react with the outside world, could not result in a change in personality. Family members have described the loss of personality as a 'living bereavement'-the person remains, but the person once known has gone. Personality change is most frequently one of loss of awareness and normal responsiveness to the environment. Individuals may become more anxious or fearful, there is a flattening of affect, and a withdrawal from challenging situations. Catastrophic reactions are short-lived emotional reactions that occur when the patient is confronted, and cannot avoid, such a challenging situation. Less commonly, personality changes may be of disinhibition with inappropriate sexual behaviours or inappropriate affect. Aggressiveness is, as noted above, often accompanied by psychosis, but it may be part of a more general personality change. Other behavioural manifestations Behavioural complications in AD have become a target of therapy. However, the term encompasses a wide rage of behaviours, some of which include neuropsychiatric syndromes, some caused by neuropsychiatric syndromes, and some of which have little apparent relationship to mood or to thought content. Behavioural complication is itself a largely subjective term that relies to a great extent on informer evaluation: but a behaviour may be a complication in one context, although not in another. Behaviours exhibited in AD include wandering, changes in eating habit, altered sleep or circadian rhythms, and incontinence. These behaviours are closely linked to disease severity and occur to some extent in the majority of patients with AD. Wandering may be a manifestation of topographical confusion, a need for the toilet, or it may reflect hunger, boredom, or anxiety. Sleep is freqaently disturbed, with many patients exhibiting altered sleep- wake cycles and others experiencing increased confusion towards evening Csundowning'

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4.1.3 Dementia: Alzheimer's disease
Simon Lovestone
Introduction
Alzheimer's disease (AD) and other dementias incur huge costs to
society, to the families of those affected, and to the individuals themselves.
Costs to society include both direct costs to health and social
services and indirect economic costs in terms of lost productivity, as
carers are taken out of the workplace, and the economic costs to those
families caring for or funding the care of their relative. Increasingly, as
treatments become available, these costs are targets for change and are
part of the cost- benefit analysis of new compounds, especially the
largest single direct cost, that of the provision of nursing and other
forms of continuing care. Apart from the financial cost to families
there is the emotional impact resulting in distress and psychiatric
morbidity.
As the population ages, these costs pose substantial social and eco.
nomic problems. Although lifespan itself has remained static, the
387
388 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
numbers of elderly in both developed and developing societies is
increasing rapidly. In the developed world the sharpest projected
growth is in the very elderly cohort- precisely the one that is at most
risk of AD. Within the developing world the total number of elderly
people is projected to rise substantially, reflecting to a large part better
child health and nutrition. For countries in South America and Asia,
with large and growing populations, the costs involved in caring for
people with dementia in the future will become an increasing burden
on health and social services budgets. In the absence of such services
families will inevitably shoulder the main part of providing care,
although the very process of development is associated with increasing
urbanization and, to some degree, a diminution of the security provided
by extended family structures.
From discovery towards understanding
In the early part of the twentieth century, Alois Alzheimer described
his eponymous disorder in a middle-aged woman who suffered not
only cognitive deterioration and functional decline but psychotic
experiences, including delusions and auditory hallucinations. Neuropathology
included gross atrophy and plaques and tangles on microscopy.
Although all the important features of AD were described at this
stage, two important developments came much later. First, in the
1960s with the studies of Roth and colleagues in Newcastle(l) and
others elsewhere, it was appreciated that much dementia in the elderly
has an identical neuropathological appearance to that of AD in
younger people. The other development was the rediscovery that AD
has a rich phenomenology. The non-cognitive symptomatology of AD
is integral to the clinical manifestation of this disease, and is a major
cause of carer burden and medical intervention. This second phase of
research-the recognition that both the neuropathology and clinical
phenomenology described by Alzheimer occur in what had previously
been though of as senile dementia or, worse, just ageing, was accompanied
by a growing understanding of the neurotransmitter deficits in
AD. The cholinergic hypothesis provided the first glimpse of possible
interventions, and remains the most important finding from this
period of AD investigations. The third phase of AD research encompasses
the use of molec ular approaches to understanding pathogenesis.
The techniques of molecular biology have been applied to
understanding the formation of plaques and tangles, to a growing
understanding of the genetic aetiology of much of AD, and, through
the use of transgenic approaches, to developing animal and cellular
models of pathogenesis.
Just as research can broadly be seen to h~ three phases discovery,
neuropathology, and IPolecul;u aspects-so too does the
clinical response to AD. For many years cognitive impairment in the
elderly was perceived as senility. As a process thought to be an inevitable
consequence of ageing it was difficulty to establish medical-care
models. Hence the needs of the elderly with AD were not seen as
requiring speCialist intervention, carers needs were not realized, and
public appreciation of the impact of dementia on the elderly themselves
or on the family was negligible. The 'change in perception of AD
from 'just ageing' to a disease was accompanied, and to some degree
led, by the development of ' old age psychiatry' as a specialism on the
one hand and by the rapid growth of the Alzheimer disease societies on
the other. During this second phase of AD treatment, the goals have
been to ensure that the care needs of patients are met, that families' .
concerns are addressed, and that behavioural disturbance is minimized.
The third phase of AD treatment began with the arrival of specifically
designed interventions. Compounds have been introduced that
were designed to ameliorate some of the deficits incurred by the disease
process, and other approaches are being developed to treat those
disease processes themselves.
Clinical features
Cognitive impairment
Dementia is an acquired and progressive cognitive decline in multiple
areas; AD is one cause of dementia and the core clinical symptom of
AD is cognitive impairment. However, as noted above, AD is clinically
heterogeneous and includes diverse non-cognitive symptoms and
inevitable functional .impairment. Cognitive decline is manifested as
amnesia, aphasia, agnosia, and apraxia (the 4As).
Amnesia
Memory loss in AD is early and inevitable. Characteristically, recent
memories are lost before remote memories. However, there is considerable
individual variation, with some patients able to recall specific
and detailed events of childhood and others apparently having few
distant memories accessible. With disease .progression, even remote
and emotionally charged memories are lost. The discrepancy between
recent and remote memory loss suggests that the primary problem is
of acquisition or retrieval of memory rather than a destruction of
memory, and this is confirmed in early AD,(2) although as the disease
progresses it is likely that all memory processes are impaired. Retrieval
~f remote memory is assumed to be preserved for longer because of
rehearsal over life.
Aphasia
Language problems are found in many patients at presentation,
although the language deficits in AD are not as severe as those of the
frontotemporal degenerations(3) and may only be apparent on detailed
examination. Word-finding difficulties (nominal dysphasia) are the
earliest phenomena observed and are accompanied by circumlocutions
and other responses, for example repetitions and alternative
wordings. As the disorder progresses, syntax is affected and speech
becomes increasingly paraphasic. Although harder to assess, receptive
aphasia, or comprehension of speech, is almost certainly affected. In
the final stages of the disorder, speech is grossly deteriorated with
decreased fluency, preservation, echolalia, and abnormal non-speech
utterances.
Agnosia
Patients with AD may have difficulty in recognizing as well as naming
objects. This can have implications for care needs and safety if the
unrecognized objects are important for daily functioning. One particular
agnosia encountered in AD is the loss of recognition of one's
own face (autoprosopagnosia). This distressing symptom is the underlying
cause of perhaps the only clinical sign in AD- the mirror sign.
Patients exhibiting this will interpret the face in the mirror as some
other individual and respond by talking to it or by apparent fearfulness.
Autoprosopagnosia can present as an apparent hallucinatory
experience, until it is realized that the 'hallucination' is fixed in both
content and space, occurring only when self-reflection can be seen.
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
Apraxia
Difficulties with complex tasks that are not due to motor impairment
become apparent in the moderate stages of AD. Typically, difficulties
with dressing or tasks in the kitchen are noticed first, but these are
inevitably preceded by loss of ability for more difficult tasks. Strategies
. to avoid such tasks are often acquired as the disease progresses, and it
is only when these fail that the dyspraxia becomes apparent.
Other cognitive impairments
There appear to be no cognitive functions that are truly preserved in
AD. Visuospatial difficulties commonly occur in the middle stages of
the disorder and may result in topographical disorientation, wandering,
and becoming lost. Difficulties with calculation, attention, and
cognitive planning all occur.
Functional impairment
Although the cognitive decline in AD is the core symptom, it is the
functional deterioration that has the most impact on the person themselves
and it is the functional loss that necessitates most of the care
needs of patients with AD, including nursing-home residency.(4)
Increasingly, abilities to function in ordinary life (activities of daily
living (ADLs» are lost, starting with the most subtle and easily
avoided and progressing to the most basic and essentiaL In general,
functional abilities decline alongside cognitive abilities. However, the
precise correlation between these functions is not perfect, suggesting
that factors other than disease severity account for part of the variance
between patients. (5 ) Functional abilities are related to gender; for
example, cooking abilities are rehearsed more frequently in women,
and home-improvement skills in men. However, the overall pattern
shows some similarities between groups of patients with similar disease
severity. This is exploited in the Functional Assessment Staging
(FAST) scale;(6) in the original form, this is a seven-point scale of functional
impairment, with stage 1 as no impairment and stage 7 as severe
AD. A sequential decline is mapped by descriptions of the abilities that
are lost: stage 2, difficulties with language and finding objects; stage 4,
difficulties with finances; stage 6, incontinence and inability to dress or
wash oneself.
ADLs are divided into those that relate to self-care and those that
concern instrumental activities. Instrumental ADLs, those related to
the use of objects or the outside world, are lost first and can be subtle.
(7) A change in the ability to use the telephone properly or to handle
finances accurately may not be apparent. Self-care ADLs include dressing
and personal hygiene and are also lost gradually; for example,
untidiness in clothing progresses to difficulties in dressing. Personal
hygiene becomes poor as dentures are not cleaned and baths taken less
often, before finally assistance is required with all self-care tasks.
Neuropsychiatric symptoms
Mood
The relationship between AD and depression is complex. Depression is
a risk factor for AD, depression can be confused with dementia
(pseudodementia), depression occurs as part of dementia, and cognitive
impairments are found in depression. Depression occurring as a
symptom of dementia will be considered here. Assessing the mood of a
person with dementia is difficult for obvious reasoris. However,
psychomotor ******ation, apathy, crying, poor appetite, disturbed
sleep, and expressions of unhappiness all occur frequently. The rates of
depression found in cohorts of patients with AD vary widely, reflecting
changes in prevalence at different levels of severity and difficulties in
the classification of symptoms suggestive of depression in those with
cognitive loss. A major depressive episode is found in approximately
10 per cent of patients, minor depressive episode in 25 per cent, some
features of depression in 50 per cent, and an assessment of depression
by a carer in up to 85 per cent. (8- IQ) It is commonly believed that
depression is more common in the early than in the later stages of AD,
although this may reflect the difficulties of assessing depression in the
more severely affected and least communicative patients. Indeed,
severely affected patients in nursing homes may be particularly prone
to depressio~: (I J) Ei; tion, disinhibition, and hypomania all occur in
AD but are relatively infrequent, elevated mood being found in only
3.5 per cent of patients by Burns et al. (lO)
The underlying cause of mood change in AD is not known. However,
loss of serotonergic and noradrenergic markers accompanies
cholinergic loss; some studies have found a greater loss of these markers
at postmortem in AD patients with depression than in nondepressed
patients. ( 12. 1 3 )
Psychosis
Psychotic symptoms occur in many patients, although, as with depression,
the difficulty in determining the presence of delusions or hallucinatory
experiences in the moderately to severely demented gives rise
to a very wide range of frequency rates. Few studies have been able to
determine the rates of psychosis in community-dwelling, fully representative
samples of patients with AD. However, of those known to,
largely, psychiatric services, between 10 and 50 per cent suffer from
delusions and between 10 and 25 per cent experience hallucinations.<'
4-16) Delusions are frequently paranoid and the most common
delusion is one of theft. In the context of the confusion and amnesia of
dementia, it is easy to appreciate how the experience of mislaying an
object becomes translated into conviction of a theft. Other patients
become convinced that someone, often a family member, is trying to
harm them.
Hallucinations are only somewhat less frequent than delusionsthe
median of one series of studies being 28 per centY7) Visual hallucinations
are reported more commonly than auditory ones, and other
modalities are rareY6) Most studies of the non-cognitive symptomatology
of AD precede the wide recognition and accepted criteria of
dementia with Lewy bodies, one of the cardinal symptoms of which is
visual hallucinations.<' S) It is probable that a large number of those AD
patients experiencing visual hallucinations reported in the studies
would now be classified as having dementia with Lewy bodies.
Phenomena falling short of delusions or hallucinations, such as
persecutory ideas or intrusive illusionary experiences, are common in
AD as are misidentification syndromes. Cap gras' syndrome may occur,
but frequently the symptom is less fully evolved with the patient mistaking
one person for another. Failure to recognize one's own face may
be due to visuospatial difficulties or to a true misidentification
syndrome-distinguishing between the two is difficult.
Various factors have been associated with psychosis in AD, but few
have been substantiated in multiple studies. Burns et al. (16) found that
more men than women suffered delusions of theft, although others
find that psychosis occurs more often or earlier in women. An association
with polymorphic variation in serotonin receptors has been
389
390 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
reported. (I9) Patients with psychotic symptoms show regional metabolic
differences on functional neuroimaging. (20) The relationship
between psychosis and dementia severity is not as clear cut as that
between functional ability and dementia severity. Psychosis can occur
at any stage of the disease process, although most studies find the maximal
rate of psychosis in those with at least moderate dementiaY6.J7)
Although the biological basis of psychosis within AD is not fully
understood, it is probable that psychosis symptoms impact upon
carers causing increased distress, (21) and that underlying psychosis
accounts for much of the behavioural disturbance and aggression
encountered in AD. (22)
Personality
Changes in personality are an almost inevitable concomitant of AD.
Indeed, it is difficult to envisage how profound cognitive impairment
resulting in the loss of recognition of loved ones, and an understanding
of and ability to react with the outside world, could not result in a
change in personality. Family members have described the loss of personality
as a 'living bereavement'-the person remains, but the person
once known has gone. Personality change is most frequently one of
loss of awareness and normal responsiveness to the environment. Individuals
may become more anxious or fearful, there is a flattening of
affect, and a withdrawal from challenging situations. Catastrophic
reactions are short-lived emotional reactions that occur when the
patient is confronted, and cannot avoid, such a challenging situation.
Less commonly, personality changes may be of disinhibition with
inappropriate sexual behaviours or inappropriate affect. Aggressiveness
is, as noted above, often accompanied by psychosis, but it may be
part of a more general personality change.
Other behavioural manifestations
Behavioural complications in AD have become a target of therapy.
However, the term encompasses a wide rage of behaviours, some of
which include neuropsychiatric syndromes, some caused by neuropsychiatric
syndromes, and some of which have little apparent relationship
to mood or to thought content. Behavioural complication is
itself a largely subjective term that relies to a great extent on informer
evaluation: but a behaviour may be a complication in one context,
although not in another.
Behaviours exhibited in AD include wandering, changes in eating
habit, altered sleep or circadian rhythms, and incontinence. These
behaviours are closely linked to disease severity and occur to some
extent in the majority of patients with AD. Wandering may be a manifestation
of topographical confusion, a need for the toilet, or it may
reflect hunger, boredom, or anxiety. Sleep is freqaently disturbed, with
many patients exhibiting altered sleep- wake cycles and others experiencing
increased confusion towards evening Csundowning').(23) A central
defect in the regulation of circadian rhythms underlying these
phenomena is postulated.(24) Excessive or inappropriate vocalizations
(grunting and screaming) occur in the late stages.
Classification
AD is classified, as with all other disorders, by DSM-IV and by lCD-lO.
In addition, it also has a specialized classification system resulting from
the National Institute of Neurological and Communicative Disorders
and Stroke-Alzheimer's Disease and Related Disorders Association
(NINCDS-ADRDA). (25) This clinical diagnostic system is internationally
accepted and widely observed. There are other classification systems
for neuropathological diagnosis, most notably the Consortium to
Establish a Registry for Alzheimer's Disease (CERAD) criteria. (26)
DSM-IV stipulates that a dementia syndrome is characterized by a
decline in multiple cognitive deficits, including amnesia, resulting in
impairment. A gradual onset and decline in the absence of other conditions
sufficient to cause dementia indicates AD. lCD-IO shares with
DSM-IV the definition of a dementia syndrome as a deterioration in
more than one area of cognition, but including memory that is sufficient
to impair function. Again an emphasis on insidious onset and
slow decline in the absence of other disorders sufficient to cause
dementia indicates AD. The NINCDS-ADRDA criteria defines possible,
probable, and definite categories; the latter being restricted to
neuropathological confirmation of a clinical diagnosis. (25) It is important
to note that both clinical and neuropathological data are
required-no single neuropathological lesion is pathognomonic of
AD, and it is still uncertain how often or to what extent the neuropathologicallesions
of AD also occur in normal ageing. Probable AD,
according to NlNCDS-ADRDA, requires a dementia with progressive
decline in memory and other cognitive areas, cognitive impairment
established by formal testing, no disturbance of consciousness, and
absence of other disorders sufficient to cause dementia. Supporting
features include decline in function, change in behaviour, positive
family history, and decline in specific cognitive areas including aphasia,
apraxia, and agnosia. Non-specific change on electroencephalography
(EEG) and progressive changes on CT are supporting, but not
necessary, features. Possible AD should be diagnosed if there are variations
in the clinical presentation, another disorder sufficient to cause
a dementia (even if it is not thought to do so in this case), or a
restricted cognitive decline.
A number of studies have attempted to determine the accuracy of
diagnostic criteria against postmortem diagnosis. One of the difficulties
in these studies is that because AD is the most common dementia
(by some way), such studies are very likely to find a high-positive predicative
value. Kukull et al. (27) found the specificity of DSM-III to be
higher than NINCDS-ADRDA (0.8 versus 0.65), but NINCDSADRDA
had a higher sensitivity (0.92 versus 0.76); others find an even
lower specificity.(28)
Diagnosis
AD is the most common of the dementias, occur"ring in some 60 to
70 per cent of cases. However, this oft-stated figure must be treated
with some caution for two reasons. First, cases that come to postmortem
represent a biased sample, and the proportion of pathologically
confirmed AD in community-dwelling representative samples is
unknown. Second, even at postmortem the distinction between different
dementi as is not clear cut-many AD brains show the presence of
Lewy bodies and others have considerable evidence of vascular damage.
The proportion of mixed pathologies IS actually rather high,
between 15 and 30 per cent of all dementias.
History
Making a clinical diagnosis of AD is a positive process and not one of
exclusion. The most valuable diagnostic assessment is a careful
. informant history, paying attention to the pattern and timing of onset
Q-
5-
a
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
and progression. In the research context, a family history interview
conducted by telephone provides a degree of accuracy compatible with
a full clinical assessment. (29,30) Detailed semistructured family informant
diagnostic schedules are available, such as CAMDEX.(31) A history
should be taken for the presence of risk factors for AD (e.g. a positive
family history) and vascular and other risk factors (e.g. hypertension
'and head injury). Taking a family history for late-onset disorders such
as AD requires special attention. Because of attrition due to other illness,
many elderly people have had too few relatives reach the age of
onset of dementia to make a pedigree analysis informative. The ages at
death of all relatives should be established, together with cause of
death and the presence or absence of dementia or memory problems
in late life. The term 'sporadic' dementia should be avoided, and is
misleading when applied to an individual with a dementia where one
parent died young and where no sibling reached the age of 65 to
70 years. The history should also screen for the presence of other illnesses
sufficient to cause a dementia, and for systemic health in general.
The presence of any significant physical illness, from chronic pain
to delirium, may significantly alter cognitive abilities in the elderly, and
especially so in those with AD.
A careful history should also establish the presence of any behavioural
disturbance that has occurred. The relationship of aggression,
wandering, agitation, or other behaviours to care tasks and other
recent changes in the provision of the care package should be established.
As the mainstay of the management of behavioural disturbance
in all dementias is behavioural, establishing the antecedents to behaviour
is an absolute prerequisite to effective management.
Examination
In addition to an examination of the mental state to establish the presence
of disorders of mood and thought content, the examination will
establish the specific pattern of cognitive impairment and the degree of
impairment. Screening tests used to establish the presence of cognitive
impairments include the Mini Mental State Examination;(32) this is a
30-point scale routinely used in all clinical trials of drugs for the treatment
of AD, which is also a useful proxy measure for severity. It should
be accompanied, by other cognitive testing, including supplementary
examination for aphasia and apraxias. Other cognitive and physical
examinations will be necessary where the differential diagnosis is
between a lobar dementia (e.g. frontotemporal dementia) or a subcortical
dementia (e.g. that accompanying Huntington's disease).
In addition to the cognitive examination, a physical examination
should be conducted in all patients with AD, although this might not
be most effectively and conveniently performed at the initial assess ment.
Physical illness, including chronic pain, infection, cardiac insufficiency,
or anaemia are all common in the elderly and can both
complicate the diagnosis of AD and increase confusion in those known
to have AD.
Assessment of function
Clinical assessment of function can be performed by informant history
and by direct observation. The occupational therapist fulfils an invaluable
role in establishing the detailed functional ability of those with
AD, in addition to implementing changes in the home designed to
maximize function. The FAST scale(6) is based on the premise that the
pattern of decline in function is relatively uniform in AD, and hence
establishes a staging of severity on function rather than cognition. As
in most instances functional severity is of more relevance for the provision
of services, there is much to recommend such an approach.
Global assessment
Driven largely by the United States Food and Drugs Administration,
global assessment has become part of the assessment of all patients
with AD in clinical trials and is finding its way into clinical practice.
The underlying premise is that an assessment by a clinician, often supplemented
by an informant history, provides information on severity
that neither a cognitive assessment nor a functional assessment alone
can provide. One scale, the Clinicians Interview of Change, has
become widely used in this context and is an interesting attempt to
se miformaliz~ ,the t9.1!tine clinical impression without operationalized
criteria.
Investigations
At the initial assessment, patients with dementia should be investigated
for other disorders that could complicate, exacerbate, or be confused
with AD. A dementia screen might include routine biochemistry,
thyroid function tests, vitamin Bl2 and folate estimations, and a full
blood count; many would also include syphilis serology, although the
frequency of abnormal findings is low. A CT brain scan is not necessary
in many cases and is not a required investigation in the NINCDSADRDA
classification, although worsening atrophy on CT is supportive
evidence. Functional scanning (single-photon emission CT
(SPECT) in particular) can be useful where regional dementias are
suspected, and magnetic resonance imaging can provide supportive
evidence where vascular dementia is a possibility. An EEG is nearly
always non-specifically abnormal even in the early stages of AD, in
contrast with frontotemporal degenerations where an EEG remains
unaffected at a broadly equivalent severity. This can help to distinguish
the conditions, particularly where there is neuroimaging evidence of
regional insufficiency.
Aetiology and molecular neurobiology
AD is the most common dementia, affecting more than 20 per cent of
the population over the age of 85 years. Epidemiological evidence has
suggested risk factors and putative protective factors, but the greatest
advances in understanding its pathogenesis have come from the combination
of molecular and epidemiological approaches.
Neuropathology
At postmortem, the brain in AD is lighter than aged-unaffected controls
with more prominent sulci and a larger ventricular volume.
Microscopic examination reveals the most prominent lesions
described by Alzheimer-the extracellular plaque and intracellular
neurofibrillary tangleY6) No consensus has developed regarding
which of these lesions is responsible for the cognitive impairment of
AD. Plaques, or more precisely amyloid load, might correlate with the
degree of cognitive impairment,(33) although a significant amyloid
deposition is also found in normal, unimpaired, aged individualsY4)
However, there is a high degree of correlation between dementia severity
and neurofibrillary tangle formation, (35) although it is possible that
some of the features of AD are more stable than others; for example,
391
392 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
extracellular neurofibrillary tangles persist after the neurone has died,
whereas extracellular Lewy bodies are not found.
The plaque consists of an amyloid core surrounded by dystrophic
neurites, which are themselves filled with highly phosphorylated tau
protein. Studies of Down syndrome brains have suggested a temporal
course to plaque formation. First, peptides derived from the amyloid
precursor protein (APP) are deposited in a diffuse plaque.(36) Over
time this becomes organized as the amyloid pep tides become fibrillar
and form the amyloid deposit, neuritic change then occurs, and the
plaque becomes fully mature.
Neurofibrillary tangles are composed of paired helical filaments,
structures which are also found in the dystrophic neurites around
mature plaques, and together with straight filaments, in neuropil
threads. These filaments are themselves composed of the microtubuleassociated
protein, tau, which is present in a stably and highly phosphorylated
stateY7) Tau is a neuronal-specific protein, found
predominantly in the axon, that functions to stabilize micro tubules, a
property that is regulated by phosphorylation. Phosphorylated tau is
less effective in promoting tubulin polymerization into microtubules,
and in cells highly phosphorylated tau does not stabilize microtubules.
(38) In normal adult brain a proportion of tau is highly phosphorylated,
but this proportion is considerably greater in AD. Tau
deposits are a feature of other disorders, such as progressive supranuclear
palsy and some frontotemporal degenerations. Mutations have
been found in frontotemporal degenerations with parkinsonism
(FTDP-17), (39) and progressive supranuclear palsy has also been associated
with changes in the tau gene(40) thereby emphasizing the
importance of this molecule to neurodegeneration.
Braak and Braak(41) studied large numbers of brains from individuals
who died at various ages and at different stages of dementia severity,
which has resulted in the wide acceptance of the neuropathological
staging of AD. The very earliest stages, before the clinical manifestation
of dementia, are characterized by the appearance of highly phosphorylated
tau in the hippocampus. In later stages, neurofibrillary tangles
appear in the same brain regions and then become more widely
distributed.
The cholinergic hypothesis
The pathological changes in AD are localized both structurally and
functionally. Plaques and tangles first occur in the hippocampus
before spreading to involve other regions. Some areas of the brain are
relatively preserved-the occipital lobe is affected relatively late and
the cerebellum appears to be spared from neuritic change (neurofibrillary
tangles and the fully matured plaques:"1l1thOligh diffuse amyloid
deposits do occur). Functional localization was demonstrated by
evidence of the relatively greater and earlier loss of cholinergic neurotransmission.
At postmortem there is evidence of significantly greater
neuronal loss in the cholinergic nucleus basalis of Meynert and loss of
cholinergic markers. (42-44) These observations led to the cholinergic
hypothesis, which stated that the cognitive impairment of AD was due
to a disorder predominantly affecting cholinergic neurones. It was this
hypothesis that led to the development of pharmacological strategies
to rectify cholinergic loss and the introduction of the first compounds
specifically designed for and efficacious in AD. However, the cholinergic
hypothesis was something of a simplification as other neurotransmitter
systems (e.g. serotonergic and noradrenergic) are also affected
in AD.
The amyloid cascade hypothesis
In 1984, the protein deposited in blood vessels (congophilic angiopathy)
in AD was shown to be a 4-kDa peptide known as
~-amyloid. (45 ) This peptide, which is identical to the amyloid in
plaques, is derived from a larger peptide, APP, the gene for which is
coded on chromosome 21. After a series of misleading linkage studies,
mutations in the APP gene were found in a family with autosomal
dominant early-onset AD.(46) These two discoveries- the identification
of ~-amyloid and the discovery of mutations in the parent APP
gene-led the way to the amyloid cascade hypothesis, which has
remained the dominant molecular model of the disorder. (47) Many
subsequent molecular observations have been consistent with this
model, which posits the formation of ~-amyloid as the initiating, or at
least early event, leading to all the other changes observed including
tau aggregation and phosphorylation, neuronal loss, cholinergic deficits,
and clinical symptoms. Perhaps the most convincing evidence
that there is such a unidirectional cascade comes from the observation
that mutations in the APP gene give rise to plaque formation and also
to neurofibrillary tangle pathology, whereas mutations in the tau gene
give rise to tangle formation but not to plaque formation in FTDP-
17.
Much subsequent research has concentrated upon understanding
the metabolism of APP and the formation of ~ -amyloid peptide.(48.49)
APP is a ubiquitous single-pass cell-membrane protein expressed in
many cell lines with a high degree of evolutionary conservation. At
least three putative secretases cleave APP and the metabolic products
can be detected in individuals unaffected by AD; the processing is not
pathological in AD, but the balance between different metabolic routes
may be shifted in the disease state. a-Secretase cleaves APP at the outer
cell-membrane surface at a site within the ~-amyloid moiety itself.
Clearly, a-secretase cannot therefore yield intact ~-amyloid, and this
metabolic route, resulting in a secreted product, APPs, and other fragments,
is termed non-amyloidogenic. a-Secretase activity is increased
following stimulation of protein kinase C. (50) This might have some
clinical relevance as certain neuronal receptors are coupled to protein
kinase C and, indeed, muscarinic agonists do increase non-amyloidogenic
metabolism. These studies predict that therapies designed to
correct the cholinergic deficit in AD might have a disease modification
effect. (51 )
Amyloidogenic metabolism is the result of ~-secretase cleaving
APP beyond the amino terminus of ~-amyloid and of y-secretase
cleaving the resulting peptides at the carboxy terminus in the cell. The
~ - amylo id products vary in length, with predominant species having a
length of 40 or 43 amino acids. The longer pep tides are somewhat
more prone to forming fibrils in vitro. It is probable that the proportion
of ~-amyloid(4 2-43) pep tides relative to ~-amyloid ( 40) pep tides is
critical in pathogenesis, (49) and that mutations in the APP gene
increase these longer amyloid peptides. (52.53) Transgenic mice overexpressing
the mutated APP gene also produce more ~-amyloid peptide
and have amyloid deposits in brain.(54) Interestingly, these animals do
not develop other aspects of AD pathology.
The presenilin genes
Mutations in presenilin-1 (PS-I) and presenilin-2 (PS-2), two very
similar genes on chromosome 14 and chromosome 1 respectively, also
cause early-onset autosomal dominant AD. (55) The function of these
genes is not fully understood, but homology with genes in flies and
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
worms suggests that the presenilins participate III NOTCH
signalling-a complex signal-transduction cascade critical, amongst
other things, in determining neuronal cell fate. Mutations in the presenilin
genes, and hence their role in AD pathogenesis, may result in
an interference with the normal functioning of the protein or may
induce a gain in a novel pathogenic function. Whatever the mech.
anism, it is clear that mutations in the presenilins result in an increase
in the production of ~-amyloid. (49 ) Therefore the finding of mutations
in these genes adds to, rather than detracting from, the amyloid cascade
hypothesis although, as with any hypothesis, the complexity of an
originally simple idea increases.
Tangle formation and tau phosphorylation
Tangles are composed of paired helical filaments, themselves composed
of hyperphosphorylated tau. It is not fully determined whether
tau phosphorylation precedes tau aggregation, but tau is highly phosphorylated
in fetal brain and, albeit to a lesser extent, in normal adult
brain. (37) However, neuropathological evidence suggests that highly
phosphorylated tau does begin to accumulate in the brain before the
formation of tangles, and before the clinical manifestation of AD.(S6) It
seems as though, if not the only event in paired helical-filament formation,
increased tau phosphorylation is at least an early event.
Protein phosphorylation is a product of kinase and phosphatase
activity. It is likely that many such enzymes may participate in the
regulation of tau phosphorylation in the brain, but two have been
shown to be predominant. In cells, and in vitro, glycogen synthase
kinase-3 is the main tau-kinase and protein phosphatase 2A is the predominant
tau phosphatase. (57.58)
Molecular genetics
Mutations in three genes have been found to cause early-onset familial
AD, which is inherited in an autosomal dominant fashio n. (S9) Mutations
in the APP gene (on chromosome 21) are the least common, only
affecting perhaps 20 families worldwide. Mutations in PS-1 (on
chromosome 14) are somewhat more frequent, although are still a rare
cause of AD. Mutations in PS-2 (on chromosome 1) appear to be
largely restricted to an ethnic German people residing in the United
States, suggesting an individual founder effect. Mutations in these
genes have not been identified in true late-onset AD. Individuals with
Down's syndrome are at extremely high risk of AD, with neuropathological
evidence being present in virtually all individuals living to middle
age, probably because of trisomy APP.
The genetic component oflate-onset AD has been demonstrated by
epidemiological studies, showing that a family history of dementia is
the largest single risk factor for AD.(60) However many, perhaps most,
patients with AD do not have a positive family history, thus giving rise
to the idea of , sporadic' AD with a separate aetiology to 'familial' AD.
For late-onset AD this concept is outmoded and redundant. Many
patients with AD do not have a family history because of attrition of
family members due to death by other causes. For the cohort currently
suffering from AD their parents were born in the latter part of the
nineteenth century or early years of the twentieth, lived through two
major world wars, and reached adulthood before the discovery of antibiotics.
It is not surprising that few patients with late-onset AD have
two parents and more than one sibling living to the age of onset of AD,
and if one parent died young and there are no elderly siblings then the
family history is non-informative. Well-designed studies examining
the rate of AD in first-degree relatives by age find a cumulative incidence
reaching 50 per cent or higher by the age of 90 years. (61.62)
One gene has been unequivocally associated with late-onset AD,
although even this gene accounts for only something like 50 per cent of
the genetic variance.(63) The apolipoprotein E gene (APOE, gene;
apoE, protein) on chromosome 19 has three common alleles, coding
for three protein isoforms that differ by the substitution of an amino
acid at just two positions. Of the three alleles £3 is the most frequent
and £2 the least; following linkage to chromosome 18 it was demonstrated
that the £4 allele confers risk, whilst the £2 may be protective.(
M) This finding has been replicated in a huge number of studies
and in many different populations, although there are some, as yet,
unexplained differences as black African-Americans apparently do not
show an increased risk with the £4 allele. (65)
The mechanism-a1 action of the APOE gene in increasing the risk of
AD is not known. As AFOE variation is a major genetic influence on
serum cholesterol (people with the APOE £4/* genotype have higher
serum cholesterol levels), it is possible that an altered lipid
metabolism-either peripherally or locally-might affect the pathogenesis
of AD.(66) Alternative theories arise from in vitro studies, which
show a differential binding of APOE protein isoforms both to amyloid
protein and to tau protein.(64) Certainly it does seem as though APOE
isoforms affect neurones in culture in different ways, with apoE4 isoforms
inducing shorter neurites and microtubule collapse.(67)
Other genes have been associated with AD, but none have been
replicated in as many studies as APOE. It is likely that a combination of
linkage and association studies using large populations will identify
the other genes that influence AD, either alone or in interactions with
other genes or the environment.
Treatment
For many conditions the goals of treatment or intervention are selfevident-
cure, prevention of relapse, and resolution of symptoms. For
AD, however, the goals of treatment can be less obvious and differ
between patients and for individual patients over time. Ultimately, the
quality oflife of the patient should be improved, but assessing quality
of life is difficult in those with dementia, and given the early loss of
insight who is to judge such issues?(68) Quality of life may appear
poor- patients may have diminished emotional repertoires, few pleasurable
activities, and considerable handicap-but they may share
none of the negative cognitions experienced by others with a similarly
questionable quality of life induced by different illnesses. Other
patients may appear content or happy, despite the loss of the autonomy
and self-awareness normally considered an essential component
of a good quality life. Equally, the treatment unit in AD includes
carers, and there are times when the patient's quality of life is in conflict
with the quality of life for other members of the family. Resolving
such conflicts of interest and other moral and ethical issues is part of
the treatment process in AD. With the arrival of specific treatments for
AD and the prospect of disease-modifying therapies, an even harder
question arises regarding prolonging life for those with dementia: if
quality oflife appears poor to observers, is it right to prolong the process,
can quality of life in those with dementia truly be assessed, or
should carers and families be allowed to assess for themselves the
benefits and costs of treatment?(69)
393
394 4 CLINICAL SYNDRO MES OF ADULT PSYCHIATRY
There is no single model of management of patients with AD. In
many countries management is the role of the gerontologist or
neurologist. In others, as in the United Kingdom, the old-age psychiatry
team provide the core specialist services. Many, perhaps even the
majority, of those with AD are managed within primary care with the
support of social services. Referral from primary care to specialist services
will be according to local agreements, but most would concur
that behavioural disturbance or the use of specific drugs to treat AD
warrant referral to secondary care. Interventions for AD, whether provided
in primary or secondary care, can be thought of as directed
towards the patient, the patient's family, and the patient's environment
. Guidelines on the identification and management of patients
with dementia have been produced and may be a constructive
approach to ensuring best clinical practice. (70-72)
Managing the patient
Management of the patient with dementia is discussed in greater detail
in Chapter 4.1.14. Management starts with the assessment and diagnosis,
and perhaps the difficult dilemma is how much of the diagnosis
and prognosis to discuss with the patient. (73) Most practitioners do not
discuss the diagnosis with the patient themselves, although especially
in the early stages a frank cons'ultation can be beneficial. For most
patients, however, cognitive impairment renders an appreciation of
the diagnosis and prognosis difficult.
A large part of managing the patient is directed towards managing
mood and behavioural disturbance. Accurate assessment of the disturbance
is critical, and includes determining the antecedents and
responses to the behaviour as well as a full description of the behaviour
and any associated abnormalities in the mental state. Treatments of
behavioural disturbance in AD are most often behavioural and sometimes
restricted to giving information to careers. However, pharmacological
interventions are an important part of the management of
behavioural disturbance, even though caution regarding the use of
psychotropic medications in those with dementia is necessary.
Specific treatments for AD have been developed, concentrating in
clinical trials on ameliorating the core symptom of cognitive impairment.
The cholinomimetic approaches are the most advanced, but
other therapies are receiving extensive evaluation. Although designed
for the large part as strategies to enhance cognition, these compounds
also favourably appear to affect function and may reduce behavioural
disturbance. Further evaluation is being conducted to determine
whether there are disease-modifying effects. Drug treatments for AD
are described in Chapter 6.2.7.
Managing the family --
Although patients may not appreciate or be able to follow a detailed
discussion of the diagnosis and prognosis, their relatives, spouses, and
other carers will. This is an important part of the treatment process; as
the carer provides the main interventions for much of the period of the
disease process, care should be taken to ensure that appropriate and
sufficiently complete information is given.
Caring for a patient with AD can be difficult and stressful and some
carers suffer accordinglyY4) The characteristics of both carers and
patients influence the impact that this 'burden' of caring has on the
carers themselves. Men in general, and husbands in particular, seem to
be less vulnerable to the adverse effects of caring, possibly because of
the response seen in many male carers of rapidly and effectively
recruiting outside helpYS) Women may be socialized into accepting
more caring roles themselves and therefore seek less help. Non-white
carers appear to suffer from less adverse consequences of caring, perhaps
because of cultural differences in the perception of family
bonds. (76) Patient characteristics that increase the burden of caring
include behavioural disturbances, (77.78) depression, (79 ) and unawareness
of cognitive impairment,(80) but not the cognitive impairment
itself. Although the core outcome variable in clinical trials of AD drugs
is the severity of cognitive impairment, it is not the variable that
induces most stress in relatives nor is it the variable that predicts entry
to residential care. Other variables are almost certainly protective, and
caring for a loved one with dementia is not a universally negative
experience. Much caring is done willingly, effectively, with love, and
without complaint.
Carer support groups offer much to a person with a relative
afflicted by AD. Through support groups, and especially through the
national AD societies and the umbrella group-Alzheimer's Disease
International-carers can obtain up-to-date and useful information
regarding all aspects of AD. A support group can help individuals
practically and emotionally through difficult times. Many carers talk of
the support group as a life-line, although little empirical evidence
exists as to the impact on carer well being.
One particular intervention for the family is that of genetic counselling.
Many relatives are worried about inheriting AD. This concern
might arise from two sources-the frequent discussion of genes 'for'
AD in the media and the observation of familial occurrence of AD in
many individual families. For families with clinically apparent familial
AD, advice, information, and where appropriate, genetic testing can be
arranged through a genetics centre. Where predictive testing is contemplated
for genes causing autosomal dominant, early-onset AD this
will adhere to guidelines established for Huntington's disease. It is
unlikely that true predictive testing will become available for late-onset
AD.(sl)
Managing the environment
The mainstay of interventions for AD are provided by social services.
The goal of the provision of social care in people with AD is 'to provide
an environment that is comfortable, stimulating, and, above all, safe.
For most patients, and for all patients in the early stages, this means
care at home, perhaps with the support of home-meal delivery and
home-helps to provide shopping and cleaning assistance. Further
home care may become necessary as the patient requires assistance
with basic self-care tasks such as washing and dressing. The carer may
require a sitting service, either for periods during the day to allow
them time to themselves or in the evening to allow them to attend a
carers group or for socializing. Safety issues are especially important
for those with dementia living alone. There are inherent risks to the
patient themselves if they wander out of the home and risks to others if
the gas can be left on or fires started.
Day care is appropriate for many patients, ideally in a specialist
unit. In a generic facility for elderly people those with early dementia
can receive little input and those with moderate or advanced dementia
can necessitate too much input from the day-centre staff. A good
dementia specialist day-care facility will provide the staffing ratio
appropriate to patients with a range of seventies, in addition to providing
a varied programme of group and recreational facilities to
maintain interest and stimulation. Day centres, where patients are
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
arrayed around the edge of the room with a television as a focal point,
are, or should be, consigned to history. Day care provides essential
respite to many carers, and longer periods of occasional or regular
respite can prolong the period a patient can remain in their own
home.
The multidisciplinary team consisting of care workers, social ser-
. vices, community psychiatric nurse occupational therapist, and psychologist
can maintain patients at home more effectively and for longer
periods than can clinicians alone. However, long-term care becomes a
necessity for many patients at some point. The costs of providing nursing-
home care are 'huge and far outweigh the costs of providing relatively
intensive community care or relatively costly drugs. If treatments
were shown to reduce the total length of stay in nursing homes then
this would affect the cost-benefit ratio of these compounds considerably.
Preventing AD and future treatments
A number of factors such as non-steroidal anti-inflammatory drugs,
hormone replacement therapy, and the antioxidant vitamin E, might
be of some use in strategies to prevent AD. Prevention could be primary
before any signs of the disease or secondary after some manifestation
of the process. Primary preventive measures would have to be
directed at either the entire population or to groups at risk (identified
by family history or genotype, for example), and therefore would have
to be entirely benign and almost cost-free to be acceptable. Secondary
prevention, possibly in those with memory impairments not amounting
to dementia (minimal cognitive impairment), is a more realistic
prospect rendering the determination of the very earliest signs of disease
or evidence of a prodromal state a high priority. A biological
marker for AD would have immense uti lity in both clinical practice
and in clinical trials. Markers suggested have included platelet membrane
fluidity and measurement of amyloid, apoE, and tau in cerebrospinal
fluid, as well as genetic markers. (82) Of these only cerebrospinal
fluid tau appears to have any possible value as a biomarker.
Tertiary prevention or disease modification refers to treatments to
arrest or slow down the disease process after it has become clinically
evident. Some evidence exists that drugs already available might have a
disease-modifying effect, and other compounds designed to reduce
amyloid formation or aggregation or tau phosphorylation are in development.
Other approaches have been developed to reduce the inflammatory
component of pathogenesis, or to enhance function and
provide support for the remaining neurones using nerve growth factor.
This latter promising approach is made problematic by the fact
that oral or parenteral administration of a peptide would result in its
rapid degradation.
Given that AD is a chronically deteriorating condition, determining
efficacy of disease modification is diffic ult. Two approaches have
been suggested. (83) The randomized start trial assigns patients to drug
or placebo at random, and at some predetermined point those on placebo
are switched to treatment. If the treatment is symptomatic only it
would be expected that on switching to treatment these individuals
would 'catch-up' with those treated from the outset. However, if the
treatment has slowed the disease, those treated fro.m the outset would '
remain relatively improved compared to the switched group. The randomized
withdrawal trial is a reverse of this, with patients withdrawn
from active treatment failing to fall to the placebo group results if the
compound had affected the disease process.
Conclusions
For the foreseeable future, AD will remain a disorder afflicting a large
proportion of the world's elderly. The impact on developing countries
especially will be considerable. Care for these patients will continue to
be provided from many sources, with specialist services being necessary
to compliment primary and generic services, particularly for
those patients exhibiting the complex psychiatric phenomenology
described by Alzheimer and for those patients where specific drugs are
indicated. AHhe nf(11ecular pathogenesis of AD is increasingly understood
it is to be hoped that this is translated into treatments ever more
effective in modifying or preventing the disease process itself.
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57.
4.1.3 Dementia: Alzheimer's disease
Simon Lovestone
Introduction
Alzheimer's disease (AD) and other dementias incur huge costs to
society, to the families of those affected, and to the individuals themselves.
Costs to society include both direct costs to health and social
services and indirect economic costs in terms of lost productivity, as
carers are taken out of the workplace, and the economic costs to those
families caring for or funding the care of their relative. Increasingly, as
treatments become available, these costs are targets for change and are
part of the cost- benefit analysis of new compounds, especially the
largest single direct cost, that of the provision of nursing and other
forms of continuing care. Apart from the financial cost to families
there is the emotional impact resulting in distress and psychiatric
morbidity.
As the population ages, these costs pose substantial social and eco.
nomic problems. Although lifespan itself has remained static, the
387
388 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
numbers of elderly in both developed and developing societies is
increasing rapidly. In the developed world the sharpest projected
growth is in the very elderly cohort- precisely the one that is at most
risk of AD. Within the developing world the total number of elderly
people is projected to rise substantially, reflecting to a large part better
child health and nutrition. For countries in South America and Asia,
with large and growing populations, the costs involved in caring for
people with dementia in the future will become an increasing burden
on health and social services budgets. In the absence of such services
families will inevitably shoulder the main part of providing care,
although the very process of development is associated with increasing
urbanization and, to some degree, a diminution of the security provided
by extended family structures.
From discovery towards understanding
In the early part of the twentieth century, Alois Alzheimer described
his eponymous disorder in a middle-aged woman who suffered not
only cognitive deterioration and functional decline but psychotic
experiences, including delusions and auditory hallucinations. Neuropathology
included gross atrophy and plaques and tangles on microscopy.
Although all the important features of AD were described at this
stage, two important developments came much later. First, in the
1960s with the studies of Roth and colleagues in Newcastle(l) and
others elsewhere, it was appreciated that much dementia in the elderly
has an identical neuropathological appearance to that of AD in
younger people. The other development was the rediscovery that AD
has a rich phenomenology. The non-cognitive symptomatology of AD
is integral to the clinical manifestation of this disease, and is a major
cause of carer burden and medical intervention. This second phase of
research-the recognition that both the neuropathology and clinical
phenomenology described by Alzheimer occur in what had previously
been though of as senile dementia or, worse, just ageing, was accompanied
by a growing understanding of the neurotransmitter deficits in
AD. The cholinergic hypothesis provided the first glimpse of possible
interventions, and remains the most important finding from this
period of AD investigations. The third phase of AD research encompasses
the use of molec ular approaches to understanding pathogenesis.
The techniques of molecular biology have been applied to
understanding the formation of plaques and tangles, to a growing
understanding of the genetic aetiology of much of AD, and, through
the use of transgenic approaches, to developing animal and cellular
models of pathogenesis.
Just as research can broadly be seen to h~ three phases discovery,
neuropathology, and IPolecul;u aspects-so too does the
clinical response to AD. For many years cognitive impairment in the
elderly was perceived as senility. As a process thought to be an inevitable
consequence of ageing it was difficulty to establish medical-care
models. Hence the needs of the elderly with AD were not seen as
requiring speCialist intervention, carers needs were not realized, and
public appreciation of the impact of dementia on the elderly themselves
or on the family was negligible. The 'change in perception of AD
from 'just ageing' to a disease was accompanied, and to some degree
led, by the development of ' old age psychiatry' as a specialism on the
one hand and by the rapid growth of the Alzheimer disease societies on
the other. During this second phase of AD treatment, the goals have
been to ensure that the care needs of patients are met, that families' .
concerns are addressed, and that behavioural disturbance is minimized.
The third phase of AD treatment began with the arrival of specifically
designed interventions. Compounds have been introduced that
were designed to ameliorate some of the deficits incurred by the disease
process, and other approaches are being developed to treat those
disease processes themselves.
Clinical features
Cognitive impairment
Dementia is an acquired and progressive cognitive decline in multiple
areas; AD is one cause of dementia and the core clinical symptom of
AD is cognitive impairment. However, as noted above, AD is clinically
heterogeneous and includes diverse non-cognitive symptoms and
inevitable functional .impairment. Cognitive decline is manifested as
amnesia, aphasia, agnosia, and apraxia (the 4As).
Amnesia
Memory loss in AD is early and inevitable. Characteristically, recent
memories are lost before remote memories. However, there is considerable
individual variation, with some patients able to recall specific
and detailed events of childhood and others apparently having few
distant memories accessible. With disease .progression, even remote
and emotionally charged memories are lost. The discrepancy between
recent and remote memory loss suggests that the primary problem is
of acquisition or retrieval of memory rather than a destruction of
memory, and this is confirmed in early AD,(2) although as the disease
progresses it is likely that all memory processes are impaired. Retrieval
~f remote memory is assumed to be preserved for longer because of
rehearsal over life.
Aphasia
Language problems are found in many patients at presentation,
although the language deficits in AD are not as severe as those of the
frontotemporal degenerations(3) and may only be apparent on detailed
examination. Word-finding difficulties (nominal dysphasia) are the
earliest phenomena observed and are accompanied by circumlocutions
and other responses, for example repetitions and alternative
wordings. As the disorder progresses, syntax is affected and speech
becomes increasingly paraphasic. Although harder to assess, receptive
aphasia, or comprehension of speech, is almost certainly affected. In
the final stages of the disorder, speech is grossly deteriorated with
decreased fluency, preservation, echolalia, and abnormal non-speech
utterances.
Agnosia
Patients with AD may have difficulty in recognizing as well as naming
objects. This can have implications for care needs and safety if the
unrecognized objects are important for daily functioning. One particular
agnosia encountered in AD is the loss of recognition of one's
own face (autoprosopagnosia). This distressing symptom is the underlying
cause of perhaps the only clinical sign in AD- the mirror sign.
Patients exhibiting this will interpret the face in the mirror as some
other individual and respond by talking to it or by apparent fearfulness.
Autoprosopagnosia can present as an apparent hallucinatory
experience, until it is realized that the 'hallucination' is fixed in both
content and space, occurring only when self-reflection can be seen.
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
Apraxia
Difficulties with complex tasks that are not due to motor impairment
become apparent in the moderate stages of AD. Typically, difficulties
with dressing or tasks in the kitchen are noticed first, but these are
inevitably preceded by loss of ability for more difficult tasks. Strategies
. to avoid such tasks are often acquired as the disease progresses, and it
is only when these fail that the dyspraxia becomes apparent.
Other cognitive impairments
There appear to be no cognitive functions that are truly preserved in
AD. Visuospatial difficulties commonly occur in the middle stages of
the disorder and may result in topographical disorientation, wandering,
and becoming lost. Difficulties with calculation, attention, and
cognitive planning all occur.
Functional impairment
Although the cognitive decline in AD is the core symptom, it is the
functional deterioration that has the most impact on the person themselves
and it is the functional loss that necessitates most of the care
needs of patients with AD, including nursing-home residency.(4)
Increasingly, abilities to function in ordinary life (activities of daily
living (ADLs» are lost, starting with the most subtle and easily
avoided and progressing to the most basic and essentiaL In general,
functional abilities decline alongside cognitive abilities. However, the
precise correlation between these functions is not perfect, suggesting
that factors other than disease severity account for part of the variance
between patients. (5 ) Functional abilities are related to gender; for
example, cooking abilities are rehearsed more frequently in women,
and home-improvement skills in men. However, the overall pattern
shows some similarities between groups of patients with similar disease
severity. This is exploited in the Functional Assessment Staging
(FAST) scale;(6) in the original form, this is a seven-point scale of functional
impairment, with stage 1 as no impairment and stage 7 as severe
AD. A sequential decline is mapped by descriptions of the abilities that
are lost: stage 2, difficulties with language and finding objects; stage 4,
difficulties with finances; stage 6, incontinence and inability to dress or
wash oneself.
ADLs are divided into those that relate to self-care and those that
concern instrumental activities. Instrumental ADLs, those related to
the use of objects or the outside world, are lost first and can be subtle.
(7) A change in the ability to use the telephone properly or to handle
finances accurately may not be apparent. Self-care ADLs include dressing
and personal hygiene and are also lost gradually; for example,
untidiness in clothing progresses to difficulties in dressing. Personal
hygiene becomes poor as dentures are not cleaned and baths taken less
often, before finally assistance is required with all self-care tasks.
Neuropsychiatric symptoms
Mood
The relationship between AD and depression is complex. Depression is
a risk factor for AD, depression can be confused with dementia
(pseudodementia), depression occurs as part of dementia, and cognitive
impairments are found in depression. Depression occurring as a
symptom of dementia will be considered here. Assessing the mood of a
person with dementia is difficult for obvious reasoris. However,
psychomotor ******ation, apathy, crying, poor appetite, disturbed
sleep, and expressions of unhappiness all occur frequently. The rates of
depression found in cohorts of patients with AD vary widely, reflecting
changes in prevalence at different levels of severity and difficulties in
the classification of symptoms suggestive of depression in those with
cognitive loss. A major depressive episode is found in approximately
10 per cent of patients, minor depressive episode in 25 per cent, some
features of depression in 50 per cent, and an assessment of depression
by a carer in up to 85 per cent. (8- IQ) It is commonly believed that
depression is more common in the early than in the later stages of AD,
although this may reflect the difficulties of assessing depression in the
more severely affected and least communicative patients. Indeed,
severely affected patients in nursing homes may be particularly prone
to depressio~: (I J) Ei; tion, disinhibition, and hypomania all occur in
AD but are relatively infrequent, elevated mood being found in only
3.5 per cent of patients by Burns et al. (lO)
The underlying cause of mood change in AD is not known. However,
loss of serotonergic and noradrenergic markers accompanies
cholinergic loss; some studies have found a greater loss of these markers
at postmortem in AD patients with depression than in nondepressed
patients. ( 12. 1 3 )
Psychosis
Psychotic symptoms occur in many patients, although, as with depression,
the difficulty in determining the presence of delusions or hallucinatory
experiences in the moderately to severely demented gives rise
to a very wide range of frequency rates. Few studies have been able to
determine the rates of psychosis in community-dwelling, fully representative
samples of patients with AD. However, of those known to,
largely, psychiatric services, between 10 and 50 per cent suffer from
delusions and between 10 and 25 per cent experience hallucinations.<'
4-16) Delusions are frequently paranoid and the most common
delusion is one of theft. In the context of the confusion and amnesia of
dementia, it is easy to appreciate how the experience of mislaying an
object becomes translated into conviction of a theft. Other patients
become convinced that someone, often a family member, is trying to
harm them.
Hallucinations are only somewhat less frequent than delusionsthe
median of one series of studies being 28 per centY7) Visual hallucinations
are reported more commonly than auditory ones, and other
modalities are rareY6) Most studies of the non-cognitive symptomatology
of AD precede the wide recognition and accepted criteria of
dementia with Lewy bodies, one of the cardinal symptoms of which is
visual hallucinations.<' S) It is probable that a large number of those AD
patients experiencing visual hallucinations reported in the studies
would now be classified as having dementia with Lewy bodies.
Phenomena falling short of delusions or hallucinations, such as
persecutory ideas or intrusive illusionary experiences, are common in
AD as are misidentification syndromes. Cap gras' syndrome may occur,
but frequently the symptom is less fully evolved with the patient mistaking
one person for another. Failure to recognize one's own face may
be due to visuospatial difficulties or to a true misidentification
syndrome-distinguishing between the two is difficult.
Various factors have been associated with psychosis in AD, but few
have been substantiated in multiple studies. Burns et al. (16) found that
more men than women suffered delusions of theft, although others
find that psychosis occurs more often or earlier in women. An association
with polymorphic variation in serotonin receptors has been
389
390 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
reported. (I9) Patients with psychotic symptoms show regional metabolic
differences on functional neuroimaging. (20) The relationship
between psychosis and dementia severity is not as clear cut as that
between functional ability and dementia severity. Psychosis can occur
at any stage of the disease process, although most studies find the maximal
rate of psychosis in those with at least moderate dementiaY6.J7)
Although the biological basis of psychosis within AD is not fully
understood, it is probable that psychosis symptoms impact upon
carers causing increased distress, (21) and that underlying psychosis
accounts for much of the behavioural disturbance and aggression
encountered in AD. (22)
Personality
Changes in personality are an almost inevitable concomitant of AD.
Indeed, it is difficult to envisage how profound cognitive impairment
resulting in the loss of recognition of loved ones, and an understanding
of and ability to react with the outside world, could not result in a
change in personality. Family members have described the loss of personality
as a 'living bereavement'-the person remains, but the person
once known has gone. Personality change is most frequently one of
loss of awareness and normal responsiveness to the environment. Individuals
may become more anxious or fearful, there is a flattening of
affect, and a withdrawal from challenging situations. Catastrophic
reactions are short-lived emotional reactions that occur when the
patient is confronted, and cannot avoid, such a challenging situation.
Less commonly, personality changes may be of disinhibition with
inappropriate sexual behaviours or inappropriate affect. Aggressiveness
is, as noted above, often accompanied by psychosis, but it may be
part of a more general personality change.
Other behavioural manifestations
Behavioural complications in AD have become a target of therapy.
However, the term encompasses a wide rage of behaviours, some of
which include neuropsychiatric syndromes, some caused by neuropsychiatric
syndromes, and some of which have little apparent relationship
to mood or to thought content. Behavioural complication is
itself a largely subjective term that relies to a great extent on informer
evaluation: but a behaviour may be a complication in one context,
although not in another.
Behaviours exhibited in AD include wandering, changes in eating
habit, altered sleep or circadian rhythms, and incontinence. These
behaviours are closely linked to disease severity and occur to some
extent in the majority of patients with AD. Wandering may be a manifestation
of topographical confusion, a need for the toilet, or it may
reflect hunger, boredom, or anxiety. Sleep is freqaently disturbed, with
many patients exhibiting altered sleep- wake cycles and others experiencing
increased confusion towards evening Csundowning').(23) A central
defect in the regulation of circadian rhythms underlying these
phenomena is postulated.(24) Excessive or inappropriate vocalizations
(grunting and screaming) occur in the late stages.
Classification
AD is classified, as with all other disorders, by DSM-IV and by lCD-lO.
In addition, it also has a specialized classification system resulting from
the National Institute of Neurological and Communicative Disorders
and Stroke-Alzheimer's Disease and Related Disorders Association
(NINCDS-ADRDA). (25) This clinical diagnostic system is internationally
accepted and widely observed. There are other classification systems
for neuropathological diagnosis, most notably the Consortium to
Establish a Registry for Alzheimer's Disease (CERAD) criteria. (26)
DSM-IV stipulates that a dementia syndrome is characterized by a
decline in multiple cognitive deficits, including amnesia, resulting in
impairment. A gradual onset and decline in the absence of other conditions
sufficient to cause dementia indicates AD. lCD-IO shares with
DSM-IV the definition of a dementia syndrome as a deterioration in
more than one area of cognition, but including memory that is sufficient
to impair function. Again an emphasis on insidious onset and
slow decline in the absence of other disorders sufficient to cause
dementia indicates AD. The NINCDS-ADRDA criteria defines possible,
probable, and definite categories; the latter being restricted to
neuropathological confirmation of a clinical diagnosis. (25) It is important
to note that both clinical and neuropathological data are
required-no single neuropathological lesion is pathognomonic of
AD, and it is still uncertain how often or to what extent the neuropathologicallesions
of AD also occur in normal ageing. Probable AD,
according to NlNCDS-ADRDA, requires a dementia with progressive
decline in memory and other cognitive areas, cognitive impairment
established by formal testing, no disturbance of consciousness, and
absence of other disorders sufficient to cause dementia. Supporting
features include decline in function, change in behaviour, positive
family history, and decline in specific cognitive areas including aphasia,
apraxia, and agnosia. Non-specific change on electroencephalography
(EEG) and progressive changes on CT are supporting, but not
necessary, features. Possible AD should be diagnosed if there are variations
in the clinical presentation, another disorder sufficient to cause
a dementia (even if it is not thought to do so in this case), or a
restricted cognitive decline.
A number of studies have attempted to determine the accuracy of
diagnostic criteria against postmortem diagnosis. One of the difficulties
in these studies is that because AD is the most common dementia
(by some way), such studies are very likely to find a high-positive predicative
value. Kukull et al. (27) found the specificity of DSM-III to be
higher than NINCDS-ADRDA (0.8 versus 0.65), but NINCDSADRDA
had a higher sensitivity (0.92 versus 0.76); others find an even
lower specificity.(28)
Diagnosis
AD is the most common of the dementias, occur"ring in some 60 to
70 per cent of cases. However, this oft-stated figure must be treated
with some caution for two reasons. First, cases that come to postmortem
represent a biased sample, and the proportion of pathologically
confirmed AD in community-dwelling representative samples is
unknown. Second, even at postmortem the distinction between different
dementi as is not clear cut-many AD brains show the presence of
Lewy bodies and others have considerable evidence of vascular damage.
The proportion of mixed pathologies IS actually rather high,
between 15 and 30 per cent of all dementias.
History
Making a clinical diagnosis of AD is a positive process and not one of
exclusion. The most valuable diagnostic assessment is a careful
. informant history, paying attention to the pattern and timing of onset
Q-
5-
a
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
and progression. In the research context, a family history interview
conducted by telephone provides a degree of accuracy compatible with
a full clinical assessment. (29,30) Detailed semistructured family informant
diagnostic schedules are available, such as CAMDEX.(31) A history
should be taken for the presence of risk factors for AD (e.g. a positive
family history) and vascular and other risk factors (e.g. hypertension
'and head injury). Taking a family history for late-onset disorders such
as AD requires special attention. Because of attrition due to other illness,
many elderly people have had too few relatives reach the age of
onset of dementia to make a pedigree analysis informative. The ages at
death of all relatives should be established, together with cause of
death and the presence or absence of dementia or memory problems
in late life. The term 'sporadic' dementia should be avoided, and is
misleading when applied to an individual with a dementia where one
parent died young and where no sibling reached the age of 65 to
70 years. The history should also screen for the presence of other illnesses
sufficient to cause a dementia, and for systemic health in general.
The presence of any significant physical illness, from chronic pain
to delirium, may significantly alter cognitive abilities in the elderly, and
especially so in those with AD.
A careful history should also establish the presence of any behavioural
disturbance that has occurred. The relationship of aggression,
wandering, agitation, or other behaviours to care tasks and other
recent changes in the provision of the care package should be established.
As the mainstay of the management of behavioural disturbance
in all dementias is behavioural, establishing the antecedents to behaviour
is an absolute prerequisite to effective management.
Examination
In addition to an examination of the mental state to establish the presence
of disorders of mood and thought content, the examination will
establish the specific pattern of cognitive impairment and the degree of
impairment. Screening tests used to establish the presence of cognitive
impairments include the Mini Mental State Examination;(32) this is a
30-point scale routinely used in all clinical trials of drugs for the treatment
of AD, which is also a useful proxy measure for severity. It should
be accompanied, by other cognitive testing, including supplementary
examination for aphasia and apraxias. Other cognitive and physical
examinations will be necessary where the differential diagnosis is
between a lobar dementia (e.g. frontotemporal dementia) or a subcortical
dementia (e.g. that accompanying Huntington's disease).
In addition to the cognitive examination, a physical examination
should be conducted in all patients with AD, although this might not
be most effectively and conveniently performed at the initial assess ment.
Physical illness, including chronic pain, infection, cardiac insufficiency,
or anaemia are all common in the elderly and can both
complicate the diagnosis of AD and increase confusion in those known
to have AD.
Assessment of function
Clinical assessment of function can be performed by informant history
and by direct observation. The occupational therapist fulfils an invaluable
role in establishing the detailed functional ability of those with
AD, in addition to implementing changes in the home designed to
maximize function. The FAST scale(6) is based on the premise that the
pattern of decline in function is relatively uniform in AD, and hence
establishes a staging of severity on function rather than cognition. As
in most instances functional severity is of more relevance for the provision
of services, there is much to recommend such an approach.
Global assessment
Driven largely by the United States Food and Drugs Administration,
global assessment has become part of the assessment of all patients
with AD in clinical trials and is finding its way into clinical practice.
The underlying premise is that an assessment by a clinician, often supplemented
by an informant history, provides information on severity
that neither a cognitive assessment nor a functional assessment alone
can provide. One scale, the Clinicians Interview of Change, has
become widely used in this context and is an interesting attempt to
se miformaliz~ ,the t9.1!tine clinical impression without operationalized
criteria.
Investigations
At the initial assessment, patients with dementia should be investigated
for other disorders that could complicate, exacerbate, or be confused
with AD. A dementia screen might include routine biochemistry,
thyroid function tests, vitamin Bl2 and folate estimations, and a full
blood count; many would also include syphilis serology, although the
frequency of abnormal findings is low. A CT brain scan is not necessary
in many cases and is not a required investigation in the NINCDSADRDA
classification, although worsening atrophy on CT is supportive
evidence. Functional scanning (single-photon emission CT
(SPECT) in particular) can be useful where regional dementias are
suspected, and magnetic resonance imaging can provide supportive
evidence where vascular dementia is a possibility. An EEG is nearly
always non-specifically abnormal even in the early stages of AD, in
contrast with frontotemporal degenerations where an EEG remains
unaffected at a broadly equivalent severity. This can help to distinguish
the conditions, particularly where there is neuroimaging evidence of
regional insufficiency.
Aetiology and molecular neurobiology
AD is the most common dementia, affecting more than 20 per cent of
the population over the age of 85 years. Epidemiological evidence has
suggested risk factors and putative protective factors, but the greatest
advances in understanding its pathogenesis have come from the combination
of molecular and epidemiological approaches.
Neuropathology
At postmortem, the brain in AD is lighter than aged-unaffected controls
with more prominent sulci and a larger ventricular volume.
Microscopic examination reveals the most prominent lesions
described by Alzheimer-the extracellular plaque and intracellular
neurofibrillary tangleY6) No consensus has developed regarding
which of these lesions is responsible for the cognitive impairment of
AD. Plaques, or more precisely amyloid load, might correlate with the
degree of cognitive impairment,(33) although a significant amyloid
deposition is also found in normal, unimpaired, aged individualsY4)
However, there is a high degree of correlation between dementia severity
and neurofibrillary tangle formation, (35) although it is possible that
some of the features of AD are more stable than others; for example,
391
392 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
extracellular neurofibrillary tangles persist after the neurone has died,
whereas extracellular Lewy bodies are not found.
The plaque consists of an amyloid core surrounded by dystrophic
neurites, which are themselves filled with highly phosphorylated tau
protein. Studies of Down syndrome brains have suggested a temporal
course to plaque formation. First, peptides derived from the amyloid
precursor protein (APP) are deposited in a diffuse plaque.(36) Over
time this becomes organized as the amyloid pep tides become fibrillar
and form the amyloid deposit, neuritic change then occurs, and the
plaque becomes fully mature.
Neurofibrillary tangles are composed of paired helical filaments,
structures which are also found in the dystrophic neurites around
mature plaques, and together with straight filaments, in neuropil
threads. These filaments are themselves composed of the microtubuleassociated
protein, tau, which is present in a stably and highly phosphorylated
stateY7) Tau is a neuronal-specific protein, found
predominantly in the axon, that functions to stabilize micro tubules, a
property that is regulated by phosphorylation. Phosphorylated tau is
less effective in promoting tubulin polymerization into microtubules,
and in cells highly phosphorylated tau does not stabilize microtubules.
(38) In normal adult brain a proportion of tau is highly phosphorylated,
but this proportion is considerably greater in AD. Tau
deposits are a feature of other disorders, such as progressive supranuclear
palsy and some frontotemporal degenerations. Mutations have
been found in frontotemporal degenerations with parkinsonism
(FTDP-17), (39) and progressive supranuclear palsy has also been associated
with changes in the tau gene(40) thereby emphasizing the
importance of this molecule to neurodegeneration.
Braak and Braak(41) studied large numbers of brains from individuals
who died at various ages and at different stages of dementia severity,
which has resulted in the wide acceptance of the neuropathological
staging of AD. The very earliest stages, before the clinical manifestation
of dementia, are characterized by the appearance of highly phosphorylated
tau in the hippocampus. In later stages, neurofibrillary tangles
appear in the same brain regions and then become more widely
distributed.
The cholinergic hypothesis
The pathological changes in AD are localized both structurally and
functionally. Plaques and tangles first occur in the hippocampus
before spreading to involve other regions. Some areas of the brain are
relatively preserved-the occipital lobe is affected relatively late and
the cerebellum appears to be spared from neuritic change (neurofibrillary
tangles and the fully matured plaques:"1l1thOligh diffuse amyloid
deposits do occur). Functional localization was demonstrated by
evidence of the relatively greater and earlier loss of cholinergic neurotransmission.
At postmortem there is evidence of significantly greater
neuronal loss in the cholinergic nucleus basalis of Meynert and loss of
cholinergic markers. (42-44) These observations led to the cholinergic
hypothesis, which stated that the cognitive impairment of AD was due
to a disorder predominantly affecting cholinergic neurones. It was this
hypothesis that led to the development of pharmacological strategies
to rectify cholinergic loss and the introduction of the first compounds
specifically designed for and efficacious in AD. However, the cholinergic
hypothesis was something of a simplification as other neurotransmitter
systems (e.g. serotonergic and noradrenergic) are also affected
in AD.
The amyloid cascade hypothesis
In 1984, the protein deposited in blood vessels (congophilic angiopathy)
in AD was shown to be a 4-kDa peptide known as
~-amyloid. (45 ) This peptide, which is identical to the amyloid in
plaques, is derived from a larger peptide, APP, the gene for which is
coded on chromosome 21. After a series of misleading linkage studies,
mutations in the APP gene were found in a family with autosomal
dominant early-onset AD.(46) These two discoveries- the identification
of ~-amyloid and the discovery of mutations in the parent APP
gene-led the way to the amyloid cascade hypothesis, which has
remained the dominant molecular model of the disorder. (47) Many
subsequent molecular observations have been consistent with this
model, which posits the formation of ~-amyloid as the initiating, or at
least early event, leading to all the other changes observed including
tau aggregation and phosphorylation, neuronal loss, cholinergic deficits,
and clinical symptoms. Perhaps the most convincing evidence
that there is such a unidirectional cascade comes from the observation
that mutations in the APP gene give rise to plaque formation and also
to neurofibrillary tangle pathology, whereas mutations in the tau gene
give rise to tangle formation but not to plaque formation in FTDP-
17.
Much subsequent research has concentrated upon understanding
the metabolism of APP and the formation of ~ -amyloid peptide.(48.49)
APP is a ubiquitous single-pass cell-membrane protein expressed in
many cell lines with a high degree of evolutionary conservation. At
least three putative secretases cleave APP and the metabolic products
can be detected in individuals unaffected by AD; the processing is not
pathological in AD, but the balance between different metabolic routes
may be shifted in the disease state. a-Secretase cleaves APP at the outer
cell-membrane surface at a site within the ~-amyloid moiety itself.
Clearly, a-secretase cannot therefore yield intact ~-amyloid, and this
metabolic route, resulting in a secreted product, APPs, and other fragments,
is termed non-amyloidogenic. a-Secretase activity is increased
following stimulation of protein kinase C. (50) This might have some
clinical relevance as certain neuronal receptors are coupled to protein
kinase C and, indeed, muscarinic agonists do increase non-amyloidogenic
metabolism. These studies predict that therapies designed to
correct the cholinergic deficit in AD might have a disease modification
effect. (51 )
Amyloidogenic metabolism is the result of ~-secretase cleaving
APP beyond the amino terminus of ~-amyloid and of y-secretase
cleaving the resulting peptides at the carboxy terminus in the cell. The
~ - amylo id products vary in length, with predominant species having a
length of 40 or 43 amino acids. The longer pep tides are somewhat
more prone to forming fibrils in vitro. It is probable that the proportion
of ~-amyloid(4 2-43) pep tides relative to ~-amyloid ( 40) pep tides is
critical in pathogenesis, (49) and that mutations in the APP gene
increase these longer amyloid peptides. (52.53) Transgenic mice overexpressing
the mutated APP gene also produce more ~-amyloid peptide
and have amyloid deposits in brain.(54) Interestingly, these animals do
not develop other aspects of AD pathology.
The presenilin genes
Mutations in presenilin-1 (PS-I) and presenilin-2 (PS-2), two very
similar genes on chromosome 14 and chromosome 1 respectively, also
cause early-onset autosomal dominant AD. (55) The function of these
genes is not fully understood, but homology with genes in flies and
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
worms suggests that the presenilins participate III NOTCH
signalling-a complex signal-transduction cascade critical, amongst
other things, in determining neuronal cell fate. Mutations in the presenilin
genes, and hence their role in AD pathogenesis, may result in
an interference with the normal functioning of the protein or may
induce a gain in a novel pathogenic function. Whatever the mech.
anism, it is clear that mutations in the presenilins result in an increase
in the production of ~-amyloid. (49 ) Therefore the finding of mutations
in these genes adds to, rather than detracting from, the amyloid cascade
hypothesis although, as with any hypothesis, the complexity of an
originally simple idea increases.
Tangle formation and tau phosphorylation
Tangles are composed of paired helical filaments, themselves composed
of hyperphosphorylated tau. It is not fully determined whether
tau phosphorylation precedes tau aggregation, but tau is highly phosphorylated
in fetal brain and, albeit to a lesser extent, in normal adult
brain. (37) However, neuropathological evidence suggests that highly
phosphorylated tau does begin to accumulate in the brain before the
formation of tangles, and before the clinical manifestation of AD.(S6) It
seems as though, if not the only event in paired helical-filament formation,
increased tau phosphorylation is at least an early event.
Protein phosphorylation is a product of kinase and phosphatase
activity. It is likely that many such enzymes may participate in the
regulation of tau phosphorylation in the brain, but two have been
shown to be predominant. In cells, and in vitro, glycogen synthase
kinase-3 is the main tau-kinase and protein phosphatase 2A is the predominant
tau phosphatase. (57.58)
Molecular genetics
Mutations in three genes have been found to cause early-onset familial
AD, which is inherited in an autosomal dominant fashio n. (S9) Mutations
in the APP gene (on chromosome 21) are the least common, only
affecting perhaps 20 families worldwide. Mutations in PS-1 (on
chromosome 14) are somewhat more frequent, although are still a rare
cause of AD. Mutations in PS-2 (on chromosome 1) appear to be
largely restricted to an ethnic German people residing in the United
States, suggesting an individual founder effect. Mutations in these
genes have not been identified in true late-onset AD. Individuals with
Down's syndrome are at extremely high risk of AD, with neuropathological
evidence being present in virtually all individuals living to middle
age, probably because of trisomy APP.
The genetic component oflate-onset AD has been demonstrated by
epidemiological studies, showing that a family history of dementia is
the largest single risk factor for AD.(60) However many, perhaps most,
patients with AD do not have a positive family history, thus giving rise
to the idea of , sporadic' AD with a separate aetiology to 'familial' AD.
For late-onset AD this concept is outmoded and redundant. Many
patients with AD do not have a family history because of attrition of
family members due to death by other causes. For the cohort currently
suffering from AD their parents were born in the latter part of the
nineteenth century or early years of the twentieth, lived through two
major world wars, and reached adulthood before the discovery of antibiotics.
It is not surprising that few patients with late-onset AD have
two parents and more than one sibling living to the age of onset of AD,
and if one parent died young and there are no elderly siblings then the
family history is non-informative. Well-designed studies examining
the rate of AD in first-degree relatives by age find a cumulative incidence
reaching 50 per cent or higher by the age of 90 years. (61.62)
One gene has been unequivocally associated with late-onset AD,
although even this gene accounts for only something like 50 per cent of
the genetic variance.(63) The apolipoprotein E gene (APOE, gene;
apoE, protein) on chromosome 19 has three common alleles, coding
for three protein isoforms that differ by the substitution of an amino
acid at just two positions. Of the three alleles £3 is the most frequent
and £2 the least; following linkage to chromosome 18 it was demonstrated
that the £4 allele confers risk, whilst the £2 may be protective.(
M) This finding has been replicated in a huge number of studies
and in many different populations, although there are some, as yet,
unexplained differences as black African-Americans apparently do not
show an increased risk with the £4 allele. (65)
The mechanism-a1 action of the APOE gene in increasing the risk of
AD is not known. As AFOE variation is a major genetic influence on
serum cholesterol (people with the APOE £4/* genotype have higher
serum cholesterol levels), it is possible that an altered lipid
metabolism-either peripherally or locally-might affect the pathogenesis
of AD.(66) Alternative theories arise from in vitro studies, which
show a differential binding of APOE protein isoforms both to amyloid
protein and to tau protein.(64) Certainly it does seem as though APOE
isoforms affect neurones in culture in different ways, with apoE4 isoforms
inducing shorter neurites and microtubule collapse.(67)
Other genes have been associated with AD, but none have been
replicated in as many studies as APOE. It is likely that a combination of
linkage and association studies using large populations will identify
the other genes that influence AD, either alone or in interactions with
other genes or the environment.
Treatment
For many conditions the goals of treatment or intervention are selfevident-
cure, prevention of relapse, and resolution of symptoms. For
AD, however, the goals of treatment can be less obvious and differ
between patients and for individual patients over time. Ultimately, the
quality oflife of the patient should be improved, but assessing quality
of life is difficult in those with dementia, and given the early loss of
insight who is to judge such issues?(68) Quality of life may appear
poor- patients may have diminished emotional repertoires, few pleasurable
activities, and considerable handicap-but they may share
none of the negative cognitions experienced by others with a similarly
questionable quality of life induced by different illnesses. Other
patients may appear content or happy, despite the loss of the autonomy
and self-awareness normally considered an essential component
of a good quality life. Equally, the treatment unit in AD includes
carers, and there are times when the patient's quality of life is in conflict
with the quality of life for other members of the family. Resolving
such conflicts of interest and other moral and ethical issues is part of
the treatment process in AD. With the arrival of specific treatments for
AD and the prospect of disease-modifying therapies, an even harder
question arises regarding prolonging life for those with dementia: if
quality oflife appears poor to observers, is it right to prolong the process,
can quality of life in those with dementia truly be assessed, or
should carers and families be allowed to assess for themselves the
benefits and costs of treatment?(69)
393
394 4 CLINICAL SYNDRO MES OF ADULT PSYCHIATRY
There is no single model of management of patients with AD. In
many countries management is the role of the gerontologist or
neurologist. In others, as in the United Kingdom, the old-age psychiatry
team provide the core specialist services. Many, perhaps even the
majority, of those with AD are managed within primary care with the
support of social services. Referral from primary care to specialist services
will be according to local agreements, but most would concur
that behavioural disturbance or the use of specific drugs to treat AD
warrant referral to secondary care. Interventions for AD, whether provided
in primary or secondary care, can be thought of as directed
towards the patient, the patient's family, and the patient's environment
. Guidelines on the identification and management of patients
with dementia have been produced and may be a constructive
approach to ensuring best clinical practice. (70-72)
Managing the patient
Management of the patient with dementia is discussed in greater detail
in Chapter 4.1.14. Management starts with the assessment and diagnosis,
and perhaps the difficult dilemma is how much of the diagnosis
and prognosis to discuss with the patient. (73) Most practitioners do not
discuss the diagnosis with the patient themselves, although especially
in the early stages a frank cons'ultation can be beneficial. For most
patients, however, cognitive impairment renders an appreciation of
the diagnosis and prognosis difficult.
A large part of managing the patient is directed towards managing
mood and behavioural disturbance. Accurate assessment of the disturbance
is critical, and includes determining the antecedents and
responses to the behaviour as well as a full description of the behaviour
and any associated abnormalities in the mental state. Treatments of
behavioural disturbance in AD are most often behavioural and sometimes
restricted to giving information to careers. However, pharmacological
interventions are an important part of the management of
behavioural disturbance, even though caution regarding the use of
psychotropic medications in those with dementia is necessary.
Specific treatments for AD have been developed, concentrating in
clinical trials on ameliorating the core symptom of cognitive impairment.
The cholinomimetic approaches are the most advanced, but
other therapies are receiving extensive evaluation. Although designed
for the large part as strategies to enhance cognition, these compounds
also favourably appear to affect function and may reduce behavioural
disturbance. Further evaluation is being conducted to determine
whether there are disease-modifying effects. Drug treatments for AD
are described in Chapter 6.2.7.
Managing the family --
Although patients may not appreciate or be able to follow a detailed
discussion of the diagnosis and prognosis, their relatives, spouses, and
other carers will. This is an important part of the treatment process; as
the carer provides the main interventions for much of the period of the
disease process, care should be taken to ensure that appropriate and
sufficiently complete information is given.
Caring for a patient with AD can be difficult and stressful and some
carers suffer accordinglyY4) The characteristics of both carers and
patients influence the impact that this 'burden' of caring has on the
carers themselves. Men in general, and husbands in particular, seem to
be less vulnerable to the adverse effects of caring, possibly because of
the response seen in many male carers of rapidly and effectively
recruiting outside helpYS) Women may be socialized into accepting
more caring roles themselves and therefore seek less help. Non-white
carers appear to suffer from less adverse consequences of caring, perhaps
because of cultural differences in the perception of family
bonds. (76) Patient characteristics that increase the burden of caring
include behavioural disturbances, (77.78) depression, (79 ) and unawareness
of cognitive impairment,(80) but not the cognitive impairment
itself. Although the core outcome variable in clinical trials of AD drugs
is the severity of cognitive impairment, it is not the variable that
induces most stress in relatives nor is it the variable that predicts entry
to residential care. Other variables are almost certainly protective, and
caring for a loved one with dementia is not a universally negative
experience. Much caring is done willingly, effectively, with love, and
without complaint.
Carer support groups offer much to a person with a relative
afflicted by AD. Through support groups, and especially through the
national AD societies and the umbrella group-Alzheimer's Disease
International-carers can obtain up-to-date and useful information
regarding all aspects of AD. A support group can help individuals
practically and emotionally through difficult times. Many carers talk of
the support group as a life-line, although little empirical evidence
exists as to the impact on carer well being.
One particular intervention for the family is that of genetic counselling.
Many relatives are worried about inheriting AD. This concern
might arise from two sources-the frequent discussion of genes 'for'
AD in the media and the observation of familial occurrence of AD in
many individual families. For families with clinically apparent familial
AD, advice, information, and where appropriate, genetic testing can be
arranged through a genetics centre. Where predictive testing is contemplated
for genes causing autosomal dominant, early-onset AD this
will adhere to guidelines established for Huntington's disease. It is
unlikely that true predictive testing will become available for late-onset
AD.(sl)
Managing the environment
The mainstay of interventions for AD are provided by social services.
The goal of the provision of social care in people with AD is 'to provide
an environment that is comfortable, stimulating, and, above all, safe.
For most patients, and for all patients in the early stages, this means
care at home, perhaps with the support of home-meal delivery and
home-helps to provide shopping and cleaning assistance. Further
home care may become necessary as the patient requires assistance
with basic self-care tasks such as washing and dressing. The carer may
require a sitting service, either for periods during the day to allow
them time to themselves or in the evening to allow them to attend a
carers group or for socializing. Safety issues are especially important
for those with dementia living alone. There are inherent risks to the
patient themselves if they wander out of the home and risks to others if
the gas can be left on or fires started.
Day care is appropriate for many patients, ideally in a specialist
unit. In a generic facility for elderly people those with early dementia
can receive little input and those with moderate or advanced dementia
can necessitate too much input from the day-centre staff. A good
dementia specialist day-care facility will provide the staffing ratio
appropriate to patients with a range of seventies, in addition to providing
a varied programme of group and recreational facilities to
maintain interest and stimulation. Day centres, where patients are
4.1.3 DEMENTIA: ALZHEIMER'S DISEASE
arrayed around the edge of the room with a television as a focal point,
are, or should be, consigned to history. Day care provides essential
respite to many carers, and longer periods of occasional or regular
respite can prolong the period a patient can remain in their own
home.
The multidisciplinary team consisting of care workers, social ser-
. vices, community psychiatric nurse occupational therapist, and psychologist
can maintain patients at home more effectively and for longer
periods than can clinicians alone. However, long-term care becomes a
necessity for many patients at some point. The costs of providing nursing-
home care are 'huge and far outweigh the costs of providing relatively
intensive community care or relatively costly drugs. If treatments
were shown to reduce the total length of stay in nursing homes then
this would affect the cost-benefit ratio of these compounds considerably.
Preventing AD and future treatments
A number of factors such as non-steroidal anti-inflammatory drugs,
hormone replacement therapy, and the antioxidant vitamin E, might
be of some use in strategies to prevent AD. Prevention could be primary
before any signs of the disease or secondary after some manifestation
of the process. Primary preventive measures would have to be
directed at either the entire population or to groups at risk (identified
by family history or genotype, for example), and therefore would have
to be entirely benign and almost cost-free to be acceptable. Secondary
prevention, possibly in those with memory impairments not amounting
to dementia (minimal cognitive impairment), is a more realistic
prospect rendering the determination of the very earliest signs of disease
or evidence of a prodromal state a high priority. A biological
marker for AD would have immense uti lity in both clinical practice
and in clinical trials. Markers suggested have included platelet membrane
fluidity and measurement of amyloid, apoE, and tau in cerebrospinal
fluid, as well as genetic markers. (82) Of these only cerebrospinal
fluid tau appears to have any possible value as a biomarker.
Tertiary prevention or disease modification refers to treatments to
arrest or slow down the disease process after it has become clinically
evident. Some evidence exists that drugs already available might have a
disease-modifying effect, and other compounds designed to reduce
amyloid formation or aggregation or tau phosphorylation are in development.
Other approaches have been developed to reduce the inflammatory
component of pathogenesis, or to enhance function and
provide support for the remaining neurones using nerve growth factor.
This latter promising approach is made problematic by the fact
that oral or parenteral administration of a peptide would result in its
rapid degradation.
Given that AD is a chronically deteriorating condition, determining
efficacy of disease modification is diffic ult. Two approaches have
been suggested. (83) The randomized start trial assigns patients to drug
or placebo at random, and at some predetermined point those on placebo
are switched to treatment. If the treatment is symptomatic only it
would be expected that on switching to treatment these individuals
would 'catch-up' with those treated from the outset. However, if the
treatment has slowed the disease, those treated fro.m the outset would '
remain relatively improved compared to the switched group. The randomized
withdrawal trial is a reverse of this, with patients withdrawn
from active treatment failing to fall to the placebo group results if the
compound had affected the disease process.
Conclusions
For the foreseeable future, AD will remain a disorder afflicting a large
proportion of the world's elderly. The impact on developing countries
especially will be considerable. Care for these patients will continue to
be provided from many sources, with specialist services being necessary
to compliment primary and generic services, particularly for
those patients exhibiting the complex psychiatric phenomenology
described by Alzheimer and for those patients where specific drugs are
indicated. AHhe nf(11ecular pathogenesis of AD is increasingly understood
it is to be hoped that this is translated into treatments ever more
effective in modifying or preventing the disease process itself.
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57.
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reply
Report
#6
Part 2 (2 other common and important types of dementia - there are several others which are either rare or complex - I am assuming that you are doing a course of similar level to A levels, so I have included the parts that are of most relevance for you, bearing in mind also the title of your course. You will probs need to present info in your assignment that has a particular application in the social care scheme of things, and include details of other aspects with less vigorous coverage.
Another comment I would make is that the book I have taken this from:-
a) is aimed at specialist trainees in psychiatry who are already qualified doctors, so if you feel overwhelmed by the complexity of technical info, don't panic!
b) the book is a slightly older edition, so, although the majority of info [particularly symptoms, signs and clinical features] will be very similar to current schools of thought, the treatment aspects will have moved on a little - try and search more recent research papers for the latest developments in the pharmacotherapy of the dementias. Having said that, it might be a good idea to peruse some of the references listed in these two sections as a starting point.
r
422 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
4.1.7 Dementia in Parkinson's disease
R. H. S. Mindhom
Introduction
The psychiatric complications of Parkinson's disease have attracted
attention for two reasons: first, they are of practical importance in the
management of patients suffering from this disease and, second, their
study provides insight into a range of psychiatric conditions.
The nature of dementia in Parkinson's
disease
There have been numerous reports of the impairment of specific cognitive
functions in patients with Parkinson's disease. Some of the
impairments described are often only identifiable by specially designed
methods of assessment, but some are revealed by tests of cognitive
function that are in widespread use. Mortimer and his colleagues have
reported a very high prevalence of cognitive impairment-93 per cent
in a substantial group of patients with Parkinson's disease.") Examination
of their data showed neither a clear distinction between impaired
groups nor the presence of subtypes of Parkinson's disease in which
cognitive impairment was a more frequent occurrence. Their findings
led them to propose that cognitive impairment in Parkinson's disease
lies on a continuum of severity, rather than arising as a feature of particular
subgroups. The impairments identified include deficits in
memory, language, visuospatial functioning, abstract reasoning, slowness
in intellectual tasks, and difficulty in shifting from task to task. .
Not only are these deficits widespread among patients with Parkinson's
disease but they have been shown to occur at a very early stage of the
disorder. (2,3)
A proportion of patients with Parkinson's disease show impairment
of a range of cognitive functions, which is more akin to the
global impairment seen in dementing disorders such as Alzheimer's
disease, (4) However, the pattern of this impairment is frequently less
severe than that seen in Alzheimer's disease where the pathological
changes in the brain are known to be widespread, This observation,
together with the occurrence of cognitive impairment in a range of
movement disorders where the main neuropathological changes reside
in the subcortical region of the brain, has led to the concept of'subcortical
dementia'-a form of intellectual imV<rirment of lesser degree
than in Alzheimer's disease, but affecting several cognitive functions
and associated with a disorder of movement. In 1974 Albert and his
colleagues gave a description of the syndrome in which the main features
were listed as emotional or personality changes, impaired memory,
defective ability to manipulate acquired knowledge, and a striking
slowness in the rate of information processing. ( 5)
This concept has carried some conviction, as the impairment seen
in many subjects with disease in the subcortical region of the brain
shows a pattern of cognitive impairment distinctly different from that
of Alzheimer's disease, However, many issues have arisen as to the
nature of ' subcortical dementia', Is subcortical dementia a clinical or a
pathological concept? Is the difference between this and other forms of
dementia simply one of degree? Do the pathological changes occur in
the subcortical region of the brain alone? Is the syndrome of cognitive
impairment distinctly different from other dementias or does the presence
of motor features of the disorder simply give the intellectual
impairment a distinct character? Is subcortical dementia a stable condition
or a transitional state leading eventually to global dementia?
Opinion has ranged from full acceptance of ' subcortical dementia' as a
distinct form of cognitive impairment to scepticism. (6-B)
McHugh(9) has gone further than Albert et aI., (5) suggesting that the
subcortical region subserves functions not only in motor control and
cognitive function but also in the control and display of mood. He
suggests that some syndromes arising from subcortical disease
represent a 'subcortical triad' of symptoms. This combination of
symptoms is most convincingly seen in Huntington's disease. A notable
difference between this concept and that of Albert and his colleagues
is that the pathological disturbance of mood is only
intermittently present, whereas the motor and cognitive changes are
persistent.
Cummings( 1 0 ) has suggested a useful development of the concept of
'subcortical dementia'. He believes that the concept is applicable to disorders
of movement to varying degrees. He suggests that cognitive
impairment in Parkinson's disease takes three forms: a form which is
relatively mild and meets the criteria for subcortical dementia, a more
severe form showing wider impairment of cognitive function but
neuropathologically distinct from senile dementia Alzheimer type
(SDAT), and a severe form which shows neuropathological changes in
both the subcortical region of the brain and in the cortex, the latter of
Alzheimer type. This proposal does not resolve some of the questions
that have arisen over the nature of subcortical dementia, but it does
provide a basis for viewing cognitive changes in Parkinson's disease,
albeit provisional.
Many reports have suggested that global dementia occurs in Parkinson's
disease. Whether such a severe change in cognitive function
can be regarded as an intrinsic feature of this disease, whether it
implies an extension of a neuropathological process more widely in the
brain, or whether it suggests a different neuropathology from the outset
which initially presented with disordered movement is, as yet,
uncertain.
The methodology of studies of
dementia in Parkinson's disease
Research to establish the status of dementia in Parkinson's disease has
confronted a range of methodological issues. (1 1)
A major problem in research on dementia in Parkinson's disease
has been in the diagnosis of Parkinson's disease itself. The original
description of paralysis agitans by Parkinson was, in fact, the identification
of a syndrome rather than of a disease. The part played by such
agents as heavy metals, infection, and vascular disease was recognized
more than 50 years ago. More recently, the importance of druginduced
parkinsonism, where patients generally recover following
withdrawal of the drug, has been recognized, The term Parkinson's
disease had come to be regarded as synonymous with idiopathic Parkinson's
disease and paralysis agitans, and to be a degenerative disease
of unknown cause. In spite of the use of standardized methods of diagnosis,
recent studies have shown that a substantial proportion of
patients diagnosed as suffering from Parkinson's disease in life do not
show the expected findings in the brain postmortem."2.13) In the study
by Hughes et al., (12) 80 per cent of cases were shown to have neuropathological
changes of Parkinson's disease after death and over 20 per
cent were diagnosed as having suffered from progressive supranuclear
palsy, multiple system atrophy, or Alzheimer's disease. Furthermore,
some dementing illnesses may show movement disorder as a clinical
feature, often late in the course of the disease, but further confusing
the issue of diagnosis.
Studies of dementia in Parkinson's
disease
Cases of dementia in Parkinson's disease have been reported for over a
hundred years. Frequently, the relationship between dementia and this
disease in reported cases is impossible to discern.
A number of cross-sectional or prevalence studies of dementia in
Parkinson's disease have been carried out. The frequency of dementia
reported ranges from zero to 81 per cent. In a review of 17 studies
Brown and Marsden found that, overall, 35 per cent of subjects were
regarded as demented." 4) However, if more stringent criteria for
dementia were applied then the proportions demented fell to between
15 and 20 per cent. The authors regarded these figures to be more
realistic, and this level has proved to be in keeping with more recent
cross-sectional studies.
Follow-up studies have great advantages in studying the frequency
of dementia in Parkinson's disease: they allow the diagnosis of Parkinson's
disease to be checked; repeated assessment reduces errors in the
recognition of dementia; the pattern of evolution of dementia may be
followed; the underestimation of dementia by selective loss through
death is avoided; and they reveal the incidence rather than the prevalence
of the condition. The problems of fo llow-up studies include the
difficulties in the choice of those methods of diagnosis and assessment
that will remain appropriate throughout the period of the follow-up.
No prospective controlled study of the incidence of dementia in
Parkinson's disease has been entirely satisfactory in its methodology.
Probably the most satisfactory is that reported by Biggins et aI., (1 5 ) and
subsequently after a longer period of follow-up by Hughes et al. (I 6)
Although this study employed satisfactory methods in most respects,
its greatest weakness was in the selection of-the original samples of
both patients and controls. Biggins et al. (15 ) reported an incidence of
dementia of 19 per cent after 4.5 years observation, or 48 per 1000
person-years of observation. A later report on the same cohorts of subjects
showed an incidence of dementia of 47.8 per cent after 10 years of
observation, or 46.9 cases per 1000 person-years of observation. The
study shows a substantial incidence of dementia in Parkinson's disease
increasing with the passage of the years. The control group showed
cases of cognitive impairment but none amounting to dementia,
thereby demonstrating a substantial excess risk in those subjects with
Parkinson's disease.
Prediction of dementia in Parkinson's
disease
There is a consensus from a number of studies as to which of those
subjects with Parkinson's disease are most likely to suffer from dementia:
older people, patients with Parkinson's disease of longer duration,
subjects who have a greater severity of motor symptoms and signs of
Parkinson's disease, and those who show greater. physical disability.
CIS.16) Some studies have shown that Parkinson's disease in men or
of late onset is more likely to be associated with dementia.cI9) In parkinsonism,
as distinct from Parkinson's disease, the likelihood of
dementia is closely related to the pathological changes that underlie
the symptoms of parkinsonism, which include diseases in which
dementia is a leading feature, such as Alzheimer's disease. The explanation
of an apparent association between the treatment of Parkinson's
disease with levodopa and dementia is probably that successful treatment
of the motor symptoms of Parkinson's disease prolongs life and
thereby increases the risk of dementia.
Neuropathology
The characteristic neuropathological changes of Parkinson's disease
were described before the Second World War. The basic lesion is ~he
degeneration of the pigmented neurone cells in the pars compacta of
the substantia ***** in the brainstem, the presence"ofLewy bodies, and
accompanying gliosis. There is also a degeneration of neurones in the
striatum and globus pallidus, but these changes may be secondary. (20)
Clinical Parkinson's disease does not appear until about 80 per cent of
the' nigro striatal dopaminergic neurones have died. A correlation
between the extent of cell loss in the pars compacta and the severity
"and duration of Parkinson's disease has been demonstrated. Lewy bodies
had come to be regarded as pathognomonic of Parkinson's disease,
but are now known to be present in other diseases (see Chapter
4.1.6).
Although the degenerative changes in the substantia ***** are
known to be closely linked with decreased dopaminergic neurotransmission
in the brain, and that it is this deficiency which leads to
the main motor features of the disease, other neurotransmitters are
also deficient. Some of these deficiencies are of a type that has been
associated with cognitive impairment in other disorders, including a
deficiency in acetylcholinesterase in the cortex, a deficiency of noradrenaline
in the cortex, and a deficiency of serotonin (5-hydroxytryptamine)
in the striatum and cortex. The concentration of a range
of neuropeptides may also be altered.
The neuropathology of cases of Parkinson's disease showing
dementia is inconsistent; some show neuropathological changes
extending to parts of the brain beyond the subcortical region, whereas
in others the changes are similar to those seen in patients with Parkinson's
disease without dementia and with neuropathological changes
restricted to the subcortical region. In some patients with dementia
the neuropathological diagnosis is of Alzheimer's disease or of other .
recognized degenerated conditions of the brainYl) An interesting case
is that of Lewy body disease, which is dealt with in Chapter 4.1.6.
Just as there are difficulties in isolating Parkinson's disease from
other conditions which closely resemble it, there are problems in
understand the interrelationships of dementing disorders. At present,
the aetiology of Parkinson's disease is unknown. Parkinson's disease
shares this situation with a number of 'neurodegenerative' disorders,
including Alzheimer's disease. Several distinct neurodegenerative diseases
share some aetiological factors, which may represent an interaction
between environmental factors and the ageing process but with
differing end results arising from specific factors in the process. (22.23)
Problems in the diagnosis of Parkinson's disease, the shrinking category
of idiopathic Parkinson's disease, and the difficulties encountered
in explaining the occasional development of dementia in this
disease, suggests that the interrelationship between causative agents,
the clinical features of disorders of movement, the occurrence of cognitive
impairment, and the neuropathology of this group of disorders
requires substantial further work before it is understood.
The influence of dementia on mortality
Dementia of any origin is associated with an increased risk of premature
death. A number of studies have shown an increased mortality
in Parkinson's disease to be associated with age, late age of onset of this
disease, cognitive impairment, dementia, and, in some studies, male
sex. Certain medications have been associated with increased mortality.
Many of the studies that have been carried out have been methodologically
faulty, making comparisons between studies and the
identification of the effect of particular factors, including dementia,
problematic. A study, meeting most of the requirements for an accurate
assessment of mortality, showed a hazard ratio for Parkinson's disease
compared with controls of 1.64, in general, and of 1.94 for
Parkinson's disease with dementia.(24) The occurrence of depression
with Parkinson's disease led to increased mortality even more than
dementia, with a hazard ratio of 2.66.
Clinical aspects of Parkinson's disease
with dementia
The recognition of cognitive impairment in patients with Parkinson's
disease has major implications for their management. Although prospective
studies of patients with Parkinson's disease show that the illness
usually follows a course extending over many years, dementia
brings with it important changes in the care a patient will require and
in their life expectancy. These needs will progressively increase and will
place an increasing burden upon the patient's immediate family and
carers. The timing of wills and other legal procedures may be
affected.
The most important step in the recognition of dementia in Parkinson's
disease is to suspect its presence. There are many features of Parkinson's
disease that tend to obscure the appearance of new clinical
features of the disease. The typical blank facial expression seen in Parkinson's
disease may obscure a decline in intellectual activity, slowness
in movement may conceal intellectual slowness, and sadness may suggest
that morbid depression of mood is the reason for a reduction in
liveliness. These clinical features may seem to account for increasing
disability. The clinical picture can usually be clarified by careful examination
of the mental state. Examination of cognitive functions by
more extensive standardized psychological tests may be useful in some
cases.
The clinical importance of dementia in Parkinson's disease is that
there is a marked increase in disability, with problems arising in areas
of functioning not previously affected by motor impairment alone.
The development of drug treatments for dementia makes its recognition
in Parkinson's disease especially important. Dementia may be
accompanied by an increased liability to confusional episodes from the
toxic effects of drugs and other causes.
Management of dementia is similar to that for patients suffering
from other dementing disorders, but with attention to the presence or
a movement disorder.
References
1. Pirozzolo, ET., Hansch, E.C, and Mortimer, T.A. (1982). Dementia in
Parkinson's disease: a neuropsychological analysis. Brain and Cognition.
1,71- 83.
2. Levin, B.E. and Katzen, H.L. (1995). Early cognitive changes and nondementing
behavioural abnormalities in Parkinson's disease. Advances .
Neurology, 65, 85- 95 .
3. Owen, A.M., Tames, M., Leigh, P.N., et al. (1992). Fronto-striatal
cognitive deficits at different stages of Parkinson's disease. Brain, US,
1727-51.
4. Pollack, M. and Hornabrook, R.W. (1966). The prevalence, natural
history and dementia of Parkinson's disease. Brain, 89, 429- 48.
5. A1bert, M.L., Feldman, R.G., and Willis, A.L. (1974). The 'subcortical
dementia' of progressive supra-nuclear palsy. Journal of Neurology,
Neurosurgery and Psychiatry, 37, 121-30.
6. Mayeux, R., Stern, Y, Rosen, J., and Benson, D.F. (1983). Is'subcorti=
dementia' a recognisable clinical entity? Annals of Neurology, 14, 278-S.5
7. Whitehouse, P.T. (1986). The concept of cortical and subcortical
dementia: another look. Annals of Neurology, 19, 1-6.
8. Brown, R.G. and Marsden, CD. (1988). Subcortical dementia: the
neuropsychological evidence. Neuroscience, 25, 363-87.
9. McHugh, P.R. (1990) . The basal ganglia: the region, the integration oi
its systems and implications for psychiatry and neurology. In Function
and dysfunction in the basal ganglia (ed. A.J. Franks, J.W. Ironside,
R.H.S. Mindham, RJ Smith, E.G.S. Spokes, and W. Winlow), pp.
259-69. Manchester University Press.
10. Cummings, J.L. (1988). The dementia of Parkinson's disease: preval=
characteristics, neurobiology, and comparison with dementia of the
A1zheimer type. European Neurology, 28, 15-23.
11 . Mindham, R.H.S. The place of dementia in Parkinson's disease: a
methodological saga. Advances in Neurology, in press.
12. Hughes, A.J., Daniel, S.E., Kilford, L., and Lees, A.T. (1992). Accuracy
diagnosis of idiopathic Parkinson's disease: a c1inico-pathological s
of 100 cases. Journal of Neurology, Neurosurgery and Psychiatry, 55 ,
181-4.
428 4 CLIN ICAL SYNDROMES OF ADULT PSYCHIATRY
Vascular dementia
Introduction
Vascular dementia is the second most frequent cause of dementia.(1,2)
Because vascular causes of cognitive impairment are common, may be
preventable, and the patients could benefit from therapy, early detection
and accurate diagnosis of vascular dementia is desirable. (3)
Vascular dementia is not only multi-infarct dementia, but is related
to other vascular mechanisms and pathological changes in the
brain, and has other causes and clinical manifestations. Vascular
dementia is not a disease, but a syndrome. The origin of of this syndrome
reflects complex interactions between vascular aetiologies
(cerebrovascular disorders and vascular risk factors), changes in the
4.1.9 VASCULAR DEMENTIA
brain (infarcts, white-matter lesions, atrophy), host factors (age, education),
and cognition.(4-B)
Conceptual issues related to of vascular dementia include the definition
of the cognitive syndrome (type, extent, and combination of
impairments in different cognitive domains), and the vascular causes
(vascular aetiologies and changes in the brain). Variations in these definitions
has led to different estimates of point prevalence, to different
groups of patients', and to reports of different types and distribution of
brain lesions. (9-1l) The cognitive syndrome of vascular dementia is
characterized by predominate executive dysfunction rather than deficits
in memory and language function. (l2) Although the course of cognitive
decline may be stepwise, it is often slowly progressive, and may
include periods of stability or even some improvement.
The relationship between vascular lesions in the brain and cognitive
impairment is important, but which type, extent, side, site, and
tempo of vascular lesions in the brain relates to different types of vascular
dementia is not established in detail. (4-6,13)
Current criteria for vascular dementia are based on the concept of
cerebral infarcts, For example the widely used NINDS-AIREN criteria
include dementia, cerebrovascular disease, and a relationship between
these two disorders. The main tools for the diagnosis include detailed
history, neurological examination, mental state examination, relevant
laboratory examinations, and preferably magnetic resonance imaging
of the brain.
Vascular dementia research, until recently overshadowed by that
into Alzheimer's disease, is now developing rapidly. There is great
promise for intervention. Developments in classification, diagnosis,
and treatment are likely.
Aetiology and pathophysiology
Aetiology
The main causes of vascular dementia are cerebrovascular disorders
and their risk factors. The prevalent cerebrovascular disorders include
large artery disease (artery-to-artery embolism, occlusion of an extraor
intracranial artery), cardiac embolic events, small vessel disease
(lacunar infarcts, ischaemic white-matter lesions) and haemodynamic
mechanisms. (13-15) Less frequent causes include specific arteriopathies,
haemorrhage (intracranial haemorrhage, subarachnoidal haemorrhage),
haematological factors, venous disease, and hereditary disorders.
There may be as yet undiscovered causes.
In most patients diagnosed with vascular dementia, several aetiological
factors are involved. However, the roles these factors play have
not been identified in detail, and it is not certain which of these mech.
anisms distinguish vascular dementia from cerebrovascular disease
without dementia. (4.5.7.16, 17)
Risk factors for vascular dementia can be divided into vascular factors
(e.g. arterial hypertension, atrial fibrillation, myocardial infarction,
coronary heart disease, diabetes, generalized atherosclerosis, lipid
abnormalities, smoking), demographic factors (e.g age, education),
genetic factors (e.g. family history, individual genetic features), and
stroke-related factors (e.g. type of cerebrovascular disease, site and size
of stroke),os.19) Hypoxic ischaemic events (cardiac arrhythmias, ~on gestive
heart failure, myocardial infarction, seizures, pneumonia) may
be an important risk factor for incident dementia in patients, with
stroke. (20)
Changes in the brain
Vascular dementia is related to both ischaemic and non-ischaemic
changes in the brain.(4.5.13,14) The ischaemic lesions include arterial territorial
infarct, distal field (watershed) infarct, lacunar infarct, ischaemic
white-matter lesions, and incomplete ischaemic injury.
Incomplete ischaemic injury incorporates laminar necrosis, focal gliosis,
granular atrophy, and incomplete white-matter infarction.(21,22) In
addition, both focal (around the ischaemic lesion) and remote (disconnection,
diaschisis) functional ischaemic changes relate to vascular
dementia, and the volume of functionally inactive tissue exceeds that
of focal ischaemic lesions in vascular dementia. (23) Limitation in current
clinical methods have hampered the detection of both incomplete
ischaemic injury and functional ischaemic changes related to vascular
dementia. Atrophy -is thenon-ischaemic factor related to vascular
dementia. However, there are no methods to distinguish between
ischaemic and degenerative causes of atrophy.
Brain imaging findings
Work on the relationship between brain lesions and cognition in vascular
dementia has used varying definitions and measures of cognitive
impairment, varying techniques to reveal brain changes, and varying
criteria for the selection of patients.(17)
CT and magnetic resonance imaging (MRI) studies on vascular
dementia have shown that bilateral ischaemic lesions are important.
( ,5,7,17) Some studies emphasize deep infarcts in the frontal and
limbic areas, while others report cortical lesions especially in the temporal
and parietal areas. There is disagreement about the number and
volume of the infarcts, as well as the extent and location of atrophy.
Diffuse and extensive white-matter lesions have been suggested as an
important factor leading to functional disconnection of cortical brain
areas. Some general conclusions on brain lesions in vascular dementia
may be drawn,
1. There is no single pathological feature, but a combination of
infarcts, ischaemic white-matter lesions of varying size and type,
and atrophy of varying degree and site.
2, Infarcts associated with vascular dementia tend to be bilateral,
multiple (more than two), and located in the dominant hemisphere
and in the limbic structures (frontolimbic or prefrontalsubcortical
and medial-limbic or medial-hippocampal circuits).
3, White-matter lesions on CT or magnetic resonance imaging
(MRI) associated with vascular dementia are extensive, extending
in periventricular white matter, and confluent to extending in the
deep white matter.
4. It is doubtful whether a single small lesion on imaging can be
accepted as evidence for vascular dementia.
5. Absence of cerebrovascular lesions on CT or MRI is contrary to a
diagnosis of vascular dementia.
Pathophysiology
To what extent pathological changes in the brain cause, compound, or
only coexist with the vascular dementia syndrome is still not known
precisely. The vascular changes in the brain can be the main cause of
cognitive impairment (as assumed in vascular dementia(24,25)), they
can contribute to the clinical picture of other dementia syndromes
including Alzheimer's disease, (7,26) or they may be coincidental.
It is not certain which are the critical changes in the brain leading
to the clinical picture of vascular dementia. the syndrome has been
related to the volume of brain infarcts (with a critical threshold), the
number of infarcts, the site of infarcts (bilateral, in strategic cortical or
subcortical, or affecting white matter), to other ischaemic factors
(incomplete ischaemic injury, delayed neuronai death, functional
changes), to the atrophic changes (origin, location, extent), and finally
to the additive effects of other pathologies (Alzheimer's disease, Lewy
body dementia, frontal lobe dementias). But it is uncertain which type,
extent, side, site, and tempo of vascular lesions in the brain, and which
combination with other pathologies, relate to vascular dementia.
Classification and clinical criteria
Classification
Vascular dementia has been divided into subtypes on the basis of clinical,
radiological, and neuropathological features. It is uncertain
whether these subtypes are distinct disorders, with separate pathological
and clinical features, and responses to therapy. (27) If homogenous
subtypes could be identified the comparability of research studies
would be greater and multicentre studies easier. (28)
The subtypes of vascular dementia included in most classifications
include multi-infarct dementia (cortical lesions), small-vessel dementia
(subcortical deep lesions), and strategic infarct dementia.
(12,14,27.29-32) Many include also hypoperfusion dementia.<' 2. '4,30,33)
Further suggested subtypes include haemorrhagic dementia, hereditary
vascular dementia, and combined or mixed dementia (Alzheimer's
disease with cerebrovascular disease).
DSM-IV(34) does not specify subtypes. ICD-1Q(35) includes six subtypes
(acute onset, multi-infarct, subcortical, mixed cortical and subcortical,
other, and unspecified). The NINDS-AlREN criteria(3O)
include, without detailed description, cortical vascular dementia, subcortical
vascular dementia, Binswanger's disease, and thalamic
dementia.
Main subtypes
Multi-infarct dementia or cortical vascular dementia, and small-vessel
dementia or subcortical vascular dementia are the two common subtypes,
although their frequencies vary in different series(I2,14,31 )
Cortical vascular dementia relates to large-vessel disease, cardiac
embolic events, and hypoperfusion. InfaJ;CJ;s are. predominantly in the
cortical and corticosubcortical arterial territories, and their distal
fields (watershed). Typical clinical features are lateralized sensimotor
changes and the abrupt onset of cognitive impairment and aphas ia. (31 )
A combination of different cortical neuropsychological syndromes has
been suggested to occur in cortical vascular dementia.(36)
Subcortical vascular dementia, or small-vessel dementia, incorporates
the entities 'lacunar state' and 'Binswanger's disease'. It relates to
small-vessel disease and hypoperfusion, with predominately lacunar
infarcts, focal and diffuse ischaemic white-matter lesions, and incomplete
ischaemic injury. (31,36.37) Clinically, small-vessel dementia is characterized
by pure motor hemiparesis, bulbar signs, dysarthria,
depression, and emotionallability, and especially deficits in executive
functioning. (36-39)
Table 1 The DSM-IV definition of vascular dementia
Focal neurological signs and symptoms (e.g. exaggeration of deep tendon
reflexes, extensor plantar response, pseudobulbar palsy, gait
abnormalities, weakness of an extremity, etc.)
or
Laboratory evidence of focal neurological damage (e.g. multiple
infarctions involving cortex and underlying white matter)
The cognitive deficits cause significant impairment in social or
occupational functioning and represent a significant decline from a
previously higher level of functioning
The focal neurological signs, symptoms, and laboratory evidence are
judged to be aetiologically related to the disturbance
The deficits do not occur exclusively during the course of delirium
Course characterized by sustained periods of clinical stability punctuated
by sudden significant cognitive and functional losses
Clinical criteria
Since the 1970s several clinical criteria for vascular dementia have been
published.(l,,40,4I) The most widely used include those in DSM-IV, (34)
ICD-10,(35) and NINDS-AIREN. (30)
The two cardinal elements of any clinical criteria for vascular
dementia are the definition of the cognitive syndrome(42) and the definition
of the cause.(l1,41,43) All clinical criteria are consensus criteria,
derived neither from prospective community-based studies on vascular
factors affecting the cognition, nor on detailed natural histories.
(28,30,40.4 1,44) All these criteria are based on the concept of ischaemic
infarcts. They are designed to have high specificity, but have been
poorly validated.(4o,44) An important consequence of the different definitions
of the dementia syndrome,(9,42) and the vascular cause,(l O,ll ) is
that the different diagnostic criteria identify different populations.
The DSM-IV definition of vascular dementia (Table 1) requires
focal neurological signs and symptoms or laboratory evidence of focal
neurological damage clinically judged to be related to the disturbance.(
34) The course is specified by sudden cognitive and functional
losses. The DSM-IV criteria do not detail brain imaging requirements.
The DSM -IV definition of vascular dementia is reasonably broad and
lacks detailed clinical and radiological guidelines,
The ICD-IQ criteria(35) (Table 2) require unequal distribution of
cognitive deficits, focal signs as evidence of focal brain damage, and
significant cerebrovascular disease judged to be aetiologically related
to the dementia. The criteria do not detail brain imaging requirements.
The ICD-10 criteria specify six subtypes of vascular dementia
(Table 3). The ICD- lO criteria for vascular dementia have been shown
to be highly selective and only some of those fulfilling the general criteria
for ICD-lO vascular dementia can be classified into one of the
subtypes.(1l ,43) The shortcoming of these criteria include lack of
detailed guidelines (e.g. of unequal cognitive deficits and changes on
neuroimaging), lack of aetiological criteria, and heterogeneity
11,43)
The NINDS-AIREN research criteria for vascular dementia(30)
include a dementia syndrome, cerebrovascular disease, and a relationship
between these (Table 4), Cerebrovascular disease is defined by the
presence of focal neurological lesions and brain imaging evidence of
ischaemic changes in the brain. A relationship between dementia and
Table 2 The ICD-1 0 criteria for vascular dementia
Unequal distribution of deficits in higher cognitive functions with some
affected and others relatively spared. Thus, memory may be quite
marked ly affected while thinking, reasoning, and information
processing may show only mild decline
There is evidence for focal brain damage, manifest as at least one of the
following: unilateral ******* weakness of the limbs, unilaterally
increased tendon reflexes, an extensor plantar response,
pseudobulbar palsy
There is evidence from the history, examination, or test of significant
cerebrovascular disease, which may reasonably be judged to be
aetiologically related to the dementia (histo ry of stroke, evidence of
cerebral infarction)
cerebrovascular disorder is inferred from the onset of dementia within
3 months following a recognized stroke, or on abrupt deterioration in
cognitive functions, or fluctuating stepwise progression of cognitive
deficits. The criteria include a list of features consistent with the diagnosis,
as well as a list of features that make the diagnosis uncertain or
unlikely. Also, different levels of certainty of the clinical diagnosis
(probable, possible, defin ite) are included. The NINDS-AIREN criteria
recognize h eterogeneity('I5) of the syndrome and variability of the
clinical course in vascular dementia, and highlight detection of ischaemic
lesions and a relationship between lesion and cognition, as well as
stroke and dementia onset.
Table 3 Characteristics of the vascular dementia subtypes in
ICD-10
Acute onset (F01.0)
The dementia develops rapidly (i.e. usually within 1 month but within no
longer than 3 months) after a succession of strokes, or (rarely) after a
single large infarction
Multi-infarct (F01 .1 )
The onset of the dementia is more gradual (i.e. within 3-6 months)
following a number of minor ischaemic episodes. Comments: it is
presumed that there is an accumulation of infarcts i ~ the cerebral
parenchyma. Between the ischaemic episodes there may be periods of
actual clinical improvement
Subcortical (F01.2)
A history of hypertension, and evidence from clinical examination and
special investigations of vascular disease located in the deep white
matter of the cerebral hemispheres, with preservation of the cerebral
cortex.
Mixed cortical and subcortical (F01.3)
Mixed cortical and subcortical components of vascular dementia may be
suspected from the clinical features, the results of investigation, or
both
Other (F01.8)
Unspecified (F01.9)
In the ICD-10 criteria no specific diagnostic guidelines are given for these
two vascular dementia sybtypes
Table 4 The NINDS-AIREN criteria for probable vascular dementia
The criteria for the clinical diagnosis of PROBABLE vascular dementia
include all of the following
1. Dementia
2. Cerebrovascular disease, defined by the presence of focal signs on
neurological examination, such as hemiparesis, lower facial
weakness, Babinski sign, sensory deficit, hemianopia, dysarthria, etc.
consistent with stroke (with or without history of stroke), and
evidence of relevant CVD by brain imaging (CT or MRI) including
multiple large-vessel strokes or a single strategically placed infarct
(angu lar gyrus, thalamus, basal forebrain , PCA or ACA territories),
as well as m ~ li:iple ba';al ganglia and white-matter lacunes or
extensive periventricular white-matter lesions, or combinations
thereof
3. A relationship between the above two disorders, manifested or inferred by
the presence of one or more of the following
(a) Onset of dementia within 3 months following a recognized
stroke
(b) Abrupt deterioration in cognitive functions, or fluctuating
stepwise progression of cognitive deficits
11. Clinical features consistent with the diagnosis of PROBABLE vascular
dementia include the following
(a) Early presence of a gait disturbance (small-step gait or marche cl
petits-pas, apraxic-ataxic or parkinsonian gait)
(b) History of unsteadiness and frequent unprovoked falls
(c) Early uri nary frequency, urgency, and other uri nary symptoms
not explained by urological disease
(d) Personality and mood changes, abulia, depression, emotional
incontinence, other subcortical deficits including psychomotor
******ation and abnormal executive funct ion
Ill. Features that make the diagnosis of vascular dementia uncertain or
unlikely include the following
(a) Early onset of memory deficit and progressive worsening of
memory and other cognitive functions such as language
(transcortical sensory aphasia), motor skills (apraxia), and
perception (agnosia), in the absence of corresponding focal
lesions on brain imaging
(b) Absence of focal neurological signs, other than cognitive
di sturbance
(c) Absence of cerebrovascular lesions on brain CT or MRI
CVD. cerebrovascular disease; PCA. posterior cerebral" artery; ACA. anterior cerebral
artery.
The NINDS-AlREN criteria are currently most widely used in clinical
drug trials on vascular dementia. In a neuropathological series,
sensitivity of the NINDS-AlREN criteria was 58 per cent and specificity
80 per cent.(47) The criteria successfully excluded Alzheimer's disease
in 91 per cent of cases, and the proportion of combined cases
misclassified as probable vascular dementia was 29 per cent. (47) The
inter-rater reliability of the NINDS-AIREN criteria is moderate to substantial
(K = 0.46-0.72 ). (48)
These three sets of criteria for vascular dementia are not interchangeable;
they identify different numbers and clusters of patients.
The DSM-IV criteria are less restrictive than the IeD-lO and NINDSAlREN
criteria. ( 1 1.46)
431
432 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
CLinical features
Cognitive syndrome
The cognitive syndrome of vascular dementia is characterized by
memory deficit, dysexecutive syndrome, slowed information processing,
and mood and personality changes. These features are found especially
among patients with subcortical lesions. Patients with cortical
lesions often have additional cortical neuropsychological syndromes.
(36)
The memory deficit in vascular dementia is often less severe than in
Alzheimer's disease. It is characterized by impaired recall, relatively
intact recognition, and more benefit from cues.(49) The dysexecutive'
syndrome in vascular dementia includes impairment in goal formulation,
initiation, planning, organizing, sequencing, executing, setsifting
and set-maintenance, as well as in abstractingY2,36,49) The
dysexecutive syndrome in vascular dementia relates to lesions affecting
the prefrontal subcortical circuit including prefrontal cortex, caudate,
pallidum, thalamus, and the thalamocortical circuit (capsular genu,
anterior capsule, anterior centrum semiovale, and anterior corona
radiata) .(50) Typically, personality and insight are relatively preserved
in mild and moderate cases of vascular dementia,
Features that make the diagnosis of vascular dementia disease
uncertain or unlikely include early and progressive worsening of memory,
and other cognitive cortical deficits in the absence of corresponding
focal lesions on brain imaging.(30)
Neurological findings
Frequent neurological findings indicating focal brain lesion early in
the course of vascular dementia include mild motor or sensory deficits,
decreased co-ordination, brisk tendon reflexes, Babinski 's sign,
visual field loss, bulbar signs including dysarthria and dysphagia,
extrapyramidal signs (mainly rigidity and akinesia ), disordered gait
(hemiplegic, apraxic-ataxic, or small-stepped), unsteadiness, unprovoked
falls, and urinary frequency and urgency.(30,3 l,37-39) Features that
make the diagnosis of vascular dementia uncertain or unlikely include
absence of focal neurological signs, other than cognitive disturbance.
C30)
In cortical vascular dementia, typical clinical features are lateralized
sensorimotor changes and abrupt onset of cognitive impairment and
aphasia, and in subcortical vascular dementia disease pure motor
hemiparesis, bulbar signs, and dysarthria. c3l)
Behavioural and psychological symptoms of
dementia
Depression, anxiety, emotional lability and incontinence, and other
psychiatric symptoms are frequent in vascular dementia. Depression,
abulia, emotional incontinence, and psychomotor ******ation are
especially frequent in subcortical vascular dementia diseaseY2,36)
Ischaemic scores
Cardinal features of vascular dementia disease are incorporated in the
Hachinski Ischaemia Score(5l) (Table 5). In a recent neuropathological
series, stepwise deterioration (odds ratio, 6.0), fluctuating course
(odds ratio, 7.6), history of hypertension (odds ratio, 4.3), history of
stroke (odds ratio, 4.3), and focal neurological symptoms (odds ratio,
Table 5 Hachinski Ischaemia Score
Item
Abrupt onset
Stepwise deterioration
Fluctuating course
Nocturnal confusion
Relative preservation of personality
Depression
Somatic complaints
Emotional incontinence
Histo ry of hypertension
History of strokes
Evidence of associated
atherosclerosis
Focal neurological symptoms
Focal neurological signs
Score value
2
2
2
1
2
2
4.4) differentiated patients with definite vascular dementia from those
with definite Alzheimer's disease. (52) Nocturnal confusion and depression
did not discriminate. However, the ischaemia score was unable to
differentiate the Alzheimer's disease patients with cerebrovascular disease
from those with vascular dementia.
Course and prognosis
Traditionally, vascular dementia has been characterized by a relative
abrupt onset (days to weeks), a stepwise deterioration (some recove ~after
worsening), and fluctuating course (e.g, differences between
days) of cognitive functions. These features are seen in patients with
repeated lesions affecting cortical and corticosubcortical brain structures,
i,e.large-vessel multi-infarct vascular dementia, and with watershed
infarcts related to haemodynamic problems. However, in patient5
with small-vessel dementia, i.e. subcortical vascular dementia, the
onset is more insidious and course more slowly progressive. (28,30,37,53
The mean duration of vascular dementia is around 5 years, (2) In
most studies survival is less than for the general population or those
with Alzheimer's disease.(54,55) Surprisingly little is known about the
rate and pattern of cognitive decline, either overall or among differem
subgroups of vascular dementia. (56) This underlines the lack of studies
detailing the natural history of vascular dementia.
Diagnosis and differential diagnosis
The clinical evaluation of patients with memory impairment has two
stages, the symptomatic diagnosis, i.e. evaluation of the type and
extent of cognitive impairment, and the aetiological diagnosis, i.t!.
evaluation of vascular cause(s) and related factors. The symptomatic
categorie s other than dementia include delirium, circumscribed
neuropsychological syndromes (e.g. aphasia) and functional psychiatric
disorders (e.g, depression). (44) Stages of aetiological diagno 'include
diagnosis of the specific causes, especially the potentially treatable
conditions, evaluation of secondary factors able to affect the cognitive
functioning, and more detailed differentiation between specific
4.1.9 VASCULAR DEMENTIA
causes, especially that between vascular dementia disease and Alzheimer's
disease.
Clinical evaluation
The cornerstone in the evaluation of a patient with suspected vascular
dementia is detailed clinical and neurological history and examination,
including interview of a close informant. Assessment of social
functions, activities of daily living, as well as psychiatric and behavioural
symptoms, is part of the basic evaluation. These patients are
challenging and enough time should be allocated time for the consultation,
often 40 to 60 min.
Mental status examination
Bedside mental status examination includes the Mini-Mental State
Examination. (S7) However, this has limitations as it emphasizes language,
does not include timed elements and the recognition portion of
the memory tests, is insensitive to mild deficits, and is influenced by
education and age. Other proposed screening instruments for vascular
dementia include a ten-word memory test with delayed recall, cube
drawing test for copy, verbal fluency test (number of animals named in
1 min), Luria's alternating hand sequence, or finger rings and letter
cancellation test (neglect).(30)
Frequently a more detailed neuropsychological test is needed. It
s!wuld cover the main cognitive domains including memory functions
- and long-term memory), abstract thinking, judgement, aphas-
-,,-raxia, agnosia, orientation, attention, executive functions, and
speed of information processing( 42,58)
Brain imaging
Brain imaging should be performed at least once during the initial
diagnostic workout. MRI is preferred because it has high sensitivity
and the ability to demonstrate medial temporal lobe and basal
forebrain areas. Depending on the criteria of vascular dementia used,
focal brain infarcts have been revealed in 70 to 100 per cent, and
more extensive white-matter lesions in 70 to 100 per cent of
cases. (13,25,30,59.60)
Single-photon emission CT and positron-emission tomography
may reveal patchy reduction of regional blood flow and metabolism, as
well as decreased white-matter flow and metabolism. (61)
Other investigations
Chest X-ray, elelectrocardiography, and screening laboratory tests are
part of the basic evaluation.(IS,62,63) In selected cases extended laboratory
investigations, analysis of the cerebrospinal fluid, and EEG are
performed, as well as examinations ofthe extra- and intracranial arteries
and detailed cardiological investigations, (1 5,62,63)
In vascular dementia EEG is more often normal than in Alzheimer's
disease, and if abnormal more frequently suggests a focal abnormality.
Abnormalities increase with more severe intellectual decline
both in vascular dementia disease and Alzheimer's disease,(53)
At present there is no specific laboratory test for vascular dementia.
Tests may reveal risk factors and concomitant disorders such as hyperlipidaemia,
diabetes, and cardiac abnormality. (53) Apolipoprotein E4 is
a established risk factor for Alzheimer's disease, but its relationship to
vascular dementia has not been consistent.(64) Determination of apolipoprotein
E status is currently not part of clinical evaluation in vascular
dementia.
Differential diagnosis of vascular dementia
disease
Alzheimer's disease
Typical Alzheimer's disease is characterized by insidious onset and
slowly progressive intellectual deterioration, absence of symptoms and
signs indicating focal brain damage, and absence of any other specific
disease affecting ~ brain.(6S) Alzheimer's disease has typical clinical
stages ranging from early changes to profound dementia, (66,67)
When patients with vascular dementia have a clinical history,
neurological examination, and brain imaging findings compatible
with ischaemic changes of the brain, the differentiation from Alzheimer's
disease can be made clinically. (25)
Diagnostic problems arise when Alzheimer's disease is combined
with cerebrovascular disease, Difficult clinical problems include stroke
unmasking Alzheimer's disease in patients with post-stroke dementia,
insidious onset, and/or slow progressive course in vascular dementia
patients, and cases where it is difficult to assess the role of white-matter
lesions or of infarcts found on neuroimaging. This clinical challenge
may be solved when a sensitive and specific ante-mortem marker for
Alzheimer's disease is available. The distinction would be less difficult
if there were more detailed knowledge of the sites, type, and extent of
ischaemic brain changes critical for vascular dementia, and the extent
and type of medial temporal lobe atrophy critical for Alzheimer's disease.
Other important conditions to be diffentiated from vascular
dementia include normal pressure hydrocephalus, (68) white-matter
lesions and dementia,(I 7,30) fro ntal lobe tumours and other intracranial
masses, (15) Lewy body dementia, (69) frontotemporal dementia,(7O)
Parklnsons's disease and dementia,<71) progressive supranuclear
palsy, (72) and multisystem atrophy.(73)
Epidemiology
Vascular dementia is the second most common cause of dementia
accounting for 10 to 50 per cent of cases, depending on the geographic
location, patient population, and clinical methods used. (1,2) The
prevalence of vascular dementia is from 1.2 to 4.2 per cent of persons
aged 65 years and older, and the incidence is 6 to 12 cases per 1000
persons aged over 70 years per year.(2) The prevalence and the incidence
of vascular dementia disease increases with increasing age, and
men seem to have a higher prevalence of vascular dementia than
women. Epidemiology of vascular dementia has been affected by variations
in the definition of the disorder, the clinical criteria used, and
the clinical methods applied,(18,74,75)
The frequency of vascular dementia disease has been higher than
previously reported in recent series comprising older subjects, (IO)
Stroke and cerebrovascular disorders relate also to a high risk of cognitive
impairment and dementia. (24,76) Finally, vascular factors such as
stroke and white-matter lesions have a clinical effect on Alzheimer's
disease. (26) Thus, vascular factors may even be the leading cause of
cognitive impairment worldwide.(77)
433
/
434 4 CLIN ICAL SYNDROMES OF ADULT PSYCHIATRY
Treatment
The objectives of targeted treatment of vascular dementia include
symptomatic improvement of core symptoms (e.g. cognitive, behavioural),
slowing progression of the disorder, and treatment of secondary
factors affecting cognition (e.g. depression, anxiety, agitation).
A number of drugs have been studied in the symptomatic treatment
of vascular dementia including cerebro- and vasoactive drugs,
nootropics, and some calcium antagonists, but largely these studies
have shown negative results. (78) Studies on symptomatic improvement
in vascular dementia have mostly had small numbers, short treatment
periods, variations in diagnostic criteria and tools, mixed populations,
and have had variation in clinical endpoints applied.
Recently nimodipine,(79) memantine,(80) and propentofylline(81 )
have raised expectations for a symptomatic treatment of vascular
dementia. A number of phase 3 double-blind randomized placebocontrolled
trials in patients with vascular dementia using these compounds
are in progress. ( 82 )
Possibilities for prevention
For primary prevention the target is the brain at risk of cerebrovascular
disease and cognitive impairment. The methods relate to the treatment
of putative risk factors of vascular dementia, and the promotion
of potential protective factors. Risk factors include those related to
cerebrovascular disorders and stroke, to vascular dementia, to poststroke
dementia, to white-matter lesions, and to cognitive impairment
or dementia, and also those related to Alzheimer's disease. (S) The vascular
risk factors include arterial hypertension, atrial fibrillation, myocardial
infarction, coronary heart disease, diabetes, generalized
atherosclerosis, lipid abnormalities, and smoking. The demographic
factors include age and education. One putative protective factor is
oestrogen. (83)
Knowledge of effects of primary prevention on these risk factors in
populations free of cognitive impairment is still scant. (8,84 ) In a European
study, treatment of mild systolic hypertension decreased the incidence
of dementia,(SS) Positive effects in primary prevention of stroke
support the idea 'that action on vascular risk factors could reduce the
numbers of patients with vascular dementia.
For secondary prevention the target is the brain already affected by
cerebrovascular disease and at risk of vascular dementia. Actions
include diagnosis and treatment of acute stroke in order to limit the
extent of ischaemic brain changes, prevention of recurrence of stroke,
and treatment of risk factors. Treatment is guided by the aetiology of
cerebrovascular disorder such as large artery disease (e.g. aspirin,
dipyridamole, carotid endarterectomy), Gardiac. embolic events (e.g.
anticoagulation, aspirin), small-vessel disease (e.g. antiplatelet therapy),
and h aemodynamic mechanisms (e.g. control of hypotension
and cardiac arrhythmias) (15.29,44) Hypoxic ischaemic events (cardiac
arrhythmias, congestive heart failure, myocardial infarction, seizures,
pneumonia) are an important risk factor for incident dementia in
patients with stroke and should be taken into account in the secondary
prevention of vascular dementia.(20)
Detailed knowledge of the effects of secondary prevention of vascular
dementia is lacking, In a small series of patients with established
vascular dementia, control of high arterial blood pressure,(86) cessation
of smoking, (86) and use of aspirin(S?) improved or stabilized cognition,
It has been suggested that lowering of plasma viscosity could also have
an effect in vascular dementia. (88) The absence of progressive cognitive
decline in patients receiving placebo in treatment trials of vascular
dementia may also reflect an effect of intensified risk factor control.
(SI)
References
1. Rocca, W,A" Hofman, A., and Brayne, c., et al. (1991), The prevalence
of vascular dementia in Europe: facts and fragments from 1980-1990
studies. EURODEM-Prevalence Research Group, Annals of Neurology,
30,817-24,
2. Hebert, R. and Brayne, C. (1995 ), Epidemiology of vascular dementia.
Neuroepidemiology, 14, 240-57,
3, Bowler, J,V and Hachinski, V (1995), Vascular cognitive impairment: a
new approach to vascular dementia, Baillieres Clinical Neurology, 4,
357-76.
4. Tatemichi, TK. (1990) , How acute brain fai lure becomes chronic, A
view of the mechanisms and syndromes of dementia related to stroke.
Neurology, 40, 1652- 9,
5. Chui, H.C. (1989), Dementia: a review emphasizing clinicopathologic
correlation and brain-behavior relationships, Archives of Neurology, 46,
806-14.
6. Desmond, D.W. (1996), Vascular dementia: a construct in evolution.
CerebrovasCIIlar and Brain Metabolism Reviews, 8, 296-325.
7. Pasquier, F. and Leys, D. (1997), Why are stroke patients prone to
develop dementia? Journal of Neurology, 244, 135-42.
8. Skoog, J. (1998), Status of risk factors for vascular dementia,
Nwroepidemiology, 17,2-9.
9. Pohjasvaara, T, Erkinjuntti, T, Vataj a, R., and Kaste, M, (1997),
Dementia three months after stroke. Baseline frequency and effect of
different definitions of dementia in the Helsinki Stroke Aging Memory
Study (SAM) cohort. Stroke, 28, 785-92 ,
10, Skoog, I., Nilsson, L., Palmertz, B., Andreasson, L.A., and Svanborg, A.
( 1993). A population-based study of dementia in 85-year-olds. New
England Journal of Medicine, 328, 153-8,
11. Wetterling, T., Kanitz, R.D., and Borgis, K.J, (1996), Comparison of
different diagnostic criteria for vascular dementia (ADDTC, DSM-IV,
ICD-I0, NINDS-AIREN), Stroke, 27, 30-6.
12, Cummings, J,L. (1994), Vascular subcortical dementias: clinical aspects.
Dementia, 5, 177-80,
13, Erkinjuntti, T (1996), Clinicopathological study of vascu lar dementia,
In Vascular dementia. Current concepts (ed, I. Prohovnik, J. Wade,S,
Knezevic, TK, Tatemichi, and T Erkinjuntii ), pp, 73-112, Wiley,
Chichester.
14, Brun, A. (1994), Pathology and pathophysiology of cerebrovascular
dementia: pure subgroups of obstructive and hypoperfusive etiology.
Dementia, 5, 145-7.
15. Amar, K. and Wilcock, G. (1996), Vascular dementia, British Medical
Journal, 312, 227-3 1.
16, Pantoni, L. and Garcia, J.H. (1995). The significance of cerebral white
matter abnormalities 100 years after Binswanger's report. A review,
Stroke, 26, 1293-301.
17. Erkinjuntti, T and Hachinski, Vc. (1993), Rethinking vascular
dementia. Cerebrovascular Disease, 3, 3- 23.
18. Skoog, I. (1994) . Risk factors for vascular dementia: a review, Dementia,
5, 137-44.
19. Gorelick, P.B. (1997). Status of risk factors for dementia associated with
stroke. Stroke, 28, 459-63.
20. Moroney, J.T, Bagiella, E., Desmond, D.W., Paik, M.C., Stern, Y., and
Tatemichi, TK. (1996). Risk factors for incident dementia after stroke,
Role of hypoxic and ischemic disorders, Stroke, 27, 1283-9,
21. Pantoni, Land Garcia, J.H, (1997), Pathogenesis ofleukoaraiosis: a
review, Stroke, 28, 652-9.
22, Englund, E., Brun, A" and Alling, C. (1988), White matter changes in
Another comment I would make is that the book I have taken this from:-
a) is aimed at specialist trainees in psychiatry who are already qualified doctors, so if you feel overwhelmed by the complexity of technical info, don't panic!

b) the book is a slightly older edition, so, although the majority of info [particularly symptoms, signs and clinical features] will be very similar to current schools of thought, the treatment aspects will have moved on a little - try and search more recent research papers for the latest developments in the pharmacotherapy of the dementias. Having said that, it might be a good idea to peruse some of the references listed in these two sections as a starting point.
r
422 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
4.1.7 Dementia in Parkinson's disease
R. H. S. Mindhom
Introduction
The psychiatric complications of Parkinson's disease have attracted
attention for two reasons: first, they are of practical importance in the
management of patients suffering from this disease and, second, their
study provides insight into a range of psychiatric conditions.
The nature of dementia in Parkinson's
disease
There have been numerous reports of the impairment of specific cognitive
functions in patients with Parkinson's disease. Some of the
impairments described are often only identifiable by specially designed
methods of assessment, but some are revealed by tests of cognitive
function that are in widespread use. Mortimer and his colleagues have
reported a very high prevalence of cognitive impairment-93 per cent
in a substantial group of patients with Parkinson's disease.") Examination
of their data showed neither a clear distinction between impaired
groups nor the presence of subtypes of Parkinson's disease in which
cognitive impairment was a more frequent occurrence. Their findings
led them to propose that cognitive impairment in Parkinson's disease
lies on a continuum of severity, rather than arising as a feature of particular
subgroups. The impairments identified include deficits in
memory, language, visuospatial functioning, abstract reasoning, slowness
in intellectual tasks, and difficulty in shifting from task to task. .
Not only are these deficits widespread among patients with Parkinson's
disease but they have been shown to occur at a very early stage of the
disorder. (2,3)
A proportion of patients with Parkinson's disease show impairment
of a range of cognitive functions, which is more akin to the
global impairment seen in dementing disorders such as Alzheimer's
disease, (4) However, the pattern of this impairment is frequently less
severe than that seen in Alzheimer's disease where the pathological
changes in the brain are known to be widespread, This observation,
together with the occurrence of cognitive impairment in a range of
movement disorders where the main neuropathological changes reside
in the subcortical region of the brain, has led to the concept of'subcortical
dementia'-a form of intellectual imV<rirment of lesser degree
than in Alzheimer's disease, but affecting several cognitive functions
and associated with a disorder of movement. In 1974 Albert and his
colleagues gave a description of the syndrome in which the main features
were listed as emotional or personality changes, impaired memory,
defective ability to manipulate acquired knowledge, and a striking
slowness in the rate of information processing. ( 5)
This concept has carried some conviction, as the impairment seen
in many subjects with disease in the subcortical region of the brain
shows a pattern of cognitive impairment distinctly different from that
of Alzheimer's disease, However, many issues have arisen as to the
nature of ' subcortical dementia', Is subcortical dementia a clinical or a
pathological concept? Is the difference between this and other forms of
dementia simply one of degree? Do the pathological changes occur in
the subcortical region of the brain alone? Is the syndrome of cognitive
impairment distinctly different from other dementias or does the presence
of motor features of the disorder simply give the intellectual
impairment a distinct character? Is subcortical dementia a stable condition
or a transitional state leading eventually to global dementia?
Opinion has ranged from full acceptance of ' subcortical dementia' as a
distinct form of cognitive impairment to scepticism. (6-B)
McHugh(9) has gone further than Albert et aI., (5) suggesting that the
subcortical region subserves functions not only in motor control and
cognitive function but also in the control and display of mood. He
suggests that some syndromes arising from subcortical disease
represent a 'subcortical triad' of symptoms. This combination of
symptoms is most convincingly seen in Huntington's disease. A notable
difference between this concept and that of Albert and his colleagues
is that the pathological disturbance of mood is only
intermittently present, whereas the motor and cognitive changes are
persistent.
Cummings( 1 0 ) has suggested a useful development of the concept of
'subcortical dementia'. He believes that the concept is applicable to disorders
of movement to varying degrees. He suggests that cognitive
impairment in Parkinson's disease takes three forms: a form which is
relatively mild and meets the criteria for subcortical dementia, a more
severe form showing wider impairment of cognitive function but
neuropathologically distinct from senile dementia Alzheimer type
(SDAT), and a severe form which shows neuropathological changes in
both the subcortical region of the brain and in the cortex, the latter of
Alzheimer type. This proposal does not resolve some of the questions
that have arisen over the nature of subcortical dementia, but it does
provide a basis for viewing cognitive changes in Parkinson's disease,
albeit provisional.
Many reports have suggested that global dementia occurs in Parkinson's
disease. Whether such a severe change in cognitive function
can be regarded as an intrinsic feature of this disease, whether it
implies an extension of a neuropathological process more widely in the
brain, or whether it suggests a different neuropathology from the outset
which initially presented with disordered movement is, as yet,
uncertain.
The methodology of studies of
dementia in Parkinson's disease
Research to establish the status of dementia in Parkinson's disease has
confronted a range of methodological issues. (1 1)
A major problem in research on dementia in Parkinson's disease
has been in the diagnosis of Parkinson's disease itself. The original
description of paralysis agitans by Parkinson was, in fact, the identification
of a syndrome rather than of a disease. The part played by such
agents as heavy metals, infection, and vascular disease was recognized
more than 50 years ago. More recently, the importance of druginduced
parkinsonism, where patients generally recover following
withdrawal of the drug, has been recognized, The term Parkinson's
disease had come to be regarded as synonymous with idiopathic Parkinson's
disease and paralysis agitans, and to be a degenerative disease
of unknown cause. In spite of the use of standardized methods of diagnosis,
recent studies have shown that a substantial proportion of
patients diagnosed as suffering from Parkinson's disease in life do not
show the expected findings in the brain postmortem."2.13) In the study
by Hughes et al., (12) 80 per cent of cases were shown to have neuropathological
changes of Parkinson's disease after death and over 20 per
cent were diagnosed as having suffered from progressive supranuclear
palsy, multiple system atrophy, or Alzheimer's disease. Furthermore,
some dementing illnesses may show movement disorder as a clinical
feature, often late in the course of the disease, but further confusing
the issue of diagnosis.
Studies of dementia in Parkinson's
disease
Cases of dementia in Parkinson's disease have been reported for over a
hundred years. Frequently, the relationship between dementia and this
disease in reported cases is impossible to discern.
A number of cross-sectional or prevalence studies of dementia in
Parkinson's disease have been carried out. The frequency of dementia
reported ranges from zero to 81 per cent. In a review of 17 studies
Brown and Marsden found that, overall, 35 per cent of subjects were
regarded as demented." 4) However, if more stringent criteria for
dementia were applied then the proportions demented fell to between
15 and 20 per cent. The authors regarded these figures to be more
realistic, and this level has proved to be in keeping with more recent
cross-sectional studies.
Follow-up studies have great advantages in studying the frequency
of dementia in Parkinson's disease: they allow the diagnosis of Parkinson's
disease to be checked; repeated assessment reduces errors in the
recognition of dementia; the pattern of evolution of dementia may be
followed; the underestimation of dementia by selective loss through
death is avoided; and they reveal the incidence rather than the prevalence
of the condition. The problems of fo llow-up studies include the
difficulties in the choice of those methods of diagnosis and assessment
that will remain appropriate throughout the period of the follow-up.
No prospective controlled study of the incidence of dementia in
Parkinson's disease has been entirely satisfactory in its methodology.
Probably the most satisfactory is that reported by Biggins et aI., (1 5 ) and
subsequently after a longer period of follow-up by Hughes et al. (I 6)
Although this study employed satisfactory methods in most respects,
its greatest weakness was in the selection of-the original samples of
both patients and controls. Biggins et al. (15 ) reported an incidence of
dementia of 19 per cent after 4.5 years observation, or 48 per 1000
person-years of observation. A later report on the same cohorts of subjects
showed an incidence of dementia of 47.8 per cent after 10 years of
observation, or 46.9 cases per 1000 person-years of observation. The
study shows a substantial incidence of dementia in Parkinson's disease
increasing with the passage of the years. The control group showed
cases of cognitive impairment but none amounting to dementia,
thereby demonstrating a substantial excess risk in those subjects with
Parkinson's disease.
Prediction of dementia in Parkinson's
disease
There is a consensus from a number of studies as to which of those
subjects with Parkinson's disease are most likely to suffer from dementia:
older people, patients with Parkinson's disease of longer duration,
subjects who have a greater severity of motor symptoms and signs of
Parkinson's disease, and those who show greater. physical disability.
CIS.16) Some studies have shown that Parkinson's disease in men or
of late onset is more likely to be associated with dementia.cI9) In parkinsonism,
as distinct from Parkinson's disease, the likelihood of
dementia is closely related to the pathological changes that underlie
the symptoms of parkinsonism, which include diseases in which
dementia is a leading feature, such as Alzheimer's disease. The explanation
of an apparent association between the treatment of Parkinson's
disease with levodopa and dementia is probably that successful treatment
of the motor symptoms of Parkinson's disease prolongs life and
thereby increases the risk of dementia.
Neuropathology
The characteristic neuropathological changes of Parkinson's disease
were described before the Second World War. The basic lesion is ~he
degeneration of the pigmented neurone cells in the pars compacta of
the substantia ***** in the brainstem, the presence"ofLewy bodies, and
accompanying gliosis. There is also a degeneration of neurones in the
striatum and globus pallidus, but these changes may be secondary. (20)
Clinical Parkinson's disease does not appear until about 80 per cent of
the' nigro striatal dopaminergic neurones have died. A correlation
between the extent of cell loss in the pars compacta and the severity
"and duration of Parkinson's disease has been demonstrated. Lewy bodies
had come to be regarded as pathognomonic of Parkinson's disease,
but are now known to be present in other diseases (see Chapter
4.1.6).
Although the degenerative changes in the substantia ***** are
known to be closely linked with decreased dopaminergic neurotransmission
in the brain, and that it is this deficiency which leads to
the main motor features of the disease, other neurotransmitters are
also deficient. Some of these deficiencies are of a type that has been
associated with cognitive impairment in other disorders, including a
deficiency in acetylcholinesterase in the cortex, a deficiency of noradrenaline
in the cortex, and a deficiency of serotonin (5-hydroxytryptamine)
in the striatum and cortex. The concentration of a range
of neuropeptides may also be altered.
The neuropathology of cases of Parkinson's disease showing
dementia is inconsistent; some show neuropathological changes
extending to parts of the brain beyond the subcortical region, whereas
in others the changes are similar to those seen in patients with Parkinson's
disease without dementia and with neuropathological changes
restricted to the subcortical region. In some patients with dementia
the neuropathological diagnosis is of Alzheimer's disease or of other .
recognized degenerated conditions of the brainYl) An interesting case
is that of Lewy body disease, which is dealt with in Chapter 4.1.6.
Just as there are difficulties in isolating Parkinson's disease from
other conditions which closely resemble it, there are problems in
understand the interrelationships of dementing disorders. At present,
the aetiology of Parkinson's disease is unknown. Parkinson's disease
shares this situation with a number of 'neurodegenerative' disorders,
including Alzheimer's disease. Several distinct neurodegenerative diseases
share some aetiological factors, which may represent an interaction
between environmental factors and the ageing process but with
differing end results arising from specific factors in the process. (22.23)
Problems in the diagnosis of Parkinson's disease, the shrinking category
of idiopathic Parkinson's disease, and the difficulties encountered
in explaining the occasional development of dementia in this
disease, suggests that the interrelationship between causative agents,
the clinical features of disorders of movement, the occurrence of cognitive
impairment, and the neuropathology of this group of disorders
requires substantial further work before it is understood.
The influence of dementia on mortality
Dementia of any origin is associated with an increased risk of premature
death. A number of studies have shown an increased mortality
in Parkinson's disease to be associated with age, late age of onset of this
disease, cognitive impairment, dementia, and, in some studies, male
sex. Certain medications have been associated with increased mortality.
Many of the studies that have been carried out have been methodologically
faulty, making comparisons between studies and the
identification of the effect of particular factors, including dementia,
problematic. A study, meeting most of the requirements for an accurate
assessment of mortality, showed a hazard ratio for Parkinson's disease
compared with controls of 1.64, in general, and of 1.94 for
Parkinson's disease with dementia.(24) The occurrence of depression
with Parkinson's disease led to increased mortality even more than
dementia, with a hazard ratio of 2.66.
Clinical aspects of Parkinson's disease
with dementia
The recognition of cognitive impairment in patients with Parkinson's
disease has major implications for their management. Although prospective
studies of patients with Parkinson's disease show that the illness
usually follows a course extending over many years, dementia
brings with it important changes in the care a patient will require and
in their life expectancy. These needs will progressively increase and will
place an increasing burden upon the patient's immediate family and
carers. The timing of wills and other legal procedures may be
affected.
The most important step in the recognition of dementia in Parkinson's
disease is to suspect its presence. There are many features of Parkinson's
disease that tend to obscure the appearance of new clinical
features of the disease. The typical blank facial expression seen in Parkinson's
disease may obscure a decline in intellectual activity, slowness
in movement may conceal intellectual slowness, and sadness may suggest
that morbid depression of mood is the reason for a reduction in
liveliness. These clinical features may seem to account for increasing
disability. The clinical picture can usually be clarified by careful examination
of the mental state. Examination of cognitive functions by
more extensive standardized psychological tests may be useful in some
cases.
The clinical importance of dementia in Parkinson's disease is that
there is a marked increase in disability, with problems arising in areas
of functioning not previously affected by motor impairment alone.
The development of drug treatments for dementia makes its recognition
in Parkinson's disease especially important. Dementia may be
accompanied by an increased liability to confusional episodes from the
toxic effects of drugs and other causes.
Management of dementia is similar to that for patients suffering
from other dementing disorders, but with attention to the presence or
a movement disorder.
References
1. Pirozzolo, ET., Hansch, E.C, and Mortimer, T.A. (1982). Dementia in
Parkinson's disease: a neuropsychological analysis. Brain and Cognition.
1,71- 83.
2. Levin, B.E. and Katzen, H.L. (1995). Early cognitive changes and nondementing
behavioural abnormalities in Parkinson's disease. Advances .
Neurology, 65, 85- 95 .
3. Owen, A.M., Tames, M., Leigh, P.N., et al. (1992). Fronto-striatal
cognitive deficits at different stages of Parkinson's disease. Brain, US,
1727-51.
4. Pollack, M. and Hornabrook, R.W. (1966). The prevalence, natural
history and dementia of Parkinson's disease. Brain, 89, 429- 48.
5. A1bert, M.L., Feldman, R.G., and Willis, A.L. (1974). The 'subcortical
dementia' of progressive supra-nuclear palsy. Journal of Neurology,
Neurosurgery and Psychiatry, 37, 121-30.
6. Mayeux, R., Stern, Y, Rosen, J., and Benson, D.F. (1983). Is'subcorti=
dementia' a recognisable clinical entity? Annals of Neurology, 14, 278-S.5
7. Whitehouse, P.T. (1986). The concept of cortical and subcortical
dementia: another look. Annals of Neurology, 19, 1-6.
8. Brown, R.G. and Marsden, CD. (1988). Subcortical dementia: the
neuropsychological evidence. Neuroscience, 25, 363-87.
9. McHugh, P.R. (1990) . The basal ganglia: the region, the integration oi
its systems and implications for psychiatry and neurology. In Function
and dysfunction in the basal ganglia (ed. A.J. Franks, J.W. Ironside,
R.H.S. Mindham, RJ Smith, E.G.S. Spokes, and W. Winlow), pp.
259-69. Manchester University Press.
10. Cummings, J.L. (1988). The dementia of Parkinson's disease: preval=
characteristics, neurobiology, and comparison with dementia of the
A1zheimer type. European Neurology, 28, 15-23.
11 . Mindham, R.H.S. The place of dementia in Parkinson's disease: a
methodological saga. Advances in Neurology, in press.
12. Hughes, A.J., Daniel, S.E., Kilford, L., and Lees, A.T. (1992). Accuracy
diagnosis of idiopathic Parkinson's disease: a c1inico-pathological s
of 100 cases. Journal of Neurology, Neurosurgery and Psychiatry, 55 ,
181-4.
428 4 CLIN ICAL SYNDROMES OF ADULT PSYCHIATRY
Vascular dementia
Introduction
Vascular dementia is the second most frequent cause of dementia.(1,2)
Because vascular causes of cognitive impairment are common, may be
preventable, and the patients could benefit from therapy, early detection
and accurate diagnosis of vascular dementia is desirable. (3)
Vascular dementia is not only multi-infarct dementia, but is related
to other vascular mechanisms and pathological changes in the
brain, and has other causes and clinical manifestations. Vascular
dementia is not a disease, but a syndrome. The origin of of this syndrome
reflects complex interactions between vascular aetiologies
(cerebrovascular disorders and vascular risk factors), changes in the
4.1.9 VASCULAR DEMENTIA
brain (infarcts, white-matter lesions, atrophy), host factors (age, education),
and cognition.(4-B)
Conceptual issues related to of vascular dementia include the definition
of the cognitive syndrome (type, extent, and combination of
impairments in different cognitive domains), and the vascular causes
(vascular aetiologies and changes in the brain). Variations in these definitions
has led to different estimates of point prevalence, to different
groups of patients', and to reports of different types and distribution of
brain lesions. (9-1l) The cognitive syndrome of vascular dementia is
characterized by predominate executive dysfunction rather than deficits
in memory and language function. (l2) Although the course of cognitive
decline may be stepwise, it is often slowly progressive, and may
include periods of stability or even some improvement.
The relationship between vascular lesions in the brain and cognitive
impairment is important, but which type, extent, side, site, and
tempo of vascular lesions in the brain relates to different types of vascular
dementia is not established in detail. (4-6,13)
Current criteria for vascular dementia are based on the concept of
cerebral infarcts, For example the widely used NINDS-AIREN criteria
include dementia, cerebrovascular disease, and a relationship between
these two disorders. The main tools for the diagnosis include detailed
history, neurological examination, mental state examination, relevant
laboratory examinations, and preferably magnetic resonance imaging
of the brain.
Vascular dementia research, until recently overshadowed by that
into Alzheimer's disease, is now developing rapidly. There is great
promise for intervention. Developments in classification, diagnosis,
and treatment are likely.
Aetiology and pathophysiology
Aetiology
The main causes of vascular dementia are cerebrovascular disorders
and their risk factors. The prevalent cerebrovascular disorders include
large artery disease (artery-to-artery embolism, occlusion of an extraor
intracranial artery), cardiac embolic events, small vessel disease
(lacunar infarcts, ischaemic white-matter lesions) and haemodynamic
mechanisms. (13-15) Less frequent causes include specific arteriopathies,
haemorrhage (intracranial haemorrhage, subarachnoidal haemorrhage),
haematological factors, venous disease, and hereditary disorders.
There may be as yet undiscovered causes.
In most patients diagnosed with vascular dementia, several aetiological
factors are involved. However, the roles these factors play have
not been identified in detail, and it is not certain which of these mech.
anisms distinguish vascular dementia from cerebrovascular disease
without dementia. (4.5.7.16, 17)
Risk factors for vascular dementia can be divided into vascular factors
(e.g. arterial hypertension, atrial fibrillation, myocardial infarction,
coronary heart disease, diabetes, generalized atherosclerosis, lipid
abnormalities, smoking), demographic factors (e.g age, education),
genetic factors (e.g. family history, individual genetic features), and
stroke-related factors (e.g. type of cerebrovascular disease, site and size
of stroke),os.19) Hypoxic ischaemic events (cardiac arrhythmias, ~on gestive
heart failure, myocardial infarction, seizures, pneumonia) may
be an important risk factor for incident dementia in patients, with
stroke. (20)
Changes in the brain
Vascular dementia is related to both ischaemic and non-ischaemic
changes in the brain.(4.5.13,14) The ischaemic lesions include arterial territorial
infarct, distal field (watershed) infarct, lacunar infarct, ischaemic
white-matter lesions, and incomplete ischaemic injury.
Incomplete ischaemic injury incorporates laminar necrosis, focal gliosis,
granular atrophy, and incomplete white-matter infarction.(21,22) In
addition, both focal (around the ischaemic lesion) and remote (disconnection,
diaschisis) functional ischaemic changes relate to vascular
dementia, and the volume of functionally inactive tissue exceeds that
of focal ischaemic lesions in vascular dementia. (23) Limitation in current
clinical methods have hampered the detection of both incomplete
ischaemic injury and functional ischaemic changes related to vascular
dementia. Atrophy -is thenon-ischaemic factor related to vascular
dementia. However, there are no methods to distinguish between
ischaemic and degenerative causes of atrophy.
Brain imaging findings
Work on the relationship between brain lesions and cognition in vascular
dementia has used varying definitions and measures of cognitive
impairment, varying techniques to reveal brain changes, and varying
criteria for the selection of patients.(17)
CT and magnetic resonance imaging (MRI) studies on vascular
dementia have shown that bilateral ischaemic lesions are important.
( ,5,7,17) Some studies emphasize deep infarcts in the frontal and
limbic areas, while others report cortical lesions especially in the temporal
and parietal areas. There is disagreement about the number and
volume of the infarcts, as well as the extent and location of atrophy.
Diffuse and extensive white-matter lesions have been suggested as an
important factor leading to functional disconnection of cortical brain
areas. Some general conclusions on brain lesions in vascular dementia
may be drawn,
1. There is no single pathological feature, but a combination of
infarcts, ischaemic white-matter lesions of varying size and type,
and atrophy of varying degree and site.
2, Infarcts associated with vascular dementia tend to be bilateral,
multiple (more than two), and located in the dominant hemisphere
and in the limbic structures (frontolimbic or prefrontalsubcortical
and medial-limbic or medial-hippocampal circuits).
3, White-matter lesions on CT or magnetic resonance imaging
(MRI) associated with vascular dementia are extensive, extending
in periventricular white matter, and confluent to extending in the
deep white matter.
4. It is doubtful whether a single small lesion on imaging can be
accepted as evidence for vascular dementia.
5. Absence of cerebrovascular lesions on CT or MRI is contrary to a
diagnosis of vascular dementia.
Pathophysiology
To what extent pathological changes in the brain cause, compound, or
only coexist with the vascular dementia syndrome is still not known
precisely. The vascular changes in the brain can be the main cause of
cognitive impairment (as assumed in vascular dementia(24,25)), they
can contribute to the clinical picture of other dementia syndromes
including Alzheimer's disease, (7,26) or they may be coincidental.
It is not certain which are the critical changes in the brain leading
to the clinical picture of vascular dementia. the syndrome has been
related to the volume of brain infarcts (with a critical threshold), the
number of infarcts, the site of infarcts (bilateral, in strategic cortical or
subcortical, or affecting white matter), to other ischaemic factors
(incomplete ischaemic injury, delayed neuronai death, functional
changes), to the atrophic changes (origin, location, extent), and finally
to the additive effects of other pathologies (Alzheimer's disease, Lewy
body dementia, frontal lobe dementias). But it is uncertain which type,
extent, side, site, and tempo of vascular lesions in the brain, and which
combination with other pathologies, relate to vascular dementia.
Classification and clinical criteria
Classification
Vascular dementia has been divided into subtypes on the basis of clinical,
radiological, and neuropathological features. It is uncertain
whether these subtypes are distinct disorders, with separate pathological
and clinical features, and responses to therapy. (27) If homogenous
subtypes could be identified the comparability of research studies
would be greater and multicentre studies easier. (28)
The subtypes of vascular dementia included in most classifications
include multi-infarct dementia (cortical lesions), small-vessel dementia
(subcortical deep lesions), and strategic infarct dementia.
(12,14,27.29-32) Many include also hypoperfusion dementia.<' 2. '4,30,33)
Further suggested subtypes include haemorrhagic dementia, hereditary
vascular dementia, and combined or mixed dementia (Alzheimer's
disease with cerebrovascular disease).
DSM-IV(34) does not specify subtypes. ICD-1Q(35) includes six subtypes
(acute onset, multi-infarct, subcortical, mixed cortical and subcortical,
other, and unspecified). The NINDS-AlREN criteria(3O)
include, without detailed description, cortical vascular dementia, subcortical
vascular dementia, Binswanger's disease, and thalamic
dementia.
Main subtypes
Multi-infarct dementia or cortical vascular dementia, and small-vessel
dementia or subcortical vascular dementia are the two common subtypes,
although their frequencies vary in different series(I2,14,31 )
Cortical vascular dementia relates to large-vessel disease, cardiac
embolic events, and hypoperfusion. InfaJ;CJ;s are. predominantly in the
cortical and corticosubcortical arterial territories, and their distal
fields (watershed). Typical clinical features are lateralized sensimotor
changes and the abrupt onset of cognitive impairment and aphas ia. (31 )
A combination of different cortical neuropsychological syndromes has
been suggested to occur in cortical vascular dementia.(36)
Subcortical vascular dementia, or small-vessel dementia, incorporates
the entities 'lacunar state' and 'Binswanger's disease'. It relates to
small-vessel disease and hypoperfusion, with predominately lacunar
infarcts, focal and diffuse ischaemic white-matter lesions, and incomplete
ischaemic injury. (31,36.37) Clinically, small-vessel dementia is characterized
by pure motor hemiparesis, bulbar signs, dysarthria,
depression, and emotionallability, and especially deficits in executive
functioning. (36-39)
Table 1 The DSM-IV definition of vascular dementia
Focal neurological signs and symptoms (e.g. exaggeration of deep tendon
reflexes, extensor plantar response, pseudobulbar palsy, gait
abnormalities, weakness of an extremity, etc.)
or
Laboratory evidence of focal neurological damage (e.g. multiple
infarctions involving cortex and underlying white matter)
The cognitive deficits cause significant impairment in social or
occupational functioning and represent a significant decline from a
previously higher level of functioning
The focal neurological signs, symptoms, and laboratory evidence are
judged to be aetiologically related to the disturbance
The deficits do not occur exclusively during the course of delirium
Course characterized by sustained periods of clinical stability punctuated
by sudden significant cognitive and functional losses
Clinical criteria
Since the 1970s several clinical criteria for vascular dementia have been
published.(l,,40,4I) The most widely used include those in DSM-IV, (34)
ICD-10,(35) and NINDS-AIREN. (30)
The two cardinal elements of any clinical criteria for vascular
dementia are the definition of the cognitive syndrome(42) and the definition
of the cause.(l1,41,43) All clinical criteria are consensus criteria,
derived neither from prospective community-based studies on vascular
factors affecting the cognition, nor on detailed natural histories.
(28,30,40.4 1,44) All these criteria are based on the concept of ischaemic
infarcts. They are designed to have high specificity, but have been
poorly validated.(4o,44) An important consequence of the different definitions
of the dementia syndrome,(9,42) and the vascular cause,(l O,ll ) is
that the different diagnostic criteria identify different populations.
The DSM-IV definition of vascular dementia (Table 1) requires
focal neurological signs and symptoms or laboratory evidence of focal
neurological damage clinically judged to be related to the disturbance.(
34) The course is specified by sudden cognitive and functional
losses. The DSM-IV criteria do not detail brain imaging requirements.
The DSM -IV definition of vascular dementia is reasonably broad and
lacks detailed clinical and radiological guidelines,
The ICD-IQ criteria(35) (Table 2) require unequal distribution of
cognitive deficits, focal signs as evidence of focal brain damage, and
significant cerebrovascular disease judged to be aetiologically related
to the dementia. The criteria do not detail brain imaging requirements.
The ICD-10 criteria specify six subtypes of vascular dementia
(Table 3). The ICD- lO criteria for vascular dementia have been shown
to be highly selective and only some of those fulfilling the general criteria
for ICD-lO vascular dementia can be classified into one of the
subtypes.(1l ,43) The shortcoming of these criteria include lack of
detailed guidelines (e.g. of unequal cognitive deficits and changes on
neuroimaging), lack of aetiological criteria, and heterogeneity

The NINDS-AIREN research criteria for vascular dementia(30)
include a dementia syndrome, cerebrovascular disease, and a relationship
between these (Table 4), Cerebrovascular disease is defined by the
presence of focal neurological lesions and brain imaging evidence of
ischaemic changes in the brain. A relationship between dementia and
Table 2 The ICD-1 0 criteria for vascular dementia
Unequal distribution of deficits in higher cognitive functions with some
affected and others relatively spared. Thus, memory may be quite
marked ly affected while thinking, reasoning, and information
processing may show only mild decline
There is evidence for focal brain damage, manifest as at least one of the
following: unilateral ******* weakness of the limbs, unilaterally
increased tendon reflexes, an extensor plantar response,
pseudobulbar palsy
There is evidence from the history, examination, or test of significant
cerebrovascular disease, which may reasonably be judged to be
aetiologically related to the dementia (histo ry of stroke, evidence of
cerebral infarction)
cerebrovascular disorder is inferred from the onset of dementia within
3 months following a recognized stroke, or on abrupt deterioration in
cognitive functions, or fluctuating stepwise progression of cognitive
deficits. The criteria include a list of features consistent with the diagnosis,
as well as a list of features that make the diagnosis uncertain or
unlikely. Also, different levels of certainty of the clinical diagnosis
(probable, possible, defin ite) are included. The NINDS-AIREN criteria
recognize h eterogeneity('I5) of the syndrome and variability of the
clinical course in vascular dementia, and highlight detection of ischaemic
lesions and a relationship between lesion and cognition, as well as
stroke and dementia onset.
Table 3 Characteristics of the vascular dementia subtypes in
ICD-10
Acute onset (F01.0)
The dementia develops rapidly (i.e. usually within 1 month but within no
longer than 3 months) after a succession of strokes, or (rarely) after a
single large infarction
Multi-infarct (F01 .1 )
The onset of the dementia is more gradual (i.e. within 3-6 months)
following a number of minor ischaemic episodes. Comments: it is
presumed that there is an accumulation of infarcts i ~ the cerebral
parenchyma. Between the ischaemic episodes there may be periods of
actual clinical improvement
Subcortical (F01.2)
A history of hypertension, and evidence from clinical examination and
special investigations of vascular disease located in the deep white
matter of the cerebral hemispheres, with preservation of the cerebral
cortex.
Mixed cortical and subcortical (F01.3)
Mixed cortical and subcortical components of vascular dementia may be
suspected from the clinical features, the results of investigation, or
both
Other (F01.8)
Unspecified (F01.9)
In the ICD-10 criteria no specific diagnostic guidelines are given for these
two vascular dementia sybtypes
Table 4 The NINDS-AIREN criteria for probable vascular dementia
The criteria for the clinical diagnosis of PROBABLE vascular dementia
include all of the following
1. Dementia
2. Cerebrovascular disease, defined by the presence of focal signs on
neurological examination, such as hemiparesis, lower facial
weakness, Babinski sign, sensory deficit, hemianopia, dysarthria, etc.
consistent with stroke (with or without history of stroke), and
evidence of relevant CVD by brain imaging (CT or MRI) including
multiple large-vessel strokes or a single strategically placed infarct
(angu lar gyrus, thalamus, basal forebrain , PCA or ACA territories),
as well as m ~ li:iple ba';al ganglia and white-matter lacunes or
extensive periventricular white-matter lesions, or combinations
thereof
3. A relationship between the above two disorders, manifested or inferred by
the presence of one or more of the following
(a) Onset of dementia within 3 months following a recognized
stroke
(b) Abrupt deterioration in cognitive functions, or fluctuating
stepwise progression of cognitive deficits
11. Clinical features consistent with the diagnosis of PROBABLE vascular
dementia include the following
(a) Early presence of a gait disturbance (small-step gait or marche cl
petits-pas, apraxic-ataxic or parkinsonian gait)
(b) History of unsteadiness and frequent unprovoked falls
(c) Early uri nary frequency, urgency, and other uri nary symptoms
not explained by urological disease
(d) Personality and mood changes, abulia, depression, emotional
incontinence, other subcortical deficits including psychomotor
******ation and abnormal executive funct ion
Ill. Features that make the diagnosis of vascular dementia uncertain or
unlikely include the following
(a) Early onset of memory deficit and progressive worsening of
memory and other cognitive functions such as language
(transcortical sensory aphasia), motor skills (apraxia), and
perception (agnosia), in the absence of corresponding focal
lesions on brain imaging
(b) Absence of focal neurological signs, other than cognitive
di sturbance
(c) Absence of cerebrovascular lesions on brain CT or MRI
CVD. cerebrovascular disease; PCA. posterior cerebral" artery; ACA. anterior cerebral
artery.
The NINDS-AlREN criteria are currently most widely used in clinical
drug trials on vascular dementia. In a neuropathological series,
sensitivity of the NINDS-AlREN criteria was 58 per cent and specificity
80 per cent.(47) The criteria successfully excluded Alzheimer's disease
in 91 per cent of cases, and the proportion of combined cases
misclassified as probable vascular dementia was 29 per cent. (47) The
inter-rater reliability of the NINDS-AIREN criteria is moderate to substantial
(K = 0.46-0.72 ). (48)
These three sets of criteria for vascular dementia are not interchangeable;
they identify different numbers and clusters of patients.
The DSM-IV criteria are less restrictive than the IeD-lO and NINDSAlREN
criteria. ( 1 1.46)
431
432 4 CLINICAL SYNDROMES OF ADULT PSYCHIATRY
CLinical features
Cognitive syndrome
The cognitive syndrome of vascular dementia is characterized by
memory deficit, dysexecutive syndrome, slowed information processing,
and mood and personality changes. These features are found especially
among patients with subcortical lesions. Patients with cortical
lesions often have additional cortical neuropsychological syndromes.
(36)
The memory deficit in vascular dementia is often less severe than in
Alzheimer's disease. It is characterized by impaired recall, relatively
intact recognition, and more benefit from cues.(49) The dysexecutive'
syndrome in vascular dementia includes impairment in goal formulation,
initiation, planning, organizing, sequencing, executing, setsifting
and set-maintenance, as well as in abstractingY2,36,49) The
dysexecutive syndrome in vascular dementia relates to lesions affecting
the prefrontal subcortical circuit including prefrontal cortex, caudate,
pallidum, thalamus, and the thalamocortical circuit (capsular genu,
anterior capsule, anterior centrum semiovale, and anterior corona
radiata) .(50) Typically, personality and insight are relatively preserved
in mild and moderate cases of vascular dementia,
Features that make the diagnosis of vascular dementia disease
uncertain or unlikely include early and progressive worsening of memory,
and other cognitive cortical deficits in the absence of corresponding
focal lesions on brain imaging.(30)
Neurological findings
Frequent neurological findings indicating focal brain lesion early in
the course of vascular dementia include mild motor or sensory deficits,
decreased co-ordination, brisk tendon reflexes, Babinski 's sign,
visual field loss, bulbar signs including dysarthria and dysphagia,
extrapyramidal signs (mainly rigidity and akinesia ), disordered gait
(hemiplegic, apraxic-ataxic, or small-stepped), unsteadiness, unprovoked
falls, and urinary frequency and urgency.(30,3 l,37-39) Features that
make the diagnosis of vascular dementia uncertain or unlikely include
absence of focal neurological signs, other than cognitive disturbance.
C30)
In cortical vascular dementia, typical clinical features are lateralized
sensorimotor changes and abrupt onset of cognitive impairment and
aphasia, and in subcortical vascular dementia disease pure motor
hemiparesis, bulbar signs, and dysarthria. c3l)
Behavioural and psychological symptoms of
dementia
Depression, anxiety, emotional lability and incontinence, and other
psychiatric symptoms are frequent in vascular dementia. Depression,
abulia, emotional incontinence, and psychomotor ******ation are
especially frequent in subcortical vascular dementia diseaseY2,36)
Ischaemic scores
Cardinal features of vascular dementia disease are incorporated in the
Hachinski Ischaemia Score(5l) (Table 5). In a recent neuropathological
series, stepwise deterioration (odds ratio, 6.0), fluctuating course
(odds ratio, 7.6), history of hypertension (odds ratio, 4.3), history of
stroke (odds ratio, 4.3), and focal neurological symptoms (odds ratio,
Table 5 Hachinski Ischaemia Score
Item
Abrupt onset
Stepwise deterioration
Fluctuating course
Nocturnal confusion
Relative preservation of personality
Depression
Somatic complaints
Emotional incontinence
Histo ry of hypertension
History of strokes
Evidence of associated
atherosclerosis
Focal neurological symptoms
Focal neurological signs
Score value
2
2
2
1
2
2
4.4) differentiated patients with definite vascular dementia from those
with definite Alzheimer's disease. (52) Nocturnal confusion and depression
did not discriminate. However, the ischaemia score was unable to
differentiate the Alzheimer's disease patients with cerebrovascular disease
from those with vascular dementia.
Course and prognosis
Traditionally, vascular dementia has been characterized by a relative
abrupt onset (days to weeks), a stepwise deterioration (some recove ~after
worsening), and fluctuating course (e.g, differences between
days) of cognitive functions. These features are seen in patients with
repeated lesions affecting cortical and corticosubcortical brain structures,
i,e.large-vessel multi-infarct vascular dementia, and with watershed
infarcts related to haemodynamic problems. However, in patient5
with small-vessel dementia, i.e. subcortical vascular dementia, the
onset is more insidious and course more slowly progressive. (28,30,37,53
The mean duration of vascular dementia is around 5 years, (2) In
most studies survival is less than for the general population or those
with Alzheimer's disease.(54,55) Surprisingly little is known about the
rate and pattern of cognitive decline, either overall or among differem
subgroups of vascular dementia. (56) This underlines the lack of studies
detailing the natural history of vascular dementia.
Diagnosis and differential diagnosis
The clinical evaluation of patients with memory impairment has two
stages, the symptomatic diagnosis, i.e. evaluation of the type and
extent of cognitive impairment, and the aetiological diagnosis, i.t!.
evaluation of vascular cause(s) and related factors. The symptomatic
categorie s other than dementia include delirium, circumscribed
neuropsychological syndromes (e.g. aphasia) and functional psychiatric
disorders (e.g, depression). (44) Stages of aetiological diagno 'include
diagnosis of the specific causes, especially the potentially treatable
conditions, evaluation of secondary factors able to affect the cognitive
functioning, and more detailed differentiation between specific
4.1.9 VASCULAR DEMENTIA
causes, especially that between vascular dementia disease and Alzheimer's
disease.
Clinical evaluation
The cornerstone in the evaluation of a patient with suspected vascular
dementia is detailed clinical and neurological history and examination,
including interview of a close informant. Assessment of social
functions, activities of daily living, as well as psychiatric and behavioural
symptoms, is part of the basic evaluation. These patients are
challenging and enough time should be allocated time for the consultation,
often 40 to 60 min.
Mental status examination
Bedside mental status examination includes the Mini-Mental State
Examination. (S7) However, this has limitations as it emphasizes language,
does not include timed elements and the recognition portion of
the memory tests, is insensitive to mild deficits, and is influenced by
education and age. Other proposed screening instruments for vascular
dementia include a ten-word memory test with delayed recall, cube
drawing test for copy, verbal fluency test (number of animals named in
1 min), Luria's alternating hand sequence, or finger rings and letter
cancellation test (neglect).(30)
Frequently a more detailed neuropsychological test is needed. It
s!wuld cover the main cognitive domains including memory functions
- and long-term memory), abstract thinking, judgement, aphas-
-,,-raxia, agnosia, orientation, attention, executive functions, and
speed of information processing( 42,58)
Brain imaging
Brain imaging should be performed at least once during the initial
diagnostic workout. MRI is preferred because it has high sensitivity
and the ability to demonstrate medial temporal lobe and basal
forebrain areas. Depending on the criteria of vascular dementia used,
focal brain infarcts have been revealed in 70 to 100 per cent, and
more extensive white-matter lesions in 70 to 100 per cent of
cases. (13,25,30,59.60)
Single-photon emission CT and positron-emission tomography
may reveal patchy reduction of regional blood flow and metabolism, as
well as decreased white-matter flow and metabolism. (61)
Other investigations
Chest X-ray, elelectrocardiography, and screening laboratory tests are
part of the basic evaluation.(IS,62,63) In selected cases extended laboratory
investigations, analysis of the cerebrospinal fluid, and EEG are
performed, as well as examinations ofthe extra- and intracranial arteries
and detailed cardiological investigations, (1 5,62,63)
In vascular dementia EEG is more often normal than in Alzheimer's
disease, and if abnormal more frequently suggests a focal abnormality.
Abnormalities increase with more severe intellectual decline
both in vascular dementia disease and Alzheimer's disease,(53)
At present there is no specific laboratory test for vascular dementia.
Tests may reveal risk factors and concomitant disorders such as hyperlipidaemia,
diabetes, and cardiac abnormality. (53) Apolipoprotein E4 is
a established risk factor for Alzheimer's disease, but its relationship to
vascular dementia has not been consistent.(64) Determination of apolipoprotein
E status is currently not part of clinical evaluation in vascular
dementia.
Differential diagnosis of vascular dementia
disease
Alzheimer's disease
Typical Alzheimer's disease is characterized by insidious onset and
slowly progressive intellectual deterioration, absence of symptoms and
signs indicating focal brain damage, and absence of any other specific
disease affecting ~ brain.(6S) Alzheimer's disease has typical clinical
stages ranging from early changes to profound dementia, (66,67)
When patients with vascular dementia have a clinical history,
neurological examination, and brain imaging findings compatible
with ischaemic changes of the brain, the differentiation from Alzheimer's
disease can be made clinically. (25)
Diagnostic problems arise when Alzheimer's disease is combined
with cerebrovascular disease, Difficult clinical problems include stroke
unmasking Alzheimer's disease in patients with post-stroke dementia,
insidious onset, and/or slow progressive course in vascular dementia
patients, and cases where it is difficult to assess the role of white-matter
lesions or of infarcts found on neuroimaging. This clinical challenge
may be solved when a sensitive and specific ante-mortem marker for
Alzheimer's disease is available. The distinction would be less difficult
if there were more detailed knowledge of the sites, type, and extent of
ischaemic brain changes critical for vascular dementia, and the extent
and type of medial temporal lobe atrophy critical for Alzheimer's disease.
Other important conditions to be diffentiated from vascular
dementia include normal pressure hydrocephalus, (68) white-matter
lesions and dementia,(I 7,30) fro ntal lobe tumours and other intracranial
masses, (15) Lewy body dementia, (69) frontotemporal dementia,(7O)
Parklnsons's disease and dementia,<71) progressive supranuclear
palsy, (72) and multisystem atrophy.(73)
Epidemiology
Vascular dementia is the second most common cause of dementia
accounting for 10 to 50 per cent of cases, depending on the geographic
location, patient population, and clinical methods used. (1,2) The
prevalence of vascular dementia is from 1.2 to 4.2 per cent of persons
aged 65 years and older, and the incidence is 6 to 12 cases per 1000
persons aged over 70 years per year.(2) The prevalence and the incidence
of vascular dementia disease increases with increasing age, and
men seem to have a higher prevalence of vascular dementia than
women. Epidemiology of vascular dementia has been affected by variations
in the definition of the disorder, the clinical criteria used, and
the clinical methods applied,(18,74,75)
The frequency of vascular dementia disease has been higher than
previously reported in recent series comprising older subjects, (IO)
Stroke and cerebrovascular disorders relate also to a high risk of cognitive
impairment and dementia. (24,76) Finally, vascular factors such as
stroke and white-matter lesions have a clinical effect on Alzheimer's
disease. (26) Thus, vascular factors may even be the leading cause of
cognitive impairment worldwide.(77)
433
/
434 4 CLIN ICAL SYNDROMES OF ADULT PSYCHIATRY
Treatment
The objectives of targeted treatment of vascular dementia include
symptomatic improvement of core symptoms (e.g. cognitive, behavioural),
slowing progression of the disorder, and treatment of secondary
factors affecting cognition (e.g. depression, anxiety, agitation).
A number of drugs have been studied in the symptomatic treatment
of vascular dementia including cerebro- and vasoactive drugs,
nootropics, and some calcium antagonists, but largely these studies
have shown negative results. (78) Studies on symptomatic improvement
in vascular dementia have mostly had small numbers, short treatment
periods, variations in diagnostic criteria and tools, mixed populations,
and have had variation in clinical endpoints applied.
Recently nimodipine,(79) memantine,(80) and propentofylline(81 )
have raised expectations for a symptomatic treatment of vascular
dementia. A number of phase 3 double-blind randomized placebocontrolled
trials in patients with vascular dementia using these compounds
are in progress. ( 82 )
Possibilities for prevention
For primary prevention the target is the brain at risk of cerebrovascular
disease and cognitive impairment. The methods relate to the treatment
of putative risk factors of vascular dementia, and the promotion
of potential protective factors. Risk factors include those related to
cerebrovascular disorders and stroke, to vascular dementia, to poststroke
dementia, to white-matter lesions, and to cognitive impairment
or dementia, and also those related to Alzheimer's disease. (S) The vascular
risk factors include arterial hypertension, atrial fibrillation, myocardial
infarction, coronary heart disease, diabetes, generalized
atherosclerosis, lipid abnormalities, and smoking. The demographic
factors include age and education. One putative protective factor is
oestrogen. (83)
Knowledge of effects of primary prevention on these risk factors in
populations free of cognitive impairment is still scant. (8,84 ) In a European
study, treatment of mild systolic hypertension decreased the incidence
of dementia,(SS) Positive effects in primary prevention of stroke
support the idea 'that action on vascular risk factors could reduce the
numbers of patients with vascular dementia.
For secondary prevention the target is the brain already affected by
cerebrovascular disease and at risk of vascular dementia. Actions
include diagnosis and treatment of acute stroke in order to limit the
extent of ischaemic brain changes, prevention of recurrence of stroke,
and treatment of risk factors. Treatment is guided by the aetiology of
cerebrovascular disorder such as large artery disease (e.g. aspirin,
dipyridamole, carotid endarterectomy), Gardiac. embolic events (e.g.
anticoagulation, aspirin), small-vessel disease (e.g. antiplatelet therapy),
and h aemodynamic mechanisms (e.g. control of hypotension
and cardiac arrhythmias) (15.29,44) Hypoxic ischaemic events (cardiac
arrhythmias, congestive heart failure, myocardial infarction, seizures,
pneumonia) are an important risk factor for incident dementia in
patients with stroke and should be taken into account in the secondary
prevention of vascular dementia.(20)
Detailed knowledge of the effects of secondary prevention of vascular
dementia is lacking, In a small series of patients with established
vascular dementia, control of high arterial blood pressure,(86) cessation
of smoking, (86) and use of aspirin(S?) improved or stabilized cognition,
It has been suggested that lowering of plasma viscosity could also have
an effect in vascular dementia. (88) The absence of progressive cognitive
decline in patients receiving placebo in treatment trials of vascular
dementia may also reflect an effect of intensified risk factor control.
(SI)
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