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 economic problems. Although lifespan itself has remained static, the 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.
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(1) 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 noncognitive 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 molecular 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 have three phases—discovery, neuropathology, and molecular 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 medicalcare 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 AD 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 acquired cognitive decline in multiple areas resulting in functional impairment; AD is one cause of dementia and the core clinical symptom of AD is cognitive loss. However, as noted above, AD is clinically heterogeneous and includes diverse noncognitive symptoms. Cognitive decline is manifested as amnesia, aphasia, agnosia, and apraxia (the 4As).
(a) 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 of remote memory is assumed to be preserved for longer because of rehearsal over life.
(b) Aphasia
Language problems are found in many patients at presentation, although the language deficits in AD are not as severe as those of the fronto-temporal 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.
(c) 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.
(d) 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 impairment
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.
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
(a) 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 reasons. However, psychomotor retardation, 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.(8,9,10,11,12) 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 depression.(13) Elation, 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.(10)
(b) Psychosis
Psychotic symptoms occur in many patients, although, as with depression, there is an inherent difficulty in determining the presence of delusions or hallucinatory experiences in the moderately to severely demented. In community-based surveys, between 20 and 70 per cent are reported to suffer from some form of psychotic symptom with delusions being more common than hallucinations.(11,17,18) 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 delusions— the median of one series of studies being 28 per cent.(19) Visual hallucinations are reported more commonly than auditory ones, and other modalities are rare. 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. 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. Capgras’ 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.(20) 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 reported.(21,22,23) 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 dementia.
(c) 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 body 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.
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 body 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.
(d) Other behavioural manifestations
Behavioural complications in AD have become a target of therapy. However, the term encompasses a wide range 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 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 frequently disturbed, with many patients exhibiting altered sleep-wake cycles and others experiencing increased confusion towards evening (‘sundowning’). A central defect in the regulation of circadian rhythms underlying these phenomena is postulated.(27) Excessive or inappropriate vocalizations (grunting and screaming) occur in the late stages.
Classification
Alzheimer’s disease is classified, as with all other disorders, by DSM-IV and by ICD-10. In addition, it also has a specialized classification system resulting from the National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDS-ADRDA).(28) This clinical diagnostic system is internationally accepted and widely observed. There are also classification systems for neuropathological diagnosis, most notably the Consortium to Establish a Registry for AD (CERAD) criteria.(29)
DSM-IV stipulates that a dementia syndrome is characterized by deterioration in multiple cognitive deficits, including amnesia, resulting in functional impairment. A gradual onset and decline in the absence of other conditions sufficient to cause dementia indicates AD. ICD-10 shares with DSM-IV the definition of a dementia syndrome and notes that an 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.(28) 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 neuropathological lesions of AD also occur in normal ageing.(30) Probable AD, according to NINCDS-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 post-mortem 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 highpositive predicative value. Kukull et al.(31) found the specificity of DSM-III to be higher than NINCDS-ADRDA (0.8 versus 0.65), but NINCDS-ADRDA had a higher sensitivity (0.92 versus 0.76), Mok et al. find broadly similar findings for both primary care physicians and for neurologists;(32) some others find an even lower specificity.(33)
Diagnosis
Alzheimer’s disease is the most common of the dementias, occurring 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 post-mortem represent a biased sample and in the community a large proportion (up to a third) of non-demented individuals have pathological signs of AD such as neuritic plaques.(30) Second, even at post-mortem the distinction between different dementias 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. Thirdly, even the gold-standard of neuropathological diagnosis is not infallible. Neuropathologists show a very high degree of inter-rater agreement on the diagnosis of probable AD and Dementia with Lewy Bodies (DLB) but a rather lower rate of agreement when there is vascular damage, when the diagnosis is of fronto-temporal dementia (FTD) and on the more equivocal cases of AD.(34)
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 and progression. In the research context, a family history interview conducted by telephone provides a degree of accuracy compatible with a full clinical assessment.(35) Detailed semi-structured family informant diagnostic schedules are available, such as Cambridge Mental Disorders of the Elderly Examination (CAMDEX).(36) 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.
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;(37) 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. FTD) 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 assessment. 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. Key to an assessment of function is a careful informant history seeking to establish where there has been a functional decline and remembering that instrumental ADLs are lost before basic activities. Instrumental ADLs are highly individual and require careful interviewing to assess—one patient may have a modest decline in their ability to use information technology whilst another may have trouble using all the appropriate settings on the central heating. 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. Scales used in research that can also be usefully employed in the clinic include the Bristol ADL Scale(38) and the Disability Assessment for Dementia.(39)
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