- Email: [email protected]
Dementia: current developments
Biomed & Pharmacother 1997;51 : 112-117 © Elsevier, Paris
Dossier "Dementia"
Dementia: current developments R Eastwood Health Science Center, School c~f Medicine, Saint Louis University,
1221 South Grand Blvd, Saint Louis, MO 63104, USA
Summary - This is a short review of the current developments taking place in the field of the dementias. This branch of medicine is growing apace with IYesh research findings being published continually in respect to etiology, risk and protective factors, clinical typology and treatment effects. At the same time we know remarkably little about the natural history of cognitive decline and in effect, normal aging. There is clearly a vital need for longitudinal studies. Also, new hypotheses are needed to explain the critical memory defect in dementia. In fact, better treatment of the memory defect, and the associeted behavorial problems found in dementia is urgently needed and even demended by an increasingly more sophisticated public. INTRODUCTION Dementia was ascribed its present meaning in the 19th century based upon anatomy, pathology and clinical features. It was established that the key aspects of the condition were memory loss and intellectual impairment. Other psychopathology was epiphenomena [1]. However, both of these features were described by Alzheimer in his paper in 1907.
Patient study The first noticeable symptom of illness shown by this 51-year-old woman was suspiciousness of her husband. Soon, a rapidly increasing memory impairment became evident. She could no longer orientate herself in her own dwelling, dragged objects here and there and hid them, and, at times, believing that people were out to murder her, started to scream loudly. Sometimes, she would greet the doctor as if he were a stranger and made excuses for herself that she had not finished her work; on other occasions, she screamed that he wanted to cut her open; on others yet she dismissed him, full of indignation and with expressions indicating that she fears him as a threat to her honor as a woman. At times she seemed to have auditory hallucinations [2].
Dementia The main types, Alzheimer dementia and vascular dementia, were described fully by the beginning
of the 20th century, but medical interest largely languished until the middle of the century. The main reason was that people simply did not live as long in those days, so the dementing illnesses were less frequent. During the 20th century the life span has increased from an average of 50 to 80 years. As countries have aged, health authorities have started to take an interest in geriatrics and gerontology. Countries, however, do not age identically since the median age varies from country to country. Economically advantaged countries tend to have proportionately more elderly and the economically disadvantaged, more children. Nevertheless, paradoxically, in terms of sheer numbers, it is the latter that has the most elderly and therefore, dementia. In individual terms, aging is a complicated, but inevitable process, with great individual variation. In contrast, dementia is not inevitable, as argued later. Something that has a bearing on this discussion is that, although human tissue decays with age, the brain is remarkable in that its cells are not replaced. The dementias seem to satisfy the criteria for illnesses but it should be noted that there are sub-syndromal forms of cognitive decline which, in our current state of knowledge, require further explanation. Dementia means "losing the mind". The term is generic and covers many illnesses, some of which we understand. In a recent paper on the evaluation of dementia, Geldmacher and Whitehouse [3] say that there are more than 55 illnesses which can cause dementia. The definition that they adopt is that "dementia is the clinical syndrome characterized by acquired
Dementia: current dcvelopments
losses of cognitive and emotional abilities severe enough to interfere with daily functioning and the quality of life". As an example, Alzheimer's disease (AD) lasts about 8 years from start to finish with part functions being lost in a roughly sequential manner. It starts with memory loss, followed by abnormal behavior, apraxia, agnosia, aphasia and eventually the patient is reduced to a vegetative state. It is thought to be one of the most common causes of death, indirectly through infection or a close down of vital organs. There have been about 100 prevalence studies, and a handful of incidence studies, which suggest that the rates for dementia are roughly equivalent throughout the world; although there is variation by sub-types. About 7% of Caucasians over 65 years of age have dementia with 5% having AD. As age increases, so does the rate of disease. The figures in the elderly (over 80) are probably not accurate, but perhaps 50% of those reaching 100 years have a dementia. The outstanding and fascinating example of Jeanne Calment from Arles, France who at 121 is the oldest living human being is a case-in-point. She has sensory deficits, but can hold a conversation and showed lots of charm and affect in a video tape recently presented by French clinical investigator Karen Ritchie in Sydney, Australia. Dementia seems to be a group of medical conditions (diseases or syndromes) with the frail, confused medical end-state being the final common pathway for practically all. There are many kinds of dementia documented, with the traditional breakdown being 70% AD, 20% vascular disease (VAD) and 10% other (made up of uncommon conditions and the so-called reversible dementias). While this breakdown is still taught in medical schools, it does not bear serious scientific scrutiny. Strong arguments have been made to indicate that VAD is more common than suggested above, possibly 40%, and conditions like Lewy Body disease and the frontal lobe aphasias are also significantly represented. Furthermore, there are racial differences, with those from parts of Southeast Asia having an excess of VAD over AD. Even more importantly, hypertension was recently found to be a risk factor for both AD and VAD [4]. These changes in knowledge are not academic since, in our current understanding, cerebro-vascular disease is better prevented, with anti-hypertension drugs, blood thinners and lifestyle changes, than Alzheimer's disease where preventive interven-
Il3
tion has hardly started. Given all of that, many drug trials are underway to treat AD with central nervous system (CNS) acetylcholine boosters. While clinical criteria are always used in these cases to substantiate the diagnosis of AD, it seems obvious that the sensitivity and specificity of the tests used to make the diagnosis are inadequate. The drugs are therefore likely given to sub-types of AD and to non-AD dementias inadvertently.
DEVELOPMENTS It is abundantly clear that research developments are taking place. Old classifications and viewpoints are under scrutiny. The Lancet conference, "The Challenge of the Dementias", held in Edinburgh in April 1996 brought together epidemiologists; geneticists; experts in neuroimaging; neuropsychology and neuropathology; and those concerned with social, ethical and legal aspects of dementia. Equal time was given to formal presentation and panel discussion. A subsequent writing committee produced a report which appeared in the Lancet (May I I , 1996) [5] and was accompanied by an editorial. The latter especially called for collaborative research. This may not be easy, however, since epidemiology generally goes to the government for money and putative treatments and tests to the private sector.
Epidemiology Since the conference was divided into four sessions, what did each specifically suggest? Epidemiology raised four main points: 1) How common are subtle degrees of cognitive impairment? 2 ) H o w frequent are cognitive impairment/dementia in the very old? 3) What effect does culture/ethnicity have on rates? 4 ) W i l l changes in vascular diseases over time alter rates of cognitive impairment? In effect t h e n ' "The most pressing issue is our remarkable lack of understanding about the natural history of cognitive decline.., what is normal aging?" There is a vital need J~r longitudinal studies. So called Alzheimer's disease and vascular disease should not be addressed separately since it is clear [4] that hypertension is a risk factor for both VAD and AD. These studies will further clarify the place of risk .factors for AD which,
114
R Eastwood
according to the Lancet conference, currently stand as presented in table I.
Table I. Risk factors for Alzheimer's disease [5].
Definite
Less definite
Least definite (other sources)
Old age Downs syndrome Family history ApoE genotype 4
Female History of head injury Downs in the family Vascular risk factors
Aluminum Herpes simplex virus I
In contrast, so-called protective factors are: - ApoE 2 genotype - High I Q / e d u c a t i o n a l achievement - Post menopause estrogens - Non-steroidal anti-inflammatory drugs Treatment, therefore, can be imagined along the lines of treating high risk groups with drugs causing acetylecholine increase in the brain; or, alternatively, using a different strategy which makes sure that vascular risk factors are modified in an otherwise healthy population. Genetic m a r k e r s There is a need to separate the susceptibility ApoE 4 allele from the autosomal dominant genes. ApoE 4 can assist in making a probable diagnosis of AD definite, but cannot be used as a screening instrument for dementia since individuals can have this allele and never have the disease. The autosomal dominant genes are on chromosomes 21, 14 and 1. Not that many families are known to be affected throughout the world, but intense interest is given to these findings since their study might lead to clarification of mechanisms. There are likely more susceptibility and autosomal dominant genes to be found since about 50% of AD cases have a first degree relative or more with dementia. The conference saw the need to find other genes and the function of those already known. Other needs identified included : longitudinal studies; a determination of relative risk and an estimate of the sensitivity and specificity of ApoE genotyping; better case definition of AD; more information about interactions between genetic and environmental factors; and better animal models.
N e u r o - i m a g i n g , p s y c h o l o g y and pathology These approaches serve to give us an idea of pathology and normality. The conference thought that neuropathology, which should rest on standardized histological criteria, ought to be done blind of data from neuroimaging and neuropsychology. More needs to be known about the psychometric properties of standard neuropsychological tests. Neuroimaging should focus on all areas in the brain. Again, we need longitudinal studies of neuroimaging, neurotransmitting and neuropathology. Finally, education, health and social class should be definitively correlated with cognitive decline. Armed with this information, it would be possible to embark upon a multi-factor intervention trial in normal, healthy individuals. Social and ethical aspects The conference organizers decided that adequate attention should be given to social and ethical aspects of dementia. Firstly, caregiver intervention strategies need examining. Certainly the caregivers need assistance with different kinds of care, education and support. Second, these efforts should be increased and it is desirable that dependable instruments are used to measure the different aspects of caregiving. Third, there is no effective treatment for AD at present, but undoubtedly, medications will begin to appear which will give palliative help or even relief. This all has to be examined in the context of quality of life. Extending life in dementia may only be burdensome for the patient and all concerned. Finally, thinking about the ethics of medication : "Patients who comply with treatment can enjoy the ordinary presumption of competence, whereas refusal of treatment will raise questions of competence .... consent to treatment can only be given by a person capable of giving it, but an incompetent person can assent (ie, not object) by being willing to let things happen." There is a need for guidelines about consent in clinical drug trials and for the use of different kinds of tissues in research. In our present state of knowledge, genetic testing is not permissible. Tests like the ApoE are not 100% predictive of dementia and such testing might lead to a demand by insurance companies for such information. There is certainly a need for better communication on such issues between the scientists and the public.
Dementia: current developments
NOSOLOGY What else has been reported lately? For a condition like AD, which is probably a mixture of disorders and has a number of putative causes, it is to be expected that recent findings are equally diverse. We can start with depression. This is part of the differential diagnosis for dementia and in at least 50% percent of cases, is a comorbidity. But is it a precursor or a risk factor as some have suggested? Recent findings from France suggest not [6]. While there is a strong cross-sectional relationship between depression and cognitive function, this did not obtain when looked at longitudinally. The authors see this as important in measuring cognition in the elderly in such settings as clinical practice, epidemiology studies, and clinical trials. This certainly has a bearing on the differential diagnosis of dementia which usually includes delirium and depression amongst others. Delirium is a common medical condition, especially in the acute hospital setting. It is a complicated disorder with the most conspicuous feature being clouding of consciousness and varying concentration. Thus, the patient may be quietly picking at the bedclothes, or running around the hospital in a state of severe agitation. Most cases of delirium are due to infections in the chest or bladder, or through taking too much medication. Either way, with appropriate treatment, the patient should respond to treatment unless the delirium is superadded onto a previous dementing illness. So delirium and depression are important alternative diagnoses, but once diagnosed are readily treated. What about the diagnosis of dementia itself? Dementia is a generic term and a useful concept when compared with theoretically reversible syndromes like depression and delirium. However, within the concept of dementia itself there are many mansions. The typical breakdown into AD and VAD plus miscellany is no longer acceptable. The NINCDS-ADRDA criteria for AD, set up in 1984 [7] have served their purpose but need refining. Isolating AD cross-sectionally, free from 'contaminating' conditions like VAD and Parkinson's disease (PD), no longer carries heuristic value. Furthermore, there is skepticism about the agreement between the clinical picture, neuroimaging and the putative causes. A number of within-group comparisons show that there are many clinical presentations under the rubric of
1 15
dementia and each has a protagonist. In other words, doctors get interested in subtypes of dementia and speak about them with a territorial imperative. However, when all these subtypes are added up, they come to more than 100%, So a lot of sorting out is required, particularly if etiology and treatments become clarified. ETIOLOGY Etiology offers a very mixed picture. A few cases appear to be due to a Mendelian dominant gene, albeit with variable penetration; others are due to risk factors of uncertain effect in a given case. Clearly, the interaction of intelligence, education, work history, age, gender, family history, exposure to anti-inflammatory drugs, estrogens, aluminum, head injury, vascular risk factors, Down's syndrome and ApoE status is complicated and confusing. Some of these are regarded as risk factors and others protective factors. The interaction between protective and risk factors is not known. Only extensive longitudinal studies will disentangle these variables which look bewilderingly inchoate. While recent research into the causes and protective factors for AD grows apace, there have been three studies this year which are of particular importance. The first involved nuns who were seen late in life and then subjected to a retrospective analysis of their writings while they were young [8]. Those exhibiting limited imagination when young on joining the religious order were significantly more predisposed to having AD when old. Limited imagination may well be a proxy for limited intelligence or as was suggested in the article, an early manifestation of the disease. (A study being carried out by our group in St Louis on bright, well-educated Jesuit priests suggests from preliminary data that the very bright carry less risk for AD.) The second study involves the role of estrogens in AD. Some preliminary work has indicated that lack of estrogen predisposes women to have AD while, conversely, adequate levels of estrogen protect. This notion was tested in New York recently [9] with a finding that those who had been exposed to regular estrogen medication post-menopausaly stood less chance of having AD over a 5-year period. However, criticism was leveled at the study for not sufficiently adjusting for age and education. A third study looked at the sensitivity and speci-
116
R Eastwood
ficity of the ApoE allele in terms of validating the diagnosis of AD [10]. In a series of patients at Duke University, they found that, when a person was suspected of having probable AD (for which traditionally the best clinicians can expect 85% reliability), the sensitivity of ApoE was 75%, the specificity was 100%, the positive predictive value was 100% and the negative predictive value was 42%. In other words, there were no false negatives, but definitely false positives. To the Duke University group, this meant that the ApoE testing corroborated the suspect AD in all cases and could be called part of the clinical workup. (Nevertheless it cannot be used as a screening test in general populations because of the inadequate sensitivity figures.) While two other groups in Oxford, UK and Perth, Australia had very similar specificity findings in their series, at a recent meeting, Roses suggested placing the specificity at around 97% [10]. Finally, and most amusingly, Amaducci, in a letter to the journal Science [11] suggested that the original case described by Alzheimer was not in fact a case of Alzheimer's disease, but a late form of metachromatic leukodystrophy where plaques and tangles are also present. The delicious aspect of this is that AD is a descriptive diagnosis and, even in the best hands, there is some lack of agreement over cases and, in fact, it is likely not a unitary diagnosis and is probably a mixture of conditions with multiple etiology. TREATMENT
adequate, and replacing cerebral acetylcholine is insufficient. New hypotheses are needed if the above drugs are given to improve memory. There is also a behavioral problem. Demented people go through typical stages as their brains deteriorate. These have been well described. Reversing memory defects seems impossible at the moment, but what of associated behavioral difficulties? These are described in tables II and III [12]. Some of these behaviors can be controlled with appropriate medication while others are beyond help. Nevertheless, the psychopathology surrounding dementia requires attention to detail as does treatment and outcome. Table IL The more common behavioural disturbances in dementia Agitation Abnormal eating behaviours Affective disorders/mood disturbances Incontinence Delusions Kluver-Bncy syndrome Hallucinations Anxiety, phobias, fears Illusions Shouting / screaming Restlessness Demanding / critical behaviour Wandering Personality change Rage / violence Disinhibition Sleep-wake disturbances Sexual behaviours Sundowning Compulsive / ritualistic behaviours Adapted from Rapp et al [12].
Nevertheless, there is a sense of urgency amongst the medical profession and lay public for a cure, or at least, a palliative treatment. Drug trials today test the acetylcholine deficiency hypothesis enunciated 20 years ago. It is obviously insufficient. The drug Cognex/Tacrine ®, which was introduced a few years ago as the prototype for drug intervention, is clearly only modest in its effect. It has an effect lasting perhaps 4 months with severe gastrointestinal side-effects at higher doses. (All subsequent such drugs from other pharmaceutical companies are very similar with hopefully more effect and less side effects.) Cognex/Tacrine ® was given general release during the last few years in the United States, very limited release in France, and denied release in the United Kingdom and Canada. The hypothesis that acetylcholine deficiency is the cause of AD is in-
Table III. Frequency of abnormal behaviours associated with dementia Agitation Wandering Depression Psychosis Screaming Violence Sexuality
up up up up up up up
to to to to to to to
75 60 50 30 25 20 10
percent percent percent percent percent percent percent
CONCLUSIONS In summary, AD amongst the dementias is well described. It cannot be strongly validated in life and the post mortem is the gold standard. How-
Dementia: current developments
e v e r , in t h e h a n d s o f c o m p e t e n t s p e c i a l i s t p h y s i c i a n s , t h e a c c u r a c y r a t e f o r A D is a b o u t 85 %. T h e d i a g n o s i s is d e s c r i p t i v e a n d p r e s e n t l y , t h e r e are almost too many putative etiologies and an equal number of confusing, challenging treatments. The o t h e r i m p o r t a n t d e m e n t i a s are v a s c u l a r d e m e n t i a , Lewy Body disease and frontal lobe dementias. T h e s t u d y o f t h e d e m e n t i a s is n o w e x c i t i n g as medical scientists pit wits against each other. Nevertheless, the problem of dementia grows e a c h y e a r as t h e e l d e r l y p o p u l a t i o n i n c r e a s e s a n d the public demands specifics.
REFERENCES 1 Berrios GE. Dementia: Historical Review in Dementia. In: Burns A, Levy R, eds. Dementia. London: Chapman and Hall, 1994 2 Alzheimer A. (Jarvik U Greenson H, Translation) About a peculiar disease of the cerebral cortex. AIzheimer's Dis Assoc Disord 1987;1:728 3 Geldmacber BS, Whitehouse PJ, Evaluation of dementia. New Eng J Med 1996;3-5:330-6 4 Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA et al. Fifteen year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141-5
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5 Writing Committee. Lancet Conference 1996 (Chair, Eastwood R) The Challenge of the Dementias. Lancet 1996;347:1303-7 6 Dufouil C, Fuhrer R, Dartigues JF, Alperovitch A. Longitudinal analysis of the association between depressive symptomotology and cognitive deterioration. Ame J Epidemiol 1996;144:634-41 7 McKhann F, Drachman D, Folstein M, Katzman R, Price D, Stadlane EM. Clinical diagnosis of Alzheimer's disease : Report of the NINCDS-ADRDA Workgroup under the auspices of Dept of Health and Human Services. Task Force on Alzheimer's Disease. Neurology 1984;34:939-44 8 Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. JAMA 1996;275:528-32 9 Teng MX, Jacobs B, Stern Y et al. Effective estrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996;348:429-35 10 Saunders AM, Hulett C, Welsh-Bohmer KA et al. Specificity, sensitivity and predictive value of Apo-lipoprotein-E genotyping for sporadic Alzheimer's disease. Lancet 1996;348:90-3 11 Amaducci L, Alzheimer's original patient. Science 1996;274:328 12 Rapp MS, Flint AJ, Hermann N, Proulx GB. Behavioral disturbances in the demented elderly: phenomonology, pharmacotberapy and behavioral management. Can J Psychiatry 1992;37:65 l-7
Dossier "Dementia"
Dementia: current developments R Eastwood Health Science Center, School c~f Medicine, Saint Louis University,
1221 South Grand Blvd, Saint Louis, MO 63104, USA
Summary - This is a short review of the current developments taking place in the field of the dementias. This branch of medicine is growing apace with IYesh research findings being published continually in respect to etiology, risk and protective factors, clinical typology and treatment effects. At the same time we know remarkably little about the natural history of cognitive decline and in effect, normal aging. There is clearly a vital need for longitudinal studies. Also, new hypotheses are needed to explain the critical memory defect in dementia. In fact, better treatment of the memory defect, and the associeted behavorial problems found in dementia is urgently needed and even demended by an increasingly more sophisticated public. INTRODUCTION Dementia was ascribed its present meaning in the 19th century based upon anatomy, pathology and clinical features. It was established that the key aspects of the condition were memory loss and intellectual impairment. Other psychopathology was epiphenomena [1]. However, both of these features were described by Alzheimer in his paper in 1907.
Patient study The first noticeable symptom of illness shown by this 51-year-old woman was suspiciousness of her husband. Soon, a rapidly increasing memory impairment became evident. She could no longer orientate herself in her own dwelling, dragged objects here and there and hid them, and, at times, believing that people were out to murder her, started to scream loudly. Sometimes, she would greet the doctor as if he were a stranger and made excuses for herself that she had not finished her work; on other occasions, she screamed that he wanted to cut her open; on others yet she dismissed him, full of indignation and with expressions indicating that she fears him as a threat to her honor as a woman. At times she seemed to have auditory hallucinations [2].
Dementia The main types, Alzheimer dementia and vascular dementia, were described fully by the beginning
of the 20th century, but medical interest largely languished until the middle of the century. The main reason was that people simply did not live as long in those days, so the dementing illnesses were less frequent. During the 20th century the life span has increased from an average of 50 to 80 years. As countries have aged, health authorities have started to take an interest in geriatrics and gerontology. Countries, however, do not age identically since the median age varies from country to country. Economically advantaged countries tend to have proportionately more elderly and the economically disadvantaged, more children. Nevertheless, paradoxically, in terms of sheer numbers, it is the latter that has the most elderly and therefore, dementia. In individual terms, aging is a complicated, but inevitable process, with great individual variation. In contrast, dementia is not inevitable, as argued later. Something that has a bearing on this discussion is that, although human tissue decays with age, the brain is remarkable in that its cells are not replaced. The dementias seem to satisfy the criteria for illnesses but it should be noted that there are sub-syndromal forms of cognitive decline which, in our current state of knowledge, require further explanation. Dementia means "losing the mind". The term is generic and covers many illnesses, some of which we understand. In a recent paper on the evaluation of dementia, Geldmacher and Whitehouse [3] say that there are more than 55 illnesses which can cause dementia. The definition that they adopt is that "dementia is the clinical syndrome characterized by acquired
Dementia: current dcvelopments
losses of cognitive and emotional abilities severe enough to interfere with daily functioning and the quality of life". As an example, Alzheimer's disease (AD) lasts about 8 years from start to finish with part functions being lost in a roughly sequential manner. It starts with memory loss, followed by abnormal behavior, apraxia, agnosia, aphasia and eventually the patient is reduced to a vegetative state. It is thought to be one of the most common causes of death, indirectly through infection or a close down of vital organs. There have been about 100 prevalence studies, and a handful of incidence studies, which suggest that the rates for dementia are roughly equivalent throughout the world; although there is variation by sub-types. About 7% of Caucasians over 65 years of age have dementia with 5% having AD. As age increases, so does the rate of disease. The figures in the elderly (over 80) are probably not accurate, but perhaps 50% of those reaching 100 years have a dementia. The outstanding and fascinating example of Jeanne Calment from Arles, France who at 121 is the oldest living human being is a case-in-point. She has sensory deficits, but can hold a conversation and showed lots of charm and affect in a video tape recently presented by French clinical investigator Karen Ritchie in Sydney, Australia. Dementia seems to be a group of medical conditions (diseases or syndromes) with the frail, confused medical end-state being the final common pathway for practically all. There are many kinds of dementia documented, with the traditional breakdown being 70% AD, 20% vascular disease (VAD) and 10% other (made up of uncommon conditions and the so-called reversible dementias). While this breakdown is still taught in medical schools, it does not bear serious scientific scrutiny. Strong arguments have been made to indicate that VAD is more common than suggested above, possibly 40%, and conditions like Lewy Body disease and the frontal lobe aphasias are also significantly represented. Furthermore, there are racial differences, with those from parts of Southeast Asia having an excess of VAD over AD. Even more importantly, hypertension was recently found to be a risk factor for both AD and VAD [4]. These changes in knowledge are not academic since, in our current understanding, cerebro-vascular disease is better prevented, with anti-hypertension drugs, blood thinners and lifestyle changes, than Alzheimer's disease where preventive interven-
Il3
tion has hardly started. Given all of that, many drug trials are underway to treat AD with central nervous system (CNS) acetylcholine boosters. While clinical criteria are always used in these cases to substantiate the diagnosis of AD, it seems obvious that the sensitivity and specificity of the tests used to make the diagnosis are inadequate. The drugs are therefore likely given to sub-types of AD and to non-AD dementias inadvertently.
DEVELOPMENTS It is abundantly clear that research developments are taking place. Old classifications and viewpoints are under scrutiny. The Lancet conference, "The Challenge of the Dementias", held in Edinburgh in April 1996 brought together epidemiologists; geneticists; experts in neuroimaging; neuropsychology and neuropathology; and those concerned with social, ethical and legal aspects of dementia. Equal time was given to formal presentation and panel discussion. A subsequent writing committee produced a report which appeared in the Lancet (May I I , 1996) [5] and was accompanied by an editorial. The latter especially called for collaborative research. This may not be easy, however, since epidemiology generally goes to the government for money and putative treatments and tests to the private sector.
Epidemiology Since the conference was divided into four sessions, what did each specifically suggest? Epidemiology raised four main points: 1) How common are subtle degrees of cognitive impairment? 2 ) H o w frequent are cognitive impairment/dementia in the very old? 3) What effect does culture/ethnicity have on rates? 4 ) W i l l changes in vascular diseases over time alter rates of cognitive impairment? In effect t h e n ' "The most pressing issue is our remarkable lack of understanding about the natural history of cognitive decline.., what is normal aging?" There is a vital need J~r longitudinal studies. So called Alzheimer's disease and vascular disease should not be addressed separately since it is clear [4] that hypertension is a risk factor for both VAD and AD. These studies will further clarify the place of risk .factors for AD which,
114
R Eastwood
according to the Lancet conference, currently stand as presented in table I.
Table I. Risk factors for Alzheimer's disease [5].
Definite
Less definite
Least definite (other sources)
Old age Downs syndrome Family history ApoE genotype 4
Female History of head injury Downs in the family Vascular risk factors
Aluminum Herpes simplex virus I
In contrast, so-called protective factors are: - ApoE 2 genotype - High I Q / e d u c a t i o n a l achievement - Post menopause estrogens - Non-steroidal anti-inflammatory drugs Treatment, therefore, can be imagined along the lines of treating high risk groups with drugs causing acetylecholine increase in the brain; or, alternatively, using a different strategy which makes sure that vascular risk factors are modified in an otherwise healthy population. Genetic m a r k e r s There is a need to separate the susceptibility ApoE 4 allele from the autosomal dominant genes. ApoE 4 can assist in making a probable diagnosis of AD definite, but cannot be used as a screening instrument for dementia since individuals can have this allele and never have the disease. The autosomal dominant genes are on chromosomes 21, 14 and 1. Not that many families are known to be affected throughout the world, but intense interest is given to these findings since their study might lead to clarification of mechanisms. There are likely more susceptibility and autosomal dominant genes to be found since about 50% of AD cases have a first degree relative or more with dementia. The conference saw the need to find other genes and the function of those already known. Other needs identified included : longitudinal studies; a determination of relative risk and an estimate of the sensitivity and specificity of ApoE genotyping; better case definition of AD; more information about interactions between genetic and environmental factors; and better animal models.
N e u r o - i m a g i n g , p s y c h o l o g y and pathology These approaches serve to give us an idea of pathology and normality. The conference thought that neuropathology, which should rest on standardized histological criteria, ought to be done blind of data from neuroimaging and neuropsychology. More needs to be known about the psychometric properties of standard neuropsychological tests. Neuroimaging should focus on all areas in the brain. Again, we need longitudinal studies of neuroimaging, neurotransmitting and neuropathology. Finally, education, health and social class should be definitively correlated with cognitive decline. Armed with this information, it would be possible to embark upon a multi-factor intervention trial in normal, healthy individuals. Social and ethical aspects The conference organizers decided that adequate attention should be given to social and ethical aspects of dementia. Firstly, caregiver intervention strategies need examining. Certainly the caregivers need assistance with different kinds of care, education and support. Second, these efforts should be increased and it is desirable that dependable instruments are used to measure the different aspects of caregiving. Third, there is no effective treatment for AD at present, but undoubtedly, medications will begin to appear which will give palliative help or even relief. This all has to be examined in the context of quality of life. Extending life in dementia may only be burdensome for the patient and all concerned. Finally, thinking about the ethics of medication : "Patients who comply with treatment can enjoy the ordinary presumption of competence, whereas refusal of treatment will raise questions of competence .... consent to treatment can only be given by a person capable of giving it, but an incompetent person can assent (ie, not object) by being willing to let things happen." There is a need for guidelines about consent in clinical drug trials and for the use of different kinds of tissues in research. In our present state of knowledge, genetic testing is not permissible. Tests like the ApoE are not 100% predictive of dementia and such testing might lead to a demand by insurance companies for such information. There is certainly a need for better communication on such issues between the scientists and the public.
Dementia: current developments
NOSOLOGY What else has been reported lately? For a condition like AD, which is probably a mixture of disorders and has a number of putative causes, it is to be expected that recent findings are equally diverse. We can start with depression. This is part of the differential diagnosis for dementia and in at least 50% percent of cases, is a comorbidity. But is it a precursor or a risk factor as some have suggested? Recent findings from France suggest not [6]. While there is a strong cross-sectional relationship between depression and cognitive function, this did not obtain when looked at longitudinally. The authors see this as important in measuring cognition in the elderly in such settings as clinical practice, epidemiology studies, and clinical trials. This certainly has a bearing on the differential diagnosis of dementia which usually includes delirium and depression amongst others. Delirium is a common medical condition, especially in the acute hospital setting. It is a complicated disorder with the most conspicuous feature being clouding of consciousness and varying concentration. Thus, the patient may be quietly picking at the bedclothes, or running around the hospital in a state of severe agitation. Most cases of delirium are due to infections in the chest or bladder, or through taking too much medication. Either way, with appropriate treatment, the patient should respond to treatment unless the delirium is superadded onto a previous dementing illness. So delirium and depression are important alternative diagnoses, but once diagnosed are readily treated. What about the diagnosis of dementia itself? Dementia is a generic term and a useful concept when compared with theoretically reversible syndromes like depression and delirium. However, within the concept of dementia itself there are many mansions. The typical breakdown into AD and VAD plus miscellany is no longer acceptable. The NINCDS-ADRDA criteria for AD, set up in 1984 [7] have served their purpose but need refining. Isolating AD cross-sectionally, free from 'contaminating' conditions like VAD and Parkinson's disease (PD), no longer carries heuristic value. Furthermore, there is skepticism about the agreement between the clinical picture, neuroimaging and the putative causes. A number of within-group comparisons show that there are many clinical presentations under the rubric of
1 15
dementia and each has a protagonist. In other words, doctors get interested in subtypes of dementia and speak about them with a territorial imperative. However, when all these subtypes are added up, they come to more than 100%, So a lot of sorting out is required, particularly if etiology and treatments become clarified. ETIOLOGY Etiology offers a very mixed picture. A few cases appear to be due to a Mendelian dominant gene, albeit with variable penetration; others are due to risk factors of uncertain effect in a given case. Clearly, the interaction of intelligence, education, work history, age, gender, family history, exposure to anti-inflammatory drugs, estrogens, aluminum, head injury, vascular risk factors, Down's syndrome and ApoE status is complicated and confusing. Some of these are regarded as risk factors and others protective factors. The interaction between protective and risk factors is not known. Only extensive longitudinal studies will disentangle these variables which look bewilderingly inchoate. While recent research into the causes and protective factors for AD grows apace, there have been three studies this year which are of particular importance. The first involved nuns who were seen late in life and then subjected to a retrospective analysis of their writings while they were young [8]. Those exhibiting limited imagination when young on joining the religious order were significantly more predisposed to having AD when old. Limited imagination may well be a proxy for limited intelligence or as was suggested in the article, an early manifestation of the disease. (A study being carried out by our group in St Louis on bright, well-educated Jesuit priests suggests from preliminary data that the very bright carry less risk for AD.) The second study involves the role of estrogens in AD. Some preliminary work has indicated that lack of estrogen predisposes women to have AD while, conversely, adequate levels of estrogen protect. This notion was tested in New York recently [9] with a finding that those who had been exposed to regular estrogen medication post-menopausaly stood less chance of having AD over a 5-year period. However, criticism was leveled at the study for not sufficiently adjusting for age and education. A third study looked at the sensitivity and speci-
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ficity of the ApoE allele in terms of validating the diagnosis of AD [10]. In a series of patients at Duke University, they found that, when a person was suspected of having probable AD (for which traditionally the best clinicians can expect 85% reliability), the sensitivity of ApoE was 75%, the specificity was 100%, the positive predictive value was 100% and the negative predictive value was 42%. In other words, there were no false negatives, but definitely false positives. To the Duke University group, this meant that the ApoE testing corroborated the suspect AD in all cases and could be called part of the clinical workup. (Nevertheless it cannot be used as a screening test in general populations because of the inadequate sensitivity figures.) While two other groups in Oxford, UK and Perth, Australia had very similar specificity findings in their series, at a recent meeting, Roses suggested placing the specificity at around 97% [10]. Finally, and most amusingly, Amaducci, in a letter to the journal Science [11] suggested that the original case described by Alzheimer was not in fact a case of Alzheimer's disease, but a late form of metachromatic leukodystrophy where plaques and tangles are also present. The delicious aspect of this is that AD is a descriptive diagnosis and, even in the best hands, there is some lack of agreement over cases and, in fact, it is likely not a unitary diagnosis and is probably a mixture of conditions with multiple etiology. TREATMENT
adequate, and replacing cerebral acetylcholine is insufficient. New hypotheses are needed if the above drugs are given to improve memory. There is also a behavioral problem. Demented people go through typical stages as their brains deteriorate. These have been well described. Reversing memory defects seems impossible at the moment, but what of associated behavioral difficulties? These are described in tables II and III [12]. Some of these behaviors can be controlled with appropriate medication while others are beyond help. Nevertheless, the psychopathology surrounding dementia requires attention to detail as does treatment and outcome. Table IL The more common behavioural disturbances in dementia Agitation Abnormal eating behaviours Affective disorders/mood disturbances Incontinence Delusions Kluver-Bncy syndrome Hallucinations Anxiety, phobias, fears Illusions Shouting / screaming Restlessness Demanding / critical behaviour Wandering Personality change Rage / violence Disinhibition Sleep-wake disturbances Sexual behaviours Sundowning Compulsive / ritualistic behaviours Adapted from Rapp et al [12].
Nevertheless, there is a sense of urgency amongst the medical profession and lay public for a cure, or at least, a palliative treatment. Drug trials today test the acetylcholine deficiency hypothesis enunciated 20 years ago. It is obviously insufficient. The drug Cognex/Tacrine ®, which was introduced a few years ago as the prototype for drug intervention, is clearly only modest in its effect. It has an effect lasting perhaps 4 months with severe gastrointestinal side-effects at higher doses. (All subsequent such drugs from other pharmaceutical companies are very similar with hopefully more effect and less side effects.) Cognex/Tacrine ® was given general release during the last few years in the United States, very limited release in France, and denied release in the United Kingdom and Canada. The hypothesis that acetylcholine deficiency is the cause of AD is in-
Table III. Frequency of abnormal behaviours associated with dementia Agitation Wandering Depression Psychosis Screaming Violence Sexuality
up up up up up up up
to to to to to to to
75 60 50 30 25 20 10
percent percent percent percent percent percent percent
CONCLUSIONS In summary, AD amongst the dementias is well described. It cannot be strongly validated in life and the post mortem is the gold standard. How-
Dementia: current developments
e v e r , in t h e h a n d s o f c o m p e t e n t s p e c i a l i s t p h y s i c i a n s , t h e a c c u r a c y r a t e f o r A D is a b o u t 85 %. T h e d i a g n o s i s is d e s c r i p t i v e a n d p r e s e n t l y , t h e r e are almost too many putative etiologies and an equal number of confusing, challenging treatments. The o t h e r i m p o r t a n t d e m e n t i a s are v a s c u l a r d e m e n t i a , Lewy Body disease and frontal lobe dementias. T h e s t u d y o f t h e d e m e n t i a s is n o w e x c i t i n g as medical scientists pit wits against each other. Nevertheless, the problem of dementia grows e a c h y e a r as t h e e l d e r l y p o p u l a t i o n i n c r e a s e s a n d the public demands specifics.
REFERENCES 1 Berrios GE. Dementia: Historical Review in Dementia. In: Burns A, Levy R, eds. Dementia. London: Chapman and Hall, 1994 2 Alzheimer A. (Jarvik U Greenson H, Translation) About a peculiar disease of the cerebral cortex. AIzheimer's Dis Assoc Disord 1987;1:728 3 Geldmacber BS, Whitehouse PJ, Evaluation of dementia. New Eng J Med 1996;3-5:330-6 4 Skoog I, Lernfelt B, Landahl S, Palmertz B, Andreasson LA et al. Fifteen year longitudinal study of blood pressure and dementia. Lancet 1996;347:1141-5
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5 Writing Committee. Lancet Conference 1996 (Chair, Eastwood R) The Challenge of the Dementias. Lancet 1996;347:1303-7 6 Dufouil C, Fuhrer R, Dartigues JF, Alperovitch A. Longitudinal analysis of the association between depressive symptomotology and cognitive deterioration. Ame J Epidemiol 1996;144:634-41 7 McKhann F, Drachman D, Folstein M, Katzman R, Price D, Stadlane EM. Clinical diagnosis of Alzheimer's disease : Report of the NINCDS-ADRDA Workgroup under the auspices of Dept of Health and Human Services. Task Force on Alzheimer's Disease. Neurology 1984;34:939-44 8 Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. JAMA 1996;275:528-32 9 Teng MX, Jacobs B, Stern Y et al. Effective estrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet 1996;348:429-35 10 Saunders AM, Hulett C, Welsh-Bohmer KA et al. Specificity, sensitivity and predictive value of Apo-lipoprotein-E genotyping for sporadic Alzheimer's disease. Lancet 1996;348:90-3 11 Amaducci L, Alzheimer's original patient. Science 1996;274:328 12 Rapp MS, Flint AJ, Hermann N, Proulx GB. Behavioral disturbances in the demented elderly: phenomonology, pharmacotberapy and behavioral management. Can J Psychiatry 1992;37:65 l-7