INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, VOL. 9: 173-1 79 (1994)

EDITORIAL Reflections on the NINCDWADRDA criteria for the

Diagnosis of Alzheimer’s Disease

In the early 1980s, in the United States, a ‘work group’ on the diagnosis of Alzheimer’s disease, established by the National Institute of Neurologi- cal and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA), reported its findings. These derived from delibe- rations by subgroups which had addressed separa- tely the medical history, clinical examination, neuropsychological testing and laboratory assess- ment of individuals with Alzheimer’s disease. Sub- sequently, their conclusions were discussed in plenary session and, ‘based on a consensus of the participants’, criteria for the clinical diagnosis of Alzheimer’s disease were specified. The Work Group emphasized that these were tentative. Their validity could not be assumed and would need cor- roboration from longitudinal clinical studies utilis- ing postmortem data to confirm diagnosis (McKhann et al., 1984, p. 939).

Since that time the NINCDS-ADRDA criteria have been widely adopted in research studies and clinical trials. Despite some problems of definition and application, they are perceived as a substantial advance in a field where, hitherto, vague and het- erogeneous clinical criteria abounded (see, for example, Jorm et al., 1987). Their potential import- ance is emphasized by many references in the litera- ture to benefits arising from accurate clinical diagnosis of subtypes of dementia (eg Small, 1985; McKeith et al., 1992).

Here we should like briefly to discuss the NINCDS-ADRDA criteria, placing emphasis on certain problems to which they give rise and ways in which these might be addressed. The review does not claim to be comprehensive and the issues raised naturally reflect our own interests and experience.

THE CRITERIA

The Work Group preceded their discussion of Alz- heimer’s disease with a definition of the ‘dementia

syndrome’, which, they suggested, was character- ized by a decline in memory and other cognitive functions associated with a deterioration in func- tioning and performance. This occurred in clear consciousness. They emphasized that such a diag- nosis was based on behaviour, not laboratory tests. They then elaborated criteria that distinguished Alzheimer’s disease as a subtype of dementia with a characteristic onset, symptomatology and course. Clinical criteria were given for probable, possible and definite Alzheimer’s disease. as follows.

Probable Alzheimer’s disease The criteria ‘include’ (p. 940):

1.

2.

3.

4. 5. 6 .

Dementia established by clinical examination and documented by the Mini-Mental State ‘or some similar examination’ (p. 940) and con- firmed by neuropsychological tests. Deficits in at least two areas of cognition. In this context, mental state examination should include assessment of orientation, registration, attention, calculation, reading, writing and abi- lity to draw or copy. Progressive worsening of memory and other cognitive functions. No disturbance of consciousness. Onset between 40 and 90 years. Absence of brain diseases/systemic disorders ‘that in and of themselves could account for the progressive deficits in memory and cognition’ (p. 940).

Factors supporting a diagnosis of probable Alz- heimer’s disease include: 1. Progressive deterioration of specific cognitive

functions (eg language). (This appears indis- tinguishable from 3 above.)

2. Impaired activities of daily living and altered behaviour.

3. Family history of a similar disorder, especially if confirmed neuropathologically.

CCC 0885-6230/94/030173-07 0 1994 by John Wiley & Sons, Ltd.

174 EDITORIAL

4. The results of certain investigations, ie: (i) normal lumbar puncture

(ii) normal EEG or non-specific changes only (iii) cerebral atrophy on CT with serial scanning

suggesting progression

Possible Alzheimer s diseuse

These criteria apply to individuals, presumed to have a degenerative dementia, who fail to satisfy criteria for probable Alzheimer’s disease. Possible Alzheimer’s disease is diagnosed:

1. ‘. . . in the absence of other neurologic, psychi- atric, or systemic disorders sufficient to cause dementia, and in the presence of variations in the onset, in the presentation, or in the clinical course.. .’

2. ‘. . . in the presence of a second systemic or brain disorder sufficient to produce dementia which is not considered to be the cause of the dementia

3. ‘. . .in research studies when a single, gradually progressive severe cognitive deficit is identified in the absence of other identifiable cause’ (p. 940, author’s italics).

Definite Alzheimer ‘s diseuse

This diagnosis is made when criteria for probable Alzheimer’s disease are met and there is ‘histopath- ologic evidence’ (p. 940) of the illness from post- mortem examination or biopsy.

SOME PROBLEMS

Consideration of the above suggests a number of theoretical and practical problems. These affect interpretation and application, and some of the more important are listed below.

Probable Alzheimer’s diseuse

A small and potentially soluble difficulty arises from the criterion for dementia as involving ‘two areas of cognition’. The delimitation of an ‘area of cognition’ may vary according to one’s point of view, for example various components of memory can be considered as either separate areas or one area i.e.

1 . The criteria are non-specific in respect of Alz- heimer’s disease and other degenerative

dementias. It is said, for example, that the diag- nosis of probable Alzheimer’s disease can be made ‘with confidence if there is typical insi- dious onset of dementia with progression? (p. 940). Similarly, ‘progressive degeneration of specific cognitive functions’ (p. 940) is thought to lend support to the diagnosis. Broad criteria of this kind pose considerable operational diffi- culties. How, on the basis of the above, would one distinguish Alzheimer’s disease from, say, Pick’s disease? Non-specific positive criteria are buttressed by negative criteria, ie Alzheimer’s disease tends to be defined as any presumed degenerative dementia for which no other cause can be ascer- tained. The Work Group seem to assume that most cases of degenerative dementia result from Alz- heimer’s disease (see discussion of differential diagnosis on pp. 940-941). DSM-111-R takes a similar view (American Psychiatric Association, 1987, p. 119). This position is increasingly diffi- cult to sustain and perceptions as to how the degenerative dementias should be classified have changed. During the last decade, combined cli- nical and neuropathological studies have sug- gested hitherto unsuspected subtypes of degenerative dementia. Examples include: dementia of frontal lobe type (Gustafson et ul., 1985; Neary et al., 1986) and dementias asso- ciated with the presence of Lewy bodies (Byrne el al., 1989; Gibbet al., 1989).

That these constitute separate clinical entities is suggested by differences in inheritance, sex distribution, symptoms and neuropathology. Dementia of frontal lobe type, for example, may occur at an earlier age than Alzheimer’s disease and have a different sex distribution (Neary et ul., 1986). ‘Senile dementia of Lewy body type’ shows characteristic clinical features: fluctuat- ing cognitive impairment, psychotic and depres- sive symptoms, falling and unexpected losses of consciousness occur significantly more often than in Alzheimer’s disease (McKeith et ul., 1992). The neuropathological changes found in these individuals differ from those of Alz- heimer’s disease (Hansen et al. 1990).

In important respects, therefore, knowledge has advanced and the NINCDS-ADRDA cri- teria have been overtaken by events. The criteria are not specific enough to exclude, and thereby delineate, other degenerative dementias. The lat- ter are likely to be designated ‘possible Alz-

EDITORIAL 175

heimer’s disease’ showing ‘variations in the onset, in the presentation, or in the clinical course’ (p. 940). The diagnosis of probable Alzheimer’s disease is said to be supported by impaired activities of daily living. Again, this reflects a view of DSM-III-R (American Psychiatric Association, 1987, p. 107). The difficulties of such a position, given cross-cultural differences in respect of ‘appropriate performance’ and the influence of externally imposed changes such as unemploy- ment, have been pointed out by the authors of ICD-10 (World Health Organisation, 1992, p. 45). The requirement that onset should occur between the ages of 40 and 90 years is arbitrary and would exclude cases with first symptoms outside this range otherwise meeting the criteria.

Possible Alzheimer’s disease The first two problems discussed in respect of

probable Alzheimer’s disease also apply to possible Alzheimer’s disease. In addition, the diagnosis of possible Alzheimer’s disease may be made ‘in the presence of a second systemic or brain disorder sufficient to produce dementia’ (p. 940) which is not, however, considered to be the cause of the dementia. This raises two questions. How are such judgements made? How might this process be stan- dardized so that resulting data are comparable? Some examples illustrate the problem. Among the elderly there is a high prevalence of periventricular white matter changes of unknown significance (Brayne, 1993). These occur in demented indivi- duals and controls and in some Alzheimer’s disease patients. How are they to be interpreted? What are the quantitative and qualitative levels below which it is valid to discount them as aetiologically signifi- cant in dementia? Hypertension, similarly, may be postulated as a contributory factor to dementia in some individuals. But at what level and for how long?

Dejnite Alzheirner S disease The category of definite Alzheimer’s disease

seems to assume agreed neuropathological criteria for this disorder. In fact, there is considerable heter- ogeneity, both in the criteria themselves and the laboratory methods used to elicit pathology (Wis- niewski et al., 1988; Bryne et al., 1991). Where dif- ferent pathologies coexist, diagnosis has been

particularly idiosyncratic. Ulrich e f al. (1986), for example, found wide divergences in the reported frequency of Alzheimer’s disease depending on the weighting giving to coexisting Alzheimer and vas- cular changes.

VALIDITY AND RELIABILITY

Do these problems have practical consequences, ie impair accurate diagnosis of Alzheimer’s disease by the criteria? This can be answered, to some extent, by considering the criteria’s validity and reliability.*

Validity

Those assessing validity by means of clinicopath- ological studies have employed a number of criteria whose respective meanings have sometimes been confused. We will begin, therefore, by defining the main indices used:

(a) Sensitivity refers to true disease state and is the proportion of these true cases identified by the diagnostic procedure.

(b) Specificity refers to true absence of disease and is the proportion of these true non-cases so identified by the diagnostic procedure.

(c) Positive predictive value is the proportion of all diagnosed as having the disease who have this confirmed at postmortem.

(d) Negative predictive value is the proportion of all diagnosed as not having the disease who have this confirmed at postmortem.

Sensitivity, specificity and negative predictive value can only be calculated if all cases of dementia have been assessed (Brayne, 1993).

Tierney et al. (1988) investigated validity by ascertaining the confirmation rate of the NINCDS- ADRDA criteria using different neuropathological criteria for Alzheimer’s disease. In a sample of 57, the criteria were very successful in distinguishing Alzheimer’s disease from non-Alzheimer’s disease, the values ranging from 81-88”% and showing little variation across the nine sets of neuropathological criteria used. Sensitivity values, representing ‘the percentage of the 22 cases of probable AD that

* The qualification is necessary because the question of validity is complicated by the problems of neuropathological criteria referred to above. Progress in standardization of criteria is a prerequisite of adequate validation.

176 EDITORIAL

were classified pathologically as pure AD (p. 362) varied between 6486%) depending on the neuro- pathological criteria. The authors concluded that the ‘accuracy rate’ (p. 363) of diagnosis was consi- derably higher than that previously reported . . . and speaks to the quality of the Work Group cri- teria’ (p. 363).

Burns et al. (1990) employed NINCDS-ADRDA criteria to select 180 elderly psychiatric patients liv- ing in the Camberwell Health Authority and reported on autopsies carried out on 50 of them. They claimed that the sensitivities of the criteria in respect of probable and possible Alzheimer’s dis- ease were 88% and 78% respectively. This stimu- lated a lively correspondence in which the findings and their interpretation were disputed (British Medical Journal, 1991). It was suggested, for exam- ple, that an assessment of diagnostic accuracy was not possible in the absence of postmortem data on subjects initially judged, on the basis of the criteria, not to have Alzheimer’s disease (p. 47).

Risse er al. (1990) attempted to assess prospecti- vely the accuracy of the NINCDS-ADRDA cri- teria. They undertook autopsies on 25 patients who met the criteria for probable Alzheimer’s disease using Khachaturian’s neuropathological criteria as their yardstick for validation (Khachaturian, 1985). Seventeen patients (68%)) met these criteria, but interpretation of this result is complicated by diver- gent findings for ‘senile onset’ and ‘presenile onset’ cases. The clinical diagnosis was validated in 86% (six of seven) of the former and 56% (10 of 18) of the latter.

Kukull et a1 (1990a,b) examined the validity of three sets of criteria for diagnosing Alzheimer’s dis- ease: NINCDS-ADRDA; the American Psychi- atric Association diagnostic criteria from the Diagnostic and Statistical Manual (American Psy- chiatric Association, 1987); and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC) (Eisdorfer and Cohen, 1980). Diagnostic outcome was validated using Khachaturian’s neuropathological criteria (Khachaturian, 1985). Four physicians, exper- ienced in the evaluation of dementia, applied these criteria to 62 patients using information from medi- cal records.*

* The question as to whether a NINCDS-ADRDA diagnosis can be made from case notes alone is not addressed by the Work Group, although much of their discussion seems to imply that direct assessment of the patient and informapt is necessary (see, for example, ‘Medical History’, p. 941).

Raters were blind to clinical and pathological diagnosis. The authors found the NINCDS- ADRDA criteria to have the highest sensitivity (0.92) but lower specificity (0.65). They noted that, for all the diagnostic criteria sets, considerably more misclassification occurred for the non-Alz- heimer dementias than for Alzheimer’s disease.

Reliability

Kukull et al. (1990a,b), cited above, assessed the interrater reliability of the NINCDS-ADRDA cri- teria. They found them to have higher average interrater reliability (kappa = 0.64) than the DSM- 111 (0.55) and the ECRDC (0.37).

In the study of Lopez et al. (1990), two neurolo- gists and two psychiatrists independently reviewed clinical data from medical records on 30 patients with dementia and 10 non-demented controls. These were participating in a longitudinal study of Alzheimer’s disease. The raters were blind to clinical and pathological diagnosis and categorized each case according to NINCDS-ADRDA criteria. The interrater agreement for all possible two-way combinations of clinicians was calculated using the kappa statistic. This ranged from 0.36 to 0.64. The authors concluded that ‘current NINCDS- ADRDA criteria enable moderate levels of agree- ment among clinicians in general’ (p. 1517). The most frequent source of diagnostic disagreement was whether patients had probable or possible Alz- heimer’s disease. Disagreement, in this context, was particularly likely where other potential sources of dementia existed or where the course of the illness was judged atypical.

It is difficult to interpret these findings. Very few studies investigating NINCDS-ADRDA validity and reliability have been undertaken and the numbers of subjects investigated have generally been small. The uncertain influence of other fac- tors, such as age of onset in the work of Risse et a/. (1990), further complicates assessment. The appraisal of validity is particularly problematic: this is partly due to the lack ofdefinitive neuropath- ological criteria for Alzheimer’s disease already dis- cussed; in part, it reflects issues of prevalence and sampling. Discrepant findings on validity may be attributable to variable prevalence of Alzheimer’s disease in the populations investigated. This arises because the positive predictive value of a test is diminished as the prevalence of a disease in a popu- lation decreases (British Medical Journal, 199 1, p. 48). Brayne ( l993), discussing sampling, suggests

EDITORIAL 177

that a description of ‘typical’ cases of a subtype of dementia will only be possible if the sampling frame represents the entire population with that dementia. This cannot be assumed in any of the studies cited.

There are no simple solutions to these problems. This is obvious enough, but it is important to make it explicit in case our discussion is taken as a denig- ration of the Work Group’s work. This is not our intention. The criteria are valuable, both in provid- ing a model as to how consensual criteria might be generated and in highlighting problems that impede further progress. They have limitations, but these were clearly perceived and acknowledged by the Work Group. ‘The criteria are not yet fully operational because of insufficient knowledge about the disease . . . [they] . . . must be regarded as tentative and subject to change’ (p. 939). It might be added that the same is likely to be true of any clinical criteria, for any subtype of dementia, pro- duced in the foreseeable future.

This is not to suggest that progress cannot be made. The widely perceived need for accurate diag- nostic criteria for the dementias and an awareness of shortcomings of previous work make advances in this field likely. We conclude by outlining ele- ments of a research framework which might be use- ful in this context.

MAKING PROGRESS

The generation of valid and reliable clinical criteria for Alzheimer’s disease and other dementias would be facilitated by a strategy which incorporates three complementary elements: prospective clinical stu- dies; unambiguously defined operational criteria; and an epidemiological and statistical perspective which, when applied in individual studies, facili- tates the assessment and generalization of data. It will be appreciated from previous remarks that, in respect of validity, the strategy assumes clear and agreed neuropathological criteria exist for the dif- ferent dementias. This is not discussed further.

Prospective clinical studies

Prospective clinical studies have clear benefits in terms of quality of data. The assessor is blind to outcome and diagnosis and derives information from observation and examination rather than hav- ing to interpret indirect sources such as case notes. An example is provided by the work of Gustafson

et al. (1990), who, in a longitudinal prospective study, followed up patients with presenile and senile dementia over a 20-year period. These indivi- duals had comprehensive clinical and laboratory assessments during life and many were followed from the very early to the last stages of different dementing disorders. About 80% of those who died (more than 250 individuals) went to postmortem. Using item analysis to investigate associations between clinical features and neuropathological diagnosis, the authors were able to devise and dif- ferentially weight rating scales for Alzheimer’s dis- ease and ‘dementia with frontotemporal degeneration’. They were motivated by the belief that ‘. . . a clinical diagnosis should be based on positive criteria for the disease and not only on exclusion of other possible causes’ (p. 360). To der- ive the maximum benefit from such work, clinical and laboratory data must be detailed and standar- dized. They should be correlated with results from a comprehensive regional examination of brain tis- sue for all types of pathology (Brayne, 1993).

Defined operational criteria

Clear definitions form the basis of valid replica- tive studies. We have commented on the ambigui- ties and uncertainty that result from non-specific terminology and an awareness of these problems has prompted attempts to tighten operational defi- nitions.

The Consortium to Establish a Registry for Alz- heimer’s Disease (CERAD, 1992), for example, in a diagnostic protocol based on the NINCDS- ADRDA criteria, operationalized the concept of ‘medical or neurological conditions that are believed to contribute to the dementing process’ (p. 27) by listing examples in its sections on clinical history and examination.

In a separate development, we have attempted further to operationalize CERAD’s diagnostic pro- tocol by basing its scoring on the answers to specific questions in the CAMDEX (Roth et al., 1986). We are employing this modified schedule in a prospec- tive study of dementia in the Camberwell Health Authority.

Small (1985), discussing the ischaemic score of Hachinski et al. (1975), refers to an ‘absence of specific descriptors (anchoring statements)’ (p. 5 15) for some of its items. In his ‘revised ischaemic score’, he makes useful amendments designed to overcome this. In his revision, each item is assigned a clearly defined ‘severity subscore’. For example,

178 EDITORIAL

‘fluctuating course (episodes of delirium with clouding of consciousness lasting days to weeks)’ (p. 516) is categorized and scored as: 0 = absent; 1 = mild (one or two episodes); 2 = moderate (> two episodes). Gustafson e t al. (1990), referred to above, might usefully have adopted a similar approach. Their analysis suggested, for example, that ‘early signs of disinhibition’ (p. 361) character- ized dementia with frontotemporal degeneration but not Alzheimer’s disease. They did not, however, define ‘early’. We have incorporated the frontotem- poral dementia rating scale into our Camberwell study, amending it where necessary to operationa- lize undefined items. ‘Early’, for example, is defined as ‘within 6 months of onset’. Such definitions at least ensure that the scale is applied uniformly by different assessors. The validity of the definitions will be assessed, in due course,by investigating cli- nicalheuropathological correlations.

The epidemiological and statistical framework

Prospective studies using tightly defined criteria are effective to the extent that the population of interest is delineated and a representative sample taken. A prospective study of Alzheimer’s disease patients, for example, contacted via hospital wards will not yield data which can be generalized to the total community population with Alzheimer’s dis- ease. This will clearly be the case irrespective of sampling. Where the basis of sampling is uncertain, no interpretation of the data is possible. These con- siderations are particularly apposite to the gene- ration of diagnostic criteria since the latter, by definition, refer to a population. The fundamental importance of these issues is increasingly empha- sized (see British Medical Journal, 199 1; Brayne, 1993).

JOHN LEACH RAYMOND LEVY

Institute of Psychiatry, London

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