Journal of the neurological Sciences, 1975, 26: 81-98 ~h Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands


Specificity of the Clinical Diagnosis of Dementia A. B. TODOROV, R. C. P. GO, J. CONSTANTINIDIS AYD R. C. ELSTON

University Psychiatric Clinic (A.B.T. and J.C.), Geneva (Switzerland), Department qf Biostatistics and The Genetics Curriculum (R.C.P.G. and R.C.E.) and Biological Sciences Research Center (A.B.T. and R.C.E.), University of North Carolina, Chapel Hill, N.C. 27514 (U.S.A.) (Received 10 February, 1975)


During the past few years encouraging investigations on the pathophysiology of ageing and dementia have been reported, such as studies on cerebral lipids, regional blood flow, dopamine metabolism or the experimental reproduction of Alzheimer-like lesions. But the difficulty of applying sound experimental laboratory techniques to a heterogeneous population of demented persons makes progress in this area slow. Persons over 65 yr of age represent a growing segment of the population: 9.5 ~ in the U.S.A., 12.3~ in France. A significant number will develop some manifestations of senility, in the sense of pathological ageing of mental functions, grouped in the U.S.A. under the 2 general headings of vascular and degenerative dementias (we exclude rare dementias such as Creutzfeldt-Jacob disease, Huntington's chorea, etc.). European countries probably pay more attention to the problems of ageing and are more concerned with nosological refinements. A narrow definition of the different classes has the advantage of reducing heterogeneity in what is termed dementia, but has the disadvantage of reducing the precision of diagnosis within the general class of degenerative and vascular dementias. An essential question in any study of dementia is to define terminology and to perceive the relationship between the clinical picture and pathological findings. Several studies have shown a significant relationship between symptoms and lesions (Corsellis 1962; Willanger, Thygesen, Nielsen, and Peterson 1968). Nevertheless, this correspondence between symptoms and lesions has exceptions, especially on the borderline between the normal on the one hand and early stages of dementia on the other. One of the criteria used in quantitative neuropathological studies of dementia has been the presence of senile plaques at the cortical level. Blessed, Tomlinson and Roth (1968) have shown a positive relationship between the severity of senile dementia and the number of senile plaques. On the other hand, Supported in part by U.S.P.H.S. Research Grants HD-03110, GM 16697 and I-K3-GM-31,732, National Institutes of Hearth.

A . B . TODOROV et aL


senile plaques may be found at death in mentally normal persons (qomlinson, Blessed and Roth 1968, 1970). Wildi and Dago (1968), Dago (1969), and Dayan (1970) noted the presence of senile plaques in a population of general non-psychiatric hospital patients, the number increasing with age at death. Alzheimer's neurofibrillary tangles are certainly a more reliable index of previous mental malfunction. Although they may be seen in mentally well-preserved aged persons at the level of the hippocampus, they occur only exceptionally in the cerebral isocortex of persons who have not manifested dementia. To add to the diffuseness of the correlation between symptoms and lesions, there are clinical cases of apparent dementia in which no distinctive pathologic correlates are found at biopsy or autopsy (Hughes, Myers, Smith and Torack 1973). The primary aim of this paper is to investigate the specificity of the clinical diagnosis, using an anatomical diagnosis as the point of reference. We are more interested in specificity (the proportion of all cases with a given clinical diagnosis that are confirmed by an anatomical examination) than in sensitivity (the proportion of all cases with a given anatomical diagnosis that are correctly classified clinically). An important corollary, however, is to investigate the statistical characteristics of the different anatomical classes. This enables us to determine with greater precision the way in which the anatomical classes differ from each other, and whether they are in fact distinct pathological entities. The fact that we use anatomical data as the basis for the "true" diagnosis should not be misunderstood; we do not wish to imply that the anatomical diagnosis is always correct, nor, in cases of discrepancy, that the clinical diagnosis is always wrong. The anatomical diagnosis is merely used as a point of reference, and the results on specificity must be interpreted in the light of how the anatomical classes are defined.


The first pitfall in any work on dementia is the problem of nosology (Alexander 1972). We adopt for the present work the nosology currently accepted at the University Psychiatric Clinic of Geneva, and as outlined elsewhere (Richard and Constantinidis 1970). We accept the division of dementia into degenerative and vascular varieties, degenerative dementia being subdivided into presenile (Alzheimer's disease) and senile forms (senile dementia and Alzheimerized senile dementia). We have also tried to identify a form of dementia characterized by elements of vascular and degenerative dementia (combined senile-vascular dementia). Altogether we consider 7 classes of individuals, determined either clinically or anatomically; every patient on whom an autopsy was performed at the University Psychiatric Clinic of Geneva between 1st January, 1960 and 31 st December, 1969, and on whom sufficient data are available (776 out of 982 cases), has been included in a single clinical class and in a single anatomical class.

Clinical classification Since we are primarily interested in the specificity of the clinical diagnosis, we have



accepted as the clinical diagnosis that given by the clinician before he had any knowledge of the anatomical findings. Other clinical data were not reviewed, in order to avoid any inference from information obtained after the death of the patient: otherwise the clinical diagnosis might have been seriously biased toward the anatomical diagnosis. However, the age of onset of the disease, the length of hospitalization and the age at death were noted from the original patient folders and used in the analyses presented later. The criteria for the clinical diagnosis can be summarized as follows : (1) No dementia (101 cases). This is any diagnosis in which there is no evidence of dementia. These patients are hospitalized for disorders unrelated to a dementing process; they may have schizophrenia, manic-depressive psychosis, or other psychiatric conditions. (2) Senile dementia (SD, 170 cases). In this disorder the onset is usually slow and insidious. Appearing by the age of 70 yr, amnesic dysfunction may be the first manifestation of SD. Intellectual fatigability and dysthymia (mainly depressive mood) may be early symptoms. Delirious ideas with accusatory construct are not exceptional. With a more pronounced intellectual impairment other symptoms appear, such as temporo-spatial disorientation, amnesia for registration and recall, confabulation, wrong recognitions, failure to recognize and perseveration. Simplified language, paraphasia, missing words, and constructive aphasia may exist, without other aphaso-apraxo-agnosic symptoms. The neurological evaluation may show some opposition hypertonicity and occasionally a grasping reflex. The evolution is slowly progressive and lasts 3-8 yr. With the advance of SD, disorientation may become total. The mnesic and operative functions may be nil, without any significant affect on the instrumental functions. (3) Alzheimerized senile dementia (ASD, 67 cases). This ig characterized by an aphaso-apraxo-agnosic symptomatology overlying a clinical picture of SD. In ASD there is a decrease of operative functions and release of primitive pre-frontal reflexes (grasp reflex, sucking reflex, palmomental reflex, conservation of postures). Opposition hypertonicity, stereotypies and disintegration of oculo-motor function are usually observed. The concomitant disintegration of language, praxis and gnosis may be divided into several periods as the dependency of the patient and the severity of the condition increases. In the usual form of ASD there are neither pyramidal signs, nor cerebellar or labyrinthic involvement. Seizures are common. (4) Alzheimer's presenile dementia (APD, 36 cases). Usually, but not invariably, this condition begins before the age of 65 yr. The clinical picture is comparable to the description given above for ASD, but the aphaso-apraxo-agnosic symptomatology has a more rapid and dramatic course. An autosomal dominant hereditary pattern is usual. (5) Vascular dementia (VD, 193 cases). This is a demented state with either focal symptomatology (history of stroke ; focal neurological signs such as hemiplegia and cortical blindness ; clinical evidence of vascular dysfunction of the brain) or diffuse symptomatology (lacunar loss of memory, heterogeneous disturbances of instrumental functions, nosognosia to some extent). (6) Combined senile-vascular dementia (CD, 159 cases). This is an ill-defined


A . B . TODOROV et a /

diagnosis with symptoms of both degenerative dementia and vascular mental deterioration in varying degree. (7) Undefined dementia (50 cases). This includes all cases of dementia in which the clinician was unable to reach a satisfactory diagnosis. It is thus expected to be a heterogeneous class. Cases with rare dementing conditions such as Huntington's chorea, Pick's disease or Creutzfeld-Jacob syndrome are not included in the study.

Anatomical class!fication A routine anatomical examination was performed by the person who conducted the autopsy, following the same protocol of macroscopic and microscopic examination throughout the whole study. Histological sections were in each case obtained in the same areas of the neocortex (prefrontal, central parietal, temporal and occipital) and of the allocortex (hippocampus). Twenty-four variables were recorded. These were used for subsequent analyses as well as to provide a basis for the anatomical classification. Three of the 24 variables were quantitative : cerebral weight (1), cranial capacity (2) and Reichart's coefficient (3). Seven variables were recorded in 2 grades (absent = 0, present = 1) ; these were scalariform arteriosclerosis (4), vascular lesions in the grey matter (5), white matter (6), basal ganglia or brain stem (7) ; granular atrophy of the cortex (8), gliosis (9) and traumatic lesions (10). In the case of the following 9 variables 5 grades were recognized (no lesions=0: very mild = 1 : mild = 2 ; severe = 3 ; very severe =4) : they were cerebral arteriosclerosis (11), cerebral atrophy (12), ventricular dilatation (13), density of senile plaques (14), Alzheimer's neurofibrillary tangles in the frontal cortex (15), occipital cortex (16), and hippocampus (17); astrogliosis (18), and microscopical vascular lesions (19). In the following 2 variables 4 grades were recognized (no lesions=0, mild= 1. severe=2, very severe= 3): these were alcoholic lesions such as acute superior haemorrhagic polio-encephalitis (Wernicke's encephalopathy), astrocytic proliferation with neuronal loss (especially in the third layer of the frontal cortex), cerebellar degeneration (20), and intensity of vascular lesions (21). Finally 3 grades were recognized in the remaining 3 variables (no lesions = 0, mild = 1, severe = 2), viz. : intensity of the Alzheimerization process (22), lacunar degeneration of the white matter (23), congophilic degeneration and dyshoric angiopathy of the arterioles (24). The criteria for using the above data to obtain the anatomical diagnosis were as follows: (1) No encephalopathy (94 cases); these were cases in which there was no neuropathological evidence of involvement of the central nervous system. (2) Senile dementia (SD, 82 cases). In SD the macroscopical examination showed a smooth, moderate and diffuse brain atrophy. Lateral ventricles were somewhat enlarged. Histologically, there were numerous senile plaques with some glial reaction, particularly in the association areas of the cortex. At the subcortical level senile plaques were usually seen in the amygdaloid nucleus, the hypothalamus, the corpora mammillaria and the corpora quadrigemina. Neurofibrillary tangles (NFT) were observed in the iso- and the allo-cortex of the hippocampus. The pyramidal cells of



the hippocampus sometimes exhibited granulo-vacuolar changes. In the present work we have included in the category senile dementia cases with cortical NFT limited only to the hippocampus. Two other interneuronal lesions might also be observedcongophilic degeneration of the arterioles and dyshoric angiopathy. The congophilic degeneration of the arteriolar walls involves arterioles of the size of the perforating arterioles. It is characterized by a deposit of congo- and argyrophilic material within the arteriolar walls. The dyshoric angiopathy usually involves smaller caliber vessels than the congophilic degeneration of the arterioles. This is characterized by the presence of argyrophilic material within the surrounding arteriolar walls, producing a glio-adventitial symphysis. (3) Alzheimerized senile dementia (ASD, 102 cases). In ASD cerebral atrophy was widespread. There was gyral wasting, and the cerebral surface was not smooth as in SD. The convolutional atrophy involved the areas of projection and essentially the association areas of the brain. NFT were present in the hippocampus and in the neocortex, especially in the temporal, pre-frontal and parieto-occipital cortex. NFT were sometimes found in the basal ganglia. Congophilic degeneration of the arterioles and dyshoric angiopathy were frequently observed. (4) Alzheimer's presenile dementia (APD, 32 cases). Neuropathologically APD cannot be distinguished from ASD. The anatomical label "Alzheimer's presenile dementia" was used when the onset of the condition had been recognized clinically before the age of 65 yr and the criteria described for ASD had been fulfilled. (5) Vascular dementia (VD, 132 cases). Parenchymatous lesions of vascular origin were the diagnostic features : arteriosclerotic plaques in the circle of Willis were insufficient evidence to support this diagnosis. (6) Combined senile-vascular dementia (CD, 250 cases) exhibited concomitant features of degenerative and vascular lesions in various proportions. (7) Undefined encephalopathy (84 cases). In this group were pooled all of the cases with neuropathological lesions other than those observed in the above-defined categories. STATISTICAL METHODS

Standard statistical methods were used for regression, correlation and all univariate tests of significance. In the case of multivariate tests 3 standard tests were performed : Hotelling's T 2, Wilk's 2-criterion (likelihood ratio test) and Roy's maximum root criterion (see, e.g., Morrison 1967). In no cases were the results of these 3 tests found to differ in a manner of any practical importance. The linear discriminant functions corresponding to the 2 largest characteristic roots of the appropriate matrix were used to obtain a visual plot of the separation of the classes. The results for each individual were plotted as a point on a plane on the basis of his 2 discriminant scores. The smallest convex polygon that enclosed the points obtained for all the individuals of a particular class was used to determine the limits of that class ; the area of overlap between the polygons for 2 classes, expressed as a percentage of the area of the smaller polygon, was used to determine how distinct the classes were. Zero overlap was termed separable, up to 10~ overlap was termed nearly separable, and between 10~ and 50~ overlap was termed partially separable ;

A . B . TODOROV el al.


unseparabte was defined as more than 50~o overlap. The importance of each variable in the discriminant functions was judged by its correlation, over the whole sample, with the discriminant score for each individual, and by performing a stepwise regression of the discriminant scores, over the whole sample, on the variables.


Summary classification of the cases studied Table 1 shows how the total of 776 cases studied were classified according to the clinical and anatomical criteria given above. The fact that larger numbers occur in the main diagonal of the table than in the off-diagonal cells reflects the association between the clinical and anatomical diagnoses. This association is also reflected in the fact that the percentage specificity for each clinical class is always greater than the marginal percentage of cases in each corresponding anatomical class. The latter figure is what the expected specificity would be if the clinical diagnosis were assigned at random, but with the appropriate proportions of cases in each class. An overall measure of the agreement between the clinical and anatomical diagnoses is given by Cohen's (1960) coefficient x = 0.27; this has a standard error of 0.021, and so is highly significantly different from zero. Similarly a weighted r (Cohen 1968) can be calculated, from TABLE 1 CLASSIFICATION OF 776 CASES ON THE BASIS OF CLINICAL AND ANATOMICAL CRITERIA. Marginal percentages, percentage specificities and percentage sensitivities are given for each clinical and

anatomical class.

Clinical diaonosis

No. of ' cases

No enceph- SD ASD APD VD CD Unalopathy defined (94) (82) (102) (32) (132) (250) (84)

°,/o Sensitivity

Marginal ",,

No dementia











Senile dementia











Alzheimerised senile dementia











Alzheimer's presenile dementia











Vascular dementia











C o m b i n e d dementia






















Percentage specificity








Marginal percentage











Table 1, for any set of weights that are thought to reflect the seriousness of each type of misclassification. Taking as a point of reference the anatomical diagnosis, the specificities of the clinical diagnosis were as follows : (1) In the SD class the specificity of the clinical diagnosis was only 19.4~. In 48 of 170 cases the clinical diagnosis of SD was made instead of ASD. In 49 other cases, a confusion with CD occurred. (2) In theASD class, the specificity was 43.4~o. The existence of a degenerative process was erroneously suspected in only 5 of 67 cases. (3) In the A P D class, the specificity was 77.8~. In 8 of 36 cases, a diagnosis of A D P was erroneously made. (4) In the VD class, the specificity was 38.9~. In 84 of 193 cases, a diagnosis of VD instead of CD was made. (5) In the CD class the specificity was 47.8~o. In 58 out of 159 cases, a diagnosis of CD instead of another form of dementia was made. Taking as a point of reference the clinical diagnosis, the sensitivities of the clinical diagnosis were the following : (1) In the SD class, the sensitivity of the clinical diagnosis was 40.2~. In 19 of 82 cases a confusion with the diagnosis CD occurred. (2) In the ASD class, the sensitivity was 28.4~. In 48 of 102 cases a confusion with the diagnosis of SD occurred. (3) The sensitivity of A P D was 87.5~. Only in 4 of 32 cases was a diagnosis other than APD made. (4) In the VD class the sensitivity was 56.8~o. In 22 of 132 cases, a diagnosis of CD instead of VD was made. (5) In the CD class, the sensitivity TABLE 2 MEANS FOR THE 7 ANATOMICALCLASSES

No Variable name




Senile Alzheimerized dementia dementia



Alzheimer's disease


Vascular Combined dementia dementia



Undefined (84)

Age at death (yr)


62.55 69.32

81.20 81.58

80.00 81.35

68.21 70.66

77.11 78.51

81.93 83.51

78.61 80.93

Age of onset (yr)


44.56 57.47

79.40 78.31

75.94 76.49

59.35 61.26

72.88 72.71

75.75 78.60

72.48 75.28








1253.25 1131.29

1283.75 1109.36

Length of hospitalization (yr) Brain weight (g)


1324.89 1204.53

1197.06 1069.33

Vascular lesions a Senile plaques" Alzheimer's lesions a (hippocampus) Alzheimer's lesions a (frontal cortex) " Qualitative scores (see text).





1287.55 1145.96

1246.83 1137.22












1339.82 1145.78



A . B . TODOROV e t


of the clinical diagnosis was 30.4,90. In 84 of 250 cases, a diagnosis of VD instead of CD was made; and in another 49 a diagnosis of SD instead of CD was made.

Effect of sex Table 2 gives the most important means for each anatomical class. In a 2-way multivariate analysis of variance, the 2 factors being sex and anatomical class, sex was found to be highly significant. Seven variables showed a sex effect significant at the 5 ~ level by univariate F-tests. These were (approximate significance levels are indicated): age at death (P = 0.002), age of onset (P = 0.013), brain weight (P < 0.001), cerebral arteriosclerosis (P = 0.012), degree of cerebral atrophy (P = 0.004), cranial capacity (P< 0.001) and degree of ventricular dilation (P = 0.022). Two variables showed significant sex by class interaction by univariate F-tests, viz. : age of onset (P = 0.005) and cranial capacity (P = 0.016); the multivariate tests, however, indicated no overall significant sex by class interaction. In view of this, in all subsequent analyses the results for the 2 sexes were pooled, after adjusting each variable for sex by using the same additive difference for all 7 groups. Relationship between brain weight and age Table 3 gives the correlations, in our sample, between brain weight on the one hand and age of onset, length of hospitalization, and age at death on the other. In most classes there were no significant correlations between brain weight and age of onset. Only in the class with no encephalopathy was there a correlation which was significant at the 5 ~o level (P=0.042). The regression, though significant, was small (--0.090 TABLE3 CORRELATION COEFFICIENTS AND REGRESSION COEFFICIENTS FROM A REGRESSION OF BRAIN WEIGHT ON AGE OF ONSET. LENGTH OF HOSPITALIZATION~ AND AGE AT DEATH

A g e at o n s e t Anatomical

No. o[





1. N o encephalopathy


-0.028 -0.090±0.044

2. Senile dementia


- 0 . 0 9 2 -0.132-+0.161

3. Alzheimerised senile dementia


4. Alzheimer's presenile dementia


5. Vascular dementia 6. Combined dementia 7. Undefined

Length of hospitalization ra




A,qe at d e a t h r~


- 0 . 2 1 4 ~ -0.150±0.071

-0.055 -0.141±0.285

- O . 130



0.198 ± 0.210 - 0 . 0 7 9 - 0.360± 0.453




0.959__+0.495 -0,111 - 0 . 2 8 7 + 0 . 4 6 9


0.073 ± 0.432


- 0 . 0 6 5 -0.066-+0.088 -0.185¢-0.205-+0.095




- 0 , 1 1 0 -0.098-+0.056 - 0 . 0 4 5 -0.054+__0.076

-0,203 ~ -0.314+0.096

-0.085 -0.079+0.103

- 0 . 3 0 0 ¢ - 0 . 5 0 5 -+0.177


"Correlation coefficient. bRegression coefficient g/month. c P < 0.05.

-0.166 -0.195+0.128



g/month). A much larger positive regression was found for Alzheimer's presenile dementia (0.959 g/month), but, with the smaller sample size, this was barely significant (P = 0.059). There was a significant negative correlation between brain weight and length of hospitalization for the class of vascular encephalopathy (P=0.032, a regression of 0.205 g/month); otherwise none of the correlations with length of hospitalization approached significance. In the case of age at death, there were significant negative correlations with brain weight in 4 of the classes; viz.: no encephalopathy (P=0.036, -0.150 g/month), vascular dementia (P=0.013, -0.215 g/month), combined dementia (P=0.002, - 0.203 g/month) and undefined encephalopathy (P = 0.006, - 0.300 g/month). In the case of both Alzheimer's presenile and Alzheimerized senile dementia there was no significant correlation (P >0.8) and the observed correlations were positive. Separation of the classes Various discriminant analyses have been performed among the 7 anatomical classes, with a view to better identifying how distinct these classes are. In the first place 2 separate analyses were attempted, using either the 24 anatomical variables described above or the 3 "clinical" variables; i.e., age of onset, length of hospitalization and age at death. Using the 2 discriminant scores to see how the classes cluster on the basis of the clinical variables only, Alzheimerized senile dementia (ASD) and Alzheimer's presenile dementia (ADP) were clearly separable (Table 4, upper half); that these should be separable is of course an expected result, since they were defined to differ only in age of onset. SD and APD were partially separable on the basis of these variables, which again was to be expected. Better separation, however, was evident when the anatomical variables were used (Table 4, lower half) ; in particular, vascular dementia (VD) was nearly separable from no encephalopathy, and combined dementia (CD) was completely separable from no encephalopathy. This latter result was somewhat surprising, especially as it represented the only 2 classes, based on the anatomical variables alone, that were completely distinct. When all 27 variables were analyzed together in a similar manner, there was a great increase in the separation of the classes (Table 5, lower half). Most pairs of classes were now at least partially separable. The only exceptions were SD vs. CD, CD vs. undefined and ASD vs. APD. Fig. 1 shows the convex polygons on which the lower half of Table 5 is based. Of course, if the same linear discriminant functions were used on an independent set of data, the separation would not be as great ; but the fact that the 2 discriminant functions are highly significant indicates that the separation was not just due to chance. Since there may be some doubt as to whether ASD is in fact a distinct disease entity, this last discriminant analysis was repeated, but with this class pooled together with senile dementia ; thus only 6 different classes were used to obtain the discriminant functions. When these discriminant scores were plotted, and then all 7 anatomical classes were identified on the plot, the result was virtually the same as shown in the upper half of Table 5. Although the overlap between ASD and SD was increased, the 2 classes were still partially separable (less than 50~ overlap). This strongly suggested


A.B. TODOROV et al.









Specificity of the clinical diagnosis of dementia.

The specificity of anatomo-clinical observations were investigated on 776 out of 982 consecutive persons hospitalized at the University Psychiatric Cl...
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