What contribution can the Hachinski ischemic scale make to the differential diagnosis between multi-infarct dementia and primary degenerative dementia?

Arch. Gerontol. Geriatr., 11 (1990) 63-75

63

Elsevier AGG 00337

What contribution can the Hachinski Ischemic Scale make to the differential diagnosis between multi-infarct dementia and primary degenerative dementia? Elmar Gr~isel, Steve Cameron and Siegfried Lehrl Department of Medical Psychology and Psychopathometry, University of Erlangen-Niirnberg~ D-8520 Erlangen, F.R.G. (Received 5 December 1989; revised version received 24 April 1990; accepted 31 May 1990)

Summary Five research studies in which clinical diagnoses using the Hachinski Ischemic Scale (HIS) underwent neuropathological verification were analysed. These studies reveal that the HIS differentiates between multi-infarct dementia (MID) and dementia of the Alzheimer type (DAT) with only limited accuracy. To some extent, there are considerable differences between the studies as regards the methodology and the patient population. However, there are indications that some items of the ischemic scale clearly distinguish between MID and DAT, whereas others hardly do so or some do not distinguish at all between these two conditions. If the HIS is revised according to the present findings, it can become a more valid differential diagnostic instrument. Such a diagnostic instrument which may be applied without any other technical equipment is required today, since epidemiological data and demographic prognoses show that the prevalence of dementing illnesses will markedly increase in the future. Hachinski Ischemic Scale; Multi-infarct dementia; Primary degenerative dementia; Dementia of the Alzheimer type; Alzheimer's disease

Introduction Senile dementia has major epidemiological significance. It is estimated that about 10% of people over 65 years old show a mild to moderate decrease in intellectual ability and additionally that about 4-5% suffer from severe dementia (Terry and Katzman, 1983). It is supposed that more than 15% of people over 85 years old

Correspondence to: Elmar Gr~isel, Department of Medical Psychology and Psychopathometry, University of Erlangen-Niirnberg, Schwabachanlage 6 and 10, D-8520 Erlangen, F.R.G. 0167-4943/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)

64 suffer from severe dementia (Gruenberg, 1961). Considering the demographic tendency for a proportional rise of people over 65 years old in the total population, a substantial increase of those suffering from dementia is to be expected. Projected calculations estimate a triphng of the prevalence of dementia of the Alzheimer type (DAT) up to the year 2050 (Karp and Samuels Mirra, 1987). An increase in dementia of vascular etiology is also predicted (Salam-Adams and Adams, 1988). However, according to large-scale neuropathological studies of demented patients, DATs represent the vast majority of dementing illnesses (Tomlinson et al., 1970; Jelhnger, 1976). In half of the cases exclusively pathological changes of the Alzheimer type were diagnosed. Arteriosclerotic lesions were found in 20% of the cases. The frequency of cases with combined pathological changes (in the sense of DAT and multi-infarct dementia (MID)) amounted to 10%. Cases with other causes of dementia and cases without pathological indications of dementia were found at the same frequency. Because of the growing significance of dementia, research in this field is presently receiving high priority (AUard et al., 1988). Various hypotheses are being considered (Proctor et al., 1988; Haynes et al., 1989; Marcus et al., 1989). Since MID and DAT are based on different etiopathology, the development, testing and application of specific therapeutic strategies require an exact diagnosis. The Hachinski Ischemic Scale (HIS) was introduced in 1975 to standardize the differential diagnosis between MID and primary degenerative dementia (Hachinski et al., 1975). This objective evaluation scale consists of items for systematic registration of anamnestic information, present complaints and medical examination findings (Fig. 1). Since its apphcation does not require any technical apparatus, it might be a useful instrument for physicians and in clinics. For this reason, it is of importance to know whether the HIS really does differentiate between MID and DAT.

Materials and Methods The Hachinski lschemic Scale

The original form consists of thirteen items, which are thought to be characteristic of MID (Fig. 1). The selection of these items may be traced back to a publication of Mayer-Gross et al. (1969) which correlated autopsy findings (ischemic changes in the brain) with chnical criteria. Items 1-3, 9 and 10 (see Fig. 1) comprise data from the patient's history. The remaining eight items refer to complaints of the patient, to findings of the internist and above all to the neurological and psychiatric examinations. According to Hachinski et al. (1975), an observed item is evaluated with one or two points (see Fig. 1) depending upon its correlation with ischemic changes in the study of Mayer-Gross et al. (1969). Therefore the HIS score may vary between 0 and 18.

65 Item

Score

l Abrupt onset

2

2 Stepwlse deterioration 3 Fluctuating course

2

4 Nocturnal confusion 5 Relative preservation of personality 6 Depression 7 Somatic complaints 8 E~tlonal incontinence 9 History of hypertension IO History of strokes

2

II Evidence of associated atherosclerosls

l

12 Focal neurological symptoms

2

13 Focal neurological signs

2

Total:

0 to 4 points: 7 to 18 points:

Primary degenerative dementia Hulti-lnfarct d ~ n t l a

Figure l: Ischemlc-scale from Hachinskl et el. (1975)

Using the ischemic scale, Hachinski et al. (1975) obtained a bimodal distribution of the scores. On the basis of the first concentration at 2 points, they interpreted the results between 0 and 4 points as a consequence of primary degenerative dementia. High scores (7 points or more) around the second concentration at 8 'were classed as having multi-infarct dementia'. None of the 24 patients examined by Hachinski ¢t el. (1975) received a score between both intervals (5 or 6 points). Later this interval was assigned to the mixed form (MIX). Hachinski et el. (1975) supposed that their classification was confirmed by the fact that patients classed as MIDs showed a (significantly) lower mean cerebral blood flow (CBF; xenon-133 method; Hachinski et el., 1975; Harrison et el., 1979) compared to patients 'labeled as having primary degenerative dementia'. However, other publications dealing with CBF showed either opposite results (lower CBF in primary degenerative dementia; Ingvar et el., 1978; Deutsch and Tweedy, 1987) or no differences between the two groups (Kohlmeyer, 1982). These inconsistencies could be due to varying duration or severity of dementia (Rogers et al., 1986). Since the use of cerebral blood flow shows different results, another criterion of validity should be used to verify the HIS.

Verifying the H I S on the basis of neuropathological findings Apart from measurement of cerebral blood flow (CBF), the differential diagnosis between MID and DAT was confirmed mainly by computer tomography (CT). Whereas the measurement of CBF led to contradictory results, the differential diagnosis of dementia types by CT is considered to be more valid (Kohlmeyer, 1982; Lceb and Gandolfo, 1983; Wagner et el., 1985; Erkinjuntti et al., 1986; Filley

66 et al., 1986). The sensitiveness of this technique can, however, be seen as not yet sufficient enough to be able to establish the 'correct' diagnosis with an adequate degree of certainty (Jacoby and Schmidt, 1985). Therefore, only neuropathological evidence will be taken as the validity criterion in the present analysis. This evidence should be adequate since MID and DAT are essentially defined neuropathologically (e.g., Tomlinson and CorseUis, 1984). Moreover, the 'criteria for diagnosis of definite Alzheimer's disease' (or of dementia of the Alzheimer type) comprise 'histopathologic evidence obtained from a biopsy or autopsy' and the clinical criteria, which render DAT probable (Karp and Samuels Mirra, 1987). In our article, the results of five known studies will be systematically presented and analyzed. The diagnoses which are based on HIS scores will be compared with neuropathological findings. We refer to one retrospective and four prospective studies published between 1980 and 1988: (A) Rosen et al. (1980); (B) Gustafson and Nilsson (1982); (C) Mt~lsa et al. (1985); (D) Wade et al. (1987); (E) Homer et al. (1988).

Results

Frequency of dementia types in the neuropathologicai studies In four studies (A-D), the neuropathologically confirmed frequency of MID approximately corresponds to the data published in large-scale neuropathological studies (20% MID cases; Tomlinson et al., 1970; Jellinger, 1976). An exception is the Homer study (E) with a very high proportion of MIDs (70%) and a correspondingly low proportion of dementias of Alzheimer type (26%; Table I).

Comparison of HIS results with neuropathological findings A typical bimodal distribution of the HIS scores, as described by Hachinski et al. (1975), which constituted the classification in DAT at 0 to 4 HIS points and MID at 7 to 18 points, was not shown in any of the five studies (Figs. 2 and 3). In order to obtain a general survey of the ability of the HIS to differentiate between MID, MIX and DAT, the total distributions of the HIS scores are presented, including a synopsis of the results from all five studies (Table II and Fig. 4). Since differences in methodology exist between the studies (compare 'Discussion'), the resulting distributions will only be analyzed descriptively. The cluster of those cases neuropathologically verified as DAT between 0 and 4 HIS points is remarkable (concentration at I point, Fig. 4), so that altogether 84% of the DATs were correctly rated using the HIS. These are 80 of 95 cases (Table II). The fact that so many DATs were classified correctly is not only a result of the summation, but is also to be found in all five studies (compare Figs. 2 and 3 as well as Table I, columns III and IV).

67 TABLE I Comparison between HIS results and neuropathological findings II Pathological diagnosis

III HIS: correctly classified

IV HIS: incorrectly classified

V Correct : incorrect classifications (error rate)

Study of

I

(A) Rosen et al. (1980) n = 14

MID MIX DAT

4 (0.28) 5 (0.36) 5 (0.36)

4 0 3

0 5 2

7 : 7 (0.50)

(B) Gustafson and Nilsson (1982) n = 22

MID MIX DAT

4 (0.18) 0 (0) 18 (0.82)

1 0 16

3 0 2

17 : 5 (0.23)

(C) Mt~lsa et al. (1985) n = 45

MID MIX DAT

11 (0.25) 6 (0.13) 28 (0.62)

7 1 20

4 5 8

28 : 17 (0.38)

(D) Wade et al. (1987) n = 54

MID MIX DAT

6 (0.11) 10 (0.19) 38 (0.70)

2 3 35

4 7 3

40 : 14 (0.26)

(E) Homer et al. (1988) n = 23

MID MIX DAT

16 (0.70) 1 (0.04) 6 (0.26)

4 0 6

12 1 0

10:13 (0.57)

n, number of subjects with neuropathologically verified diagnosis (without cases with another specific diagnosis, e.g., Parkinson's disease). Column I: MID, Multi-infarct dementia; MIX, Mixed form (combined MID and DAT); DAT, Dementia of the Alzheimer type (primary degenerative dementia). Column II: Number of subjects with specific neuropathological diagnosis (in parentheses the relative frequency in relation to n). Column Ill/IV: Frequency, according to the HIS, of correctly classified (III) or incorrectly classified (IV) cases, when the following classification is used - 0-4 HIS points indicate DAT; 5-6, HIS points indicate MIX; 7-18, HIS points indicate MID. Column V: Relationship between the total correctly or incorrectly classified cases (error rate: relative frequency of the incorrectly classified cases in relation to n).

H o w e v e r , this is d i f f e r e n t w i t h M I D a n d M I X . F r o m all 41 n e u r o p a t h o l o g i c a l l y verified M I D s o n l y 18 (44%) were classified a c c o r d i n g to the H I S as M I D ( T a b l e II). H o w e v e r , the results i n the s t u d i e s m e n t i o n e d a b o v e a r e n o t u n i f o r m . I n s t u d y (A) all 4 M I D s received m o r e t h a n 6 H I S p o i n t s a n d were t h e r e f o r e c o r r e c t l y classified b y the i s c h e m i c scale (Fig. 2). O n t h e o t h e r h a n d , i n s t u d y (E), i n w h i c h M I D s were relatively f r e q u e n t l y d i a g n o s e d b y m e a n s of p a t h o l o g y , o n l y 25% o b t a i n e d m o r e t h a n 6 p o i n t s (Fig. 3). U s i n g the H I S , the m i x e d f o r m s ( M I X ) w e r e r a r e l y d i a g n o s e d c o r r e c t l y i n all five s t u d i e s ( c o m p a r e T a b l e I, c o l u m n s I I I a n d IV). O n l y 18% of the M I X s (4 f r o m 22) were classified c o r r e c t l y ( T a b l e II), since the H I S scores of t h e n e u r o p a t h o l o g i c a l l y verified M I X s r a n g e d e q u a l l y b e t w e e n 1 a n d 14 p o i n t s (Fig. 4).

68 Rosen et al., 1980:

Retrospective study

14 cases (?/?)a) age: 74-93b)yeors(84.2) c) 1

Number of cases

it

h I+ '

0

1

2

3

,I

4 I 5 I

6 ; 7 ' 8 ' 9 I HIS score

~Jl 10

11

m 12

13

14

1

MID

~

Mzx

15'16'17'18'

Legend: o) proportion of female to male subjects b) range c) a r i t h m e t i c mean Comment: Cases with other specific diagnoses were not included in the study.

Gustafson and Nilsson, 1982:

Prospective study

28 cases (7/7), age: average approximately 64 years

1

Number of cases

MID AIz&P

6

~

other

4. 2. O. I

10

I

11

12

13

14

15

16

17

18

HIS score Comments: NO mixed forms (between h,t[D and AIz &P) were neuropothologically found. Since mean HIS scores ( f r o m t w o indipendent raters) were published, classified HIS scores are given here ( f o r example HIS scores of 1.0 and 1.5 are summarized w i t h a score of 1).

C

M~Is/~ et al.,

1985:

58 cases ( 4 3 / 1 5 ) ,

Prospective study age: 5 9 - 9 5 years ( 7 9 , 2 ) 1

Number of cases

MID AIz

12-

~PP ,P ,P ,P ,P ,P ,P ,P ,~M I X

108" 64-

o-

Z

13 I

14

15

16

17

18

HIS score

Comment: HIS scores f o r the 13 cases w i t h o t h e r specific diagnosis w e r e not published.

Fig. 2. Distribution of HIS scores in relation to the neuropathological diagnosis (studies A, B, C). (A, B, C) MID, multi-infarct dementia; DAT, dementia of the Alzhcimer-type; AIz, dementia by Alzheimer's disease; Alz & P, demvntia by Alzheimer's or Pick's disease; MIX, mixed form; other, other specific diagnoses (e.g., Parkin.~3n'sdisease, Jacob-Creutzfeldt's disease).

69

al., 1987: 65 cases (32/33), age: 52-92 years (76,5)

Prospective study

Wade et

Number of

I

cases

MID

DAT m

1o

MIX

iiii~!

68

~

other

: : : : : I

4 o.

+___I~ I

0

__ 2

3 I

HIS score

Homer et al., 1988: 27 cases ( 1 7 / / 1 0 ) , age: 70-94 years(82) Number of

Prospective

I

cases

study MID

4 2 0 I

I

HIS

Fig. 3. Distribution of HIS scores in relation to the neuropathological diagnosis (studies D, E). For abbreviations see legend to Fig. 2,

The cons~lucnc¢ is an error rate of the HIS diagnosis which varies in the single studies between 0.23 and 0.57 (Table I) and averages (median) at 0.38. It thus may be expected that when compared with the neuropathological findings a differential diagnosis between MID, MIX and DAT using the HIS alone, will be incorrect in

TABLE II Cross-table for HIS and neuropathological diagnosis

HIS

Neuropathology DAT

Total MIX

MID

DAT

(~

7

12

99

MIX MID

10 5

(~ 11

11 @

25 34

Total

95

22

41

158

Encircled numbers are the numbers of cases in which the HIS diagnosis corresponds to the neuropathological diagnosis ('correct' HIS diagnosis).

70 Number

Neuropat hological diagnosis:

o f cases

24.

MID

22~

'81

...

..........

DAT

....

MIX

'.

16"

"..

14 12

10

:'...

8

i

.

4

"'.. / ' ~

2

j , - - % , /-7-,. -.- _ . . , ,

0

/

0

,' 1

2

3

I

4 I 5

,

6 I 7

8

A 9

10

11

12

13

14

. 15 . . 16 . . .17

18

H I S score

Fig. 4. Total distribution of HIS scores for the neuropathological diagnosis of MID, MIX and DAT.

every third case on average. The fact that HIS results over~6 points do not exist for all other mentioned diseases which led to dementia is interesting (Figs. 2 and 3). There is no 'mixture' between MID and other specific diagnoses, as for example Parkinson's disease, Jacob-Creutzfeldt's disease, etc. Which items of the HIS are suitable for differentiation between MID and DA T?

One reason for the weak differentiation by the HIS may perhaps consist in the insufficient or hardly existing selectivity of several items. On the one hand, this may be deduced from theoretical considerations. On the other hand, this explanation is corroborated by empirical data. Theoretical considerations Introducing the ischemic scale, Hachinski et al. (1975) only referred to the correlation of the items with ischemic changes of the brain. The absence of a specific delimitation of the items to primary degenerative dementia (the items should hardly or not at all apply to primary degenerative dementia) could have led to their lack of selectivity. Moreover, the lack of selectivity of some items may be deduced from conclusions concerning the psychopathology of organic psychoses (Wieck, 1967; Kinzel, 1972); i.e., 'The short-term findings of organic psychoses do not allow a differential diagnosis to be made'. This means that vascular and degenerative causes of organic psychoses lead to the same short-term findings (see also Erkinjuntti et al., 1986). The symptoms 'Nocturnal confusion', 'Relative preservation of personality' and 'Depression' (Fig. 1, items 4-6) as weU as 'Emotional incontinence' (Fig. 1, item 8)

71 d e p e n d u p o n the s e v e r i t y of the d e m e n t i n g illness, b u t n o t u p o n its e t i o l o g y . T h e y t h e r e f o r e r e v e a l the l e n g t h of the illness p r o c e s s , b u t t h e y are i n d e p e n d e n t of its cause.

Empirical data E m p i r i c a l d a t a o n the i t e m level w e r e r e p o r t e d in o n l y t w o o f the five s t u d i e s ( R o s e n et al., 1980; M o l s a et al., 1985). I n a d d i t i o n , the results o f F i s c h e r et al. (1989) are to b e t a k e n i n t o c o n s i d e r a t i o n . T h i s s t u d y e x a m i n e s s p e c i f i c a l l y the d i s c r i m i n a t i v e p o w e r of the H I S i t e m s a n d uses as well the n e u r o p a t h o l o g i c a l d i a g n o s i s as the v a l i d i t y c r i t e r i o n . T h e f o l l o w i n g s t i p u l a t i o n s are to b e m a d e w i t h r e g a r d to selective i t e m s w h i c h d i f f e r e n t i a t e b e t w e e n M I D a n d D A T : f r e q u e n t o c c u r r e n c e in the c a s e of M I D a n d s i m u l t a n e o u s l y r a r e o c c u r r e n c e in the c a s e o f D A T . TABLE III Relative frequency in which the HIS items occurred in MID and DAT patients (selective items are marked by border) HIS item

1. Abrupt onset

2' St~pwise det~ri°rati°n

Neuropathological diagnosis and No. of cases Rosen et al. (1980)

M01stt et al. (1985)

Fischer et al. (1989)

MID : DAT 4:5

MID : DAT 11:28

MID : DAT 11:16

V-----"-'q [0.75:0 I

0.45 : 0.21

0.45 : 0.25

[ 0"55:0"11

0.45 : 0.38

I ~

I

J

0:8 ]

3. Fluctuating course

0.25 : 0.40

I 0.64: 0.18

4. Nocturnal confusion 5. Relative preservation of personality 6. Depression 7. Somatic complaints 8. Emotional incontinence 9. History of hypertension

0.50 : 0.60 mc : mc 0.25 : 0.60 0.25 : 0 0 :0 0.75 : 0.40

0.36 : 0.18 0.27 : 0 0.27 : 0.07 0.27 : 0.21 0.27 : 0.04 0.27 : 0.14

0.27 : 0.44 0.45 : 0.31 0.45 : 0.56 0.45:0.13 0.18:0.31 0.55 : 0.56

10.55:0.14

10.91:0-19 I

0.64: 0.39

0.64 : 0.63

10. History of strokes

~

11. Evidence of associated atherosclerosis

1

12. Focal neurological symptoms 13. Focal neurological signs

:1 0.75:0.20 I

I

10.55:0.07 0.45 : 0.29

Definition of selectiveitems: items which by means of ncuropathologically verifieddiagnosis frequently occur in the M I D patient group (relativefrequency > 0.50) and simultaneously seldom occur in D A T patients ( ~< 0.25).mc: missing case (the frequency of thisitem could not be retrospectivelydetermined by

Rosen et al., 1980). a 'Because there is no differentiation between 'signs' and 'symptoms' in German-speaking neurology, these two items of the HIS were scored together' (Fischer et al., 1989).

72 These requirements are met for example by the following stipulations: in the case of MID, the relative frequency should be at least 0.50; at the same time, the item should occur with a frequency not exceeding 0.25 in the case of DAT. Using this procedure, only six items have discriminative power (Table III). The items concerning onset and course of the disease prove to be selective in one ('Abrupt onset') or in two of three studies ('Stepwise deterioration', 'Fluctuating course'). Whereas the item 'History of strokes' shows discriminative power in all three studies, 'Focal neurological symptoms' and 'Focal neurological signs' differentiate between MID and DAT in at least two studies.

Discussion

Comparing the five HIS score distributions (Figs. 2 and 3), the discrepancy between them is quite obvious. The following differences concerning the patient populations and the methodology could be responsible for this: (a) Different numbers of patients and in some cases different average ages (compare Figs. 2 and 3). (b) Selective mechanisms could have led to different compositions of the population samples, as for example the inclusion-criterion 'mental deterioration starting between 40 and 65 years' in the study of Gustafson and Nilsson (1982). (c) Since item definitions binding for the users are lacking, the examiners interpreted some of the items according to their own criteria (for example the diagnosis 'Aphasia' was excluded as a focal neurological sign in the sense of item 13 by Wade et al., 1987). (d) The average latency period between application of the HIS and autopsy varied (for example this period lasted nearly 3 years in the study of MSls~i et al. (1985) and nearly 10 years in the study of Gustafson and Nilsson (1982)). This different latency period might be responsible for differences in neuropathological findings. (e) In addition, the methodology used in the neuropathological exploration was not uniform (for example Mt~Isii et al. (1985) examined only the right hemisphere histopathologically; in the other studies, both hemispheres were examined microscopically). Liston and La Rue (1983) have already pointed out differences in methodology between the Rosen and the Gustafson and Nilsson study in a survey. Despite the above mentioned differences the comparison of the five studies shows two fundamental tendencies: (i) Compared with the neuropathological diagnosis, the differential diagnosis using the HIS is incorrect in about one third of the cases. Above all, the mixed forms are hardly rated correctly. (ii) The HIS contains several items which do not seem to be selective. They concern mainly psychiatric symptoms ('Depression', 'Emotional incontinence', 'Nocturnal confusion', 'Relative preservation of personality'). Since data on item level were not published in all studies, it is not possible to make a final assessment.

73 Several reasons for the limited validity of the H I S can be specified: (a) The items were not precisely defined by Hachinski et al. (1975). Thus, various interpretations are possible. (b) The validity of some items appears to be doubtful in view of theoretical considerations and empirical data. (c) The validation of the ischemic scale is uncertain in two respects. On the one hand, there are doubts concerning the representiveness of the patient population examined by Hachinski et al. (1975). On the other hand, the verification of the H I S diagnoses was not attained by using a 'solid' criterion (neuropathology), but rather by using a 'soft' criterion (cerebral blood flow). Before using the HIS, it is important to make the diagnosis 'dementia' with other tests, since the H I S can only contribute to the differential diagnosis. Taking into account the two following results: that 84% of the DATs were correctly diagnosed with the HIS; and that empirical data indicate the selectivity of the items concerning onset and course of the disease (item 1 to 3) as well as neurological criteria (items 10, 12 and 13); it becomes evident that the H I S contains an interesting and promising inherent feature, which justifies the further development of the ischemic scale. The first step should be to reduce the 'classical' HIS to those items which differentiate between M I D and D A T according to neuropathological findings. Furthermore, the following points should be considered: (a) the remaining items have to be exactly defined, so that a nonuniform handling will be avoided as far as possible; (b) another question as to whether further selective items exist which had not been taken into consideration when the 'classical' H I S was created; (c) the weighting of the items and the validation of the revised scale should again be based upon the neuropathological evidence. With this revision, it is possible to obtain a more reliable and valid differential diagnostic instrument compared to the 'classical' HIS.

References AUard, M., Signoret, J.-L. and Stalleicken, D. (1988): Alzheimer Demenz. Springer, Berlin, 79 pp. Deutsch, G. and Tweedy, J.R. (1987): Cerebral blood flow in severity-matched Alzheimer and multi-infarct patients. Neurology, 37, 431-438. Erkinjuntti, T., Laaksonen, R., Sulkava, R., Syrj~l~nen, R. and Palo, J. (1986): Neuropsychoiogical differentiation between normal aging, Alzheimer's disease and vascular dementia. Acta Nenrol. Seand., 74, 393-403. Filley, C.M., Kelly, J. and Heaton, R.K. (1986): Neuropsyehologic features of early- and late-onset Alzheimer's disease. Arch. Neurol., 43, 574-576. Fischer, P., Jellinger, K., Gatterer, G., Marterer, A. and Danielczyk, W. (1989): Neuropathologieal validation of the Hachinski Scale. J. Neural Transm., 1, 57. Gruenberg, E.M. (1961): A mental health survey of older persons. In: Comparative Epidemiology of the Mental Disorders, pp. 13-23. Editors: P.H. Hoch and J. Zubin. Grune and Stratton, New York. Gustafson, L. and Nilsson, L. (1982): Differential diagnosis of presenile dementia on clinical grounds. Acta Psychiat. Scand., 65, 194-209.

74 Hachinski, V.C., Iliff, L.D., Zilhka, E., Du Boulay, G.H., McAllister, V.L., Marshall, J., Ross Russell, R.W. and Symon, L. (1975): Cerebral blood flow in dementia. Arch. Neurol., 32, 632-637. Harrison, M.J.G., Thomas, D.J., Du Boulay, G.H. and Marschall, J. (1979): Multi-infarct dementia. J. Neurol. Sci., 40, 97-103. Haynes, A.R., Owen, M.J., Goate, M.A., James, L.A., MuUan, M.J., Williamson, R., Roques, P., Rossor, M.N. and Hardy, J.A. (1989): Alzheimer's disease and chromosome 21. In: Biological Markers of Alzheimer's Disease, pp. 138-145. Editors: F. Boiler, R. Katzman, A. Rascol, J.-L. Signoret and Y. Christen. Springer, Berlin. Homer, A.C., Honavar, M., Lantos, P.L., Hastie, I.R., Kellett, J.M. and Millard, P.H. (1988): Diagnosing dementia: do we get it right? Br. Med. J., 297, 894-896. Ingvar, D.H., Brun, A., Hagberg, B. and Gustafson, L. (1978): Regional cerebral blood flow in the dominant hemisphere in confirmed cases of Alzheimer's disease, Pick's disease and multi-infarct dementia: relationship to clinical symptomatology and neuropathological findings. In: Alzheimer's Disease: Senile Dementia and Related Disorders (Aging, Vol. 7), pp. 203-211. Editors: R. Katzman, R.D. Terry and K.L. Bick. Raven Press, New York. Jacoby, R. and Schmidt, U. (1985): CT bei seniler Demenz und Altersdepression. Nervenarzt, 56, 113-119. Jellinger, K. (1976): Neuropathological aspects of dementias resulting from abnormal blood and cerebrospinal fluid dynamics. Acta Neurol. Belg., 76, 83-102. Karp, H.R. and Samuels Mirra, S. (1987): Dementia in adults. In: Clinical Neurology, Vol. 3, pp. 1-74. Editor: A.B. Baker. Harper and Row, Philadelphia. Kinzel, W. (1972): Das irreversible psychische Defektsyndrom nach Hirntrauma. Eine l:Ibersicht tiber die literarische Produktion zu einem vielschichtigen Problem. Fortschr. Neurol. Psychiat., 40, 169-219. Kohlmeyer, K. (1982): Vascular (multi-infarct) dementia versus primarily degenerative (Alzheimer's) dementia: a study of rCBF and computed tomography (CT). In: Experimental Brain Research (Suppl. 5, The Aging Brain), pp. 201-207. Editor: S. Hoyer. Springer, Berlin. Liston, E.H. and La Rue, A. (1983): Clinical differentiation of primary degenerative and multi-infarct dementia: a critical review of the evidence. II: Pathological studies. Biol. Psychiat., 12, 1467-1484. Loeb, C. and Gandolfo, C. (1983): Diagnostic evaluation of degenerative and vascular dementia. Stroke, 3, 399-401. Marcus, D.L., de Leon, M.J., Goldman, J., Logan, J., Christman, D.R., Wolf, A.P., Fowler, J.S., Hunter, K., Tsai, J., Pearson, J. and Freedman, M.L. (1989): Altered glucose metabolism in microvessels from patients with Alzheimer's disease. Ann. Neurol., 26, 91-94. Mayer-Gross, W., Slater, E. and Roth, M. (1969): Clinical Psychiatry. Tindall and Carssell, London, 904 PP. Mt~lslt, P.K., Paljarvi, L., Rinne, J.O., Rinne, U.K. and S~ikS, E. (1985): Validity of clinical diagnosis in dementia: a prospective clinicopathological study. J. Neurol. Neurosurg. Psychiat., 48, 1085-1090. Procter, A.W., Lowe, S.L., Palmer, A.M., Francis, P.T., Esiri, M.M., Stratmann, G.C., Najlerahim, A., Patel, A.J., Hunt, A. and Bowen, D.M. (1988): Topographical distribution of neurochemical changes in Alzheimer's disease. J. Neurol. Sci., 84, 125-140. Rogers, R.L., Meyer, J.S., Mortel, K.F., Mahurin, R.K. and Judd, B.W. (1986): Decreased cerebral blood flow precedes multi-infarct dementia, but follows senile dementia of Alzheimer type. Neurology, 36, 1-6. Rosen, W.G., Terry, R.D., Fuld, P.A., Katzman, R. and Peck, A. (1980): A pathological verification of ischemic score in differentiation of dementias. Ann. Neurol., 7, 486-488. Salam-Adams, M. and Adams, R.D. (1988): Cerebrovascular disease by age group. In: Handbook of Clinical Neurology, Vol. 53, pp. 27-46. Editors: P.J. Vinken, G.W. Bruyn and H.L. Klawans. Elsevier Science Publishers, Amsterdam. Terry, R.D. and Katzman, R. (1983): Senile dementia of the Alzheimer type. Ann. Neurol., 14, 497-506. Tomlinson, B.E. and Corsellis, J.A.N. (1984): Aging and the dementias. In: Greenfield's Neuropathology, pp. 951-1025. Editors: J. Hume Adams, J.A.N. Corsellis and L.W. Duchen. Edward Arnold, London. Tomlinson, B.E., Blessed, G. and Roth, M. (1970): Observations on the brains of demented old people. J. Neuroi. Sci., 11,205-242.

75 Wade, J.P.H., Mirsen, T.R., Hachinski, V.C., Fisman, M., Lau, C. and Merskey, H. (1987): The clinical diagnosis of Alzheimer's disease. Arch. Neurol., 44, 24-29. Wagner, O., Oesterreich, K. and Hoyer, S. (1985): Validity of the ischemic score in degenerative and vascular dementia and depression in old age. Arch. Gerontol. Geriatr., 4, 333-345. Wieck, H.H. (1967): Lehrbuch der Psychiatrie. Scliattauer, Stuttgart, 414 pp.