‘Lewy body disease’: clinico-pathological correlations in 18 consecutive cases of Parkinson's disease with and without dementia

Clinical Neurology and Neurosurgery

ELSEVIER

Clinical Neurology and Neurosurgery 97 (1995) 13-22

'Lewy body disease" clinico-pathological correlations in 18 consecutive cases of Parkinson's disease with and without dementia R o b A.I. de VOSa'*, Ernst N.H. Jansen b, Frans C. Stam c, Rivka Ravid c, Dick F. Swaab c aDepartment of Pathology, Regional Laboratory of Pathology and Microbiology, Burg. Edo Bergsmalaan 1, 7512 AD Enschede, The Netherlands bDepartment of Neurology, Medisch Spectrum Twente, Enschede, The Netherlands CThe Netherlands Institute for Brain Research, Amsterdam, The Netherlands Received 13 July 1994; revised 18 August 1994; accepted 15 September 1994

Abstract One of the characteristic histological features of Parkinson's disease (PD), with or without dementia, is the presence of Lewy bodies (LBs) in the brainstem andl neocortical and limbic structures. They are often accompanied by Alzheimer type pathology (ATP). In the present retrospective s~udy the clinical features and post-mortem findings of 18 consecutive and unselected PD patients were compared, with special reference to the frequent but not exclusive association of LBs with ATP in Lewy body disease (LBD). LBD is the term applied to a pa~rticular pattern of neuronal degeneration associated with LBs. In this study of idiopathic PD patients ATP seems to be the major determinant of the cognitive decline in most patients. Cortical Lewy Bodies (CLBs) were present in all patients reviewed, whether or not dementia was present. It was not possible to distinguish a specific pattern in the cognitive or psychopathological symptoms of dementia that would differentiate LBD from Alzheimer's disease (AD). Although in most cases hippocampal CA2-3 ubiquitin immunoreactive neurites were observed, here again there was no correlation with the presence of dementia.

Keywords: Lewy body disease; Parkinson's disease; Dementia; Alzheimer type pathology

1. Introduction Idiopathic Parkinson's disease (IPD) is a syndrome characterised by resting tremor with rigidity, bradykinesia and impaired postural reflexes. Important, though not specific diagnostic features are unilateral onset, classical rest tremor, and marked and sustained response to levodopa [1]. Classical pathological features of PD are the loss of large neuromelanin-containing neurons and gliosis in the substantia nigra and otl~er pigmented brainstem nuclei, with typical inclusions, i.e. Lewy Bodies (LBs), in some of the remaining nerve cells [2]. However, clinical and neuropathological diagnoses do not always coincide. For example, only 76% of the brains of patients with known clinical PD, examined post-mortem by the British Park-

*Corresponding author. Tel.: (+31-53) 313263; Fax: (+31-53) 341631. 0303-8467/95/$9.50 © 1995 Elsevier Science B.V. All rights reserved S S D I 0303-8467(94)00060-3

inson's Disease Society Brain Bank, met all morphological criteria for idiopathic PD [3]. The clinical manifestations of PD are variable and heterogeneous. Additional signs and symptoms such as bradyphrenia, dysthymia, major depression and cognitive degeneration culminating in dementia, have become objects of research only in the last ten years. Studies using DSM III-R criteria [4] show that the incidence of dementia lies between 11% and 15% in the general population and rises to 19% in patients with PD [5]. The increasing awareness of this association of parkinsonism, dementia (characterised by slowing of mental processing and cognitive sequencing, set-formation and shifting deficits, and depression, all of which are features of frontal lobe dysfunction) and psychiatric symptoms (i.e. behavioural abnormalities, delusions, hallucinations) with the presence of cortical Lewy Bodies (CLBs) has led to considerable diagnostic difficulties. These cases have been variously described as 'diffuse Lewy

R.A.I. de Vos et al./Clinical Neurology and Neurosurgery 97 (1995) 13~2

14

The controls were non-demented patients (n = 6) who died in hospital from a variety of causes. None had any history of neurological or psychiatric disorder. None of these patients had been neuropsychologically investigated.

body disease' (DLBD) [6-11], cortical Lewy body dementia [12], senile dementia of Lewy body type [13], and Lewy body variant of Alzheimer's disease [14,15]. In two cases of clinically typical parkinsonism with a favourable response to levodopa, no overt dementia and no Lewy bodies, pathological changes similar to those seen in Alzheimer's disease (AD) have been demonstrated in the striatum and substantia nigra [16]. The reverse, i.e. clinically atypical, levodopa-resistant parkinsonism with a morphologically unequivocal diagnosis of Lewy body disease (LBD) has also been reported [17]. The purpose of the present retrospective study was to determine the relationship, if any, between clinical PD and the neuropathological changes associated with LBD and AD.

Clinical data The clinical data are summarized in Table 1. The mean age of the 18 patients (9 males, 9 females) was 76.3 years, and the mean duration of disease 10.1 years. Of the 12 patients with dementia, 6 were male and 6 female. All controls were male; their mean age was 71.5 years (Table 2). Cognitive decline did not precede motor disability in any patient, although in 2 (nos. 7, 8) it was both simultaneous and rapid, with no discernible intermittent or episodic pattern. There were also signs of cortical dementia, namely severe apraxia and aphasia, and in one case (no. 8) visual agnosia; however, none was bradyphrenic or depressed. Only patients nos. 9, 10, 11, 14, 16 and 17 showed no signs of cognitive decline according to the DSM-IIIR criteria for dementia [4]. Neuropsychological evaluation of these six cases however, revealed bradyphrenia, together with some degree of memory-loss, and all performed poorly in the category naming, trail-making and Wisconsin Card Sorting tests of frontal lobe function, features, which were not severe enough to fit in DSMIIIR criteria for dementia.

2. Patients and methods

Brains were obtained from 18 consecutive and otherwise unselected neurological patients, with a clinical history of PD, with or without concomitant affective, behavioural and/or cognitive changes. Patients with a clinical diagnosis of 'Parkinson plus syndrome' [18,19], and histological signs of multiple system atrophy or progressive supranuclear palsy were excluded. Dementia was defined as a Mini-Mental State examination score of less than 20 in a patient fulfilling DSMIIIR criteria for dementia [4,20]. Depression was scored on the Hamilton depression rating scale [21].

Table 1 Clinical findings in 18 P D patients Pat. No.

Age (yrs)

Sex

Brain weight

P a r k i n s o n features

Autonomic features

B e h a v i o u r a l a n d cognitive features

(g)

9 10 11 14 16 17

79 79 77 90 73 67

M F M F F M

I

74

F

72 70 75 84 74 82 70 77 77 68 86

M M M F M F F F F M M

2 3 4 5 6 7 8 12 13 15 18

1528 1200 1400 982 1165 1482 1130 1256 1188 1360 1065 1356 1142 1150 1313 1278 1070 1418

Dura-

H&Y

L-dopa Incon-Ortho-Dura-

tion (yrs)

stage*

retisponse n e n c e

stasis

1

III

+

-

-

0

4

IV IV IV III IV IV IV IV III V IV V

+ + + + + + + + + + -

+ + + + + + +

+ + + + + +

0 0 0 0 0 8 1 6 6 10 1 13

V

-

+

+

III IV IV V

+ + + +

+ +

+ -

8 10 12 20 10 5 23 10 16 5 13 1

10 5 15 14

* H & Y = H o e h n & Y a h r disability r a t i n g scale

Apa-

Mem-

Hallu-

Des-

Delu-

Confu- De-

Apha-

ory loss

cinations

orientation

sions

sion

pression

sia apraxia

+

-

+

--

+

--

+

-

+ + + + + + + + -

+ + + + + + +

--

-I-

~

--

+

--

+

_

+

+

+

--

--

_

1

-

+

2 2 5 6

+ + + +

+ + + +

tion thy (yrs o f dementia)

_

_

.

.

.

.

_ . .

q.

.

.

.

.

.

+

--

"1-

--

--

--

+

+

--

+

q-

+

+

+

+

+

--

_

+

+

+

+

--

+

--

+

+

+

--

_

--

+

+

+

+

--

+

+

+

+

-

+

+

+

+

+

+

+

+

+

+

+

+

-

--

+

+

+

--

_

+

+

--

+

--

_

+

+

-

+

--

_

R.A.I. de Vos et al./Clinical Neurology and Neurosurgery 97 (1995) 13 22

Table 2 Clinicaldata of control patients Patient Age Sex no.

Brainweight (gr)

Clinicaldiagnosis

C1

71

M

1454

C2 C3 C4 C5

61 89 69 82

M M M M

1460 1215 1366 1268

C6

57

M

1345

Urothelial carcinoma; Pneumonia Cardiac arrest Cardiac ischemia Myocardialinfarct Respiratory insufficiency Urothelial carcinoma Myocardialinfarct

In the remaining ten patients clinical features of cortical and subcortical dementia were preceded by parkinsonism. Mean delay between onset of motor symptoms and cognitive decline was 6 years. Eleven patients had episodes of visual hallucinations. Another psychotic disorder - etiologically also in close relation with dopamine therapy - was confusion, which was estimated in 13 of the 18 patients. In a minority of the cases there was a magnitude of change in overall cognitive performance between episodes of confusion and lucid intervals. These fluctuations were seen in two cases without dementia and in only 1 case with dementia. Since all of these patients had dopamimetic therapy (L-dopa and dopamine agonists) we can not reliably distinguish the etiology of these mental symptoms: the Lewy body disease itself or dopamimetic therapy. Depression [21] was observed in 7 patients (4 female, 3 males). In 2 (nos. 6 and 11) it preceded the onset of parkinsonism. One patie:at (no. 6), became severely depressed with suicidal ter~dencies and manifestations of psychosis. However, none showed symptoms of progressive depression, at least not during the period under review. This was in sharp contrast to the simultaneous and relentless progressio~a of their cognitive and motor decline. Neuropathology

Following removal at autopsy the brains were fixed in buffered 4% formaldehyde solution for at least 3 weeks. Samples were taken from the superior frontal gyrus, superior parietal lobule, superior and middle temporal gyri, occipitotemporal gyrus, nucleus basalis of Meynert and anterior part of cingulate gyrus (at the level of the midpoint of the anterior commissure), basal ganglia, hippocampal formation and entorhinal cortex, cerebellum, midbrain, pons/locus coeruleus, and medulla oblongata. They were embedded in l:,araplast (Sherwood, no. 8889501007, melting point 56°C), cut at 8-10 tim, and stained with hematoxylin and eosin, Congo red and modified Bielschowsky silver impregnation. Sections were also stained immunocytochemically, using a polyclonal antibody to ubiquitin 1:80 (DAKO

15

code no. Z458, lot no. 20), a monoclonal antibody to TAU 1:1000 (SIGMA prod no. T5530, lot no. F4830) and beta A4 1 : 50 (DAKO code no. M872, lot no. 012), and the monoclonal antibody ALZ-50 [22] (kindly supplied by Abbott Laboratories, Chicago, Illinois, USA). Sections were incubated with specific mouse monoclonal antibody or rabbit polyclonal antibody for 60 min, with the second biotinylated rabbit anti-mouse IgG or biotinylated swine anti-rabbit IgG (DAKO) for 45 min and with streptavidin-HRP (DAKO) also for 45 min, all at room temperature. Peroxidase was visualised by incubation with 3,3'-diaminobenzidine (DAB) in 0.03% H202. Between incubation steps the slides were rinsed in phosphate-buffered saline at pH 7.4. Immunocytochemical staining was performed with the anti-beta amyloid A4 following pretreatment of the sections with 100% formic acid for 10 min in order to enhance the stain [23]. Gibb's criteria were used to define Lewy and pale bodies [24]. ( S e m i ) q u a n t i t a t i v e analysis

This was performed on the cortical fields as shown in Tables 3, 4 and 5. Estimation of the number of senile neuritic plaques (SPs) and of Lewy bodies (LBs) was carried out as follows: after staining with, respectively, modified Bielschowsky silver impregnation and Ubiquitin, the slides were placed under a 100 × objective and random counts made of each region, in at least 30 fields by systematic parallel sweeps across the cortex. Exceptionally, it was only possible to count 10 fields in the entorhinal cortex. Neurofibrillary tangles (NFTs) were counted on sections stained with TAU, and dystrophic neurites (DNs, neuropil threads) on sections stained with ALZ-50, which gives better definition of the latter than TAU [22]. They were scored on a five point scale: absent (-), sporadic (+), sparse (+), moderate (++) and severe (+++). The neocortical areas studied in Table 5 were the same as stated in Table 3 and 4. Neuropathological diagnosis of AD was based on the criteria of Khachaturian [25] and CERAD [26]. Both use age-related neocortical plaque counts, but Khachaturian distinguishes four age ranges, and CERAD only three (<50, 50-75, and >75 years). Both sets of criteria integrate histological diagnosis with the presence or absence of clinical dementia. The CERAD criteria include a semiquantitative count of senile plaques in the most severely affected region of the neocortex; those of Khachaturian define the densities of SP and/or NFT per field. It was not possible to quantify diffuse plaques on sections stained with anti-beta amyloid A4. The outlines were indistinct and varied in size and distance from one other. We 'therefore scored them on a four point scale: absent, sparse, moderate, and severe. Density and size of CLB were determined morphomet-

R.A.I. de Vos et al./Clinical Neurology and Neurosurgery 97 (1995) 13-22

16

Table 3 Num ber of plaques in PD patients and controls (C) Frontal

Gyr.cinguli

Parietal

Case no

Sp

Dp

Sp

Dp

Sp

9* 10' 11" 14" 16" 17" 1 2 3 4 5 6 7 8 12 13 15 18 CI* C2" C3' C4" C5" C6"

3,87 0 0 0.40 0 0 0 1.00 0 0 4.57 0.90 5.50 9.50 1.77 5.07 10.27 0 0.44 0 0 0 0 0

++ 0 0 ++ 0 0 0 + 0 0 ++ ++ ++ ++ ++ ++ ++ + _+ 0 0 0 + 0

3.40 0 0 0,23 0 0 0 1.20 0 0 1.03 5.60 7.57 2.40 4.67 13.2 1.13 . . . . . .

++ 0 0 ++ 0 0 0 + 0 0 ++ ++ ++ ++ ++ ++ +

. 0 0 0.07 0 0 0.23 . 0 0 4.07 4.20 10.73 4.20 5.80 6,33 0.50

. . . . . .

. . . . . .

Temporal Dp .

.

Dp

0 0 0.10 0 0 0.57 . 0 0 0.43 4.90 5.77 2.80 6.47 9.67 0 0.25 0 0 0 0 0

0 0 ++ +0 0 . 0 0 ++ ++ ++ ++ ++ ++ ++ 0 0 0 +0

Sp

.

0 0 ++ 0 0 0 .

Occipital

Sp

. 0 0 ++ ++ ++ ++ ++ + +

. . . . . .

Ca 1-4 Dp

7.90 0 0 3.57 0 0 0.07

++ 0 0 ++ +0 0

0 0 1.33 0.30 1.40 12.50 0.03 2.20 8,43 0.70 0.88 0 0 0 0 0

0 0 + ++ ++ ++ + ++ ++ ++ 0 + 0 + 0

.

Entorhinal Sp

0 0 0 7.00 0 0 0 0 0 0 9.40 0 5.64 10.09 1.87 3.14 4.30 0 0 0 0 0 0 0

4.10 0 0 0.43 0 0 0 4.37 0 0 1.36 0.70 8.33 8.60 2.60 5.33 4.31 0.28 1.00 0 0 0 0 0

Senile (neuritic) plaques (Sp): average per field × 100 (area 4.9 m m 2) Diffuse plaques (Dp): 0 -- absent, + - = sparse, + = moderate, ++ = severe, - = not determined. *No dementia.

Table 4 N u m b e r of lewy bodies in PD patients and controls (C) Case no.

Frontal

Gyr.cinguli

Parietal

Temporal

Occipital

C A 1-4

Entorhinal

9* 10" 11 * 14" 16" 17" 1 2 3 4 5 6 7 8 12 13 15 18 CI * C2" C3" C4" C5" C6"

0.23 0,03 0 0,10 0,30 0 0.23 0.30 0.83 0.13 0.50 0,13 0.63 5.37 0.20 0.10 0.43 0.17 0 0 0 0 0 0

1,53 0.17 0.02 0.40 3.07 0.70 1.00 0.30 6.49 1.30 1.13 2.01 5.01 1.33 0.40 0.93 2.41 0 0 0 0 0 0

0 0 0.03 0,39 0 0,27 0.87 0 0 0.13 0.87 0 0.10 0.13 0 0 0 0 0 0 0

0 0 0 0 0 0.47 0.23 1.97 0.67 0.90 2.43 0.43 0.13 0 0 0 0 0 0 0 0

0.20 0 0 0 0 0 0 0.03 0 0 0 0.30 1.03 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0.80 0.30 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1.10 0.20 0 0 0 0 3.50 0.20 3.00 3.60 5.70 1.50 1.50 3.70 3.60 5.30 0 0 0 0 0 0 0 0

• Lewy bodies (LB): average per field x 100 (area 4.9 mm2); *No dementia. , not determined.

I~ A.L de Vos et aL / Clinical Neurology and Neurosurgery 97 (1995) 13-22

rically with a digitizer (Calcomp 2000) connected to a HP 9000/835 computer and with a Zeiss microscope using Plan 40 x objective and Plan 12.5 oculars. Numerical density and size of CLB were estimated by measuring the CLB profiles per unit area in sections of the cingulate cortex stained with anti-ubiquitin, followed by a discrete 'unfolding' procedure [27] with the Cruz-Orive modification [28] and a correction for section thickness (10 pm). The computer programs for these procedures were written by Dr. R.W.H. Verwer of the Netherlands Institute for Brain Research.

3. Results

Neuropathological findings are summarised in Tables 3, 4 and 5.

Macroscopicalfindings Although mild frontal atrophy was noted in the brains of 2 subjects (nos. 7, 8), moderately severe cortical atrophy was only seen in ca.,;e 14. The mean weight of the brains examined was 1249 + 36 g (mean + SEM). There was noticeable depigmentation of the substantia nigra and locus coeruleus in all our specimens. The mean weight of the brains of the controls was

17

1351 + 40 g (mean + SEM). There were no visible macroscopic abnormalities.

Microscopicalfindings Extra-neural melanin, gliosis and LBs were present in the substantia nigra of all subjects. This was associated with a loss of large pigmented neurons. They were accompanied by pale bodies. LBs were also seen in the locus coeruleus. In all specimens elongated intraneuritic LBs of variable shape and density were found in the nucleus basalis of Meynert, nucleus vagus dorsalis and sympathetic ganglia. LBs with a somewhat indistinct central core were also found in the cortical neurons of all subjects. LBs were generally seen in the small and medium-sized pyramidal neurons of the deeper cortical layers with a predilection for the anterior cingulate and parahippocampal cortices. They were easily visualised with ubiquitin staining. In the subjects with the two highest incidences of CLBs (nos. 3 and 8) their density and size in the cingulate cortex were determined morphometrically. Incidences were 35 and 39, respectively, densities 1.1 L B / 1 0 6 ¢tm in both subjects and mean diameters 9.9+4.7 and 11.6 + 3.1 ¢tm, respectively (mean + SEM). In 4 patients (nos. 10, 11, 16, 17) CLBs were only sporadic and no ATP was seen. Ubiquitin, TAU and ALZ-50 immunoreactive neurites were present in the

Table 5 N e u r o f i b r i l l a r y tangles a n d d y s t r o p h i c neurites in P D p a t i e n t s a n d c o n t r o l s (C) CA 1

CA2-3

CA4

Neocortex

Entorhinal

Pat. no.

NFT

DN

NFT

DN

NFT

DN

NFT

DN

NFT

DN

9* 10" 11' 14' 16' 17'

+ 0 0 ++ ± 0

+ 0 0 ++ 0 0

+ 0 0 + 0 0

++ 0 0 ++ ± +

± 0 0 ± 0 0

± 0 0 ± 0 0

± 0 0 ± 0 0

± 0 0 ± 0 0

++ 0 0 ++ + 0 ++ + 0 ± ++ ++ +++ +++ 0 +++ ++ + ± 0 ± ++ 0 ±

++ 0 0 ++ + 0 ++ + 0 ± ++ ++ +++ +++ ± +++ ++ + ± 0 + ++ 0 +

1

2 3 4 5 6 7 8 12 13 15 18 CI* C2" C3" C4" C5" C6"

+

+

+

++

0

±

0

0

0 0 ± + + ++ +++ 0 + ± + 0 0 ± 0 0 +

0 0 0 ++ + ++ +++ 0 ++ ± ± 0 0 0 0 0 0

0 0 0 0 0 ± ++ ± 0 ± + 0 0 0 0 0 0

0 +++ ± + ± ++ ++ ++ + + + 0 0 0 0 0 0

0 0 0 ± 0 0 + 0 0 ± + 0 0 0 0 0 0

0 0 0 ± 0 0 + 0 + ± ± 0 0 0 0 0 0

0 0 0 0 ± + +++ 0 + ± 0 0 0 0 0 0 0

0 0 0 0 ± + +++ 0 + 0 0 0 0 0 0 0 0

N e u r o f i b r i l l a r y tangles ( N F T ) ; d y s t r o p h i c neurites (DN). 0 = absent; + = sporadic; + = sparse; + + = m o d e r a t e ; + + + = severe. *No d e m e n t i a . 12 = control.

18

R.A.I. de Vos et al./ Clinical Neurology and Neurosurgery 97 (1995) 13~2

Fig. 1. A and B: ubiquitin-positive Lewy bodies (arrows) in the gyrus cinguli in patient no. 3 (A), compared with a negative staining reaction in a control patient no. C1 (B). Ubiquitin, x420. Bar = 50 #m.

CA2-3 region of the hippocampi of subjects no. 16 and 17 [29]. In 2 patients (nos. 3 and 4) CLBs were frequent to moderately frequent, again with no ATP (Fig. 1). Ubiquitin, TAU and ALZ-50 positive neurites were also present in the CA2-3 region of these subjects' hippocampi (Fig. 2). Varying numbers of CLBs in combination with some ATP were present in the cortices of the remaining 12 patients. NFTs were also seen in the neocortices of 7 patients. Occasionally TAU positive neurons were also present. The highest incidence of NFTs and DNs was in subject no. 8, but they were present in moderate to large numbers in the entorhinal cortices of 9 of the 18 cases. The brain of only one subject (no. 2) contained no ubiquitin, TAU, or ALZ-50 immunoreactive neurites in the CA2-3 region of the hippocampus. Congophilic angiopathy was seen in 4 subjects (nos. 5, 9, 14, 15). In another 4 (nos. 3, 4, 8, 13) spongiform changes with vacuolisation of the neuropil were found in the temporal cortex.

In a few instances minor ischaemic changes were observed. Table 6 summarises the neuropathological diagnosis of AD based on the Khachaturian [25] and CERAD [26] criteria. Only 3 subjects (nos. 7, 8 and 15) fulfilled the criteria of AD according to Khachaturian, while 4 (nos. 7, 8, 13, 15) fulfilled this diagnosis according to CERAD. Another 6 subjects who had shown signs of dementia were also diagnosed as possible or probable AD, on the basis of CERAD criteria, although none fulfilled the criteria of Khachaturian. In 3 subjects (nos. 7, 8, 13) the density of NFTs and DNs in the entorhinal cortex was quite remarkable. According to Braak and Braak [30] findings such as these are compatible with fully developed AD (isocortical stage). The histological findings of the 6 controls are also reproduced in Tables 3, 4 and 5. None of these subjects' brains contained Lewy bodies, although 1 patient (no. C1), contained a small number of SPs. Entorhinal NFTs

Fig. 2. A and B: ubiquitin-positive neurites in the CA2-3 region of the hippocampus in patient no. 3 (A), compared with a negative staining in patient no. 2 (B). Ubiquitin, x210. Bar = 50 ¢tm.

R.A.I. de Vos et al./Clinical Neurology and Neurosurgery 97 (1995) 13-22

and DNs were sporadic with the exception of no. C4, in whom moderate numbers were present.

19

plied. The CA2-3 region of all except patient no. 2 contained ubiquitin immunoreactive neurites, and their absence in a patient suffering from dementia is unique in our experience. Spongiform changes were present in the temporal cortices [31] of 4 patients (nos. 3, 4, 8, 13). All suffered some degree of dementia.

Clinico-pathological cor~,elation Six patients (nos. 9, 10, 11, 14, 16, 17)had no cognitive decline, severe enough to be diagnosed as dementia [4]. Several of these patients had exhibited behavioural and psychopathological disturbances, all with a similar neuropathological picture. Patient no. 9, uniquely, could be diagnosed of possible AD on the basis of the CERAD criteria. Ubiquitin immunoreactive neurites were seen in the CA2-3 region of the hippocampi of 4 patients (nos. 9, 14, 16 and 17), a finding which has not previously been reported in a patient with no clinical signs of dementia. Patients no. 3 and 4 had suffered severe dementia, although cortical features in the form of aphasia and apraxia were only present in patient no. 4. The clinical history of patient no. 3 contained episodes of delusion and visual hallucination. The brain of this patient contained a large number of CLBs, with ubiquitin immunoreactive neurites in the CA2-3 region of the hippocampus. The latter were also present in the CA2-3 region of the hippocampus of patient no. 4; neither brain contained ATP. Patients nos. 7 and 8 were the only ones in whom the onset of dementia and PD was simultaneous. They also underwent a steady cognitive decline, with delusions and visual hallucinations. AD was diagnosed on the basis of both CERAD and Khe~chaturian criteria. The CA2-3 regions of the hippocampi of both patients contained ubiquitin immunoreactive neurites. Dementia manifested in the remaining 8 patients (nos. 1, 2, 5, 6, 12, 13, 15, 18) only after PD became established. Nos. 12 and 15 suffered fluctuating cognitive decline, with hallucination:~, delusions and dysthymia. Patient no. 2 exhibited featares of cortical dementia. Apart from patient no. 15, the diagnosis of AD in these cases was variable and sometimes conflicting, depending on whether the CERAD or Khachaturian criteria were ap-

4. Discussion

The literature is equivocal about the correlation between clinical and neuropathological Lewy body disease (LBD, the term applied to a particular pattern of neuronal degeneration associated with LBs). Moreover there seems to be some confusion between the term LBD and DLBD. The LBs are predominantly found in certain areas of the cortex, subcortex and autonomic nervous system such as the dorsal nucleus of the vagus, the sympathetic cord and the plexus of the gastrointestinal tract [2]. CLBs appear most commonly in the frontal anterior cingulate, insular, and parahippocampal cortex. 'Diffuse', at least in respect to pure morphological findings, is therefore a misleading term in the context of LBD. Not only are they predominantly found in certain well-defined areas; their distribution within these areas tends to be uneven (Table 4). Gibbet al. [32] describe LBD as a histological diagnosis whose clinical expressions are dementia and PD, either alone or in combination. Where CLBs are present in variable densities in clinical PD with no signs of dementia they are termed 'asymptomatic' or 'presymptomatic'. Others regard Diffuse Lewy Body Disease (DLBD) as a morphological diagnosis. Kosaka [10] even defines DLBD numerically as 5 or more CLBs visible in the predilection sites (anterior frontal, cingulate, temporal and insular cortices) on HE section at a magnification of 100 ×. He also distinguishes a 'common type DLBD' in

Table 6 Clinicopathological diagnosis in 18 consecutive cases of Parkinson's disease. Patient no. 10, 14 9 4 3 18 1, 5, 13 7, 8

11, 16, 17

2, 6 12 15

Cerad No dementia No dementia No dementia Dementia Dementia Dementia Dementia Dementia Dementia Dementia Dementia

CLB CLB CLB CLB CLB CLB CLB CLB CLB CLB CLB

+ + + + ++ + + + + + ++

ARP ARP ARP ARP ARP ARP ARP ARP ARP ARP ARP

Khachaturian 0 + + 0 0 + + + ++ ++ ++

CLB = cortical lewy bodies/gyrus cinguli (+ = < 5/field, ++ = -> 5/field). ARP = age-related plaque score (0 = absent, + = sparse, + = moderate, ++ = frequent). A D = Alzheimer's disease.

Normal Normal Ad possible Normal Normal AD possible A D probable AD probable AD definite AD definite AD definite

Normal Normal Normal Nonnal Normal Normal Normal Normal Normal AD AD

20

R.A.I. de Vos et al./ Clinical Neurology and Neurosurgery 97 (1995) 13-22

which it is accompanied by ATP and a 'pure type' in which it is not. In the latter case he regards CLBs as the major determinants of clinical dementia. Others, like Dickson [29], use the criterion of widespread distribution of CLBs, but don't define quantitative data. Our data support the latter view, suggesting that it is too artificial to distinguish LBD from DLBD solely on the basis of 5 CLBs per field at a magnification of 100 ×. Moreover the lack of consensus on the correlation between density of CLBs and cognitive decline argues against the dementia implied in this morphological DLBD concept. Since the selection criterion in our study was Parkinson's disease, we are unable to deal further on the subject of the clinical diagnosis of DLBD, in which dementia is the presenting symptom [31,6,9,10]. In all patients in the present study, the clinical diagnosis of PD was confirmed histologically, as was the presence of CLBs. This latter finding supports that of Hughes et al. [3]. It seems reasonable, therefore, to regard CLBs as a normal histological finding in all cases of idiopathic PD, irrespective of clinical signs of dementia. This of course weakens the nosologic distinction between PD and DLBD, and argues against the whole concept of the latter. Our data confirm that brainstem LBs are associated with variable numbers of CLBs and usually, but not exclusively, with ATE In this study patients without dementia seem to have a lower density of CLBs. The presence of ATP in PD is not necessarily associated with clinical dementia [33], although the severity of dementia may be related to the density of CLBs. Two of our patients (nos. 3 and 4) are therefore of particular interest because they exhibited severe dementia and high densities of CLBs in the absence of ATE One (no. 3) fulfilled both Kosaka's numerical criteria [10] for 'pure type' DLBD and Gibb's [32] for 'cortical Lewy body dementia'. It should, however, be stressed that this combination of clinical dementia and CLBs in the absence of ATP was only present in two cases and that, in the other ten, dementia and CLBs were associated with ATE The changes resulting from ATP are usually sufficient apparent to distinguish LBD brains from those of age-matched elderly controls, although there are differences of opinion on the definition of 'age-matched normals' [34]. Ince et al. [35] suggest that ATP is less marked in LBD than in 'pure' AD. Patients with PD and dementia had clearly a higher degree of cortical ATP (especially in the entorhinal region, see Table 5) compared to patients without dementia. This superposition of cortical Alzheimer lesions, that accompany PD, agrees with the results of Paulus and Jellinger [36], and Duyckaerts et al. [37]. In this study ATP seems to constitute the most significant correlate of dementia with the exception of two cases. In the present study there was, however, a discrepancy between diagnoses of AD based on the Khachaturian and CERAD criteria (Table 6). Our study did not ex-

plore the subcortical pathology as a possible cause of dementia. Dickson et al. [29] distinguish DLBD from PD and AD by the presence of CA2-3 ubiquitin positive neurites. We were unable to confirm this: in one of our patients (no. 2) with clinical signs of dementia they were absent, while in 4 others (nos. 9, 14, 16, 17) who were not clinically demented they were clearly demonstrable. A recent study of Pollanen et al. [38] confirms our hypothesis of the non-specificity of this CA2-3 positivity. In our material congophilic or amyloid angiopathy was associated with ageing and ATP rather than LBD, which supports the findings of Wu et al. [39].

5. Conclusions

We were unable to establish a clear relationship between the post-mortem neuropathoiogical findings and the clinical presence of psychopathology or dementia in the patients we studied. However, our data suggest that ATP seems to be the major determinant of the cognitive decline in PD. We could confirm the very high frequency of visual hallucinations and confusion in our PD patients, as has been established by others for the diagnostic entity of DLBD [6,7,11]. However, in our patient material the presence of extrapyramidal features was quite predominant - with severe disability on the basis of parkinsonian symptoms - and the psychotic disorders (especially the confusion) had a clear fluctuating pattern in only a minority of the patients. PD, and DLBD, might cause mental symptoms other than cognitive impairment [7]. Moreover, the importance of dopamimetic therapy in provoking these psychotic symptoms in PD patients is well understood in general neurological practice, and is the basis of the frequent use of atypical neuroleptics in PD patients. Consequently it seems unjustified to infer these psychotic symptoms into a diagnostic frame of dementia, as is done in 'Lewy body dementia' and 'senile dementia of Lewy body type'. In this respect our findings confirm those of F6rstl et al. [14]. We found the same signs and symptoms of cognitive decline and behavioural disturbance in patients with dementia and CLBs but no ATP, as in those with ATP or AD, dementia and only sparse CLBs. With so much uncertainty surrounding the definition of Lewy body disease, it seems inappropriate to use terms like Lewy body dementia and DLBD as if they were undisputed diagnostic entities. Some of the confusion about the clinical features of LBD may result from the source of the referred material. The neurologist may well lay more emphasis on the patient's extrapyramidal symptoms than cognitive decline, while the geriatrician may do exactly the opposite. The available evidence suggests that dementia is a final common pathway of cerebral decline, and there is no

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essential difference between that resulting from AD and that from PD. The same applies to the decrease in glucose metabolism seen in these patients [40]. Certainly we were unable to isolate a clinical entity identifiable as Lewy body disease from the material we studied. All current data suggest that 'Lewy body disease' covers a broad spectrum of clinical and pathological features

[35]. In order to clarify this picture, a prospective study of the relative significance of CLBs, NFTs and SPs in a variety of clinical manifestations of dementia and psychopathology in PD is needed.

Acknowledgments The authors wish to thank Wies vom Bruch and Marie Schuil for their secretarial assistance, Liane Stokkink, Harry Begthel and Hanneke Ploegmakers for technical assistance, Richard Rieksen for photographic work and Phil Page, MD, for linguistic advice. This study was supported by grants of the Stichting Wetenschappelijk Onderzoek Medische Staf Streeklaboratorium (SWOMSS), Enschede, The Netherlands, and Upjohn Nederland BV. Human brain tissue (control cases) was obtained from the Netherlands Brain Bank Amsterdam (coordinator Dr. R. Ravid).

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