Cortical and amygdalar Lewy body burden in Parkinson's disease patients with visual hallucinations

Parkinsonism and Related Disorders 12 (2006) 253–256 www.elsevier.com/locate/parkreldis

Case Report

Cortical and amygdalar Lewy body burden in Parkinson’s disease patients with visual hallucinations Spiridon Papapetropoulos *, Donald S. McCorquodale, Jocely Gonzalez, Lucie Jean-Gilles, Deborah C. Mash Department of Neurology, Miller School of Medicine, University of Miami, 1501 NW 9th Avenue (NPF), Room 4004, Miami, FL 33136, USA Received 18 August 2005; received in revised form 19 October 2005; accepted 19 October 2005

Abstract Visual hallucinations (VH) are among the most common non-motor complications of Parkinson’s disease (PD). A few studies on their etiopathogenesis have suggested involvement of cortical and amygdalar areas. In order to investigate the possible association between extranigral Lewy Body (LB) distribution across cortical and amygdalar regions and the presence of VH in PD brain donors, we conducted a clinico-pathological comparison of 10 PD patients with VH vs 10 closely matched PD patients without VH. The LB burden was significantly higher across the amygdala and the frontal, temporal and parietal cortical areas in patients with VH. Although our results suggest significant extranigral involvement, the precise etiopathologic mechanisms responsible for the development of VH need further clarification. q 2005 Elsevier Ltd. All rights reserved. Keywords: Parkinson’s disease; Visual Hallucinations; Cortex; Amygdala; Neuropathology; Post-mortem

1. Introduction Parkinson’s disease (PD) is a neurodegenerative disorder initially predominated by motor symptoms that appear after w60% loss of dopaminergic neurons from the substantia nigra (SN) [1]. However, the neurodegenerative process of PD is by no means confined to the SN and with disease progression patients develop additional non-motor manifestations. Among the most common are visual hallucinations (VH) present in about 20–30% of patients [2]. The facilitating role of dopaminergic treatment in their development is well established, but it is complex and incompletely understood. Although their clinical and epidemiologic characteristics have been well described, the underlying etiopathology remains a matter of debate (for review, see [3]). Furthermore, the anatomic substrate of hallucinations is under debate and there are very few neuropathologic studies of PD patients with VH [4,5]. In an attempt to study the possible association between * Corresponding author. Tel.: C1 305 243 8461; fax: C1 305 243 3649. E-mail address: [email protected] (S. Papapetropoulos).

1353-8020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2005.10.005

extranigral Lewy bodies (LB) distribution across cortical and amygdalar regions and the presence of VH, we conducted a clinicopathologic study in a group of PD brain donors.

2. Methods PD patients were selected among subjects who consented during life to donate their brains to the University of Miami Brain Endowment Banke (UM/BEB). All donors completed the Brain bank’s PD registry form (a 128-item, selfadministered questionnaire) providing information about demographics, environmental exposures, personal and family history, activities of daily living, clinical and treatment details. Yearly updates on all brain donors were obtained until death. Medical and hospital records were collected on an annual basis and all pertinent information was entered into a database. The severity of PD at death was assessed using the Hoehn and Yahr (HY) scale [6]. For purposes of this study medical charts and registry forms of all UM/BEB donors with a clinicopathologic diagnosis of PD (nZ125) were re-evaluated by the UM/BEB’s movement disorders specialist (SP), for detailed recording of PD-related neuropsychiatric symptoms. Only

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patients with complete records and at least one neurological, geriatric or psychiatric evaluation in the last 18 months prior to death were included (nZ97). We identified 14 PD donors with a clear history of complex VH recorded in their medical charts that started after at least 3 years into their disease and lasted for a period of at least 1 year. Of these patients, four were excluded due to co-existing, documented, severe cognitive impairment at the time they were experiencing VH. Since our study is based on retrospective data, cognitive impairment was measured using a global impression scale (0: no benefit, 1: mild, 2: moderate, 3: marked) based on clinical findings reported in the medical charts, such as a diagnosis by a psychiatrist (nZ3), formal psychometric testing (nZ2) and/or Mini-Mental State examination (MMSE) (nZ5). From the review of our records, we also identified 41 PD patients without evidence of hallucinations or any other psychotic symptom. From this group we also excluded patients with the diagnosis of severe cognitive impairment (nZ20) using the same methods. We compared sex, ageand duration- group matched patients with VH (group 1) with patients without VH (group 2). For neuropathologic examination, all brains were formalin-fixed and sectioned according to standard protocols [7]. In addition to standard histochemistry, special immunohistochemistry for tau (AT8; Pierce Endogen, Chicago, IL), and alpha-synuclein (LB 509; Zymed, San Francisco, CA), were carried out.

Three cortical regions [frontal (Brodmann area 9), temporal (area 20), parietal (area 39)] and the amygdala at its greatest cross-sectional area were assessed quantitatively for LBs. LB pathology was classified by the density and distribution of inclusions [8] (brainstem, transitional and diffuse Lewy Body Disease—LBD). The assessment of neurofibrillary tangles in adjacent sections stained with antibodies to tau enabled the semi-quantitative assessment of the distribution of tangles for Braak and Braak staging of Alzheimer’s disease [9]. Statistical analysis was performed using the SPSS for Windows release 11.0 (SPSS, Inc., Chicago, IL, USA). Mann–Whitney U-test for two samples was used in nonparametric comparisons, and chi-square with Yates corrected p-value in the comparison of proportions (p!0.05 was accepted as being statistically significant). The study was approved by the local Institutional Review Board (IRB).

3. Results The clinical and neuropathological characteristics of all PD patients are presented in Table 1. Patients with and without VH were closely matched for gender, age at death and disease onset as well as HY stage. There were no significant differences between clinical symptoms at disease

Table 1 Characteristics of our PD cohort included in our analysis Case

Age

Sex

Onset

Onset symptom

HY

CI

Braak stage

Pathologic diagnosis

Hallucinators

PD1 PD2 PD3 PD4 PD5 PD6 PD7 PD8 PD9 PD10 Mean (SD) or %

83 67 68 74 82 80 91 82 85 85 79.7 (7.7)

M M M F F M M M F M 70%M

61 47 58 60 74 66 74 62 74 71 64.7 (8.8)

Slowness Tremor Tremor Stiffness Gait Tremor Slowness Tremor Slowness Tremor –

4 5 4 4 4 5 4 5 4 4 4.2 (0.5)

C C C CC CC CC C CC CC CC 60/40

1.0 1.0 1.5 2.0 3.0 4.5 2.0 5.0 3.0 3.0 2.6 (1.4)

DLBD DLBD DLBD TLBD TLBD DLBD DLBD DLBD DLBD TLBD 30/70

Non-hallucinators

PD11 PD12 PD13 PD14 PD15 PD16 PD17 PD18 PD19 PD20 Mean (SD) or % p

73 77 66 75 85 84 85 84 86 83 79.8 (6.7)

M M M M M M F M F F 70%M

56 71 61 62 60 80 65 66 78 75 67.4 (8.2)

Stiffness Gait Gait Tremor Gait Tremor Stiffness Tremor Tremor Tremor –

4 3 4 4 5 4 5 5 4 4 4.3 (0.6)

C CC C C C CC C C C CC 70/30

3.0 2.0 .0 .0 1.0 5.0 2.0 2.5 2.0 2.0 2.0 (1.5)

BLBD TLBD BLBD BLBD BLBD DLBD TLBD TLBD TLBD TLBD 40/50/10

1.0

1.0

0.5

0.3

0.8

0.1

0.3

0.01

CI: cognitive impairment (C: mild, CC: moderate, CCC: severe), BLDB: brain stem Lewy Body disease, TLBL: transitional (limbic) Lewy Body disease, DLBL: diffuse Lewy Body disease.

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onset or the presence and degree of cognitive impairment. LB densities were higher across the amygdala and the cortical areas studied in PD patients with VH (Fig. 1). All comparisons between groups yielded statistically significant results (frontal pZ0.02, temporal pZ0.04, parietal pZ0.02, amygdalar pZ0.008). As expected by the increased LB density, more PD patients with VH had the neuropathological diagnosis of diffuse LBD. However, differences in neuropathological diagnosis were not significant. There were no statistically significant differences in Braak and Hoehn and Yahr stages between groups. The majority of our cases had memory impairment-dominant cognitive impairment. Only one case from the VH group and one from the control group had evidence frontal lobe-dominant cognitive impairment.

4. Discussion The present study compares the clinical and pathological features of a group of well-characterized PD patients with VH and a closely age-, onset-, gender- and HY stagematched group of PD patients without VH. High LB densities in the frontal, temporal, parietal cortex and the amygdala were associated with the presence of VH. In patient with VH, LB densities were higher in regions traditionally related to visual hallucinations (temporal lobe and amygdala) as well as others not apparently related (frontal and parietal cortex).

Fig. 1. Comparison of the LB burden between patients with and without VH. Bars represent the mean LB counts and the standard error of the mean. Lewy body burden was determined by adding the maximum number of LBs per !20 microscopic field. All comparisons yielded statistically significant results (frontal pZ0.02, temporal pZ0.04, parietal pZ0.02, amygdalar pZ 0.008).

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The amygdala has long been suspected to contribute to psychotic symptoms because its stimulation (often by temporal lobe epilepsy) could provoke positive symptoms, such as hallucinations [10]. In a study of the amygdalar pathology in PD patients [5], the proportion of LBcontaining neurons in the amygdala was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nuclear complex contributes to this clinical feature. Recent experiments have also implicated the amygdala in visual dysfunction by showing its important role in the integration of parallel visual systems [11]. The presence of an increased amygdalar LB burden is likely to be related with a more pronounced neurodegeneration resulting in the disruption of its ability to integrate visual systems. It has been suggested that this situation, in association with dopamine replacement therapies may precipitate the VH in PD [3]. Cortical LB pathology in PD has been mainly related to cognitive impairment. However, a striking association between LB distribution in the temporal lobe and the presence of VH has been reported in patients with Lewy Body Disease [4]. In a study using 99mTc-labeled hexamethyl-propyleneamine-oxime SPECT, patients experiencing VH showed significantly lower cerebral blood flow in temporal regions than non-hallucinatory patients, which might reflect neurodegenerative abnormalities of mesocorticolimbic regions [12]. Temporal pathology has been associated with visual hallucinations in other neurodegenerative diseases. Parkinsonism and exaggerated cognitive decline are significant predictors of visual hallucinations in Alzheimer’s disease (AD) patients [13], with studies showing cortical LB in such cases [14]. This suggests that a similar distribution of cortical LB in cases with AD may contribute to the clinical manifestation of visual hallucinations [4]. The involvement of the frontal and parietal lobes in the development of VH has not been well characterized. We report an increase in frontal and parietal lobe LB burden in patients with VH. A [18F] fluoro-deoxyglucose PET study also found frontal and parietal lobe abnormalities in PD patients with VH [15]. Our report has certain limitations commonly seen in retrospective clinico-pathological studies. Although PD cases were carefully selected based on methods extensively described, the possibility of ascertainment bias should be considered. Furthermore, due to our strict inclusion and exclusion criteria used to clearly separate patients who experienced visual hallucinations from those who did not, only a small number of patients were studied-possibly limiting the statistical power of our results. Although evaluation of cognitive impairment was based on retrospective chart review, every effort was made to match our sample for this variable. The possibility of diagnostic errors should not be excluded. In summary, we report the association of cortical and amygdalar LB pathology with the presence of VH in PD.

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Evidence in the existing literature supports our findings. Although our results suggest significant extranigral involvement, the precise etiopathologic mechanisms responsible for the development of VH remain unknown. Larger studies on the subject are warranted.

Acknowledgements The Brain Endowment Banke is funded in part by the National Parkinson Foundation (NPF). This work was supported in part by a grant from the National Parkinson Foundation (NPF no. 662891). We would like to thank Dr DW Dickson (Departments of Pathology and Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL) for his valuable help with the neuropathological analysis of the University of Miami Endowment Bank tissues.

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