Dementia and visual hallucinations associated with limbic pathology in Parkinson's disease

Abstract

The pathological basis of dementia and visual hallucinations in Parkinson's disease (PD) is not yet fully understood. To investigate this further we have conducted a clinico-pathological study based on 30 post-mortem PD brains. PD cases were stratified into groups according to clinical characteristics as follows: (1) cognitively intact (n = 9); (2) cases with severe dementia and visual hallucinations (n = 12); (3) cases with severe dementia and no visual hallucinations (n = 4); and (4) cases with severe visual hallucinations and no dementia (n = 5). The extent of α-synuclein (αSyn), tau and amyloid β peptide (Aβ) deposition was then examined in the CA2 sector of the hippocampus and in neocortical and subcortical areas known to subserve cognitive function. We find that dementia in PD is significantly associated with αSyn in the anterior cingulate gyrus, superior frontal gyrus, temporal cortex, entorhinal cortex, amygdaloid complex and CA2 sector of the hippocampus. Aβ in the anterior cingulate gyrus, entorhinal cortex, amygdaloid complex and nucleus basalis of Meynert is also associated with dementia as is tau in the CA2 sector of the hippocampus. αSyn burden in the amygdala is strongly related to the presence of visual hallucinations but only in those PD cases with concomitant dementia. Statistical analysis revealed that αSyn burden in the anterior cingulate gyrus could differentiate demented from non-demented PD cases with high sensitivity and specificity. We conclude that αSyn in limbic regions is related to dementia in PD as well as to visual hallucinations when there is an underlying dementia.

Introduction

The pathological hallmark of Parkinson's disease (PD) is the aggregation of α-synuclein (αSyn) in Lewy bodies (LBs) and in the form of Lewy neurites (LNs). While the disease is initially characterized by motor deficits, later on dementia and visual hallucinations (VH) are commonly present [1], [2], [3], [4], [5], [6], [7] although the specific anatomical and pathological correlates of these clinical features remain unclear. The presence of LBs in limbic and neocortical regions has been suggested as a cause for cognitive impairment and dementia but this does not account for co-existent Alzheimer's disease (AD)-type changes that are often found alongside αSyn pathology. In cases with mixed pathology it is difficult to determine whether LBs or AD-type pathology are responsible for dementia. In addition, to date there have been few neuropathologic studies of PD patients with VH [8], [9], [10] and the anatomico-pathological correlate(s) for VH is/are still unknown.

In this study, we assessed the association between dementia and VH with αSyn and AD-type pathology (amyloid β peptide (Aβ) and tau) using an experimental design that enabled us to isolate clinical features of interest and study their anatomical and pathological basis.