The neuropathology of cognitive impairment in Parkinson's disease

Dementia in Parkinson's disease (PD) is estimated to occur in 10-20[percent] of patients but is neither clinically nor pathologically homogeneous. The typical brain stem pathology of PD is considered insufficient to cause dementia. Additional cortical and sub-cortical pathological features have been implicated, including numerous cortical Lewy bodies, ubiquitin immuno-reactive neurites in the hippocampal CA2-3 region, neuronal loss nucleus basalis of Meynert (nbM), Alzheimer-type pathology, neurofibrillary tangles (NFTs) in the pre-[alpha] neurons of the entorhinal cortex and widespread amyloid deposits. The association of dementia with numerous cortical Lewy bodies has led to the classification, by some authors, of distinct clinico-pathological entities including diffuse Lewy body disease, senile dementia of the Lewy body type and the Lewy body variant of Alzheimer's disease. The aim of this study was to clarify the histological counterpart's and classification of dementia in PD as encountered at the UK Parkinson's Disease Society Brain Bank. Formalin-fixed brains from 40 patients with good clinical documentation and known cognitive status ranging from normal to severe dementia, were examined. Cortical Lewy body density was assessed in ubiquitin immuno-stained sections of cingulate gyrus and frontal, entorhinal and temporal cortex. Temporal sections were also used to assess the density of ubiquitin immuno-reactive neurites in the hippocampal CA2-3 region. NbM neurons were counted in Luxol fast blue-cresyl violet preparations. Modified Bielschowsky silver stained sections of frontal and temporal cortex were used to examine for diffuse and neuritic senile plaques and NFTs in the neocortex and entorhinal pre-[alpha] neurons. Cortical Lewy bodies were found in all the cortical regions examined in all PD brains, but were absent in controls. Cortical Lewy body density significantly increased with dementia severity, although only half (12/23) of the demented PD cases showed such an increase, while in the remainder (11/23) Lewy body density was within the same range as found in the non-demented PD group. None of the demented PD cases had sufficient clinical or pathological features to diagnose diffuse Lewy body disease, senile dementia of the Lewy body type or Lewy body variant of Alzheimer's disease as distinct clinico-pathological entities. Ubiquitin immuno-reactive neurites in the hippocampal CA2-3 region and neuronal loss in the nbM occurred in the majority of PD cases regardless of cognitive state Diffuse and neuritic senile plaques with absent or few cortical NFTs and tangle involvement in the pre-a neurons were found in many PD cases, as well as controls. Frequent cortical NFTs were found in one demented PD case and this individual had the clinical and pathological characteristics of both PD and AD. Diffuse plaques and Pre-[alpha] neuron NFTs correlated with age at death in the controls, but not in PD. The density of diffuse and neuritic plaques correlated with cortical Lewy body density in the PD cases. Therefore, of the 23 demented PD cases cognitive impairment may be attributed to cortical Lewy body and senile plaque involvement in 12 cases, coexistent PD and AD in one case and the remaining 10 cases had no additional pathology which could distinguish them from the non-demented PD group