Pathophysiology of Dementia

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There is controversy regarding which features are the primary contributors to dementia in PD. PD is characterized by cell loss in the substantia nigra pars compacta (SNc), resulting in loss of dopaminergic input into the striatum. Several pathological and functional imaging studies have shown that in PD, there is greater depletion in the lateral compartment of the SNc, which projects to the putamen, than in the medial compartment, which projects to the caudate (139-141). Cognitive impairment is associated with loss of dopaminergic projections to the caudate (142). This functional division of the striatum is, perhaps, the main reason for the predominance of motor, over cognitive symptoms in PD and is likely why dopaminergic agents do not markedly improve cognition in PD (143).

A relationship between cholinergic deficiency and dementia in PD has also been reported (144). Striking cell loss is seen in the nucleus basalis of Meynert, which provides projections to the amygdala and neocortex (144,145). Additionally, choline acetyltransferase activity has consistently been reported to be decreased to approximately 40% to 60% of control values in frontal, temporal, and hippocampal cortex (146-148), and correlates with cognitive impairment. Loss of neurons in the locus ceruleus and corresponding noradrenergic deficiency may also be associated with cognitive impairment in PD, but this has not been consistently shown (149,150).

Multiple autopsy series have shown that the presence of AD pathology correlates with dementia in PD (151-153). However, because some demented PD patients can have minimal numbers of plaques and neurofibrillary tangles, the assertion that AD pathology is responsible for PD dementia remains controversial (154,155). Recently, much of the literature has focused on the presence of Lewy bodies in the cortex and limbic system, and their association with cognitive impairment. Hurtig et al. (154), in a clinicopathologic study of 22 demented and 20 nondemented PD patients, discovered that cortical Lewy bodies were highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD. In contrast, the presence of AD pathology (senile plaques and neurofibrillary tangles) was only 64% sensitive and between 70% and 75% specific for dementia. In another study, Apaydin et al. (156) looked at the brains of 13 PD patients with dementia compared to nine PD patients without dementia. The authors found that 12 of the 13 demented PD patients had a 10-fold increase in Lewy body counts compared to the nondemented group. In seven of these patients, Lewy bodies were primarily present in the limbic areas, whereas in the other five, the Lewy bodies were widespread.

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