Parkinson's disease

Neuroscience

Neuropathology

Lewy body

Autopsy

Dementia with Lewy bodies

Psychology

Cognitive decline

Dementia

Medicine

Cerebral amyloid angiopathy

Disease

Alpha-synuclein

Pathology

Journal of Neurology Neurosurgery & Psychiatry

Background Dementia is a common, debilitating feature of late Parkinson’s disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer’s disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD. Methods Systematic review of autopsy studies published in English involving PD cases with dementia. Comparison groups included PD without dementia, AD, dementia with Lewy bodies (DLB) and healthy controls. Results 44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-β pathology was moderate or severe in over half. Amyloid-β was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PDD from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-β were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology. Conclusions While significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure. Trial registration number CRD42018088691.

Neuropathology of dementia in patients with Parkinson’s disease: a systematic review of autopsy studies