Cognitive heterogeneity in Parkinson's disease: A mechanistic view

Abstract

Cognitive impairment occurs in most individuals with Parkinson's disease (PD), exacting a high toll on patients, their caregivers, and the healthcare system. In this review, we begin by summarizing the current clinical landscape surrounding cognition in PD. We then discuss how cognitive impairment and dementia may develop in PD based on the spread of the pathological protein alpha-synuclein (aSyn) from neurons in brainstem regions to those in the cortical regions of the brain responsible for higher cognitive functions, as first proposed in the Braak hypothesis. We appraise the Braak hypothesis from molecular (conformations of aSyn), cell biological (cell-to-cell spread of pathological aSyn), and organ-level (region-to-region spread of aSyn pathology at the whole brain level) viewpoints. Finally, we argue that individual host factors may be the most poorly understood aspect of this pathological process, accounting for substantial heterogeneity in the pattern and pace of cognitive decline in PD.

Keywords: Braak hypothesis; Lewy body; Parkinson’s disease; alpha-synuclein; cognition; dementia; dementia with Lewy bodies; mild cognitive impairment; strain.

Figure 1.. Appraising the Braak hypothesis as the mechanistic basis for cognitive decline in Parkinson’s Disease.

The literature supports cell-to-cell transfer of aSyn from affected to pathology-naïve cells and the subsequent ability of pathologic aSyn to cause templated misfolding of endogenous aSyn in a prion-like manner. However, disconnects emerge with respect to whether aSyn pathology always forms the basis for neuronal dysfunction and cognitive impairment, and whether aSyn pathology consistently follows a rostro-to-caudal spread pattern in the human brain.

Figure 2.. Evidence for distinct aSyn “strains” in the pathogenesis of synucleinopathies.

Cryo-EM studies support the existence of distinct conformations of aSyn in MSA vs. PD, both characterized by the presence of aSyn pathology. Studies of distinct conformations of aSyn, or aSyn species isolated from MSA vs. PD brain, demonstrate differential seeding and spreading properties in cell and animal models. CSF samples from individuals with MSA vs. PD exhibit distinct fibrillization properties in in vitro amplification assays.

Figure 3.. Factors influencing heterogeneity of cognitive outcomes in the Lewy body diseases.

Inherent pathologic features of “proteinopathy” (as exemplified by aSyn strain, or amount of co-existing AD pathology) are modulated by individual host features (genetic background and environmental exposures throughout life), resulting in varying cognitive presentations. PD-NC = Parkinson’s disease with normal cognition, PD-MCI = Parkinson’s disease with mild cognitive impairment, PDD = Parkinson’s disease with dementia, DLB = dementia with Lewy bodies.