Cognitive heterogeneity in Parkinson's disease: A mechanistic view.

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.

Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases.

The term "aging-related tau astrogliopathy" (ARTAG) describes pathological accumulation of abnormally phosphorylated tau protein in astrocytes. We evaluated the correlates of ARTAG types (i.e., subpial, subependymal, white and gray matter, and perivascular) in different neuroanatomical regions. Clinical, neuropathological, and genetic (eg, APOE ε4 allele, MAPT H1/H2 haplotype) data from 628 postmortem brains from subjects were investigated; most of the patients had been longitudinally followed at the University of Pennsylvania. We found that (i) the amygdala is a hotspot for all ARTAG types; (ii) age at death, male sex, and presence of primary frontotemporal lobar degeneration (FTLD) tauopathy are significantly associated with ARTAG; (iii) age at death, greater degree of brain atrophy, ventricular enlargement, and Alzheimer disease (AD)-related variables are associated with subpial, white matter, and perivascular ARTAG types; (iv) AD-related variables are associated particularly with lobar white matter ARTAG; and (v) gray matter ARTAG in primary FTLD-tauopathies appears in areas without neuronal tau pathology. We provide a reference map of ARTAG types and propose at least 5 constellations of ARTAG. Furthermore, we propose a conceptual link between primary FTLD-tauopathy and ARTAG-related astrocytic tau pathologies. Our observations serve as a basis for etiological stratification and definition of progression patterns of ARTAG.

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

BACKGROUND: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. OBJECTIVE: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. METHODS: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. RESULTS: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was - 0.0064 (SE = 0.002, p = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p < 0.001), Ambulatory Capacity (p < 0.001), and the Rankin (p = 0.002). CONCLUSIONS: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered.