Basal Forebrain Atrophy, Cortical Thinning, and Amyloid‐β Status in Parkinson's disease‐Related Cognitive Decline

Abstract Background Degeneration of the cortically‐projecting cholinergic basal forebrain (cBF) is a well‐established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. Objectives To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. Methods We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow‐up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear‐mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid‐β biomarker positivity on these associations. Results After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning ( P FDR < 0.05), and thinning in cBF‐associated cortical areas mediated the association between cBF degeneration and cognitive decline (r cBF‐MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid‐β status. Conclusions cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid‐β status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.