Neuropathological substrates of cognition in Parkinson's disease

Autopsy validation is still required for a definitive diagnosis of Parkinson's disease (Postuma et al., 2015), where the presence of Lewy bodies and Lewy neurites, composed primarily of alpha-synuclein, are observed in stereotyped patterns throughout regions of the brainstem, limbic, and neocortical regions of the brain (Braak et al., 2003). In spite of these relatively reliable observed patterns of alpha-synuclein pathology, there is a large degree of heterogeneity in the timing and features of neuropsychiatric and cognitive dysfunction in Parkinson's disease (Fereshtehnejad et al., 2015; Selikhova et al., 2009; Williams-Gray et al., 2013). Detailed studies of their neuropathological substrates of cognitive dysfunction and their associations with a variety of in vivo biomarkers have begun to disentangle this complex relationship, but ongoing multicentered, longitudinal studies of well-characterized and autopsy validated cases are still required.