Neuropathological changes in advanced Parkinson’s disease

Patients with advanced Parkinson’s disease (PD) show severe motor dysfunction, wearing-off, dyskinesia, dementia, and autonomic failure. These symptoms correlate with the development of neuropathological findings such as severe nigrostriatal and non-dopaminergic neuron loss and gliosis, and phosphorylated alpha-synuclein (pSyn) accumulation in the central and peripheral nervous systems. In addition, there are often co-pathological changes, including Alzheimer-related tau and amyloid accumulations. According to Braak’s PD progression hypothesis, at the time of clinical diagnosis of PD, accumulation of pSyn-positive structures is already widespread in the brainstem and peripheral nervous system, and in advanced PD, these pSyn-positive structures have spread to the limbic system and neocortex. In this review, we describe the basic neuropathology of PD, with particular attention given to the Braak hypothesis and the distribution of pSyn-positive structures in advanced PD.