Clinical and imaging evidence of brain-first and body-first Parkinson's disease

Braak's hypothesis has been extremely influential over the last two decades. However, neuropathological and clinical evidence suggest that the model does not conform to all patients with Parkinson's disease (PD). To resolve this controversy, a new model was recently proposed; in brain-first PD, the initial α-synuclein pathology arise inside the central nervous system, likely rostral to the substantia nigra pars compacta, and spread via interconnected structures - eventually affecting the autonomic nervous system; in body-first PD, the initial pathological α-synuclein originates in the enteric nervous system with subsequent caudo-rostral propagation to the autonomic and central nervous system. By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBD-positive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes. Body-first PD patients display: 1) a larger burden of autonomic symptoms - in particular orthostatic hypotension and constipation, 2) more frequent pathological α-synuclein in peripheral tissues, 3) more brainstem and autonomic nervous system involvement in imaging studies, 4) more symmetric striatal dopaminergic loss and motor symptoms, and 5) slightly more olfactory dysfunction. In contrast, only minor cortical metabolic alterations emerge before motor symptoms in body-first. Brain-first PD is characterized by the opposite clinical and imaging patterns. Patients with pathological LRRK2 genetic variants mostly resemble a brain-first PD profile whereas patients with GBA variants typically conform to a body-first profile. SNCA-variant carriers are equally distributed between both subtypes. Overall, the literature indicates that body-first and brain-first PD might be two distinguishable entities on some clinical and imaging markers.