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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. [ABSTRACT FROM AUTHOR]

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype. • Noradrenaline is associated with rest tremor in Parkinson's disease. • Noradrenaline is preserved in tremor predominant Parkinson's Disease. • Patients without tremor show loss of noradrenaline in locus coeruleus and thalamus. [ABSTRACT FROM AUTHOR]