Brain-first forms of Parkinson’s Disease are over-represented in patients with non-responsive resting tremor

Motor subtypes in Parkinson’s Disease (PD) are unstable over time, limiting mechanistic insights and biomarker discovery. We focused on Rest Tremor (RT) as a symptom to test for phenotype stability and link them to specific circuits and disease mechanisms. Using the PPMI cohort data over 5 years we found that RT we found that RT is more stable than common Tremor-Dominant definitions, a stability also seen for therapy response. At time of diagnosis, the population of therapy-resistant RT patients was enriched with a brain-first PD profile as predicted by a-Synuclein origin site and connectome (SOC) model. Resistant-RT patients have lower gastrointestinal and cardiovascular symptoms, lower prevalence of probable REM-Sleep behavior disorder, and higher dopaminergic asymmetry compared to therapy-responsive or no tremor patients. Treating RT as a distinct phenomenon revealed a relative phenotypic stability with treatment response being linked to different patterns of disease progression.