Integrity of dopaminergic terminals in the caudate nucleus is relevant for rest tremor in Parkinson's disease

Resting tremor (RT) is a Parkinsons disease (PD) symptom whose relationship with the dopaminergic system remains puzzling. To clarify this relation, we analysed data from 432 subjects from the PPMI (Parkinsons Progression Markers Initiative) database, a second cohort of 57 PD patients and controls and a third cohort of 86 subjects referred for dopamine transporter single-photon emission computed tomography (DaT-SPECT). Caudate, but not putamen binding potential (CBP, PBP) was higher in patients with RT. The presence of a higher CBP at the baseline and a relative sparing of CBP were related to the development of RT in the 2nd year. In the smaller cohorts, a 4-6 Hz oscillation-based metric extracted from inertial sensors correlated with RT amplitude and distinguished groups with DA denervation from controls. The same metric was correlated with CBP, but not PBP in subjects with a denervated DaT-SPECT. In silico modelling uncovered that higher CBP in patients with RT was fundamental to explain the associations and correlations between RT and DaT-SPECT described in our and other datasets. These results support that the integrity of caudate dopaminergic terminals could be relevant for RT pathophysiology. Unbiased assessment methods, such as inertial sensors, can be important to understand PD pathophysiology.