A transdiagnostic structural brain signature of Parkinsonian and Essential Tremor

Abstract Parkinson’s disease (PD) and Essential Tremor (ET) are heterogeneous, yet distinct disorders. At the same time, PD and ET show overlapping features such as tremor-predominant phenotypes. These heterogeneities and overlaps pose challenges for clinical management and research and may indicate shared, transdiagnostic mechanisms of tremor. We hypothesized that MRI-derived volumetric differences relate to tremor phenotypes rather than diagnostic labels. We compared regional brain volumes among three patient groups with overlapping phenotypes but distinct diagnoses: ET, PD with tremor-dominant phenotype (PD-T), and PD with non-tremor-dominant phenotype (PD-nT). We studied 164 patients (18 ET, 38 PD-T, 108 PD-nT) who underwent structural MRI and standardized assessment of motor symptoms as candidates for deep brain stimulation. We compared regional brain volumes between groups. Volumes of the thalamus, pallidum, and pre-cerebellar and upper brainstem (midbrain, pons, superior cerebellar peduncle) differed across groups, being smallest in ET, intermediate in PD-T, and largest in PD-nT. Differences reached significance when comparing ET or PD-T with PD-nT but not ET with PD-T. Thalamic and brainstem volumes correlated with more severe and less levodopa-responsive tremor in PD. In contrast to the subcortical findings, cortical thickness was thinner in fronto-parietal regions in PD-nT compared to PD-T patients, with no difference relative to ET. We identified tremor-related volume loss in cerebellothalamic and interconnected regions (pallidum) in PD and ET. These findings, though preliminary, provide novel structural MRI evidence supporting shared mechanisms of tremor and point towards a transdiagnostic structural brain signature of tremor across PD and ET.