A Transdiagnostic Structural Brain Signature of Parkinsonian and Essential Tremor

Abstract IntroductionParkinson’s disease (PD) and essential tremor (ET) are heterogeneous and show overlapping features at the same time. These heterogeneities pose challenges for clinical management and research and may indicate shared mechanisms for tremor. To test the hypothesis that regional brain volumes correspond to phenotypes rather than diagnosis, we compared structural MRI volumetrics between patients with ET or PD with (PD-T) or without tremor-dominant phenotype (PD-nT). MethodsWe studied 166 patients (109 PD-nT, 39 PD-T, 18 ET) who were evaluated for deep brain stimulation. All patients underwent MRI, and standardized assessment of motor symptoms. We compared regional brain volumes between patients with ET, PD-T, or PD-nT. ResultsWe found that three subcortical regions – namely the thalamus, pallidum, and pre-cerebellar and upper brainstem - differed across groups. These volumes were smallest in ET, intermediate (or similar to ET) in PD-T, and largest in PD-nT. Smaller volumes of the thalamus and brainstem correlated with more severe and less levodopa-responsive tremor in PD. Sub-segmentation of the brainstem indicated involvement of upper and pre-cerebellar brainstem (pons, superior cerebellar peduncle, to a lesser degree also midbrain). In contrast to the subcortical findings, cortical thickness in frontal and parietal regions was thinner in PD-nT compared to PD-T patients. ConclusionThe clinical heterogeneity and overlap of PD and ET show corresponding structural brain changes along a phenotypic spectrum. Specifically, a transdiagnostic structural brain signature of tremor consists of reduced subcortical brain volumes in the cerebello-thalamic system and interconnected regions, suggesting shared mechanisms of tremor in PD and ET.