A Transdiagnostic Structural Brain Signature of Parkinsonian and Essential Tremor

Introduction Parkinson’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). Methods We 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. Results We 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. Conclusion The 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. ### Competing Interest Statement Funding Sources and Conflict of Interest: CI: None. FC: None. HBV: Received a competitive grant from the Koetser Foundation Zurich. FB: None. ROT: None. CB: Received competitive grants from the Swiss National Science Foundation, the Hochschulmedizin Zurich (Flagship Grant), the LOOP Zurich, the Novartis Foundation, and Parkinson Schweiz, and unrestricted grants from AbbVie Pharma, and Roche. Is founder and shareholder of Tosoo AG, which invests into non-pharmacological sleep modulation technologies. Received speaker honoraria from AbbVie Pharma. SJS: None. ### Funding Statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local ethics committee (cantonal ethics committee of Zurich; BASEC 2020-02909) and patients provided informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.