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

Resting tremor (RT) is a Parkinson’s disease (PD) symptom whose relationship with the dopaminergic system remains puzzling. To clarify this relation, we analysed data from 432 subjects from the PPMI (Parkinson’s 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. ### Competing Interest Statement MM has received in the past 3 years, payment, honoraria or other support from Bial, Pharmacademy, Evidenze and AbbVie. A.J.O.-M. was a national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a treatment-resistant depression cohort in Europe, sponsored by Janssen-Cilag, Ltd. (2019-2020), a trial of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd. (EudraCT number 2017-003288-36), and a trial of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd. (EudraCT NUMBER: 2019-002992-33). He is a recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests. In the past 3 years, he received payment, honoraria or other support from Angelini, Janssen, MSD, Neurolite AG, and the European Monitoring Centre for Drugs and Drug Addiction. He is vice-president of the Portuguese Society for Psychiatry and Mental Health and Head of the Psychiatry Working Group for the National Board of Medical Examination (GPNA) at the Portuguese Medical Association and Portuguese Ministry of Health. None of the aforementioned agencies had a role in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication. Other authors report no conflict of interest. ### Funding Statement Data used in the preparation of this article were obtained on May 13, 2023, from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR 006431. For up-to-date information on the study, visit www.ppmi-info.org. PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including including 4D Pharma, AbbVie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics. MM, AJOM and JAS were supported by grant EurDyscover - EJPRD19-135, funded by FCT/MCTES through the European Joint Programme for Rare Disease (EJPRD/0001/2019). MM is supported by the Michael J. Fox Foundation (MJFF-023180). JAS was supported by the Portuguese Foundation for Technology and Science (FCT) CEEC grant (2020.03118.CEECIND). PF was supported by the Portuguese Foundation for Science and Technology (FCT) through a PhD scholarship (2023.03390.BD) and by the European Union's Horizon 2020 Research and Innovation Programme through grant H2020-SC1-DTH-2019-875358 (FAITH project) We thank Prof. Raúl Rato from Uninova (Faculty of Science and Technology, Universidade Nova de Lisboa, Lisbon) for an insightful discussion on spectral analysis of accelerometry data. ### 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 Centro Hospitalar de Lisboa Ocidental Ethics Committee and by the Champalimaud Foundation Ethics Committee. Written informed consent was obtained from all participants before any study procedure. 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 The PPMI data is part of an open database. Access to PPMI data can be requested at . The data from the Champalimaud Clinical Centre cohort will be made available upon reasonable request. Scripts of the Matlab and Python codes used for data analysis can be found at [https://github.com/jalvesdasilva/Caudate\_PD\_Tremor][1] [1]: https://github.com/jalvesdasilva/Caudate_PD_Tremor