Motor and Nonmotor Features of p.A53T Alpha-Synuclein PD vs idiopathic PD: Longitudinal Data from the PPMI Study.

Background and Objectives The phenotype of p.A53T-Parkinson’s Disease (PD) mutation carriers appears more severe than that of iPD patients, however information on comparative, prospective clinical evolution of such subjects is limited. Here we conducted a longitudinal study to investigate, using multiple parameters, the progression of motor and nonmotor features of p.A53T SNCA PD compared to iPD.

Longitudinal 3-year data, concerning both motor and non-motor features, of 16 p.A53T-PD and 48 iPD, matched for age and disease duration at baseline, were downloaded from the Parkinson’s Progression Markers Initiative (PPMI) database and compared between the two groups. Additionally, a cognitive composite score was generated by 5 cognitive tests, focused more on executive/visuospatial function [Composite Score= (MOCA+ LNST+ SDMT+ BENTON+ Semantic F)/5], to better study cognitive change over a 3-year follow-up.

Neuropsychological assessments (MOCA, LNST, BENTON, SDMT, Semantic fluency, Phonemic Fluency, HVLT.IM-REC, HVLT-RDLY) revealed significant cognitive decline in A53T-PD compared to iPD, but also across time for the group of A53T-PD. Especially in composite score, the group of A53T-PD had lower values at all time points vs baseline (p=0.004, p<0.001 and p<0.001 respectively), and vs iPD (p-values<0.001, at all time points, including baseline). Autonomic dysfunction using SCOPA-AUT, as well as specific items of MDS-UPDRS I, such as I.1. and I.2, reflecting cognitive function and psychotic features respectively, were more prominent both within the A53T-PD group over time and across several time points between the two groups. As far as motor symptoms are concerned, motor assessments, such as MDS-UPDRS.III.ON, H&Y. ON, S&E and MDS-UPDRS II showed worse performance in A53T-PD compared to iPD but also across time for the group of A53T-PD, even though LEDD was significantly higher in A53T-PD.

The current longitudinal study indicates that A53T-PD represents a rapidly progressing subtype of PD, with accelerated decline in both motor and non-motor parameters, especially in cognitive function. Such data may set the stage for the application of targeted disease-modifying therapies in this particular subtype, in which the etiological link to alpha-synuclein is established, while generated data may be widely applicable to iPD, which is largely a sporadic synucleinopathy. Competing Interest Statement The author(s) would like to disclose the following. Athina Maria Simitsi received funding from the Michael J Fox Foundation for her participation in PPMI; Evangelos Sfikas has no disclosures; Christos Koros received funding from the Michael J Fox Foundation for his participation in PPMI; Nikolaos Papagiannakis received funding from the Michael J Fox Foundation for his participation in PPMI; Ion Beratis received funding from the Michael J Fox Foundation for his participation in PPMI; Dimitra Papadimitriou has no disclosures; Roubina Antonelou received funding fromby the National Network for Research of Neurodegenerative Diseases on the basis of Medical Precision (Grant 2018 E01300001), funded by the General Secretariat of Research and Innovation (GSRI), and by Brain Precision (TAEDR-0535850), funded by the GSRI, through funds provided by the European Union (Next Generation EU) to the National Recovery and Resilience Plan; Stella Fragkiadaki received funding from the Michael J Fox Foundation for her participation in PPMI; Dionysia Kontaxopoulou received funding from the Michael J Fox Foundation for her participation in PPMI; Marina Picillo received funding from the Italian Ministry of Health, the Italian Ministry of University and Fondazione della Societa Italiana di Neurologia; Ioanna Pachi has no disclosures; Ioanna Alefanti has no disclosures; Maria Stamelou has no disclosures; Paolo Barone Prof Paolo Barone received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie and Acorda; Leonidas Stefanis over the past year has received the following grants : PPMI2 (supported by the Michael J. Fox Foundation), IMPRIND-IMI2 Number 116060 (EU, H2020) , "Transferring autonomous and non-autonomous cell degeneration 3D models between EU and USA for development of effective therapies for neurodegenerative diseases (ND) - CROSS NEUROD" (H2020-EU 1.3.3., Grant Number778003), "Chaperone-Mediated Autophagy in Neurodegeneration" (Hellenic Foundation for Research and Innovation Grant HFRI-FM17-3013), "ALAMEDA" (H2020-EU, Grant Agreement 101017558), "Next-generation antisense molecules for Parkinson's disease therapy (THERASYN)" (Greek Secretariat of Research and Technology (GSRT), Collaborator), "Brain Precision" (GSRT), and "CMA as a Means to Counteract alpha-Synuclein Pathology in Non-Human Primates" (by the Michael J. Fox Foundation (Collaborator)). He has served on Advisory Boards for Abbvie, Innovis Pharma, ITF Hellas and Biogen and has received honoraria from ITF Hellas, Innovis Pharma and Abbvie. Funding Statement This study was supported by funding from the Parkinson's Progression Markers Initiative (PPMI) study. PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, 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, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, 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. The funding sources had no involvement in the design, interpretation or writing of this manuscript. 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 Scientific Board of all PPMI sites involved (including the Scientific Board of Eginition hospital). 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 Data Availability The data used in the preparation of this article were obtained [on October 05, 2023] from the Parkinson's Progression Markers Initiative (PPMI) database (https://www.ppmi-info.org/access-data specimens/download-data), RRID:SCR_006431. For up-to-date information on the study, visit http://www.ppmi-info.org. This analysis used data openly available from PPMI.