Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients
Authors: Baldelli Luca , Schade Sebastian , Jesús Silvia , Schreglmann Sebastian R. , Sambati Luisa , Gómez-Garre Pilar , Halsband Claire , Calandra-Buonaura Giovanna , Adarmes-Gómez Astrid Daniela , Sixel-Döring Friederike , Zenesini Corrado , Pirazzini Chiara , Garagnani Paolo , Bacalini Maria Giulia , Bhatia Kailash P. , Cortelli Pietro , Mollenhauer Brit , Franceschi Claudio ,   PROPAG-AGEING consortium, Houlden Henry , Liò Pietro , Luchinat Claudio , Delledonne Massimo , Mills Kevin , Pedersen Nancy L. , Azevedo Tiago , Bartoletti-Stella Anna , Bonilla-Toribio Marta , Buiza-Rueda Dolores , Capellari Sabina , Carriòn-Claro Mario , Clayton Robert , Dal Molin Alessandra , Dimitri Giovanna Maria , Doykov Ivan , Giuliani Cristina , Hägg Sara , Hällqvist Jenny , Heywood Wendy , Huertas Ismael , Jylhävä Juulia , Labrador-Espinosa Miguel A. , Licari Cristina , Macias Daniel , Magrinelli Francesca , Rodríguez Juan Francisco Martín , Maturo Maria Giovanna , Mengozzi Giacomo , Meoni Gaia , Milazzo Maddalena , Nardini Christine , Pedersen Nancy L. , Periñán-Tocino Maria Teresa , Ravaioli Francesco , Sala Claudia , Spasov Simeon , Tejera-Parrado Cristina , Tenori Leonardo , Paola Turano , Williams Dylan , Xumerle Luciano , Zago Elisa , Broli Marcella , Buiza-Rueda Dolores , De Massis Patrizia , Escuela-Martin Rocio , Fabbri Giovanni , Gabellini Anna , Guaraldi Pietro , Houlden Henry , Macrì Stefania , Nassetti Stefania Alessandra , Scaglione Cesa Lorella Maria , Valzania Franco , Rosaria Cilea , Mignani Francesco , Ortega Rosario Vigo , Boninsegna Claudia , De Luca Silvia , Mir Pablo , Trenkwalder Claudia , Provini Federica 
Published: September 2021

A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings’ risk is not elevated.