Benjamin Roeben, Inga Liepelt-Scarfone, Stefanie Lerche, Milan Zimmermann, Isabel Wurster, Ulrike Sünkel, Claudia Schulte, Christian Deuschle, Gerhard W. Eschweiler, Walter Maetzler, Thomas Gasser, Daniela Berg, Kathrin Brockmann
{"title":"Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers","authors":"Benjamin Roeben, Inga Liepelt-Scarfone, Stefanie Lerche, Milan Zimmermann, Isabel Wurster, Ulrike Sünkel, Claudia Schulte, Christian Deuschle, Gerhard W. Eschweiler, Walter Maetzler, Thomas Gasser, Daniela Berg, Kathrin Brockmann","doi":"10.1038/s41531-024-00706-1","DOIUrl":null,"url":null,"abstract":"<p>With disease-modifying treatment for Parkinson’s disease (PD) associated with variants in the glucocerebrosidase gene (<i>GBA1</i>) under way, the challenge to design clinical trials with non-PD-manifest <i>GBA</i> mutation carriers (GBA1<sub>NMC</sub>) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1<sub>NMC</sub>, longitudinal data of 56 GBA1<sub>NMC</sub> carriers and 112 age- and sex-matched <i>GBA1</i> wildtype participants (GBA1<sub>wildtype</sub>) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan–Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1<sub>NMC</sub> showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1<sub>NMC</sub> compared to GBA1<sub>wildtype</sub>, but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan–Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1<sub>NMC</sub>. Incidence of PD was significantly higher in GBA1<sub>NMC</sub>. In conclusion, our study extends data on GBA1<sub>NMC</sub> indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1<sub>NMC</sub> enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Parkinson's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41531-024-00706-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
With disease-modifying treatment for Parkinson’s disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1NMC) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1NMC, longitudinal data of 56 GBA1NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1wildtype) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan–Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1NMC showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1NMC compared to GBA1wildtype, but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan–Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1NMC. Incidence of PD was significantly higher in GBA1NMC. In conclusion, our study extends data on GBA1NMC indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.
期刊介绍:
npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.