Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers

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

Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers

NPJ Parkinsons Dis. 2024 Apr 22;10(1):88. doi: 10.1038/s41531-024-00706-1.

Authors

Benjamin Roeben^{1

2}, Inga Liepelt-Scarfone^{3

4

5}, Stefanie Lerche^{3

4}, Milan Zimmermann^{3

4}, Isabel Wurster^{3

4}, Ulrike Sünkel^{3

6}, Claudia Schulte⁴, Christian Deuschle^{3

4}, Gerhard W Eschweiler^{6

7}, Walter Maetzler⁸, Thomas Gasser^{3

4}, Daniela Berg^{3

8}, Kathrin Brockmann^{3

4}

Affiliations

¹ Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany. benjamin.roeben@med.uni-tuebingen.de.
² German Center for Neurodegenerative Diseases, University of Tübingen, Otfried-Müller-Str. 27, 72076, Tübingen, Germany. benjamin.roeben@med.uni-tuebingen.de.
³ Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
⁴ German Center for Neurodegenerative Diseases, University of Tübingen, Otfried-Müller-Str. 27, 72076, Tübingen, Germany.
⁵ IB-Hochschule, Stuttgart, Germany.
⁶ Department of Psychiatry and Psychotherapy, University of Tübingen, Calwer Str. 14, 72076, Tübingen, Germany.
⁷ Geriatric Center at the University Hospital of Tübingen, Calwer Str. 14, 72076, Tübingen, Germany.
⁸ Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, and Kiel University, Arnold-Heller-Straße 3, 24105, Kiel, Germany.

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 (GBA1_NMC) 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_NMC, longitudinal data of 56 GBA1_NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1_wildtype) 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_NMC 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_NMC compared to GBA1_wildtype, 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_NMC. Incidence of PD was significantly higher in GBA1_NMC. In conclusion, our study extends data on GBA1_NMC 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_NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.