Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease

Rosie Morris; Douglas N Martini; Katrina Ramsey; Valerie E Kelly; Katrijn Smulders; Amie Hiller; Kathryn A Chung; Shu-Ching Hu; Cyrus P Zabetian; Kathleen L Poston; Ignacio F Mata; Karen L Edwards; Jodi Lapidus; Brenna Cholerton; Thomas J Montine; Joseph F Quinn; Fay Horak

doi:10.1038/s41531-022-00344-5

Cognition as a mediator for gait and balance impairments in GBA-related Parkinson's disease

NPJ Parkinsons Dis. 2022 Jun 20;8(1):78. doi: 10.1038/s41531-022-00344-5.

Authors

Rosie Morris^{1

2}, Douglas N Martini^{1

3}, Katrina Ramsey⁴, Valerie E Kelly⁵, Katrijn Smulders⁶, Amie Hiller^{1

7}, Kathryn A Chung^{1

7}, Shu-Ching Hu^{8

9}, Cyrus P Zabetian^{8

9}, Kathleen L Poston¹⁰, Ignacio F Mata^{8

9

11}, Karen L Edwards¹², Jodi Lapidus⁴, Brenna Cholerton¹³, Thomas J Montine¹³, Joseph F Quinn^{1

7}, Fay Horak¹⁴

Affiliations

¹ Department of Neurology, Oregon Health and Science University, Portland, OR, USA.
² Department of Sport, Exercise and Rehabilitation, Northumbria University, Newcastle-upon-Tyne, UK.
³ Department of Kinesiology, University of Massachusetts Amherst, Amherst, MA, USA.
⁴ School of Public Health, Oregon Health and Science University, Portland, OR, USA.
⁵ Department of Rehabilitation Medicine, University of Washington School of Medicine, Seattle, WA, USA.
⁶ Sint Maartenskliniek Research Department, Nijmegen, The Netherlands.
⁷ Portland Veterans Affairs Health Care System, Portland, OR, USA.
⁸ Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
⁹ Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
¹⁰ Department of Neurology and Neurological Sciences, Stanford School of Medicine, Palo Alto, CA, USA.
¹¹ Lerner Research Institute, Genomic Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA.
¹² Department of Epidemiology and Biostatistics, University of California, Irvine, CA, USA.
¹³ Department of Pathology, Stanford University School of Medicine, Palo Alto, CA, USA.
¹⁴ Department of Neurology, Oregon Health and Science University, Portland, OR, USA. [email protected].

Abstract

The extent to which the heterogeneity of gait and balance problems in PD may be explained by genetic variation is unknown. Variants in the glucocerebrosidase (GBA) gene are the strongest known genetic risk factor for PD and are associated with greater motor and cognitive severity. However, the impact of GBA variants on comprehensive measures of gait and balance and their relationship to cognition remains unknown. We aimed to determine differences in gait and balance impairments in those with and without GBA variants (mutation carriers and E326K polymorphism) and explore direct and indirect effects of GBA status on gait, balance, and cognition. 332 participants, 43 of whom had GBA variants, were recruited. Participants completed a comprehensive, objective assessment of gait and standing balance using body-worn inertial sensors. Group differences in gait and balance between PD with and without GBA variants were assessed with linear regression, adjusting for age, gender, clinical testing site, disease duration, and apolipoprotein E (APOE) ɛ4 status. Structural equation modeling (SEM) explored direct relationships between GBA status and gait and balance and indirect relationships between GBA status and gait and balance via cognition. The GBA variant group had more impaired gait (pace and variability) and balance (sway area/jerk and sway velocity), than the non-GBA variant group. SEM demonstrated cognition as a mediator of GBA status on gait and balance. The close relationships among GBA, gait/balance, and cognition suggest potential for novel therapeutics to target the GBA pathway and/or cognition to improve mobility in PD GBA variants.

Abstract

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