GABA, Glx, and GSH in the cerebellum: their role in motor performance and learning across age groups

Shanti Van Malderen; Melina Hehl; Stefanie Verstraelen; Robbe Breugelmans; Georg Oeltzschner; Stephan P Swinnen; Koen Cuypers

doi:10.3389/fnagi.2025.1626417

GABA, Glx, and GSH in the cerebellum: their role in motor performance and learning across age groups

Front Aging Neurosci. 2025 Jul 3:17:1626417. doi: 10.3389/fnagi.2025.1626417. eCollection 2025.

Authors

Shanti Van Malderen^{1

2

3}, Melina Hehl^{1

2

3

4}, Stefanie Verstraelen¹, Robbe Breugelmans⁵, Georg Oeltzschner⁶, Stephan P Swinnen^{2

3}, Koen Cuypers^{1

2

3}

Affiliations

¹ Neuroplasticity and Movement Control Research Group, Rehabilitation Research Institute (REVAL), Hasselt University, Diepenbeek, Belgium.
² KU Leuven, Leuven Brain Institute (LBI), Leuven, Belgium.
³ Movement Control and Neuroplasticity Research Group, Department of Movement Sciences, Group Biomedical Sciences, KU Leuven, Heverlee, Belgium.
⁴ Translational MRI, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
⁵ Imo-imomec, Hasselt University, Hasselt, Belgium.
⁶ Medicine, Department of Radiology and Radiological Science, Johns Hopkins, Baltimore, MD, United States.

Abstract

Introduction: The cerebellum is essential for motor control and learning, relying on structural and functional integrity. Age-related atrophy leads to Purkinje cell loss, but subtle neurochemical changes in GABA, Glx (glutamate + glutamine), and glutathione (GSH) may precede degeneration and contribute to motor decline.

Methods: 25 younger (YA) and 25 older adults (OA) were included in this study. Magnetic resonance spectroscopy (MRS), using the MEGA-PRESS sequence, was used to investigate how age affects GABA, Glx and GSH levels in the right cerebellar hemisphere, and their relationship with motor performance, measured using a visuomotor bimanual tracking task (BTT).

Results: In line with previous work YA outperformed OA on both the simple and complex task variants of the BTT. Furthermore, YA demonstrated faster short-term motor learning as compared to OA. On the metabolic level, no significant age group differences in cerebellar GABA, Glx or GSH levels, nor any task-related modulation of GABA or Glx were observed. Additionally, neither baseline neurometabolite levels nor their modulation predicted motor performance or learning.

Discussion: These results align with previous research suggesting that neurometabolic aging is region-specific, with the cerebellum potentially being more resilient due to its slower aging process. Since neither baseline nor task-related modulation of GABA, Glx, or GSH predicted motor performance or learning, cerebellar neurometabolite concentrations may not directly underlie age-related behavioral changes. Instead, volumetric decline and changes in structural and functional connectivity in the aging cerebellum may play a more significant role in motor decline as compared to neurochemical alterations. Nonetheless, it is important to consider that motor performance and learning rely on distributed brain networks-including cortical and subcortical structures-which also undergo age-related changes and may contribute to observed behavioral declines. While our findings do not support a direct role of cerebellar neurometabolite levels in age-related motor performance differences, they underscore the complexity of neurochemical aging.

Keywords: Glx; aging; cerebellum; gamma-aminobutyric acid; glutathione; magnetic resonance spectroscopy.