Free‐Water Imaging of the Substantia Nigra in GBA Pathogenic Variant Carriers

Abstract Background Pathogenic variants in the glucocerebrosidase gene (GBA) have been identified as the most common genetic risk factor for Parkinson's disease (PD). However, the features of substantia nigra damage in GBA pathogenic variant carriers remain unclear. Objective We aimed to evaluate the microstructural changes in the substantia nigra in non‐manifesting GBA pathogenic variant carriers (GBA‐NMC) and PD patients with GBA pathogenic variant (GBA‐PD) with free‐water imaging. Methods First, we compared free water values in the posterior substantia nigra between non‐manifesting non‐carriers (NMNC, n = 29), GBA‐NMC (n = 26), and GBA‐PD (n = 16). Then, free water values in the posterior substantia nigra were compared between GBA‐PD and early‐ (n = 19) and late‐onset (n = 40) idiopathic PD (iPD) patients. Furthermore, we examined whether the baseline free water values could predict the progressions of clinical symptoms. Results The free water values in the posterior substantia nigra were significantly higher in the GBA‐NMC and GBA‐PD groups compared to NMNC, and were significantly increased in the GBA‐PD group than both early‐ and late‐onset iPD. Free water values in the posterior substantia nigra could predict the progression of anxiety and cognitive decline in GBA‐NMC and GBA‐PD groups. Conclusions We demonstrate that free water values are elevated in the substantia nigra and predict the development of non‐motor symptoms in GBA‐NMC and GBA‐PD. Our findings demonstrate that a significant nigral impairment already exists in GBA‐NMC, and nigral injury may be more severe in GBA‐PD than in iPD. These results support that free‐water imaging can as a potential early marker of substantia nigra damage. © 2023 International Parkinson and Movement Disorder Society.