Objective: This study investigates possible cerebral morphological differences between GBA-gene-mutation carriers with Parkinson´s disease (PD) and PD-patients without GBA-gene-mutation depending on in- or exclusion of benign GBA-gene polymorphism.

Background: Heterozygous glycocerebrosidase (GBA) 1 gene-mutation is one of the most common genetic PD risk-factors. PD-GBA-carriers are known to show a more rapid progression of motor and non-motor symptoms including earlier cognitive decline. Furthermore, these patients seem to be at risk of faster cognitive decline after surgery for deep brain stimulation (DBS) in comparison to non-mutated PD-patients [1]. Hitherto existing voxel-based morphometry (VBM) studies detected an earlier but non-specific appearance of atrophy in GBA-mutation patients in comparison to non-mutation carriers [2]. A differentiation between carriers of benign polymorphisms and pathogenetic mutations was not done before.

Method: We investigated a cohort of 15 patients (6 with E326k or T321M polymorphism and 9 with pathogenic GBA-mutations) as well as 37 non-mutated PD-controls undergoing DBS-evaluation at Charité. MRI-data was acquired during DBS-evaluation on 3.0T Siemens Magnetom Skyra or Vida (T1 MPRAGE; TE 2.3ms; TR 2300ms; flip angle 8°, slice thickness 0.9-1mm). VBM was applied using spm12 based cat12 toolbox. Results were displayed as ROI volumes. Significance was detected using ANCOVA. Testing for multiple comparisons was done using Holm-Bonferroni test.

Results: Clinical characteristics in between mutation carriers and non-mutation carriers did not differ significantly for age, sex, motor symptoms (UPDRS III), impulsivity, depression and cognitive decline. Likewise, morphological changes did not differ significantly between the groups.  However, exclusion of patients with benign polymorphism depicted significant atrophy of the right parahippocampal gyrus (p-value 0.0109; Holm-Bonferroni corrected; p<0.05).

Conclusion: Parahippocampal atrophy, known to be associated to cognitive decline in PD, might be especially relevant in PD with pathogenic GBA-mutation. For a validation of these findings with potential implications for e.g. DBS-recommendations, larger cohorts und clinical follow-up will be needed.

References: [1] Pal G, Mangone G, Hill EJ, Ouyang B, Liu Y, Lythe V, Ehrlich D, Saunders-Pullman R, Shanker V, Bressman S, Alcalay RN, Garcia P, Marder KS, Aasly J, Mouradian MM, Link S, Rosenbaum M, Anderson S, Bernard B, Wilson R, Stebbins G, Nichols WC, Welter ML, Sani S, Afshari M, Verhagen L, de Bie RMA, Foltynie T, Hall D, Corvol JC, Goetz CG. Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers. Ann Neurol. 2022;91:424-35.

[2] Filippi M, Balestrino R, Basaia S, Agosta F. Neuroimaging in Glucocerebrosidase-Associated Parkinsonism: A Systematic Review. Mov Disord. 2022;37:1375-93.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mr-morphological-changes-in-pd-patients-with-heterozygous-gba-mutation/