Objective: To assess the clinical, cognitive, metabolic, and imaging phenotypes of PD patients carrying the variants p.E365K and p.T408M in the GBA gene (NM_000157.3).

Background: GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Biallelic mutations in GBA cause the lysosomal storage disorder Gaucher´s disease (GD) and in the heterozygous state are an important risk factor for PD. The variants p.E365K and p.T408M have also been associated with PD but do not cause GD. The role of these variants in PD, however, needs to be further explored.

Methods: GBA was sequenced in 38 PD patients using a gene panel analysis. Carriers of GBA variants were compared to wildtype (wt) regarding clinical history, UPDRS-III, cognitive and neuropsychiatric measures, metabolomics and PET imaging. Blood plasma was analyzed via untargeted gas chromatography coupled to mass spectrometry to derive metabolomic profiles. Dopamine influx constants (Ki) were computed from F-Dopa PET in four p.E365K, two p.T408M and 17 wt patients; in 6/4/20 patients FDG-PET expression of the PD related pattern (PDRP) was computed.

Results: Sequence analysis did not reveal any rare (<5%) variant in 26 patients (wt), the remaining 12 patients carried heterozygous GBA variants: p.E365K (n=6), p.T408M (n=5), and p.N409S (n=1). The latter represents a well-established mutation for GD and was excluded from further analyses. 10/11 variant carriers and 17/26 wt patients were male. There were no significant group differences concerning other demographics, disease duration and severity, age at onset, treatment, cognitive performance or self-reported mood and impulsivity. There was an increase of asparagine levels in variant carriers (p=.0089). This difference was not maintained with FDR correction (p=.4998). Ki in striatal subregions did not differ between groups. PDRP z-scores were higher in E365K and T408M carriers compared to wt (p=.004) [figure1].

Conclusions: PD patients carrying GBA variants were clinically similar to wt PD patients. In agreement with studies on GBA mutations, F-Dopa uptake was not significantly different from wt patients. The PDRP includes parietal hypometabolism, and reduced parietal cortical blood flow was already reported for PD with GBA mutations. Cortical metabolism should be further investigated in carriers of GBA risk variants, combined with a targeted approach focused on amino acid metabolism, e.g. asparagine-glutamine pathways.

References: Peng S, Ma Y, Spetsieris PG, Mattis P, Feigin A, Dhawan V, Eidelberg D. Characterization of disease-related covariance topographies with SSMPCA toolbox: effects of spatial normalization and PET scanners. Human Brain Mapping 35: 1801-14, 2014.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/fdg-pet-and-metabolomics-in-pd-associated-gba-variants/