Objective: To clinically evaluate a cohort of healthy glucocerebrosidase (GBA) mutation carriers in search of early biomarkers for neurodegeneration that may be prodromal features of Parkinson’s disease (PD).

Background: The most numerically important genetic risk factor for PD is the heterozygote GBA mutation. The GBA link to Gaucher disease (GD) in the homozygote state offers a special opportunity to study a high-risk population for phenoconversion to PD.

Method: We included 18 GBA mutation-positive non-manifesting carriers (GBA-NMC). 7 of them (39%) have the more severe GBA mutation L444P +/-. We also have a cohort of 10 GD type 1 (non-neuronopathic GD) patients, and 12 GD type 3 (with neurological affection) patients with the severe mutation L444P +/+. They have been assessed with several biomarkers that have been proposed as possible pre-motor signs of PD.

For 6 GD3 (neuronopathic GD) participants Neurofilament light (NfL) have been measured in serum, as a marker of neuronal damage, and compared to 10 healthy controls.

Results: Mean age of the GBA-NMC cohort was 54 years [range 21-84], in the GD3 cohort 47 [29-71] and in the GD1 65 [35-88].

There were no significant differences in olfactory scores between the GD 1 (mean UPSIT 27 [12-36]) and GD3 group (28 [19-34]), or the GBA-NMC group 28 [12-36].

None of the GBA-NMC had more than 4 points on the MDS-UPDRS part III motor scores. Of reported non-motor symptoms orthostatism, obstipation and restless legs were the most frequent. None had a pathologic orthostatic blood pressure, and all answered negatively on the screening question for REM sleep behaviour disorder. In the psychiatric evaluation (HADS and BDI II) assessments, they usually scored higher on anxiety than depressive questions. None had any cognitive deficits as scored by MoCA (mean 28,5, SD 1,2).

Preliminary results of S-NfL did not show increased levels among the neuronopathic GD patients (mean 2,50 pg/mL, SD 1,80, [0,07-5,14]) compared to healthy controls (2,78 pg/mL, SD 1,01 [1,71-4,3]).

Conclusion: Olfaction seems to be the most affected suggested pre-motor symptom för PD in both GD and GBA-NMC, although it cannot alone predict phenoconversion to motor manifestations of PD.

Surprisingly, S-NfL does not seem to be affected as a marker of neurodegeneration in neuronopathic GD, although the results need to be interpreted with caution due to the small number analyzed.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-possible-pre-motor-symptoms-of-parkinsons-disease-in-a-gba-mutation-positive-cohort-as-well-as-gaucher-disease-patients/