Objective: Multimodal functional assessment of striatocortical loop integrity in Parkinson’s Disease (PD) patients with and without GBA variants

Background: Biallelic GBA mutations provoke the lysosomal storage disorder Gaucher Disease (GD)[1], while heterozygous mutations and several variants that do not necessarily cause GD are associated with an increased risk for PD[6]. The variants p.E365K and p.T408M are present in 1-2% of healthy individuals and are associated with an increased risk of PD [4]. In GBA-associated PD, earlier disease onset, faster disease progression and greater cognitive decline have been reported [4,5], and a stronger involvement of the cognitive-associative striatocortical loop has been suspected in GBA-associated PD[3].

Method: In the present study, 37 PD patients, of whom seven carried a GBA variant were analyzed with respect to dopaminergic activity within the striatum, functional striatocortical connectivity and cognitive impairment. Patients underwent 18F-Dopa positron emission tomography (18F-Dopa PET), resting state fMRI acquisition as well as neuropsychological assessment. Striatal dopamine synthesis capacity was assessed by dopamine influx rate constants (Ki). Functional connectivity was analyzed by seed-to-voxel analysis.

Results: All variant carriers were heterozygous, 5 of them for p.E365K and the other 2 for p.T408M. Although cognitive assessment revealed no significant differences in performance between GBA variant carriers and noncarriers, we observed a trend towards a higher cognitive impairment in GBA variant carriers. Significantly reduced Ki-values were observed in the left caudate nucleus among PD patients with vs. without a GBA variant (p<0.05) [figure1]. Additionally, seed-to-voxel functional connectivity analysis revealed a significantly reduced functional connectivity between the left and right caudate seed regions of interest and the bilateral occipital cortex.

Conclusion: The present multimodal findings indicate greater dopaminergic deficits in the caudate in GBA-associated PD, possibly due to degeneration of more medially localized nigral neurons[3]. Concomitant functional dysconnectivity between the bilateral caudate nucleus and the occipital cortex may reflect correlates of greater impairment of certain striatocortical loops in GBA carriers and may be explanatory for a stronger cognitive impairment in GBA-associated PD [3].

References: [1] Grabowski, Gregory A. (2008): Phenotype, diagnosis, and treatment of Gaucher’s disease. In The Lancet 372 (9645), pp. 1263–1271. DOI: 10.1016/S0140-6736(08)61522-6. [2] Mallett, Victoria; Ross, Jay P.; Alcalay, Roy N.; Ambalavanan, Amirthagowri; Sidransky, Ellen; Dion, Patrick A. et al. (2016): GBA p.T369M substitution in Parkinson disease: Polymorphism or association? A meta-analysis. In Neurology. Genetics 2 (5), e104. DOI: 10.1212/ NXG.0000000000000104. [3] Goker-Alpan, Ozlem; Masdeu, Joseph C.; Kohn, Philip D.; Ianni, Angela; Lopez, Grisel; Groden, Catherine et al. (2012): The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow. In Brain : a journal of neurology 135 (Pt 8), pp. 2440–2448. DOI: 10.1093/brain/aws174. [4] Liu, Ganqiang; Boot, Brendon; Locascio, Joseph J.; Jansen, Iris E.; Winder-Rhodes, Sophie; Eberly, Shirley et al. (2016): Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. In Annals of neurology 80 (5), pp. 674–685. DOI: 10.1002/ana.24781. [5] Crosiers, David; Verstraeten, Aline; Wauters, Eline; Engelborghs, Sebastiaan; Peeters, Karin; Mattheijssens, Maria et al. (2016): Mutations in glucocerebrosidase are a major genetic risk factor for Parkinson’s disease and increase susceptibility to dementia in a Flanders-Belgian cohort. In Neuroscience letters 629, pp. 160–164. DOI: 10.1016/j.neulet.2016.07.008. [6] Schapira, Anthony H. V. (2015): Glucocerebrosidase and Parkinson disease: Recent advances. In Molecular and cellular neurosciences 66 (Pt A), pp. 37–42. DOI: 10.1016/j.mcn.2015.03.013.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/potential-involvement-of-the-caudate-nucleus-in-gba-associated-parkinsons-disease/