Objective: To study the effect of SLC6A3VNTR on PD patients’ cognition longitudinally.

Background: Solute carrier family 6 neurotransmitter transporter dopamine member 3gene (SLC6A3) has two common VNTR alleles: 10-R and 9-R. 10R/10R patients have higher dopamine reuptake and we have previously shown that PD patients with this genotype have higher cortico-striatal activity during Wisconsin-Card-Sorting-Task (WCST), an executive-function task (1).

Method: 73 PD patients (stage 2 or 3 Hoehn & Yahr) were seen at time 1 (T1) and 36 were followed 18 months later (T2). All participants had a blood draw, and their genomic DNA was extracted. The SLC6A3VNTR was amplified by PCR and the product was genotyped by running on a 2% Agarose gel with a ladder. COMTrs4680 genotyping was performed by TaqMan (C2574680950). Participants had a full cognitive assessment and 1-hour MRI session in a 3T GE scanner to obtain structural and fMRI data. Task-based fMRI data of each genetic group (10-R/10-R) vs (9-R/10-R & 9-R/9-R) was analyzed by FSL.

Results: Demographics and SLC6A3genotype for participants are shown in (table1). COMTalleles distribution was not significantly different between the two groups. In longitudinal analysis, 24 (10-R) and 12 (9-R) participants remained. PD patients in 10-R group presented better memory abilities longitudinally, and at T2 when compared to 9-R group (n=36, tL=2.52 p=0.016 and tT2=2.173, p=0.037). Also, 10-R group had significantly better average z-scores of Visuo-Spatial domain and MoCA test compared to 9-R group at T2 (Mann-Whitney(M-W) UVS= 69.5 significance-level= 0.012 and M-W UMoCA= 79.5 significance-level= 0.029).  For longitudinal fMRI analysis, 3 participants from 9-R and 2 participants from 10-R group were removed due to dementia or inability to complete WCST. No region showed activity association in within and between group analysis for planning set-shift (Figure 1 a & b). For execution of set-shift, higher activity was found in right cerebellum of 10-R group compared to 9-R. Higher activity was detected in left superior temporal gyrus of 9-R group compared to 10-R (Figure 1 c & d) (Table 2).

Conclusion: PD patients with 10-R/10-R genotype retain better memory abilities longitudinally and higher MoCA scores than 9-R group. This might be due to faster reuptake of dopamine in 10-R/10-R carriers.  fMRI data is inconsistent at this point and a larger sample size is needed to validate these findings.

References: 1-Habak C, Noreau A, Monchi O, et al. Dopamine transporter SLC6A3 genotype affects cortico-striatal activity of set-shifts in Parkinson’s disease. (2014).Brain.137(11): 3025–3035.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/specific-slc6a3-variant-shows-association-with-better-memory-in-pd-patients-longitudinally/