Objective: To determine the impact of the dopamine system (dopamine transporter [DAT] availability, dopamine-related SNPs, and dopaminergic medication use) on long-term cognitive performance in early Parkinson disease (PD).

Background: DAT SPECT imaging has been associated with decreased cognition in preliminary studies, as has the COMT val158met and the DRD2C957T genotypes. There is no evidence that choice of initial dopaminergic medication makes a difference in long-term dementia rates.

Method: Data from the Parkinson’s Progression Markers Initiative (PPMI) study was utilized. Up to 417 participants had baseline data available, and up to 238 participants had year 7 data available. Cognitive impairment was defined as: (1) MoCA: score <26; (2) detailed cognitive testing: ≥2 tests impaired (>1.5 below mean); (3) MDS-UPDRS part I cognition score ≥2; and (4) site investigator diagnosis of MCI or dementia. Two values for striatal DAT were used: (1) mean striatum and (2) lowest age- and sex-corrected putamen values. DaTscan values for baseline, and years 1, 2 and 4 were used for longitudinal models. Single nucleotide polymorphisms (SNPs) related to dopamine system function were included (N=18). Total levodopa equivalent daily dose (LEDD) for all PD medications prescribed was calculated at every post-baseline visit. Analyses included logistic regression models using MLE and generalized estimating equations. P values were uncorrected for multiple comparisons.

Results: For incident, consistent longitudinal cognitive impairment, lower baseline mean striatum DAT was associated with worse detailed cognitive testing and UPDRS Part 1 cognition score over time (Table 1). DRD3 rs6280 predicted better MoCA score over time, DRD4 rs1800955 predicted UPDRS Part 1 cognition score, and SLC18A2 rs363276 and SLC18A2 rs363227 predicted site investigator diagnosis of cognitive impairment over time (Table 2). Higher LEDD over time predicted cognitive impairment based on MoCA, UPDRS Part I score and site investigator diagnosis cognitive impairment (Table 3).

Conclusion: These results provide preliminary evidence that the dopamine system, including DAT availability, dopamine-related SNPs and longitudinal dopaminergic medication use, may predict long-term cognitive decline in PD.

References: 1. Ravina B, Marek K, Eberly S, Oakes D, Kurlan R, Ascherio A, et al. Dopamine transporter imaging is associated with long-term outcomes in Parkinson’s disease. Movement Disorders. 2012;27:1392-7.
2. Liu R, Umbach DM, Troster AI, Huang X, Chen H. Non-motor symptoms and striatal dopamine transporter binding in early Parkinson’s disease. Parkinsonism Relat Disord. 2020;72:23-30.
3. Backstrom D, Eriksson Domellof M, Granasen G, Linder J, Mayans S, Elgh E, et al. Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson’s disease. Acta Neurol Scand. 2018;137(1):91-8.
4. Group PDMC, Gray R, Ives N, Rick C, Patel S, Gray A, et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet. 2014;384(9949):1196-205.
5. Verschuur CVM, Suwijn SR, Boel JA, Post B, Bloem BR, van Hilten JJ, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380(4):315-24.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-the-dopamine-system-on-long-term-incident-cognitive-impairment-in-parkinson-disease/