Objective: This study aimed to investigate the relationships between genetic variants reportedly associated with neurological disease and cognitive decline, in patients with PD over a 5-year period.

Background: Although typically framed as a motor disorder, a plethora of non-motor symptoms are increasingly being recognised as equally debilitating features of PD. While patients with PD experience a greater incidence of cognitive decline, studies have indicated that genetic variability may explain susceptibility to cognitive impairment, helping to stratify at risk patient groups. However, there have been limited Australian longitudinal studies examining genetic variants in determining decline in PD.

Method: Patients with PD (n=70) were assessed at baseline and 60-months at the Perron Institute’s Movement Disorders Clinic. The cohort DNA samples were genotyped on the NeuroChip array, containing 179,467 variants implicated in diverse neurological diseases, and via Sanger sequencing. Computational and statistical analysis was carried out using PLINK and SPSS (v.24) software. Cognitive function was assessed using the ACE-R, and the SCOPA-Cog, with patients stratified based on performance in these assessments. PERMANOVA was used to test the relationship between variants and clinical parameters. Generalized linear models were created, controlling for confounding variables, to determine whether genetic variants were associated with cognitive dysfunction.

Results: The current study investigated polymorphisms and mutations within genes associated with the onset of PD (SNCA, LRRK2, GBA, MAPT), but multivariate model revealed no significant associations with cognitive scores or rate of longitudinal decline. Additionally, other subsets of genes were investigated, including variants associated with cognitive performance in Alzheimer’s disease. Preliminary results revealed an association between several of these variants and either cross-sectional performance in cognitive scales, or the rate of decline over 5 years.

Conclusion: Being the first 5-year longitudinal study of genetic associations with global and cognitive domain decline in an Australian PD cohort, it aids in assessing the genetic and clinical contribution to phenotypic variability. Elucidating the interplay between these factors, particularly the genetic architecture, is integral to anticipate phenotypic progression, by way of biomarkers, and to individualise treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/longitudinal-assessment-of-genetic-determinants-of-cognitive-decline-in-parkinsons-disease/