The effect of polygenic risk on white matter microstructural degeneration in Parkinson's disease: A longitudinal Diffusion Tensor Imaging study

Abstract

Background and purpose: This study was undertaken to investigate the effect of genetic risk on whole brain white matter (WM) integrity in patients with Parkinson disease (PD). Methods: Data were acquired from the Parkinson's Progression Markers Initiative (PPMI) database. Polygenic load was estimated by calculating weighted polygenic risk scores (PRS) using (i) all available 26 PD-risk single nucleotide polymorphisms (SNPs) (PRS1) and (ii) 23 SNPs with minor allele frequency (MAF) > 0.05 (PRS2). According to the PRS2, and combined with clinical and diffusion tensor imaging (DTI) data over 3-year follow-up, 60 PD patients were screened and assigned to the low-PRS group (n = 30) and high-PRS group (n = 30) to investigate intergroup differences in clinical profiles and WM microstructure measured by DTI cross-sectionally and longitudinally. RESULTS: PRS were associated with younger age at onset in patients with PD (PRS1, Spearman ρ = −0.190, p = 0.003; PRS2, Spearman ρ = −0.189, p = 0.003). The high-PRS group showed more extensive WM microstructural degeneration compared with the low-PRS group, mainly involving the anterior thalamic radiation (AThR) and inferior fronto-occipital fasciculus (IFOF) (p < 0.05). Furthermore, WM microstructural changes in AThR correlated with declining cognitive function (r = −0.401, p = 0.028) and increasing dopaminergic deficits in caudate (r = −0.405, p = 0.030). Conclusions: These findings suggest that PD-associated polygenic load aggravates the WM microstructural degeneration and these changes may lead to poor cognition with continuous dopamine depletion. This study provides advanced evidence that combined with a cumulative PRS and DTI methods may predict disease progression in PD patients.