Objective: Utilizing bidirectional two-sample Mendelian randomization, we explored the causal associations between imaging-derived phenotypes (IDPs) and Parkinson’s Disease (PD), along with its manifestations.

Background: Observational investigations propose a correlation between brain imaging alternations and PD. However, confounders and reverse causation have limited these studies, leading to conflicting results. The causal relationship between brain IDPs and PD remains elusive.

Method: We performed two-sample MR to systematically investigate the bidirectional causal associations between 3370 IDPs (n=39,691) and PD (n=482,730), as well as PD manifestation and progression (n=4,093). Subsequently, we validated these findings within our clinical cohort (HC, iRBD and PD).

Results: We identified 14 IDPs with statistically significant evidence of potential causal effects on PD, as well as potential causal effects of PD on 7 IDPs. For example, increased Median T2* in the right caudate (OR 1.23, pfdr 0.0057) and bilateral putamen (left: OR 1.25, pfdr 0.0056; right: OR 1.25, pfdr:0.0056), volume expansion of the left thalamus (OR 1.50, pfdr: 0.016), right VPL (OR 1.78, pfdr 0.0041) and left Pt (OR 2.25, pfdr 0.015) were associated with increased risk of PD. A decrease in median T2star in both pallidum correlated causally with PD severity (left: β:-0.18,pfdr 0.0029; right: β-0.16, pfdr 0.0091). In the reverse MR, an indication that PD could decrease weighted mean FA in the left uncinate fasciculus (β -0.04, pfdr 0.017) as well as the area of the left planum polare (β -0.05, pfdr 0.040) was found. Clinical validation revealed an increase in Median T2* within the caudate, putamen, and pallidum among iRBD patients, while a decrease in T2* within the same regions was observed in PD patients. Both iRBD and PD patients exhibited an increased volume of the thalamus, VPL and Pt. Additionally, PD patients demonstrated a reduction in FA within the uncinate fasciculus.

Conclusion: Our findings reveal bidirectional causative associations between IDPs and PD, providing insights into early diagnostic biomarkers and disease progression monitoring. This also enhances our understanding of PD mechanisms and offers potential strategies for disease prediction and intervention.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/refining-and-understanding-causal-relationships-between-brain-imaging-derived-phenotypes-and-parkinsons-disease-a-bidirectional-mendelian-randomization-study-and-clinical-validation/