Cerebral small vessel disease may not critically influence familial Parkinson’s disease

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Abstract Familial Parkinson’s disease (PD) and vascular parkinsonism (VP) overlap in their clinical, neuroradiologic and neuropathologic features. To investigate whether PD and VP may share a pathogenic link, we used the modified Scheltens scale and assessed the classic neuroradiological features of cerebral small vessel disease in the axial T2 MRI flair sequences in a cohort of 58 familial PD patients, 46 familial PD prodromal patients and 48 age-matched controls from the PPMI publicly available database. We next examined the protein coding variability in the main PD-causing genes and genetic risk factors in a cohort of 96 patients with familial cerebral small vessel disease (cSVD) and 243 elderly healthy individuals from the HEX database. Patients with familial and prodromal PD have a moderate but still significant burden of superficial white matter hyperintensities compared to age-matched controls (Wilcox Test p-value = 4.335e-07, OR = 4.1, 95% CI = 1.8–9.23), with moderate motor impairment and minimal and non-pathological cognitive decline (UPDRS and MoCa up to 25 and 26,respectively). In contrast, 100% of patients carrying SNCA p.A53T and 25% of patients carrying LRRK2 p.G2019S, p.R1441C or GBA p.N409S, p.E365K and p.L483P had moderate to very severe dementia (average MoCa Score = 21) and mild motor impairment (mean UPDRS III score = 20) and only very modest white matter lesions. Finally, we report no known pathogenic coding variant in the PD genes studied in cSVD patients. Our study shows that familial PD and small vessel disease likely have distinct not necessarily mutually exclusive, pathogenic mechanisms.

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