Exploring cerebral small vessel disease signatures in familial Parkinson's disease

Familial Parkinson's disease (PD) and vascular parkinsonism (VP) present overlapping features and may co-exist. To investigate whether PD and VP may share a potential pathogenic link and to what extent white matter hyperintensities may influence PD phenotype, we used the modified Scheltens scale and presented a descriptive and exploratory analysis of the classic neuroradiological features of cerebral small vessel disease (cSVD) in the axial T2-FLAIR MRI sequences in a cohort of 104 familial PD and PD prodromal patients and 48 age-matched controls from the PPMI publicly available database. We next performed whole exome sequencing to examine the protein coding variability in the main PD-causing and risk genes (VPS35, DJ1, PINK1, ATP13A2, PRKN, SNCA, LRRK2, GBA, MAPT, LAMP3, STK39) in a cohort of 96 patients with familial cSVD and 243 elderly healthy individuals (HEX database). In this cohort, patients with familial and prodromal PD present a moderate burden of superficial frontal white matter hyperintensities (p-value = 3.46e-06, Bonferroni-corrected), linked to a mild reduction of motor and cognitive function and an increased LRRK2 p.G2019S and p.R1441C variant penetrance, and bilateral basal ganglia periventricular enlarged spaces (p-value = 2.64e-03, Bonferroni-corrected). Moreover, one-third of familial PD patients displayed a burden of lacunar thalamic strokes (p-value = 0.058), associated with a moderate hypokinetic-rigid syndrome. Finally, we report no known pathogenic coding variant in the main PD causative genes and risk factors in a cohort of 96 early-onset cSVD Caucasian patients. Our study adds to the understanding of potential cSVD hallmarks within this familial LRRK2, GBA and SNCA PD-PD prodromal cohort.