NOTCH3 p.R544C variant in vascular Parkinsonism: Clinical and imaging correlates in a Taiwanese cohort

Vascular parkinsonism (VP) is a heterogeneous syndrome caused by cerebrovascular pathology. While generally distinguishable from Parkinson's disease (PD), overlap may occur in some cases. The genetic basis of VP remains unclear. The role of the NOTCH3 p.R544C variant-common in East Asian cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) cohorts-in VP has not been systematically evaluated.

We conducted a prospective study of 253 patients with parkinsonism (idiopathic PD, VP, or atypical parkinsonism), who underwent clinical evaluation, brain MRI, and testing for the NOTCH3 p.R544C variant. A comparison cohort of 48 patients with cerebral small vessel disease (CSVD) and the same variant but without parkinsonism was also included.

The NOTCH3 p.R544C variant was significantly more prevalent in VP (30.2 %) than in PD (1.7 %) or atypical parkinsonism (0 %). Among VP patients, variant carriers more often exhibited severe deep white matter hyperintensities (WMHs), external capsule involvement, prior stroke, and family history of stroke. In the CSVD variant-positive cohort, parkinsonism was independently associated with older age and family history of stroke. Compared with PD patients with CSVD, those with VP showed more severe WMH, more frequent external capsule involvement, cerebral microbleeds, cognitive decline, prior stroke, and family history of stroke.

NOTCH3 p.R544C variant is common in VP and linked to distinct clinical and imaging features. Findings suggest targeted genetic testing may improve diagnostic precision in selected VP patients. However, due to the ethnic specificity of the NOTCH3 p.R544C variant, findings may not be generalizable beyond East Asian populations.