Cerebrovascular Function in Sporadic and Genetic Cerebral Small Vessel Disease

Abstract

Objective: Cerebral small vessel diseases (SVDs) are associated with cerebrovascular dysfunction, such as increased blood-brain barrier leakage (permeability surface area product), vascular pulsatility, and decreased cerebrovascular reactivity (CVR). No studies assessed all 3 functions concurrently. We assessed 3 key vascular functions in sporadic and genetic SVD to determine associations with SVD severity, subtype, and interrelations.

Methods: In this prospective, cross-sectional, multicenter INVESTIGATE-SVDs study, we acquired brain magnetic resonance imaging in patients with sporadic SVD/cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), including structural, quantitative microstructural, permeability surface area product, blood plasma volume fraction, vascular pulsatility, and CVR (in response to CO₂) scans. We determined vascular function and white matter hyperintensity (WMH) associations, using covariate-adjusted linear regression; normal-appearing white matter and WMH differences, interrelationships between vascular functions, using linear mixed models; and major sources of variance using principal component analyses.

Results: We recruited 77 patients (45 sporadic/32 CADASIL) at 3 sites. In adjusted analyses, patients with worse WMH had lower CVR (B = -1.78, 95% CI -3.30, -0.27) and blood plasma volume fraction (B = -0.594, 95% CI -0.987, -0.202). CVR was worse in WMH than normal-appearing white matter (eg, CVR: B = -0.048, 95% CI -0.079, -0.017). Adjusting for WMH severity, SVD subtype had minimal influence on vascular function (eg, CVR in CADASIL vs sporadic: B = 0.0169, 95% CI -0.0247, 0.0584). Different vascular function mechanisms were not generally interrelated (eg, permeability surface area product~CVR: B = -0.85, 95% CI -4.72, 3.02). Principal component analyses identified WMH volume/quantitative microstructural metrics explained most variance in CADASIL and arterial pulsatility in sporadic SVD, but similar main variance sources.

Interpretation: Vascular function was worse with higher WMH, and in WMH than normal-appearing white matter. Sporadic SVD-CADASIL differences largely reflect disease severity. Limited vascular function interrelations may suggest disease stage-specific differences. ANN NEUROL 2025;97:483-498.

Figure 1

Panel showing key imaging characteristics by small vessel disease subtype. (A) Tissue volumes (ml), (B) white matter hyperintensity (WMH) volume (ml), (C) number of lacunes, and (D) number of microbleeds. WMH, white matter hyperintensity volume. CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; GM = gray matter; NAWM = normal‐appearing white matter.

Figure 2

Graphs showing regression lines (see Table 3 for details of coefficients) showing log₁₀ normalized white matter hyperintensity (WMH) volume, adjusted for age, smoking status, systolic blood pressure, and the remaining imaging variables against each tissue/vascular function in normal‐appearing white matter (blue, left) and WMH (red, right) for (A, B) permeability surface area product (PS); (C, D) blood plasma volume (v _P ); (E, F) cerebrovascular reactivity (CVR); (G, H) venous pulsatility; and (I, J) arterial pulsatility. Blood plasma volume fraction (v _P ) was substituted for PS, and arterial pulsatility for venous pulsatility in separate models, as the variables were derived from the same data source or were collinear, and to avoid overspecifying the model.

Figure 3

Graphs showing the interaction between vascular functions adjusted for age, smoking status, systolic blood pressure variability, tissue type (normal appearing white matter [NAWM, blue] and white matter hyperintensities (WMH; red), and the remaining vascular functions against WMH volume. (A) Permeability surface area product (PS); (B) blood plasma volume (vP)*, and (C) cerebrovascular reactivity (CVR)*. See Table 4 for coefficients. *Conventionally significant interaction (p ≤ 0.05) between WMH and tissue‐of‐interest (NAWM or WMH).

Figure 4

Principal component analysis. Factor loadings for each variable (y‐axis) versus variance in the data explained by each component for (A) all patients together, (B) cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy only, and (C) sporadic small vessel diseases only (x‐axis). The labels describe the variables included in each factor. Color of variables reflects their original component in the “all patient” principal components analysis. BG = basal ganglia; BPV, blood pressure variability; CS = centrum semiovale; FA = fractional anisotropy; MB = microbleed; MD = mean diffusivity; NAWM = normal appearing white matter; PS = blood–brain barrier leakage (permeability surface area); PVS = perivascular space score; v _P  = blood plasma volume; WMH = white matter hyperintensity volume.