Abstract Body: Background: Neurovascular coupling (NVC) depends on cerebral endothelial function, and was impaired in cerebral small vessel disease (CSVD), but previous studies have been small whilst the relationship between NVC and white matter microstructural changes in CSVD remains unclear. This study investigated the association between NVC and both macro- and microstructural white matter changes in the large UK Biobank population.

Methods: UK Biobank data were used to determine associations between demographics, medical history and structural MRI measures (white matter hyperintensities, WMH; peak width of skeletonized mean diffusivity, PSMD) with NVC. NVC was quantified as the z-score of the fMRI blood-oxygen-level-dependent (BOLD) response to a visual stimulus. WMH volume was calculated from T2-weighted images, normalized to total intracranial volume (ICV), and log-transformed due to skewness. PSMD was derived from diffusion-weighted data. All continuous variables were scaled.

Results: Among 37,914 participants (mean age: 64.1±7.7 years; 52% female; 1.35% with a history of ischemic stroke), mean PSMD, WMH volume, and NVC were 2.25±0.40x10^–4 mm²/s, 0.93±0.01% ICV, and 2.55±1.35, respectively. NVC significantly decreased with age (β=-0.07, p<0.001), hypertension (β=-0.12, p<0.001), diabetes (β=-0.13, p<0.001), and stroke history (β=-0.20, p<0.001).

General linear models demonstrated a significant decrease in NVC associated with higher PSMD (β=-0.03, p<0.001) and WMH (β=-0.04, p<0.001) after controlling for age, sex, hypertension, diabetes, and stroke. Additionally, there was a significant interaction such that the negative impact of PSMD and WMH on NVC was exacerbated by older age (PSMD:age β=-0.04, p<0.01; WMH:age β=-0.03, p<0.05).

Conclusion: This study highlights a strong association between impaired NVC and markers of CSVD, including both macrostructural (WMH) and microstructural (PSMD) white matter abnormalities, in a large population. The synergistic exacerbation of these effects by age underscores the potentially critical role of cerebrovascular dysfunction in the development of CSVD.