Introduction: This study investigated structural and functional impairments in asymptomatic Moyamoya Disease (MMD) patients with normal signals to support early interventions. It focused on Neurovascular Coupling (NVC), cerebral perfusion, neural activity, and white matter microstructure in adults with unilateral and bilateral MMD, examining their impact on cognitive function. materials and methods: A total of 119 adult asymptomatic MMD cases (57 unilateral, 62 bilateral) underwent functional and structural MRI. Demographic, clinical, and neuropsychological data were collected. Cerebral blood flow (CBF) was measured with 3D pseudocontinuous arterial spin labeling, while diffusion tensor imaging provided axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA). Resting-state fMRI data were processed with the GRETNA toolbox on MATLAB 2013b, calculating low frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC). Four neurovascular coupling modes (CBF-ALFF, CBF-fALFF, CBF-ReHo, CBF-DC) were identified using DPABI. A two-sample t-test compared imaging indicators between the groups. Subsequently, a non-parametric Spearman correlation analysis was conducted to explore the relationships between imaging indicators and clinical cognition. All data have been corrected for multiple comparisons. Methods: 119 asymptomatic MMD adults (57 unilateral, 62 bilateral) underwent MRI assessments. Data on demographics, clinical, and neuropsychological parameters were collected. Comparative analyses of Cerebral Blood Flow (CBF), white matter diffusion, neuronal activity, and NVC were conducted, with Spearman correlation analyses assessing the link between imaging differences and cognitive function, adjusting for multiple comparisons. results: Patients with bilateral asymptomatic MMD showed significantly lower CBF-ALFF and CBF-ReHo coupling compared to those with unilateral asymptomatic MMD (P < 0.05). They also had higher RD and lower FA in certain brain regions (P < 0.05), along with varying ALFF and fALFF values. ReHo and DC values were elevated in specific areas, but CBF changes were not statistically significant. CBF-ReHo positively correlated with FA and negatively with RD, while both CBF-ALFF and FA positively correlated with cognitive performance. Results: The study identified that patients with bilateral asymptomatic MMD had lower NVC across two coupling modes (P = 0.004/0.049) and fractional anisotropy within two clusters (P = 0.028/0.039), alongside higher radial diffusivity in three clusters (P = 0.046) compared to those with unilateral involvement. While neuronal activity differed, CBF changes were not significant. NVC demonstrated a positive correlation with fractional anisotropy (P = 0.005) and was negatively related to radial diffusivity across two clusters (P = 0.025/0.018). Furthermore, both fractional anisotropy (P = 0.031) and NVC were positively associated with cognitive performance (P = 0.003). discussion: The findings of this present study demonstrate that asymptomatic Moyamoya disease (MMD) patients with bilateral vascular involvement exhibit more pronounced impairment in neurovascular coupling (NVC) and white matter microstructural damage compared to those with unilateral involvement. These alterations are detectable even at a stage when no significant differences in cerebral blood flow (CBF) are observed. The dysfunction in NVC is closely correlated with white matter integrity markers, such as reduced fractional anisotropy (FA) and increased radial diffusivity (RD), and both are partially associated with cognitive decline, suggesting that bilateral vascular involvement may indicate higher risks of compensatory failure and clinical progression. These findings carry important clinical implications: NVC assessment appears to be more sensitive than conventional CBF measurements in detecting early microvascular dysfunction, thereby aiding in the identification of high-risk individuals among asymptomatic MMD patients, particularly those with bilateral lesions. Thus, NVC may serve as a useful neuroimaging biomarker for guiding early intervention strategies and personalized clinical management. Several limitations should be acknowledged in this study: the sample size was limited, reflecting its preliminary and exploratory nature; the cognitive assessment battery did not comprehensively cover all cognitive domains; and the lack of longitudinal follow-up data precludes clarification of the temporal relationship between NVC changes and white matter microstructural integrity, as well as their predictive value for clinical outcomes. Future studies should aim to recruit larger cohorts, employ more comprehensive neuropsychological test batteries, and incorporate long-term follow-up to further validate the predictive role of NVC in the natural history of asymptomatic MMD. Moreover, mechanistic investigations are warranted to elucidate the interrelationships between white matter microstructural damage and neurovascular unit dysfunction, which may provide novel targets for early therapeutic interventions. Discussion: This study shows that in asymptomatic MMD patients with normal signals, bilateral vascular involvement leads to more severe NVC impairments, despite similar CBF levels. This condition may worsen white matter damage and increase the risk of cognitive decline and adverse outcomes as the disease progresses. Early detection of NVC dysfunction could indicate a higher risk of future clinical issues and guide decisions on vascular reconstruction surgery. These findings suggest that NVC is an earlier indicator of brain dysfunction than traditional CBF measures in asymptomatic MMD patients. conclusion: Patients with bilateral vascular involvement in asymptomatic MMD exhibit more severe NVC impairments, which may exacerbate microstructural damage and potentially lead to cognitive impairment. Conclusion: Bilateral asymptomatic MMD is associated with greater NVC impairment, possibly worsening microstructural damage and cognitive decline, suggesting a basis for targeted interventions.
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