Structure-function coupling alterations in cognitively normal individuals with white matter hyperintensities

White matter hyperintensities (WMH) are prominent neuroimaging markers of cerebral small vessel disease (CSVD) linked to cognitive decline. Nevertheless, the pathophysiological mechanisms underlying WMH remain unclear.

This study aimed to assess the structural decoupling index (SDI) as a novel metric for quantifying the brain's hierarchical organization associated with WMH in cognitively normal older adults.

We analyzed data from 112 cognitively normal individuals with varying WMH burdens (43 high WMH burden and 69 low WMH burden). Neuroimaging data were used to calculate SDI, and gene enrichment analysis was conducted to explore related molecular pathways.

An increased spatial gradient of SDI from the sensory-motor cortex to the associative cortex was observed. Compared to the low WMH burden group, the high WMH group exhibited elevated SDI in the right superior frontal gyrus, bilateral orbital gyrus, bilateral precentral gyrus, bilateral cingulate gyrus, bilateral thalamus, and bilateral striatum. In the high WMH burden group, SDI in the left thalamus and right cingulate gyrus negatively correlated with memory, while SDI in the right orbital gyrus and left precentral gyrus positively correlated with processing speed. Gene enrichment analysis highlighted associations with pathways involved in neural system function, potassium ion transmembrane transport, synaptic signaling, neuron projection development, and cell secretion regulation.

The findings suggest SDI alterations as a potential mechanistic pathway in WMH, which is associated with significant molecular pathways and cognitive impairments. This study provides a theoretical framework for understanding the pathophysiology of WMH progression and subsequent cognitive deficits.