Altered Intersubject Variability of Morphological Connectivity in Cerebral Small Vessel Disease and Its Associations With Gene Expression and Cell Types.

BACKGROUND

Cerebral small vessel disease (CSVD) is a heterogeneous disorder; however, interindividual variability in morphometric brain connectivity remains unclear, as does its association with gene expression.

METHODS

We enrolled 65 patients with CSVD and 35 healthy controls. Individual-level morphometric brain networks were constructed from T1-weighted magnetic resonance imaging, and intersubject variability of morphometric connectivity (IVMC) was quantified using a Kullback-Leibler divergence-based gray matter similarity measure. Group differences in IVMC and its associations with cognitive and clinical measures were examined. Partial least squares regression was applied to Allen Human Brain Atlas data to relate IVMC to gene expression, cell-type specificity, and biological functions.

RESULTS

Compared with healthy controls, patients with CSVD showed globally increased IVMC (P<0.001) and significant differences across multiple functional networks (all PFalse Discovery Rate<0.05). IVMC in the sensorimotor and ventral attention networks was associated with poorer Auditory-Verbal Learning Test performance. Partial least squares regression analysis revealed that IVMC-related genes were enriched in neurodevelopmental and metabolic processes, whereas negatively weighted genes were associated with synaptic structure and glutamatergic signaling. Cell-type analyses linked IVMC alterations primarily to neuronal and glial transcriptional signatures.

CONCLUSIONS

CSVD is associated with elevated IVMC across multiple functional networks, with changes in specific networks linked to memory impairment. These alterations may be associated with genes involved in neurodevelopment, synaptic function, and diverse neuronal and glial cell types, providing new insights into the interindividual variability of brain networks and the neurophysiological mechanisms underlying CSVD.