Early frontal structural and functional changes in mild white matter lesions relevant to cognitive decline

White matter lesions (WMLs) are of considerable research interest because of their high prevalence and serious consequences, such as stroke and dementia. Most existing studies of WMLs have focused on severe WMLs, but mild WMLs, which are clinically and fundamentally significant, have been largely neglected. The present study is a comprehensive investigation on the injury pattern and on the anatomical, functional, and cognitive changes related to mild WMLs. These results may provide better understanding mild WMLs. Fifty-one human subjects with mild WMLs and 49 control participants completed serial neuropsychological tests and underwent a 3-T magnetic resonance imaging (MRI) scan that included diffusion tensor imaging, a resting-state functional MRI, and a structural MRI. We found declines in cognitive functions such as global function, executive function, and episodic memory in mild WMLs subjects. The white matter injuries in the mild WMLs subjects were mainly in the fibers that projected to frontal areas, while gray matter structures were relatively intact. The overall resting state function of the frontal area was significantly increased. The integrity of the neural fibers in the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus was significantly correlated with the cognitive scores in executive function and episodic memory in both the control and the mild WMLs group. These findings demonstrate that mild WMLs subjects exhibit abnormalities in both white matter structure and functional intrinsic brain activity and that such changes are related to several types of cognitive dysfunction.