Deep and periventricular white matter hyperintensities (dWMH/pvWMH) are bright appearing white matter tissue lesions in T2-weighted fluid attenuated inversion recovery magnetic resonance images and are frequent observations in the aging human brain. While early stages of these white matter lesions are only weakly associated with cognitive impairment, their progressive growth is a strong indicator for long-term functional decline. DWMHs are typically associated with diffuse vascular

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... for pvWMHs, however, no unifying theory exists to explain their characteristic onset locations and progression patterns. We use structural and functional patient imaging data to create anatomically accurate finite element models of the lateral ventricles, white and gray matter, and cerebrospinal fluid. We simulated the mechanical loading of the ependymal cells forming the primary brain-fluid interface, the ventricular wall, and its surrounding tissues at peak ventricular pressure during the hemodynamic cycle. We observe that both the maximum principal tissue strain and the largest ependymal cell stretch consistently localize in the anterior and posterior horns. Strikingly, these locations coincide with the pvWMHs observed in FLAIR images. We submit that the tight junctions between ependymal cells experience significant loads that cause the ventricular wall to be stretched thin and ultimately begin to leak. Besides age-related vascular degeneration, progressive wall failure causes neurotoxic fluid to diffuse into surrounding white matter structures and appear as growing pvWMHs. The physics-based approach presented here provides a novel model system to systematically study the progressive tissue deterioration associated with pvWMHs.