White matter lesions in an unselected cohort of the elderly - Molecular pathology suggests origin from chronic hypoperfusion injury

Background and Purpose - Incidental MRI white matter ( WM) lesions, comprising periventricular lesions ( PVLs) and deep subcortical lesions ( DSCLs), are common in the aging brain. Direct evidence of ischemia associated with incidental WM lesions ( WMLs) has been lacking, and their pathogenesis is unresolved. Methods - A population-based, postmortem cohort ( n = 456) of donated brains was examined by MRI and pathology. In a subsample of the whole cohort, magnetic resonance images were used to sample and compare WMLs and nonlesional WM for molecular markers of hypoxic injury. Results - PVL severity was associated with loss of ventricular ependyma ( P = 0.004). For DSCLs, there was arteriolar sclerosis compared with normal WM ( vessel wall thickness and perivascular enlargement; both P < 0.001). Capillary endothelial activation ( ratio of intercellular adhesion molecule to basement membrane collagen IV; P < 0.001) and microglial activation ( CD68 expression; P = 0.002) were elevated in WMLs. Immunoreactivity for hypoxia-inducible factors ( HIFs) HIF1 alpha and HIF2 alpha was elevated in DSCLs ( P = 0.003 and P = 0.005). Other hypoxia-regulated proteins were also increased in WMLs: matrix metalloproteinase-7 ( PVLs P < 0.001; DSCLs P = 0.009) and the number of neuroglobin-positive cells ( WMLs P = 0.02) reaching statistical significance. The severity of congophilic amyloid angiopathy was associated with increased HIF1 alpha expression in DSCLs ( P = 0.04). Conclusion - The data support a hypoxic environment within MRI WMLs. Persistent HIF expression may result from failure of normal adaptive mechanisms. WM ischemia appears to be a common feature of the aging brain.