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Objective: To investigate the relationship between age-associated MRI leukoaraiosis or white matter hyperintensities (WMH) and cortical acetylcholinesterase (AChE) activity. Background: One possible mechanism of cognitive decline in elderly individuals with leukoaraiosis is disruption of cholinergic fibers by strategically located white matter lesions. Periventricular lesions may have a higher chance of disrupting cholinergic projections compared with more superficial nonperiventricular white matter lesions because of anatomic proximity to the major cholinergic axonal projection bundles that originate from the basal forebrain. Methods: Community-dwelling, middle-aged and elderly subjects without dementia (mean age 71.0 9.2 years; 55– 84 years; n 18) underwent brain MRI and AChE PET imaging. The severity of periventricular and nonperiventricular WMH on fluid-attenuated inversion recovery MRI images was scored using the semiquantitative rating scale of Scheltens et al. [ 11 C]methyl-4piperidinyl propionate AChE PET imaging was used to assess cortical AChE activity. Agecorrected Spearman partial rank correlation coefficients were calculated. Results: The severity of periventricular (R 0.52, p 0.04) but not nonperiventricular (R 0.20, not significant) WMH was inversely related to global cortical AChE activity. Regional cortical cholinergic effects of periventricular WMH were most significant for the occipital lobe (R 0.58, p 0.02). Conclusions: The presence of periventricular but not nonperiventricular white matter hyperintensities (WMH) is significantly associated with lower cortical cholinergic activity. These findings support a regionally specific disruption of cholinergic projection fibers by WMH. Neurology ® 2009;72:1411–1416