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Bookend perfusion was used to quantify parameters in normal-appearing and lesional tissue at different relapsing-remitting MS stages in 39 patients and 19 age-matched healthy controls. Perfusion parameters such as CBF, CBV, and MTT were compared along with cognitive performance. White matter lesion but not cortical lesion perfusion was significantly reduced in cognitively impaired patients with relapsing-remitting MS versus unimpaired patients with relapsing-remitting MS. Perfusion reduction with disease progression was greater in normal-appearing gray matter and normal-appearing white matter compared with cortical lesions and white matter lesions. The authors conclude that the greatest changes are present within NAGM and NAWM, necessitating absolute rather than relative lesion perfusion measurement.