Altered white and gray matter metabolism in CADASIL - A proton MR spectroscopy and H-1-MRSI study

Objective: Subcortical white matter hyperintensities (WMH) and small cystic lesions are the radiologic hallmark of cerebral autosomal dominant arterio pathy with subcortical infarcts and leukoencephalopathy (CADASIL), a heredi tary angiopathy causing stroke in young adults. To further characterize the cerebral pathology in vivo we analyzed metabolite concentrations in normal and abnormal appearing brain tissue using single and multiple voxel proton MR spectroscopy (H-1-MRS and H-1-MRSI). Methods: Twenty patients with CADA SIL and 21 age-matched controls were studied with H-1-MRSI at the level of the centrum semiovale; short echo time H-1-MRS was performed in six patient s (WMH) and 10 controls. LCModel fits were used to estimate absolute and re lative concentrations of N-acetylaspartate (NAA), choline-containing compou nds (Cho), total creatine (Cr) within WMH, normal appearing white matter (N AWM), and cortical gray matter (GM) as well as myo-inositol (mI) and lactat e in WMH. Results: H-1-MRSI-Patients with CADASIL showed significantly redu ced NAA, Cho, Cr, and total metabolite content (Met(tot)) in WMH and NAWM. Normalization to Met(tot) revealed that NAA/Met(tot) was reduced in all reg ions, whereas Cho and Cr were relatively elevated in WMH. Short echo time H -1-MRS showed decreased NAA, Cr, Met(tot) and NAA/Met(tot) and elevated mI/ Met(tot) and lactate in WMH. Metabolite changes were larger in severely aff ected subjects. Rankin scores correlated negatively with NAA/ Met(tot) (all regions) and NAA/Cho (WMH), and positively with Cho/Met(tot) (WMH) and Cr/ Met(tot) (NAWM). Conclusion: Marked metabolic abnormalities were observed i n abnormal and normal appearing white matter in patients with CADASIL. The findings suggest axonal injury, enlarged extracellular spaces, myelin loss, and gliosis. The cortical abnormalities may reflect structural damage or f unctional neuronal impairment secondary to white matter pathology. NAA redu ctions were correlated with clinical disability emphasizing the clinicopath ologic relevance of axonal injury in CADASIL.