title: Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis.
abstract: Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to an inherited defect in the metabolic pathway of cholesterol. Early diagnosis of the disease is particularly important as patients benefit from therapy with chenodeoxycholic acid. Although the disease is clinically characterized by the concomitant presence of tendon xanthomas, juvenile cataracts and progressive neurological impairment, clinical features may vary greatly. Neuroradiological studies have suggested that the bilateral abnormality of the dentate nuclei could be typical of this disease. However, this finding has been seen inconsistently on conventional MRI. The dynamic of the CNS pathology in CTX is complex, and whether demyelination or axonopathy has primary importance in the pathogenesis of CTX pathology is not known. To clarify both neuroradiological and pathological issues, we performed combined brain MRI and spectroscopy examinations on 12 CTX patients. On conventional MRIs, bilateral hyperintensities of the dentate nuclei were clearly seen in nine out of 12 patients on T(2) -weighted MRIs, but were evident in all patients using a FLAIR sequence. On proton magnetic resonance (MR) spectroscopy, significant decreases in N: -acetylaspartate resonance intensities (P: <0.0001) and increases in lactate MR signals (P<0.05) were found in the group of CTX patients in large volumes of interest localized above the lateral brain ventricles and in the cerebellar hemispheres. Cerebral values of N -acetylaspartate resonance intensities showed a close correlation with patients' disability (Spearman rank correlation = -0.78, P<0.005). These results suggest that MR abnormalities in the dentate nuclei may be evident consistently in patients with CTX. Proton MR spectroscopy data demonstrated widespread axonal damage (as shown by the decrease in N -acetylaspartate) and diffuse brain mitochondrial dysfunction (as shown by the increase in brain parenchymal lactate) in patients with CTX. The close correlation seen between values of the putative axonal marker N-acetylaspartate and patients' disability scores suggests that proton MR spectroscopy can provide a useful measure of disease outcome in CTX.
authors.affiliation: Institute of Neurological Sciences, Neurometabolic Unit, NMR Centre and Centre for the Diagnosis, Prevention and Therapy of Neuro-handicap, University of Siena, Italy.
authors.forename: N
authors.initials: N
authors.lastname: De Stefano
authors.forename: M T
authors.initials: MT
authors.lastname: Dotti
authors.forename: M
authors.initials: M
authors.lastname: Mortilla
authors.forename: A
authors.initials: A
authors.lastname: Federico
mesh_terms: D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D001369:Axons / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002552:Cerebral Ventricles / Q000378:metabolism / Q000473:pathology; D002794:Choline / Q000032:analysis; D003401:Creatine / Q000032:analysis; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000032:analysis / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D011237:Predictive Value of Tests; D012720:Severity of Illness Index; D019294:Xanthomatosis, Cerebrotendinous / Q000175:diagnosis* / Q000378:metabolism
chemical_list: D001224:Aspartic Acid; D019344:Lactic Acid; C000179:N-acetylaspartate; D003401:Creatine; D002794:Choline