title: Development and resolution of brain lesions caused by pyrithiamine- and dietary-induced thiamine deficiency and alcohol exposure in the alcohol-preferring rat: a longitudinal magnetic resonance imaging and spectroscopy study.
abstract: Wernicke's encephalopathy (WE) is characterized by lesions in thalamus, hypothalamus (including mammillary nuclei), and inferior colliculi, results in serious disabilities, has an etiology of thiamine deficiency, is treatable with thiamine, and occurs most commonly with alcoholism. Despite decades of study, whether alcohol exposure exacerbates the neuropathology or retards its resolution remains controversial. To examine patterns of brain damage and recovery resulting from thiamine deprivation with and without alcohol exposure, we conducted in vivo magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) at 3 T in alcohol-preferring (P) rats, which had voluntarily consumed large amounts of alcohol before thiamine manipulation. A total of 18 adult male P rats (nine alcohol-exposed) received a thiamine-deficient diet for 2 weeks: 10 (five alcohol-exposed) received intraperitoneal (i.p.) pyrithiamine (PT) and eight (four alcohol-exposed) received i.p. thiamine supplementation. Neurological signs developed by day 14. Rats were scanned before thiamine depletion and 18 and 35 days after thiamine repletion. Two-dimensional J-resolved MRS single-voxel spectra with water reference were collected in a voxel subtending the thalamus; metabolite quantification was corrected for voxel tissue content. MRI identified significant enlargement of dorsal ventricles and increase in signal intensities in thalamus, inferior colliculi, and mammillary nuclei of PT compared with thiamine-treated (TT) groups from MRI 1-2, followed by significant normalization from MRI 2-3 in thalamus and colliculi, but not mammillary nuclei and lateral ventricles. Voxel-by-voxel analysis revealed additional hyperintense signal clusters in the dorsal and ventral hippocampus and enlargement of the fourth ventricle. MRS showed a significant decline and then partial recovery in thalamic N-acetylaspartate, a marker of neuronal integrity, in PT compared with TT rats, with no change detected in creatine, choline, or glutamate. PT rats with prior alcohol exposure exhibited attenuated recovery in the thalamus and arrested growth of the corpus callosum; further, two of the five alcohol-exposed PT rats died prematurely. Parenchymal and ventricular changes with thiamine manipulation concur with human radiological signs of WE. The enduring macrostructural and neurochemical abnormalities involving critical nodes of Papez circuit carry liabilities for development of amnesia and incomplete recovery from other cognitive and motor functions subserved by the affected neural systems.
authors.affiliation: Neuroscience Program, SRI International, Menlo Park, CA, USA.
authors.forename: Adolf
authors.initials: A
authors.lastname: Pfefferbaum
authors.forename: Elfar
authors.initials: E
authors.lastname: Adalsteinsson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
authors.forename: Edith V
authors.initials: EV
authors.lastname: Sullivan
mesh_terms: D020268:Alcohol-Induced Disorders, Nervous System / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002492:Central Nervous System Depressants / Q000633:toxicity; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D020915:Korsakoff Syndrome / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D011745:Pyrithiamine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D013831:Thiamine / Q000037:antagonists & inhibitors / Q000378:metabolism; D013832:Thiamine Deficiency / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000963:Antimetabolites; D015415:Biomarkers; D002492:Central Nervous System Depressants; D000431:Ethanol; D011745:Pyrithiamine; D013831:Thiamine