There is considerable variability in the neuroradiological signs of neuropathology of alcoholism;some individuals have massive brain shrinkage and others little demonstrable effect. A relationship between total lifetime alcohol dose and brain tissue volume shrinkage or CSF space expansion is typically elusive and does not account for a substantial portion of the dysmorphology. Autopsy incidence of Wernicke's encephalopathy (WE) associated lesions, undetected in life, suggests an under appreciation of the high prevalence of nutritional deficiency (especially thiamine) among alcoholics. Further, the neuroradiological findings of uncomplicated (i.e., nonamnesic) alcoholics appear as a graded version of those seen when WE progresses to the amnesic Korsakoff syndrome (KS or WKS). The human literature is sprinkled with references to the """"""""neurotoxicity of alcohol"""""""" but with little direct support for this assertion and with the following questions begged: is alcohol neurotoxic if nutrition is adequate, or do repeated bouts of subclinical nutritional deficiency underlie human alcoholic neuropathology? Animal models demonstrate acute neuronal necrosis after binge alcohol, but at very high doses in alcohol naive animals, sometimes with significant mortality. Alcohol effects are primarily described in the hippocampal-entorhinal-olfactory circuit, known for its neuroplasticity, neurogenesis and unique susceptibility to environmental insult. Thiamine deficiency studies in rodents consistently produce substantial brain pathology, including white matter and cortical lesions, typical of human alcoholics in vivo and at autopsy, but also have a signature lesion pattern involving the mammillothalamic tract, including the mammillary bodies, fornix, anterior thalamic nuclei, in addition to the superior and inferior colliculi and anterior superior vermis. We propose to develop a translational animal model, using high resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to examine thiamine deficiency, modeled as controlled dietary plus pyrithiamine-induced thiamine deficiency (PITD), acute binge ethanol treatment and their interaction in rats. We will also study WKS-at-risk alcoholics with repeated sustained binge drinking and historical reporting of poor nutrition during the binges. The overarching hypothesis is that nutritional deficiency makes as great or greater contribution than alcohol per se to the observed neuropathology, and the combination is synergistically damaging. We propose four specific aims:
Specific Aim 1 : Measure the development, extent, location and recovery of neuroradiologically-detectable brain damage with repeated bouts of PITD in rats.
Specific Aim 2 : Measure the effects on the hippocampus and fimbria of repeated 5-day, acute alcohol binge in rats.
Specific Aim 3 : Model human drinking in rats with combined alcohol binges plus thiamine deficiency.
Specific Aim 4 : Translation from rats to humans: Identify neuroradiological signs of nutritional deficiency compounding alcoholism-related dysmorphology in human alcoholics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA005965-29
Application #
8099672
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Matochik, John A
Project Start
1983-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
29
Fiscal Year
2011
Total Cost
$723,428
Indirect Cost
Name
Sri International
Department
Type
DUNS #
009232752
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
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Zahr, Natalie M; Pfefferbaum, Adolf; Sullivan, Edith V (2017) Perspectives on fronto-fugal circuitry from human imaging of alcohol use disorders. Neuropharmacology 122:189-200
Zahr, Natalie M; Carr, Rebecca A; Rohlfing, Torsten et al. (2016) Brain metabolite levels in recently sober individuals with alcohol use disorder: Relation to drinking variables and relapse. Psychiatry Res 250:42-9
Park, Jae Mo; Josan, Sonal; Jang, Taichang et al. (2016) Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model. Magn Reson Med 75:973-84
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Zahr, Natalie M; Sullivan, Edith V; Rohlfing, Torsten et al. (2016) Concomitants of alcoholism: differential effects of thiamine deficiency, liver damage, and food deprivation on the rat brain in vivo. Psychopharmacology (Berl) 233:2675-86
Zahr, Natalie M; Rohlfing, Torsten; Mayer, Dirk et al. (2016) Transient CNS responses to repeated binge ethanol treatment. Addict Biol 21:1199-1216
Nichols, B Nolan; Pohl, Kilian M (2015) Neuroinformatics Software Applications Supporting Electronic Data Capture, Management, and Sharing for the Neuroimaging Community. Neuropsychol Rev 25:356-68
Pfefferbaum, Adolf; Zahr, Natalie M; Mayer, Dirk et al. (2015) Dynamic responses of selective brain white matter fiber tracts to binge alcohol and recovery in the rat. PLoS One 10:e0124885
Cui, Changhai; Noronha, Antonio; Warren, Kenneth R et al. (2015) Brain pathways to recovery from alcohol dependence. Alcohol 49:435-52

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