Brain Docosahexaenoic Acid [DHA] Incorporation and Blood Flow Are Increased in Chronic Alcoholics: A Positron Emission Tomography Study Corrected for Cerebral Atrophy

Objective Chronic alcohol dependence has been associated with disturbed behavior, cerebral atrophy and a low plasma concentration of docosahexaenoic acid (DHA, 22∶6n-3), particularly if liver disease is present. In animal models, excessive alcohol consumption is reported to reduce brain DHA concentration, suggesting disturbed brain DHA metabolism. We hypothesized that brain DHA metabolism also is abnormal in chronic alcoholics. Methods We compared 15 non-smoking chronic alcoholics, studied within 7 days of their last drink, with 22 non-smoking healthy controls. Using published neuroimaging methods with positron emission tomography (PET), we measured regional coefficients (K*) and rates (Jin) of DHA incorporation from plasma into the brain of each group using [1-11C]DHA, and regional cerebral blood flow (rCBF) using [15O]water. Data were partial volume error corrected for brain atrophy. Plasma unesterified DHA concentration also was quantified. Results Mean K* for DHA was significantly and widely elevated by 10–20%, and rCBF was elevated by 7%–34%, in alcoholics compared with controls. Unesterified plasma DHA did not differ significantly between groups nor did whole brain Jin, the product of K* and unesterified plasma DHA concentration. Discussion Significantly higher values of K* for DHA in alcoholics indicate increased brain avidity for DHA, thus a brain DHA metabolic deficit vis-à-vis plasma DHA availability. Higher rCBF in alcoholics suggests increased energy consumption. These changes may reflect a hypermetabolic state related to early alcohol withdrawal, or a general brain metabolic change in chronic alcoholics.

[1]  A. Dorrance,et al.  The effects of hypertension on the cerebral circulation. , 2013, American journal of physiology. Heart and circulatory physiology.

[2]  S. Rapoport,et al.  Fifteen weeks of dietary n-3 polyunsaturated fatty acid deprivation increase turnover of n-6 docosapentaenoic acid in rat-brain phospholipids. , 2012, Biochimica et biophysica acta.

[3]  Duo Li,et al.  Low Docosahexaenoic Acid Content in Plasma Phospholipids is Associated with Increased Non-alcoholic Fatty Liver Disease in China , 2012, Lipids.

[4]  D. Hommer,et al.  Relationship between liver function and brain shrinkage in patients with alcohol dependence. , 2012, Alcoholism, clinical and experimental research.

[5]  S. Rapoport,et al.  Dietary n‐6 polyunsaturated fatty acid deprivation increases docosahexaenoic acid metabolism in rat brain , 2012, Journal of neurochemistry.

[6]  W. Gordon,et al.  Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. , 2011, Annual review of nutrition.

[7]  G. J. Harry,et al.  Imaging Upregulated Brain Arachidonic Acid Metabolism in HIV-1 Transgenic Rats , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  A. Saavedra-Molina,et al.  Cellular and Mitochondrial Effects of Alcohol Consumption , 2010, International journal of environmental research and public health.

[9]  D. Meyerhoff,et al.  Body mass index is associated with brain metabolite levels in alcohol dependence--a multimodal magnetic resonance study. , 2010, Alcoholism, clinical and experimental research.

[10]  S. Rapoport,et al.  Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2β (VIA)-deficient mice , 2010, Journal of Lipid Research.

[11]  E. Tan,et al.  PLA2G6 mutations and Parkinson's disease , 2010, Annals of neurology.

[12]  J. Hibbeln,et al.  Low plasma levels of docosahexaenoic acid are associated with an increased relapse vulnerability in substance abusers. , 2009, The American journal on addictions.

[13]  E. Neafsey,et al.  Binge Ethanol-induced Neurodegeneration in Rat Organotypic Brain Slice Cultures: Effects of PLA2 Inhibitor Mepacrine and Docosahexaenoic Acid (DHA) , 2009, Neurochemical Research.

[14]  J. Price,et al.  Alcohol consumption and cerebral blood flow among older adults. , 2008, Alcohol.

[15]  S. Rapoport,et al.  α‐Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid , 2005, Journal of neurochemistry.

[16]  Robert A Koeppe,et al.  Regional cerebral blood flow responses to smoking in tobacco smokers after overnight abstinence. , 2005, The American journal of psychiatry.

[17]  Richard E Carson,et al.  Brain incorporation of 11C-arachidonic acid, blood volume, and blood flow in healthy aging: a study with partial-volume correction. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[18]  N. Salem,et al.  Perspectives on alcohol consumption: liver polyunsaturated fatty acids and essential fatty acid metabolism. , 2004, Alcohol.

[19]  Pietro Pietrini,et al.  Resting state brain glucose metabolism is not reduced in normotensive healthy men during aging, after correction for brain atrophy , 2004, Brain Research Bulletin.

[20]  S. Rapoport,et al.  Energy Consumption by Phospholipid Metabolism in Mammalian Brain , 2002, Neurochemical Research.

[21]  Richard E Carson,et al.  Brain Incorporation of [11C]Arachidonic Acid in Young Healthy Humans Measured with Positron Emission Tomography , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  B. Erbaş,et al.  Regional cerebral blood flow and neuropsychological functioning in early and late onset alcoholism , 2002, Psychiatry Research: Neuroimaging.

[23]  T. Mizutani,et al.  Regional cerebral blood flow measured by the resting and vascular reserve (RVR) method in chronic alcoholics. , 2002, Alcoholism, clinical and experimental research.

[24]  B. Lilja,et al.  Cerebral perfusion deficits in age-associated memory impairment. The role of tobacco smoking , 2002, Aging clinical and experimental research.

[25]  N. Salem,et al.  Ethanol consumption alters electroretinograms and depletes neural tissues of docosahexaenoic acid in rhesus monkeys: nutritional consequences of a low n-3 fatty acid diet. , 2001, Alcoholism, clinical and experimental research.

[26]  Hee-Yong Kim,et al.  Mechanisms of action of docosahexaenoic acid in the nervous system , 2001, Lipids.

[27]  S. Rapoport,et al.  Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. , 2001, Journal of lipid research.

[28]  H. Nagura,et al.  Fatty acid uptake and incorporation in brain , 2001, Journal of Molecular Neuroscience.

[29]  S. Rapoport,et al.  Nutritional Deprivation of α‐Linolenic Acid Decreases but Does Not Abolish Turnover and Availability of Unacylated Docosahexaenoic Acid and Docosahexaenoyl‐CoA in Rat Brain , 2000, Journal of neurochemistry.

[30]  L. Sokoloff,et al.  Effects of diazepam and ketamine administered individually or in combination on regional rates of glucose utilization in rat brain. , 1999, British journal of anaesthesia.

[31]  S. Rapoport,et al.  Energy requirements for two aspects of phospholipid metabolism in mammalian brain. , 1998, The Biochemical journal.

[32]  G. Alexander,et al.  Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease , 1998, Neurology.

[33]  A. Evans,et al.  Correction for partial volume effects in PET: principle and validation. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[34]  M. Pita,et al.  Chronic Alcoholism Decreases Polyunsaturated Fatty Acid Levels in Human Plasma, Erythrocytes, and Platelets – Influence of Chronic Liver Disease , 1997, Thrombosis and Haemostasis.

[35]  Peter Herscovitch,et al.  Brain incorporation of [1–11C]arachidonate in normocapnic and hypercapnic monkeys, measured with positron emission tomography , 1997, Brain Research.

[36]  N. Salem,et al.  Ethanol exposure causes a decrease in docosahexaenoic acid and an increase in docosapentaenoic acid in feline brains and retinas. , 1995, The American journal of clinical nutrition.

[37]  F. Bloom,et al.  Psychopharmacology: The Fourth Generation of Progress , 1995 .

[38]  E. Dennis Diversity of group types, regulation, and function of phospholipase A2. , 1994, The Journal of biological chemistry.

[39]  M. Salamero,et al.  Regional cerebral blood flow-SPECT in chronic alcoholism: relation to neuropsychological testing. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[40]  I. Penttilä,et al.  Rapid separation of serum lipids for fatty acid analysis by a single aminopropyl column. , 1992, Journal of lipid research.

[41]  S. Rapoport,et al.  A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis , 1992, Brain Research Reviews.

[42]  K. Waku Origins and fates of fatty acyl-CoA esters. , 1992, Biochimica et biophysica acta.

[43]  T Nariai,et al.  Arecoline‐Stimulated Brain Incorporation of Intravenously Administered Fatty Acids in Unanesthetized Rats , 1991, Journal of neurochemistry.

[44]  O. Paulson,et al.  Regional cerebral blood flow in chronic alcoholics measured by single photon emission computerized tomography , 1990, Acta neurologica Scandinavica.

[45]  K J Rothman,et al.  No Adjustments Are Needed for Multiple Comparisons , 1990, Epidemiology.

[46]  G Durand,et al.  The effects of dietary alpha-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. , 1989, The Journal of nutrition.

[47]  S. Rapoport,et al.  Kinetics of protein binding determine rates of uptake of drugs by brain. , 1986, The American journal of physiology.

[48]  L. Gustavsson,et al.  Changes in fatty acid composition of major glycerophospholipids in erythrocyte membranes from chronic alcoholics during withdrawal. , 1984, Scandinavian journal of clinical and laboratory investigation.

[49]  M. Raichle,et al.  Brain blood flow measured with intravenous H2(15)O. I. Theory and error analysis. , 1983, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[50]  R. L. Rogers,et al.  Reductions in Regional Cerebral Blood Flow Associated with Chronic Consumption of Alcohol , 1983, Journal of the American Geriatrics Society.

[51]  E. S. Parker,et al.  Relationship between neuropsychological performance and alcohol consumption in alcoholics. , 1978, Biological psychiatry.

[52]  L. Sokoloff,et al.  RELATION BETWEEN PHYSIOLOGICAL FUNCTION AND ENERGY METABOLISM IN THE CENTRAL NERVOUS SYSTEM , 1977, Journal of neurochemistry.

[53]  R. Devonshire,et al.  An examination of the xenon clearance method , 1976, Pflügers Archiv.

[54]  M. Victor Alcoholism. II. Withdrawal, neurological syndromes, and EEG. , 1973, Annals of the New York Academy of Sciences.

[55]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[56]  O. Mogensen,et al.  Scandinavian Journal of Clinical and Laboratory Investigation , 1949 .

[57]  N. Bazan The docosanoid neuroprotectin D1 induces homeostatic regulation of neuroinflammation and cell survival. , 2013, Prostaglandins, leukotrienes, and essential fatty acids.

[58]  S. Rapoport,et al.  Upregulated liver conversion of alpha-linolenic acid to docosahexaenoic acid in rats on a 15 week n-3 PUFA-deficient diet. , 2007, Journal of lipid research.

[59]  Dean F. Wong,et al.  Positron emission tomography--a tool for identifying the effects of alcohol dependence on the brain. , 2003 .

[60]  N. Salem,et al.  The Effects of Ethanol on Polyunsaturated Fatty Acid Composition , 1993 .

[61]  C. Alling Alcohol, Cell Membranes, and Signal Transduction in Brain , 1993, Springer US.

[62]  J S Fowler,et al.  Decreased brain metabolism in neurologically intact healthy alcoholics. , 1992, The American journal of psychiatry.

[63]  Anthony N. Martonosi,et al.  The Enzymes of Biological Membranes , 1985, Springer US.

[64]  L. Horrocks,et al.  Separation and quantitation of free fatty acids and fatty acid methyl esters by reverse phase high pressure liquid chromatography. , 1983, Journal of lipid research.

[65]  M. Reivich,et al.  Blood flow metabolism couple in brain. , 1974, Research publications - Association for Research in Nervous and Mental Disease.