DIETARY OMEGA-6 FATTY ACID LOWERING INCREASES THE BIOAVAILABILITY OF PLASMA OMEGA-3 FATTY ACIDS IN HUMAN PLASMA LIPID POOLS. We evaluated the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, altered unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA. LOW UNESTERIFIED : ESTERIFIED EICOSAPENTAENOIC ACID (EPA) PLASMA CONCENTRATION RATIO IS ASSOCIATED WITH BIPOLAR DISORDER EPISODES, AND OMEGA-3 PLASMA CONCENTRATIONS ARE ALTERED BY TREATMENT. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and of n-6 PUFAs higher in BD patients compared to healthy controls (HC) and would correlate with symptom severity, and that effective treatment would increase n-3 but lower n-6 PUFA levels. We compared HC and symptomatic BD subjects when ill and after symptomatic recovery (follow-up). Plasma concentrations of fatty acids were measured in esterified (E) and unesterified (UE) forms. UE EPA was lower in BD than HC, with a large effect size at p < 0.002 that was not statistically significant after correction for multiple comparisons. Exploratory exploratory correlations revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. In conclusion, there was large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state, which may contribute vulnerability. Altered n-3 PUFA ratios indicate changes in PUFA metabolism concurrent with symptom improvement. RECONSIDERING DIETARY POLYUNSATURATED FATTY ACIDS IN BIPOLAR DISORDER: A TRANSLATIONAL PICTURE. INFLAMMATION IS AN IMPORTANT MEDIATOR OF PATHOPHYSIOLOGY IN BIPOLAR DISORDER (BD). In collaboration with Dr. Erika Saunders Penn State Hershey, I am reviewing the proposed role of PUFA metabolism in neuroinflammation, modulation of brain PUFA metabolism by antimanic medications in rodent models, and anti-inflammatory pharmacotherapy in BD and in major depressive disorder (MDD). OMEGA-3 AND OMEGA-6 POLYUNSATURATED FATTY ACIDS IN BIPOLAR DISORDER: A REVIEW OF BIOMARKER AND TREATMENT STUDIES. With Dr. Erika Saunders at Penn State Hershey, I am reviewing data on PUFA as biomarkers in bipolar disorder (BD) and n-3 PUFA used as treatment for BD. Data Sources are PubMed and CINAHL. Results of n-3 PUFA dietary supplementation trials for BD in open-label trials indicate efficacy in treatment for mania or depression, efficacy in treatment of depression in 1/7 randomized controlled trials, and signal detected for treatment of depression in one meta-analysis. Biomarker studies of PUFA and treatment studies of n-3 PUFA in BD show promise for indicating a way forward in the study of PUFA in BD. QUANTIFYING WHOLE BODY SYNTHESIS OF LONG CHAIN OMEGA (N-3) POLYUNSATURATED FATTY ACIDS IN HUMANS FROM CIRCULATING ALPHA-LINOLENIC ACID (ALA). Rodent data and human trials suggest that long chain omega (n)-3 polyunsaturated fatty acids (PUFAs), namely eicosapentaenoic (EPA) and docosahexaenoic (DHA), are critical for brain and heart function. They can be obtained from dietary fish products, or be synthesized from the circulating shorter chain nutritionally essential precursor, alpha-linolenic acid (ALA), which is found in vegetable oils. I have published a kinetic model to evaluate their whole body synthesis rates , and have shown significant rates in unanesthetized rodents using 2 hours of continuous intravenous radiolabeled ALA infusion. On this basis, I have initiated with NIAAA scientists an IRB approved clinical protocol (No. 11-AA-0028) to extrapolate the rodent infusion method and thereby quantify synthesis-secretion rates of EPA and DHA from circulating unesterified ALA in humans consuming an average US diet. We have completed studies demonstrating significant synthesis rates in two human volunteers. PATHWAYS OF POLYUNSATURATED FATTY ACID UTILIZATION: IMPLICATIONS FOR BRAIN FUNCTION IN NEUROPSYCHIATRIC HEALTH AND DISEASE. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. In a critical review with Dr. Elizabeth Sublette of columbia University, we provided an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease. DIETARY ALTERATION IN OMEGA-3 AND OMEGA-6 FATTY ACIDS FOR POST-TRAUMATIC HEADACHE. A randomized clinical trial (Ramsden et al.) subjects with chronic daily headache (CDH) showed that a high n-3 plus low n-6 (H3-L6) dietary intervention produced statistically significant, clinically relevant improvements in headache hours per day, severe headache days and headache-related quality-of-life compared to baseline, and compared to an n-6 lowering (L6) intervention (which independently produced positive effects). I am working on a clinical protocol (Dr. Ramon Diaz-Arrastia, PI) at the USUHS aimed at increasing consumption of n-3 PUFAs while reducing intake of n-6 fatty acids, with the goal of reducing chronic pain, including migraine and chronic daily headache in military personnel with traumatic headache.

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Saunders, Erika Fh; Reider, Aubrey; Singh, Gagan et al. (2015) Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disord 17:729-42
Ramsden, Christopher E; Faurot, Keturah R; Zamora, Daisy et al. (2015) Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. Pain 156:587-96
Liu, Joanne J; Green, Pnina; John Mann, J et al. (2015) Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res 1597:220-46
Taha, Ameer Y; Cheon, Yewon; Faurot, Keturah F et al. (2014) Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins Leukot Essent Fatty Acids 90:151-7
Yuan, Zhi-Xin; Rapoport, Stanley I; Soldin, Steven J et al. (2013) Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry. Biomed Chromatogr 27:422-32
Ramsden, Christopher E; Ringel, Amit; Feldstein, Ariel E et al. (2012) Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids 87:135-41