Synthesis and Preclinical Evaluation of 22-[F]Fluorodocosahexaenoic Acid as a Positron Emission Tomography Probe for Monitoring Brain Docosahexaenoic Acid Uptake Kinetics.

Docosahexaenoic acid [22:6(-3), DHA], a polyunsaturated fatty acid, has an important role in regulating neuronal functions and in normal brain development. Dysregulated brain DHA uptake and metabolism are found in individuals carrying the APOE4 allele, which increases the genetic risk for Alzheimer's disease (AD), and are implicated in the progression of several neurodegenerative disorders. However, there are limited tools to assess brain DHA kinetics that can be translated to humans.

Radiosynthesis of 20-[F]fluoroarachidonic acid for PET-MR imaging: Biological evaluation in ApoE4-TR mice.

Dysreglulated brain arachidonic acid (AA) metabolism is involved in chronic inflammation and is influenced by apolipoprotein E4 (APOE4) genotype, the strongest genetic risk factor of late-onset Alzheimer's disease (AD). Visualization of AA uptake and distribution in the brain can offer insight into neuroinflammation and AD pathogenesis. Here we present a novel synthesis and radiosynthesis of 20-[F]fluoroarachidonic acid ([F]-FAA) for PET imaging using a convergent route and a one-pot, single-purification radiolabeling procedure, and demonstrate its brain uptake in human ApoE4 targeted replacement (ApoE4-TR) mice.

Calcium-dependent cytosolic phospholipase A activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.

Calcium-dependent cytosolic phospholipase A activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Background: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known.

Association of White Matter Hyperintensities With HIV Status and Vascular Risk Factors.

Objective: To test the hypothesis that brain white matter hyperintensities (WMH) are more common in people living with HIV (PLWH), even in the setting of well-controlled infection, and to identify clinical measures that correlate with these abnormalities.

Methods: Research brain MRI scans, acquired within longitudinal studies evaluating neurocognitive outcomes, were reviewed to determine WMH load using the Fazekas visual rating scale in PLWH with well-controlled infection (antiretroviral therapy for at least 1 year and plasma viral load <200 copies/mL) and in sociodemographically matched controls without HIV (CWOH). The primary outcome measure of this cross-sectional analysis was increased WMH load, determined by total Fazekas score ≥2.

Aspirin and celecoxib may help to rectify a neurotransmission imbalance in bipolar disorder.

Background: Mood stabilizers with disparate chemical structures are approved for treating bipolar disorder, but their mechanisms of action are not agreed on. However, when administered to unanesthetized rats at clinically relevant doses, they modulate neurotransmission involving arachidonic acid and brain activity of COX-2, which oxidizes arachidonic acid within the arachidonic acid metabolic cascade.

Hypothesis: Inhibiting COX-2 directly might enhance mood stabilizer effects in bipolar disorder patients.

THERAPEUTIC TARGETING OF BRAIN ARACHIDONIC ACID CASCADE IN BIPOLAR DISORDER BY LOW DOSE ASPIRIN AND CELECOXIB.

Background: Studies in unanesthetized rats suggest that mood stabilizers approved for treating bipolar disorder downregulate brain arachidonic acid (AA) metabolism. AA plays a role in neurotransmission and neuroinflammation, among other processes. Other drugs that reduce brain AA metabolism may add to mood stabilizer action.

MRI Reveals Changes to Intracerebral Vasculature Caliber in HIV Infection.

To characterize cerebral arterial remodeling in HIV-infected (HIV+) individuals , and to study its clinical and immunological associations. T2-weighted magnetic resonance imagining sequences was used to determine cross-sectional area (vascular caliber) of the anterior (A1 segment) and middle (M1 segment) cerebral arteries in HIV- (control) and HIV+ subjects on antiretroviral therapy. Correlations of A1 caliber with clinical, demographic parameters, and immunological markers in cerebrospinal fluid (CSF) were determined using multivariable analyses.

Global and regional brain hypometabolism on FDG-PET in treated HIV-infected individuals.

Objective: To quantitatively measure brain glucose metabolism in treated HIV-positive individuals with [F]-labeled fluorodeoxyglucose (FDG) PET/CT.

Methods: We performed a cross-sectional comparison of FDG uptake in 47 treated HIV+ individuals, 10 age-matched controls (HIV-) sharing many of the comorbid conditions seen in the HIV+ group, and 19 age-matched healthy controls (HCs). We compared whole-brain (WB) and regional FDG standardized uptake values (SUVs) of select subcortical/central structures among the groups and correlated the values to clinical and neuropsychological assessments.

Quantitation of Human Whole-Body Synthesis-Secretion Rates of Docosahexaenoic Acid and Eicosapentaenoate Acid from Circulating Unesterified α-Linolenic Acid at Steady State.

The rate at which dietary α-linolenic acid (ALA) is desaturated and elongated to its longer-chain n-3 polyunsaturated fatty acid (PUFA) in humans is not agreed upon. In this study, we applied a methodology developed using rodents to investigate the whole-body, presumably hepatic, synthesis-secretion rates of esterified n-3 PUFA from circulating unesterified ALA in 2 healthy overweight women after 10 weeks of low-linoleate diet exposure. During continuous iv infusion of d5-ALA, 17 arterial blood samples were collected from each subject at -10, 0, 10, 20, 40, 60, 80, 100, 120, 150, 180, and 210 min, and at 4, 5, 6, 7, and 8 h after beginning infusion.

Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 a and AP-2 b in Frontal Cortex of Rats Treated with Lithium for 6 Weeks.

This corrects the article DOI: 10.1038/ajg.2016.

[ C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use.

Arachidonic acid (AA) is involved in signal transduction, neuroinflammation, and production of eicosanoid metabolites. The AA brain incorporation coefficient (K*) is quantifiable in vivo using [ C]AA positron emission tomography, although repeatability remains undetermined. We evaluated K* estimates obtained with population-based metabolite correction (PBMC) and image-derived input function (IDIF) in comparison to arterial blood-based estimates, and compared repeatability.

Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder.

Background: Valproic acid (VPA), used for treating bipolar disorder (BD), is teratogenic by inhibiting histone deacetylase. In unanaesthetized rats, chronic VPA, like other mood stabilizers, reduces arachidonic acid (AA) turnover in brain phospholipids, and inhibits AA activation to AA-CoA by recombinant acyl-CoA synthetase-4 (Acsl-4) in vitro. Valnoctamide (VCD), a non-teratogenic constitutional isomer of VPA amide, reported effective in BD, also inhibits recombinant Acsl-4 in vitro.

DHA brain uptake and APOE4 status: a PET study with [1-C]-DHA.

Background: The apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer's disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes.

Reconsidering Dietary Polyunsaturated Fatty Acids in Bipolar Disorder: A Translational Picture.

Inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the proposed role of PUFA metabolism in neuroinflammation, modulation of brain PUFA metabolism by antimanic medications in rodent models, and anti-inflammatory pharmacotherapy in bipolar disorder and in major depressive disorder (MDD).

Omega-3 and Omega-6 Polyunsaturated Fatty Acids in Bipolar Disorder: A Review of Biomarker and Treatment Studies.

Objective: There is growing evidence that inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the data on PUFAs as biomarkers in bipolar disorder and n-3 PUFA used as treatment for bipolar disorder.

Dietary Linoleic Acid Lowering Reduces Lipopolysaccharide-Induced Increase in Brain Arachidonic Acid Metabolism.

Linoleic acid (LA, 18:2n-6) is a precursor to arachidonic acid (AA, 20:4n-6), which can be converted by brain lipoxygenase and cyclooxygenase (COX) enzymes into various lipid mediators involved in the regulation of brain immunity. Brain AA metabolism is activated in rodents by the bacterial endotoxin, lipopolysaccharide (LPS). This study tested the hypothesis that dietary LA lowering, which limits plasma supply of AA to the brain, reduces LPS-induced upregulation in brain AA metabolism.

Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid.

Linoleic acid (LA, 18:2n-6) is the most abundant polyunsaturated fatty acid in the North American diet and is a precursor to circulating bioactive fatty acid metabolites implicated in brain disorders. This exploratory study tested the effects of increasing dietary LA on plasma and cerebral cortex metabolites derived from LA, its elongation-desaturation products dihomo-gamma linolenic (DGLA, 20:3n-6) acid and arachidonic acid (AA, 20:4n-6), as well as omega-3 alpha-linolenic (α-LNA, 18:3n-3), eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Plasma and cortex were obtained from rats fed a 0.