ABSTRACT
Docosahexaenoic acid [22:6(n-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 in vivo that can be translated to humans. Here, we report the synthesis of an ω-radiofluorinated PET probe of DHA, 22-[18F]fluorodocosahexaenoic acid (22-[18F]FDHA), for imaging the uptake of DHA into the brain. Using the nonradiolabeled 22-FDHA, we confirmed that fluorination of DHA at the ω-position does not significantly alter the anti-inflammatory effect of DHA in microglial cells. Through dynamic PET-MR studies using mice, we observed the accumulation of 22-[18F]FDHA in the brain over time and estimated DHA's incorporation coefficient (K*) using an image-derived input function. Finally, DHA brain K* was validated using intravenous administration of 15 mg/kg arecoline, a natural product known to increase the DHA K* in rodents. 22-[18F]FDHA is a promising PET probe that can reveal altered lipid metabolism in APOE4 carriers, AD, and other neurologic disorders. This new probe, once translated into humans, would enable noninvasive and longitudinal studies of brain DHA dynamics by guiding both pharmacological and nonpharmacological interventions for neurodegenerative diseases.
Subject(s)
Alzheimer Disease , Docosahexaenoic Acids , Humans , Mice , Animals , Docosahexaenoic Acids/metabolism , Docosahexaenoic Acids/pharmacology , Apolipoprotein E4/genetics , Brain/diagnostic imaging , Brain/metabolism , Positron-Emission Tomography/methods , Biological Transport , Alzheimer Disease/metabolismABSTRACT
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-[18F]fluoroarachidonic acid ([18F]-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. By examining p38 phosphorylation in astrocytes, we found that fluorination of AA at the ω-position did not significantly alter its biochemical role in cells. The brain incorporation coefficient (K*) of [18F]-FAA was estimated via multiple methods by using an image-derived input function from the right ventricle of the heart as a proxy of the arterial input function and brain tracer concentrations assessed by dynamic PET-MR imaging. This new synthetic approach should facilitate the practical [18F]-FAA production and allow its translation into clinical use, making investigations of dysregulation of lipid metabolism more feasible in the study of neurodegenerative diseases.
Subject(s)
Alzheimer Disease , Apolipoprotein E4 , Animals , Mice , Humans , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Magnetic Resonance Imaging , Brain/diagnostic imaging , Brain/metabolism , Astrocytes , Positron-Emission Tomography , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Mice, TransgenicABSTRACT
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 A2 (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. METHODS: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. RESULTS: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE3/4 compared to APOE3/3. Higher phosphorylated p38 MAPK but not ERK1/2 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. CONCLUSIONS: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.
Subject(s)
Alzheimer Disease , Apolipoprotein E4 , Apolipoproteins E/genetics , Group IV Phospholipases A2/metabolism , Alzheimer Disease/metabolism , Animals , Apolipoprotein E3/metabolism , Apolipoprotein E4/genetics , Apolipoprotein E4/metabolism , Calcium/metabolism , Humans , Leukotriene B4/metabolism , Mice , Mice, Transgenic , Neuroinflammatory Diseases , Oxidative Stress , Phospholipases A2, Cytosolic/metabolism , Synaptosomes/metabolism , Synaptosomes/pathologyABSTRACT
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 A2 (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. METHODS: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. RESULTS: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/E4 compared to APOE3/E3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. CONCLUSIONS: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.
Subject(s)
Apolipoprotein E4/metabolism , Calcium/pharmacology , Cerebral Cortex/enzymology , MAP Kinase Signaling System , Phospholipases A2, Cytosolic/metabolism , Amyloid beta-Peptides/pharmacology , Animals , Apolipoprotein E3/genetics , Apolipoprotein E3/metabolism , Apolipoprotein E3/pharmacology , Apolipoprotein E4/genetics , Apolipoprotein E4/pharmacology , Astrocytes/drug effects , Astrocytes/metabolism , Cerebral Cortex/pathology , Enzyme Activation/drug effects , Heterozygote , Humans , Inflammasomes , Inflammation , Leukotriene B4/biosynthesis , Mice , Mice, Transgenic , NF-kappa B/metabolism , Neurons/drug effects , Neurons/metabolism , Oxidative Stress , Peptide Fragments/pharmacology , Phosphorylation , Protein Processing, Post-Translational , Reactive Oxygen Species , Synaptosomes/enzymology , p38 Mitogen-Activated Protein Kinases/biosynthesisABSTRACT
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. OBSERVATIONS: This paper reviews randomized controlled trials that showed that celecoxib, a selective COX-2 inhibitor, or low-dose aspirin, which inhibits COX-1 and inhibits/acetylates COX-2, reduced bipolar symptoms in patients on mood stabilizers. More convincing are two population based pharmacoepidemiological studies that each demonstrated that chronic low dose aspirin reduced bipolar severity markers in patients on mood stabilizers. CONCLUSIONS: This clinical evidence is consistent with the hypothesis that low-dose chronic aspirin and celecoxib, which can inhibit COX-2 and enter brain, can be repurposed in bipolar disorder to enhance mood stabilizer effects on arachidonic acid metabolism and neurotransmission.
Subject(s)
Bipolar Disorder , Animals , Antimanic Agents/therapeutic use , Aspirin/therapeutic use , Bipolar Disorder/drug therapy , Celecoxib/therapeutic use , Humans , Rats , Synaptic TransmissionABSTRACT
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. Multiple logistic regression analysis was performed to evaluate the effect of HIV serostatus on WMH load and to identify MRI, CSF, and clinical variables that associate with WMH in the PLWH group. RESULTS: The study included 203 PLWH and 58 CWOH who completed a brain MRI scan between April 2014 and March 2019. The multiple logistic regression analysis, with age and history of tobacco use as covariates, showed that the adjusted odds ratio of the PLWH group for increased WMH load is 3.7 (95% confidence interval 1.8-7.5; p = 0.0004). For the PLWH group, increased WMH load was associated with older age, male sex, tobacco use, hypertension, and hepatitis C virus coinfection, and also with the presence of measurable tumor necrosis factor α in CSF. CONCLUSION: Our results suggest that HIV serostatus affects the extent of brain WMH. This effect is mainly associated with aging and modifiable comorbidities.
Subject(s)
Brain/pathology , HIV Infections/pathology , Leukoaraiosis/pathology , White Matter/pathology , Adult , Cross-Sectional Studies , Female , Humans , Leukoaraiosis/epidemiology , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Risk FactorsABSTRACT
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. METHODS: We reviewed randomized controlled trials (RCTs) and population studies to examine whether celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, and acetylsalicylate (aspirin), a COX-1 and COX-2 inhibitor and acetylator, were useful in bipolar disorder patients on mood stabilizers. COX-1 and COX-2 metabolize AA to bioactive eicosanoids. RESULTS: Celecoxib significantly enhanced mood stabilizer efficacy in two 6-week RCTs involving 86 manic bipolar inpatients, and in one 8-week RCT on 49 patients with treatment-resistant bipolar depression. With regard to aspirin, a Dutch pharmacoepidemiological study involving 5145 subjects taking lithium reported symptom reduction with added chronic low dose 30-80 mg/day aspirin, while a Danish study on 321,350 subjects taking chronic 75-150 mg/day aspirin found fewer manic episodes than in subjects not on aspirin. Finally, a recent 6-week RCT using low-dose aspirin and/or minocycline showed a specific positive effect of aspirin. CONCLUSIONS: Efficacy of both celecoxib and aspirin as adjuncts to mood stabilizers in the treatment of bipolar disorder is consistent with the AA hypothesis for mood stabilizer action in that disorder.
Subject(s)
Arachidonic Acid/metabolism , Aspirin/therapeutic use , Bipolar Disorder/drug therapy , Bipolar Disorder/metabolism , Brain/metabolism , Celecoxib/therapeutic use , Bipolar Disorder/pathology , Bipolar Disorder/physiopathology , Brain/physiopathology , Humans , Randomized Controlled Trials as TopicABSTRACT
Objective: To characterize cerebral arterial remodeling in HIV-infected (HIV+) individuals in-vivo, and to study its clinical and immunological associations. Methods: 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. Results: A1 and M1 calibers from 22 HIV- control subjects (age: median 48.5 years, range 22-60 years, 55% male) and 61 HIV+ subjects (age: median 53 years, range 25-60 years, 67% male) were studied. ANCOVA, adjusting for ethnicity and sex (age was not correlated with M1 or A1 caliber in either group), revealed that HIV+ subjects had larger caliber in the A1 segment than HIV- subjects (4.95 ± 0.14 mm2, and 4.47 ± 0.21 mm2 respectively, p = 0.048), but caliber of the M1 segment did not differ among the groups (7.21 ± 0.14 mm2 and 7.09 ± 0.23 mm2 respectively, p = 0.65). In the HIV+ cohort, longer disease duration and higher current CD4 T-cell count were associated with reduced A1 caliber (r =-0.42 and -0.33 respectively, p < 0.05). In addition, increase in cardiovascular disease risk (CVD risk) was associated with a decrease in A1 caliber in the HIV group (r = -0.35, p < 0.05). Conclusions: This cross-sectional study reveals an increase in A1 caliber in the HIV+ cohort, compared to control subjects, which is especially prominent in early phase of the disease. This increase in caliber may be associated with acute pathological processes in HIV during the initial stages of infection resulting in loss of compliance or thinning of the arterial wall. At later stages, such changes may be confounded by arteriosclerotic changes that are common in later stages of HIV infection. This study suggests there is extensive vessel remodeling in various stages of infection. Long-term longitudinal follow-up of this cohort is planned to further verify this hypothesis and to better understand this MRI marker of intracranial vascular caliber.
ABSTRACT
OBJECTIVE: To quantitatively measure brain glucose metabolism in treated HIV-positive individuals with [18F]-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. A variable selection model was used to predict SUVs in HIV+ (n = 47) and in combined HIV+ and HIV- participants (n = 57). RESULTS: We found lower WB SUVmax in HIV+ participants compared to HCs but not to HIV- participants. Among the relative SUVmean measurements (regional SUVmean/WB SUVmean), only relative thalamic uptake values were lower in HIV+ compared to HIV- participants. When HIV+ and HIV- participants were grouped, cardiovascular disease risk scores best predicted WB SUVmean and SUVmax, while HIV status best predicted thalamic relative SUVmean. CONCLUSIONS: We identified an important role for cardiovascular disease in neuronal loss/dysfunction, as measured by FDG-PET, in treated HIV+ patients. This underscores the need for shifting the focus of clinical intervention in this vulnerable population from HIV effects alone to a wider set of comorbid conditions, mainly cardiovascular disease. Only the thalamus showed significantly lower relative uptake in the HIV+ compared to the HC and HIV- groups. This needs to be further evaluated for underlying pathophysiology and potential association with memory, executive functioning, and attention deficits seen in the HIV+ population.
Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Fluorodeoxyglucose F18/metabolism , HIV Infections/diagnostic imaging , Anti-Retroviral Agents/therapeutic use , Brain/drug effects , Case-Control Studies , Cholesterol/metabolism , Cognition Disorders/etiology , Cognition Disorders/virology , Cross-Sectional Studies , Female , HIV Infections/complications , Humans , Male , Middle Aged , Neuropsychological Tests , Positron-Emission TomographyABSTRACT
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. Plasma esterified d5-n-3 PUFA concentrations were plotted against the infusion time and fit to a sigmoidal curve using nonlinear regression. These curves were used to estimate kinetic parameters using a kinetic analysis developed using rodents. Calculated synthesis-secretion rates of esterified eicosapentaenoate, n-3 docosapentaenoate, docosahexaenoic acid, tetracosapentaenate, and tetracosahexaenoate from circulating unesterified ALA were 2.1 and 2.7; 1.7 and 5.3; 0.47 and 0.27; 0.30 and 0.30; and 0.32 and 0.27 mg/day for subjects S01 and S02, respectively. This study provides new estimates of whole-body synthesis-secretion rates of esterified longer-chain n-3 PUFA from circulating unesterified ALA in human subjects. This method now can be extended to study factors that regulate human whole-body PUFA synthesis-secretion in health and disease.
Subject(s)
Docosahexaenoic Acids/blood , Eicosapentaenoic Acid/blood , alpha-Linolenic Acid/blood , Adolescent , Adult , Body Mass Index , Female , Healthy Volunteers , Humans , Middle Aged , Young AdultABSTRACT
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 0.4%, 5.2% or 10.5% energy LA diet for 15 weeks and subjected to liquid chromatography tandem mass spectrometry analysis. Total oxylipin concentrations, representing the esterified and unesterified pool, and unesterified oxylipins derived from LA and AA were significantly increased and EPA metabolites decreased in plasma at 5.2% or 10.5% energy LA compared to 0.4% energy LA. Unesterified plasma DHA metabolites also decreased at 10.5% energy LA. In cortex, total and unesterified LA and AA metabolites increased and unesterified EPA metabolites decreased at 5.2% or 10.5% LA. DGLA and α-LNA metabolites did not significantly change in plasma or cortex. Dietary LA lowering represents a feasible approach for targeting plasma and brain LA, AA, EPA or DHA-derived metabolite concentrations.
Subject(s)
Cerebral Cortex/metabolism , Dietary Fats/pharmacology , Docosahexaenoic Acids/pharmacology , Linoleic Acid/pharmacology , Oxylipins/blood , Animals , Rats , Rats, Inbred F344ABSTRACT
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 [11 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. Eleven healthy volunteers underwent a [11 C]AA scan; five repeated the scan 6 weeks later, simulating a pre- and post-treatment study design. For all scans, arterial blood was sampled to measure [11 C]AA plasma radioactivity. Plasma [11 C]AA parent fraction was measured in 5 scans. K* was quantified using both blood data and IDIF, corrected for [11 C]AA parent fraction using both PBMC (from published values) and individually measured values (when available). K* repeatability was calculated in the test-retest subset. K* estimates based on blood and individual metabolites were highly correlated with estimates using PBMC with arterial input function (r = 0.943) or IDIF (r = 0.918) in the subset with measured metabolites. In the total dataset, using PBMC, IDIF-based estimates were moderately correlated with arterial input function-based estimates (r = 0.712). PBMC and IDIF-based K* estimates were â¼6.4% to â¼11.9% higher, on average, than blood-based estimates. Average K* test-retest absolute percent difference values obtained using blood data or IDIF, assuming PBMC for both, were between 6.7% and 13.9%, comparable to other radiotracers. Our results support the possibility of simplified [11 C]AA data acquisition through eliminating arterial blood sampling and metabolite analysis, while retaining comparable repeatability and validity.
Subject(s)
Arachidonic Acids , Brain/diagnostic imaging , Brain/metabolism , Carbon Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Adult , Arachidonic Acids/blood , Carbon Radioisotopes/blood , Female , Humans , Male , Potassium/metabolism , Radiopharmaceuticals/blood , Reproducibility of Results , Time FactorsABSTRACT
This corrects the article DOI: 10.1038/ajg.2016.125.
ABSTRACT
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. HYPOTHESIS: VCD like VPA will reduce brain AA turnover in unanaesthetized rats. METHODS: A therapeutically relevant (50mg/kg i.p.) dose of VCD or vehicle was administered daily for 30 days to male rats. AA turnover and related parameters were determined using our kinetic model, following intravenous [1-14C]AA in unanaesthetized rats for 10min, and measuring labeled and unlabeled lipids in plasma and high-energy microwaved brain. RESULTS: VCD, compared with vehicle, increased λ, the ratio of brain AA-CoA to unesterified plasma AA specific activities; and decreased turnover of AA in individual and total brain phospholipids. CONCLUSIONS: VCD's ability like VPA to reduce rat brain AA turnover and inhibit recombinant Acsl-4, and its efficacy in BD, suggest that VCD be further considered as a non-teratogenic VPA substitute for treating BD.
Subject(s)
Amides/pharmacology , Antimanic Agents/pharmacology , Arachidonic Acid/antagonists & inhibitors , Bipolar Disorder/drug therapy , Brain/drug effects , Animals , Male , Phospholipids/metabolism , RatsABSTRACT
BACKGROUND: The apolipoprotein E É4 (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. METHODS: Using positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11C]-DHA (J in), and regional cerebral blood flow using [15O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19-65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed. RESULTS: The mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in) did not differ significantly between the APOE groups. CONCLUSIONS: Our findings suggest an increase in the DHA incorporation coefficient in several brain regions in APOE4 carriers. These findings may contribute to understanding how APOE4 genotypes affect AD risk.
Subject(s)
Apolipoprotein E4/metabolism , Brain/metabolism , Docosahexaenoic Acids/metabolism , Positron-Emission Tomography/methods , Adult , Aged , Brain/diagnostic imaging , Carbon Radioisotopes/pharmacokinetics , Female , Humans , Male , Metabolic Clearance Rate , Middle Aged , Molecular Imaging/methods , Radiopharmaceuticals/pharmacokinetics , Reference Values , Tissue DistributionABSTRACT
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. Male Fischer CDF344 rats fed an adequate LA (5.2 % energy (en)) or low LA (0.4 % en) diet for 15 weeks were infused with LPS (250 ng/h) or vehicle into the fourth ventricle for 2 days using a mini-osmotic pump. The incorporation rate of intravenously infused unesterified 14C-AA into brain lipids, eicosanoids, and activities of phospholipase A2 and COX-1 and 2 enzymes were measured. Dietary LA lowering reduced the LPS-induced increase in prostaglandin E2 concentration and COX-2 activity (P < 0.05 by two-way ANOVA) without altering phospholipase activity. The 14C-AA incorporation rate into brain lipids was decreased by dietary LA lowering (P < 0.05 by two-way ANOVA). The present findings suggest that dietary LA lowering reduced LPS-induced increase in brain markers of AA metabolism. The clinical utility of LA lowering in brain disorders should be explored in future studies.