ABSTRACT
BACKGROUND: Docosahexaenoic acid (DHA) shows anti-inflammatory/proresolution effects in the brain. Higher red blood cell (RBC) DHA in humans is associated with improved cognitive performance and a lower risk for suicide. Here, we hypothesized that binding to the 18 kDa translocator protein (TSPO), a proxy for microglia levels, will be higher in individuals with low DHA relative to high DHA levels. We also postulated that higher TSPO would predict poor cognitive performance and impaired stress resilience. METHODS: RBC DHA screening was performed in 320 healthy males. [11C]PBR28 positron emission tomography was used to measure binding to TSPO in 38 and 32 males in the lowest and highest RBC DHA quartiles. Volumes of distribution expressed relative to total plasma ligand concentration (VT) was derived using an arterial input function-based kinetic analysis in 14 brain regions. RESULTS: [11C]PBR28 VT was significantly lower (by 12% and 20% in C/T and C/C rs6971 genotypes) in males with low RBC DHA than in males with high RBC DHA. Regional VT was correlated positively and negatively with RBC DHA and serum triglycerides, respectively. No relationships between VT and cognitive performance or stress resilience measures were present. CONCLUSIONS: Contrary to our hypothesis, we found lower TSPO binding in low-DHA than in high-DHA subjects. It is unclear as to whether low TSPO binding reflects differences in microglia levels and/or triglyceride metabolism in this study. Future studies with specific targets are necessary to confirm the effect of DHA on microglia. These results underscore the need to consider lipid parameters as a factor when interpreting TSPO positron emission tomography clinical findings.
Subject(s)
Docosahexaenoic Acids , Receptors, GABA , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Brain , Docosahexaenoic Acids/metabolism , Docosahexaenoic Acids/pharmacology , Erythrocytes/metabolism , Humans , Kinetics , Ligands , Male , Positron-Emission Tomography/methods , Receptors, GABA/genetics , Receptors, GABA/metabolism , Triglycerides/metabolism , Triglycerides/pharmacologyABSTRACT
No in vivo human studies have examined the prevalence of Alzheimer's disease (AD) neuropathology in individuals with alcohol-use disorder (AUD), although recent research suggests that a relationship between the two exists. Therefore, this study used Pittsburgh Compound-B ([11C]PiB) PET imaging to test the hypothesis that AUD is associated with greater brain amyloid (Aß) burden in middle-aged adults compared to healthy controls. Twenty healthy participants (14M and 6F) and 19 individuals with AUD (15M and 4F), all aged 40-65 years, underwent clinical assessment, MRI, neurocognitive testing, and positron emission tomography (PET) imaging. Global [11C]PiB standard uptake value ratios (SUVRs), cortical thickness, gray matter volumes (GMVs), and neurocognitive function in subjects with AUD were compared to healthy controls. These measures were selected because they are considered markers of risk for future AD and other types of neurocognitive dysfunction. The results of this study showed no significant differences in % global Aß positivity or subthreshold Aß loads between AUD and controls. However, relative to controls, we observed a significant 6.1% lower cortical thickness in both AD-signature regions and in regions not typically associated with AD, lower GMV in the hippocampus, and lower performance on tests of attention as well as immediate and delayed memory in individuals with AUD. This suggest that Aß accumulation is not greater in middle-aged individuals with AUD. However, other markers of neurodegeneration, such as impaired memory, cortical thinning, and reduced hippocampal GMV, are present. Further studies are needed to elucidate the patterns and temporal staging of AUD-related pathophysiology and cognitive impairment. Imaging ß-amyloid in middle age alcoholics as a mechanism that increases their risk for Alzheimer's disease; Registration Number: NCT03746366 .
