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Authors: Solomon, Victoria | Hafez, Madonna | Xian, Haotian | Harrington, Michael G. | Fonteh, Alfred | Yassine, Hussein N.

Article Type: Research Article

Abstract: Background: Mechanistic studies in animal models implicate a role for saturated fatty acids in neurodegeneration, but validation of this finding in human studies is still lacking. Objective: We investigated how cerebrospinal levels of sphingomyelins (SM) and phosphatidylcholine (PC)-containing saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids associate with total tau and phosphorylated tau (p-tau). Methods: Cerebrospinal fluid (CSF) lipids were measured in two cohorts, a discovery and a confirmation cohort of older non-demented individuals from the University of Southern California and Huntington Medical Research Institutes cohorts. Lipid analysis was performed using hydrophilic interaction liquid chromatography, and individual PC …and SM lipid species were measured using tandem mass spectrometry. In addition, CSF levels of Aβ42, total tau, and p-tau-181 were measured using an MSD multiplex assay. Results: The discovery cohort (n  = 47) consisted of older individuals and more females compared to the confirmation cohort (n  = 46). Notwithstanding the age and gender differences, and a higher p-tau, Aβ42 , and LDL-cholesterol in the discovery cohort, CSF concentrations of dipalmitoyl-PC (PC32a:0) were significantly associated with p-tau in both cohorts. Similarly, total saturated PC but not mono or polyunsaturated PCs correlated with p-tau concentrations in both cohorts. Conclusion: Saturated PC species in CSF associate with early markers of neurodegeneration and are potential early disease progression biomarkers. We propose mechanisms by which saturated PC may promote tau hyperphosphorylation. Show more

Keywords: Alzheimer’s disease biomarkers, cerebrospinal fluid, lipidomics, saturated fat, tau

DOI: 10.3233/JAD-215643

Citation: Journal of Alzheimer's Disease, vol. 87, no. 2, pp. 609-617, 2022

Authors: Tomaszewski, Natalie | He, Xulei | Solomon, Victoria | Lee, Mitchell | Mack, Wendy J. | Quinn, Joseph F. | Braskie, Meredith N. | Yassine, Hussein N.

Article Type: Research Article

Abstract: Background: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer’s disease (AD) pathogenesis and neuroinflammation. Carrying the APOE ɛ 4 allele (APOE4 ) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. Objective: We sought to clarify the effect of APOE ɛ 4/ɛ 4 on both the ratio of plasma DHA and …EPA to AA, and on hippocampal volumes after DHA supplementation. Methods: Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n  = 86) and lumbar punctures (n  = 53). Results: After the intervention, DHA-treated APOE ɛ 3/ɛ 3 and APOE ɛ 2/ɛ 3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ɛ 4/ɛ 4 carriers. APOE ɛ 2/ɛ 3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ɛ 4/ɛ 4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. Conclusion: The lower increase in plasma DHA/AA and EPA/AA in APOE ɛ 4/ɛ 4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation. Show more

Keywords: Arachidonic acid, Alzheimer’s disease, apolipoprotein E, docosahexaenoic acid, eicosapentaenoic acid

DOI: 10.3233/JAD-191017

Citation: Journal of Alzheimer's Disease, vol. 74, no. 3, pp. 975-990, 2020