Recent JAMA Network Open The study evaluates the role of omega-3 polyunsaturated fatty acids (PUFAs) in reducing white matter mass (WML) and degeneration of neuronal integrity in older adults.
Study: ω-3 PUFA for secondary prevention of white matter lesions and breakdown of neuronal integrity in older adults: A randomized clinical trial. Image credit: Bk87 / Shutterstock.com
What is WML stacking?
Brain WML accumulation is associated with an increased risk of cognitive decline and Alzheimer’s disease (AD). Pathophysiological mechanisms involved in this association include reduced regenerative capacity of oligodendrocytes, cerebral hypoperfusion, degeneration of the blood-brain barrier, and endothelial cell activation. Although periventricular WMLs may indicate microglial activation, deeper subcortical WMLs may be more indicative of progressive myelin loss, astrogliosis, and axonal degeneration.
Reduced WML burden has been associated with dietary bioactive lipids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and ω-3 PUFAs. ω-3 PUFAs may act as lipophilic substrates for the synthesis of inflammation-resolving metabolites, thereby shifting cell metabolism and signaling toward a reduced inflammatory state. Previous studies have shown the ability of ω-3 PUFAs to reduce endothelial and immune cell surface CD54 protein expression, which may increase blood-brain barrier permeability and microglial cytokine release.
Meta-analyses of clinical trials have shown that plasma ω-3 levels can be directly associated with up to 25% of WML variants. In addition, higher levels of ω-3 PUFAs have been associated with a 40% reduction in the likelihood of WML in older adults. Therefore, it is important to elucidate whether ω-3 therapy offered to individuals with WML accumulation and suboptimal ω-3 status can mitigate the progression of WML and the breakdown of neuronal integrity.
About the study
The current placebo-controlled, quadruple-blind, randomized clinical trial was conducted in Oregon Health & Science University between 2014 and 2019. Treatment stratification was performed using the apolipoprotein E e4 allele (APOE*E4) carrier status and all results were compared to a placebo group.
The primary outcome of the study was the annual progression of WML, measured using magnetic resonance imaging (MRI). Fractional anisotropy diffusion tensor imaging (DTI-FA) was also used to assess the breakdown of neuronal integrity.
The study cohort included people aged 75 years and older without dementia. Study participants also had suboptimal plasma ω-3 PUFA levels of less than 5.5 percent of total body weight, as well as WMLs greater than or equal to 5 cm3.
A three-year treatment with 1.65 g of ω-3 PUFA, consisting of 975 mg of EPA and 650 mg of DHA, was administered along with a soybean oil placebo matched for appearance, taste, and odor.
Study findings
The ω-3 treatment group showed a smaller annual progression of crude WML compared to the placebo group. However, this difference was not statistically significant. These results were similar for disruption of neuronal integrity, in which the ω-3 group showed a smaller, but not statistically significant, drop in DTI-FA. Mean annual change in abdominal volume and change in total brain volume were not different between groups.
The average annual growth of WMLs in APOE*E4 The carriers treated with ω-3 was lower than in the placebo group, but not statistically significant. For APOE*E4 non-carriers, no difference in mean annual increase in WML was observed in the ω-3 and placebo groups.
Among APOE*E4 carriers, h The mean annual DTI-FA decline of the treatment group was significantly lower than that of the placebo group. Similarly, mean annual DTI-FA decline for APOE*E4 non-carriers was not different between the treated and control groups.
Adverse events (AEs) or serious AEs (SAEs) did not differ between groups. Sixteen study participants experienced SAEs in the two study groups and 26 participants were hospitalized, which included 12 and 14 subjects from the treatment and placebo groups, respectively. There were five deaths in the ω-3 group and one in the placebo group.
AEs occurred in 44 and 41 participants in the ω-3 and placebo groups, respectively. AEs included traumatic falls, gastrointestinal disorders, and musculoskeletal and connective tissue disorders.
The mean annual increase in subcortical and periventricular WML was lower in the ω-3 group compared to the control group. This pattern was similar for mean annual DTI radial diffusion and mean DTI diffusion increment. For executive cognitive function z-scores, no differences were observed between the treatment group and the control group.
conclusions
The findings of the study show that an ω-3 treatment was well tolerated and safe but ineffective in achieving a significant reduction in WML progression and breakdown of neuronal integrity in individuals at increased risk of dementia. However, for APOE*E4 carriers, the reduction in the breakdown of neuronal integrity was significant, suggesting the enhanced effects of omega-3 for these individuals.
Journal Reference:
- Shinto, LH, Murchison, CF, Sillbert, LC, et al. (2024) ω-3 PUFA for secondary prevention of white matter lesions and breakdown of neuronal integrity in older adults: A randomized clinical trial. JAMA Network Open 7(8). doi:10.1001/jamanetworkopen.2024.26872
