A recent JAMA Network Open study assesses the role of ω-3 polyunsaturated fatty acids (PUFAs) in reducing white matter lesion (WML) accumulation and neuronal integrity degeneration in older adults. What is WML accumulation? Cerebral WML accumulation is associated with an increased risk of cognitive decline and Alzheimer’s Disease (AD). The pathophysiological mechanisms involved in this association include the reduced regenerative capacity of oligodendrocytes, cerebral hypoperfusion, blood-brain barrier degeneration, and endothelial cell activation.
Although periventricular WMLs may suggest microglial activation, the deeper subcortical tissue WMLs may be more indicative of progressive myelin loss, astrogliosis, and axonal degeneration. Reduced WML burden has been associated with diet-derived bioactive lipids, such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ω-3 PUFAs. The ω-3 PUFAs may act as lipophilic inflammation-resolving metabolite synthesis substrates, thereby shifting metabolism and cell signaling towards a reduced inflammatory state.
Previous studies have demonstrated the ability of ω-3 PUFAs to reduce the expression of endothelial and immune cell surface protein CD54, which can increase blood-brain barrier permeability and microglial cytokine release. Meta-analyses of clinical trials have shown that plasma ω-3 levels can be directly related to up to 25% of WML variations. Furthermore, higher levels of ω-3 PUFAs have been associated with a 40% reduction in WML probability among older adults.
Therefore, it is crucial to clarify whether ω-3 treatment offered to individuals with WML accumulation and suboptimal ω-3 status can mitigate the progression of WML and breakdown of neuronal integrity. About the study The current placebo-controlled, quadruple-blinded, and randomized clinical trial was conducted at Oregon Health and Science University between 2014 and 2019. Treatment stratification was carried out using the apolipoprotein E ε4 allele ( APOE*E4 ) carrier status, and all results were compared against a placebo group.
The primary study outcome was annual WML progression, measured using magnetic resonance imaging (MRI). Diffusion tensor imaging of fractional anisotropy (DTI-FA) was also used to assess neuronal integrity breakdown. The study cohort comprised individuals 75 years of age and older without dementia.
Study participants also had sub-optimal plasma ω-3 PUFA levels of less than 5.5 weight percentage of the total, as well as WMLs greater than or equal to 5 cm 3 . A three-year treatment of 1.
65 g of ω-3 PUFA, which consisted of 975 mg of EPA and 650 mg of DHA, was administered, along with a soybean oil placebo matched for appearance, taste, and smell. Study findings The ω-3 treatment group exhibited less annual crude WML progression as compared to the placebo group; however, this difference was not statistically significant. These results were similar for neuronal integrity breakdown, in which the ω-3 group exhibited less, but not statistically significant, DTI-FA decline.
The average annual ventricular volume change and total brain volume change were not different across the groups. Related Stories New optical neural chip technology reveals unexpected dopamine dynamics COVID pandemic accelerated brain aging, especially in males and deprived groups UCLA launches groundbreaking clinical trial for vaccine targeting aggressive pediatric brain cancer The average annual increase in WMLs in APOE*E4 carriers who received the ω-3 treatment was lower than in the placebo group but not statistically significant. For APOE*E4 noncarriers, no difference was observed in the average annual increase in WML in the ω-3 and placebo groups.
Among APOE*E4 carriers, the treatment group's average annual DTI-FA decline was significantly lower than that of the placebo group. Likewise, the average annual DTI-FA decline for non-carriers of APOE*E4 was not different between the treated and control groups . Adverse events (AEs) or serious AEs (SAEs) did not differ between the groups.
Sixteen study participants experienced SAEs across the two study groups, and 26 participants were hospitalized, which included 12 and 14 individuals from the treatment and placebo groups, respectively. Five deaths were recorded 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 injurious falls, gastrointestinal disorders, and musculoskeletal and connective tissue disorders. The average annual increase in subcortical and periventricular WML was lower in the ω-3 group as compared to the control group. This pattern was similar for the average annual DTI radial diffusivity and DTI mean diffusivity increase.
For executive cognitive function z scores, no differences were observed between the treatment and control groups. Conclusions The study findings indicate that a ω-3 treatment was well-tolerated and safe yet ineffective in attaining a significant reduction in WML progression and neuronal integrity breakdown in individuals at an increased risk of dementia. However, for APOE*E4 carriers, the reduction in neuronal integrity breakdown was significant, which suggests the amplified effects of ω-3 for these individuals.
Shinto, L. H., Murchison, C.
F., Sillbert, L. C.
, et al. (2024) ω-3 PUFA for Secondary Prevention of White Matter Lesions and Neuronal Integrity Breakdown in Older Adults: A Randomized Clinical Trial. JAMA Network Open 7 (8).
doi:10.1001/jamanetworkopen.2024.
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