Discussion
memory deficits, MCI, dementia, atrophy, cognitive impairments, cognitive decline, OM3FLAV
SECONDARY, ATROPHY, INSULIN SENSITIVITY, CORTEX
The current study provides the first long-term data to suggest that supplementation with long-chain ω-3 fatty acids and FLAVs over 1 y does not improve cognitive function or brain volumes in individuals with subjective and objective cognitive impairments. The combined dietary intervention resulted in the expected several-fold increases in plasma EPA, DHA, and urinary flavanol metabolite concentrations.This null finding raises several questions regarding the intervention, methodology, and public health implications, which are considered in the following sections. One possibility is that the cognitive battery employed is not sensitive to changes relating to dietary intervention [A second possibility is that the 1-y intervention period was not long enough for the neurophysiological changes associated with PUFAs and FLAVs to become evident. The prodrome of dementia is 20 to 30 y or longer. In prospective cohort studies, positive associations between EPA+DHA and FLAV intakes and cognitive and brain structure represent the benefit of long-term, often decades of habitual dietary exposure [The inclusion of those with SCI and MCI profiles was chosen to increase the translatability of the findings (allowing an exploratory analysis to be conducted as to the most effective window of intervention opportunity). It may be considered as a study limitation, however, potentially increasing the heterogeneity of the response to intervention and thereby decreasing the likelihood of detecting a significant effect of intervention. Although the study is not powered to formally address this issue, we note that there were group differences, specifically for 3 cognitive tests in SCI (reaction time variability, quality of memory, and executive function score) and 2 in MCI, power of attention and picture recognition new stimuli speed). There may be value in targeting more homogenous cohorts in future studies.The lack of effect of OM3FLAV in CANN is consistent with previous interventions that have supplemented with EPA and/or DHA in isolation, as recently reviewed [The impact of intervention length on neurocognitive benefits is evidenced by comparing the 24-mo and 36-mo findings from the LipiDiDiet study [A lower calorie and protein intake in the control group relative to OM3FLAV at 12 mo may have resulted in lower body weight, which could contribute to improved cognition relative to OM3FLAV [There are a number of considerations regarding the intervention itself. One possibility is that there were changes to the interventions during the trial that reduced their functional efficacy. The shelf life of fish oils (FOs) is dependent on certain storage microenvironment conditions to prevent lipid peroxidation. The FO capsules were enriched with mixed tocopherol (3.8 mg/g oil) to prevent any loss of EPA and DHA content. Intervention product fatty acid and FLAV analysis at 1 y indicated no loss of EPA, DHA or flavan-3-ol levels. The FLAV-rich chocolate chips provided 30 mg of caffeine and 262 mg theobromine daily relative to 5.4 mg and 64 mg daily (Of the 11 broad secondary outcomes, performance on one measure of Executive Function (EF) declined in the OM3FLAV group, which was unexpected. The other widely used measures of EF, Verbal Fluency, and Category Switching (measured at baseline and 12 mo) showed no treatment effects. Additionally, EF is generally accepted to rely on prefrontal cortex activity, and we did not find evidence of differential effects on this area (with the caveat that it was not a specific focus of the study).We can be relatively confident that the interventions were consumed as directed. Compliance checks based on intervention returns were good (>95% in both arms), which were supported by plasma and urine fatty acid and flavonoid metabolite enrichment, respectively. Importantly, changes to these biomarkers did not correlate with changes in cognitive function, suggesting that there were not individual differences in intervention response that were related to detectable cognitive benefits.No effect of intervention was evident for hippocampal volume, which was the preregistered secondary outcome for structural MRI. The 0.8% decline in volume of this region over 12 mo in the group as a whole is in line with or potentially lower than would be expected in a mixed SCI/MCI group [Our lack of benefit of OM3FLAV is consistent with the only other randomized controlled trial (RCT) to cosupplement flavonoids (anthocyanins from blueberry powder [BB] and FO providing 1.6 g EPA and 0.8 g DHA per day) for 24 wk in an SCI population [Another possible factor that may contribute to these findings is that the intervention was associated with higher glucose levels, which are known to contribute to cognitive decline via central insulin sensitivity [In conclusion, 1 y intervention with EPA+DHA and cocoa FLAVs did not improve cognition or protect the brain against atrophy in older adults with evidence of memory deficits. However, based on strong prospective cohort evidence of an association between long-term fish/EPA+DHA and flavonoid intake and status and cognitive well-being, and evidence of subgroup variability of response in the current trial, the findings do not preclude modest benefits of supplementation in responsive subgroups. Given the complexity of neuropathological processes underpinning cognitive decline and dementia risk, it is emerging that, at a population level, multidomain [