- Title
- Counteracting premature cognitive decline with vasoactive nutrient supplementation
- Creator
- Kuszewski, Julia Christina
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Optimal cognitive function relies on a healthy vasculature to provide an adequate cerebral perfusion for a steady supply of nutrients and oxygen to the brain tissue. While cognitive abilities decline with increasing age, the rate of cognitive decline greatly varies between individuals and an impaired cerebrovascular function has been shown to be an early marker of cognitive decline, preceding clinical manifestations. Cardiovascular risk factors, such as obesity, hypertension and type 2 diabetes have been shown to contribute to cerebrovascular impairment by hastening age-related endothelial dysfunction and exacerbating chronic low-grade inflammation. Several studies have shown that individuals with overweight and obesity have reduced cerebral perfusion and exhibit cognitive impairments, especially in short-term memory and executive function, compared to lean individuals. These premature impairments in cerebrovascular and cognitive function translate to a greater risk of accelerated cognitive decline and potentially developing dementia later in life. Dementia is a progressive and irreversible disease with a gradual onset and has an immense physical, psychological, social and economic impact. The increase in longevity and the continuing increase in obesity prevalence will cause a substantial rise in dementia prevalence in the near future, with no effective treatment for dementia currently available. Therefore, new preventative strategies are urgently needed that are able to improve sub-optimal cognitive function in our increasingly overweight and obese older population in order to counteract premature cognitive decline. One potential, cost-effective strategy is to target cerebrovascular dysfunction by supplementing the diet with naturally occurring bioactive nutrients that are known to improve endothelial function and reduce systemic inflammation. Two such nutrients highlighted by the literature are the long-chain Omega-3 polyunsaturated fatty acids (LC-n3 PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and curcumin, the main active ingredient of the curry spice turmeric. Both nutrients have been shown to have anti-inflammatory effects, beneficial effects on vascular function and cognitive benefits. The mechanisms underlying cognitive benefits of fish oil and curcumin are however still unclear. It has been suggested that the cognitive benefits of fish oil might be mediated by neuronal effects. However, given the fact that cognitive effects were observed within a relatively short time following fish oil supplementation (<6 months) and taking the rapid circulatory benefits (within 6-12 weeks) of fish oil into account, Sinn and Howe hypothesised in 2008 that the cognitive benefits of fish oil may be due to improvements in cerebral endothelial function, thereby enhancing cerebral perfusion on demand (=neurovascular coupling, NVC), rather than having direct neuronal effects. However, to date, no study has performed a comprehensive test battery to test this hypothesis in a population at increased risk of premature cognitive decline. The cognitive benefits of curcumin were proposed to be mediated by its anti-inflammatory effects; however, no study has yet examined whether a reduction in systemic inflammation following curcumin correlates with improvements in cognitive performance. In the two literature reviews conducted as part of this thesis, we re-introduced and expanded on Sinn and Howe’s hypothesis. Given that curcumin has also been shown to have beneficial vascular effects, we hypothesised that fish oil as well as curcumin supplementation could improve sub-optimal cognitive function in overweight/obese older adults via improvements in cerebrovascular function, mediated by enhancements in endothelial vasodilator function and reductions in systemic inflammation. Furthermore, we hypothesised that combining fish oil with curcumin could lead to additive or synergistic effects on cerebrovascular function, cardiovascular risk factors and cognition, since curcumin’s anti-inflammatory and endothelial effects are achieved via both similar as well as distinct pathways compared to LCn-3 PUFA. To test these hypotheses, a randomised, double-blind, placebo-controlled 2x2 factorial intervention trial was conducted, supplementing 152 overweight or obese sedentary older adults with DHA-rich fish oil (2000mg DHA + 400mg EPA) and/or 160mg highly-bioavailable Longvida® curcumin for 16 weeks (Fish Oil and Curcumin Study, FOCUS). The main aims of this thesis were to investigate whether independent or combined supplementation with DHA-rich fish oil and curcumin can improve cerebrovascular function and cardiovascular risk factors and whether these improvements can enhance sub-optimal cognitive function in overweight/obese sedentary older adults. The independent and combined effects of fish oil and curcumin on basal cerebral haemodynamics and cerebrovascular responsiveness (CVR) to hypercapnia, assessing global cerebral vasodilator function, are presented in Chapter 3. While there was no treatment effect on the primary outcome, CVR to hypercapnia, we observed that fish oil supplementation resulted in a significant reduction of cerebral vessel stiffness in males. Furthermore, we confirmed the cardiovascular benefits of fish oil, by demonstrating reductions in heart rate, lower triglyceride levels and increased HDL cholesterol levels following fish oil supplementation compared to no fish oil. Additionally, fish oil tended to reduce systolic blood pressure and, in males only, C-reactive protein (CRP). Curcumin and the combination of fish oil and curcumin supplementation did not result in any beneficial effects on cerebrovascular function or cardiovascular risk factors. Chapter 4 discusses the effects of fish oil and curcumin on cognitive function and CVR to cognitive function, assessing cerebral perfusion on demand (NVC), and whether improvements in cerebrovascular function and cardiovascular risk factors are correlated with improvements in cognition. Fish oil supplementation increased processing speed performance; however, this was limited to males. This was accompanied by an increase in cerebral perfusion during cognitive tests assessing processing speed, and both outcomes tended to be correlated in males. Furthermore, improved processing speed performance was correlated with reductions in systolic blood pressure, pulse pressure and C-reactive protein. This is the first study showing evidence that the cognitive benefits of fish oil might be mediated by improvements in circulatory function. Curcumin improved NVC during a test assessing working memory but this was not accompanied by an increase in cognitive performance in this cognitive domain. Instead, curcumin improved verbal memory performance and tended to improve cognitive flexibility and overall cognitive performance; however, this was again limited to males. Since curcumin did not affect cerebrovascular function or any cardiovascular risk factors, including systemic inflammation, the mechanisms behind its cognitive benefits remain unclear. The combination of fish oil and curcumin did not result in additional cognitive effects. Other secondary outcomes of the FOCUS study, outlined in chapter 5, were physical wellbeing, i.e. chronic pain, and mental wellbeing, i.e. mood states and subjective memory complaints (SMC), as they are important components of quality of life (QoL) and have been shown to negatively impact cognitive performance. Chronic pain was on average mild and mostly related to osteoarthritis (OA). Fish oil supplementation significantly reduced chronic OA-related pain, which was correlated with improved mental wellbeing. A novel finding was that the pain alleviating effects of fish oil might be mediated by improved microcirculatory function, since the treatment change in pain correlated with change in small artery elasticity index, a surrogate marker for microvascular function. Curcumin and the combination of fish oil and curcumin did not improve chronic pain measures. Regarding mental wellbeing measures, we observed an increase in vigour with curcumin supplementation, confirming its mood-enhancing effects. Moreover, this was the first study to show curcumin’s potential to reduce SMC. Fish oil supplementation did not improve any mental wellbeing measures; however, closer examination revealed that the apolipoprotein E4 (APOE4) status of participants influenced the mental wellbeing response to fish oil. Secondary analysis showed that the mood-enhancing effects of fish oil, i.e. increase in vigour and reduction of total mood disturbances, were limited to APOE4 non-carriers. The combination of fish oil and curcumin did not result in additive effects on mental wellbeing measures. Lastly, a retrospective cross-sectional analysis using baseline data from the FOCUS study was performed to identify simple clinical markers that are able to reflect subtle cerebrovascular and cognitive impairments before cognitive deficits become apparent. Although overweight and obese adults are at increased risk of accelerated cognitive decline at a population level, this does not necessarily translate to an individual level. Thus, clinical markers could help health care providers in the future to screen for older adults at greater risk of accelerated cognitive decline who are thus in greater need of interventional strategies and might benefit the most from bioactive nutrient supplementation. We found that gait speed might be a useful clinical marker, as it reflected subtle impairments in both cerebrovascular and cognitive function and was a better predictor than body mass index and waist circumference, even in the absence of abnormally slow gait. In conclusion, the results presented in this thesis add further evidence to the literature concerning the beneficial effects of fish oil on cardiovascular risk factors, cerebrovascular function and cognitive performance – if given in sufficiently high doses – and contribute to a greater understanding of the mechanisms underlying the cognitive benefits of fish oil. Furthermore, we confirmed improvements in cognitive performance following curcumin supplementation, which seems to affect different cognitive domains compared to fish oil and mechanisms underlying the cognitive benefits of curcumin remain unclear. Since cognitive benefits were observed in males only, future studies are warranted to examine potential sex differences in response to fish oil and curcumin. Unfortunately, the study failed to provide evidence of synergistic effects of the fish oil-curcumin combination. Nevertheless, it highlights the need for more research, as the lack of synergistic effects might be due to the study population, sub-optimal dose combination or potential negative interactions between fish oil and curcumin in humans. Overall, while this thesis contributes new evidence regarding the potential to improve sub-optimal cognitive function and enhance QoL with bioactive nutrients in our increasingly overweight and obese older population, it also highlights the extensive work still required in this research area as well as the need for a more targeted bioactive nutrient supplementation approach in order to maximise potential benefits.
- Subject
- fish oil; curcumin; cognition; cerebrovascular function; cardiovascular function; general well-being; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1465421
- Identifier
- uon:47267
- Rights
- Copyright 2021 Julia Christina Kuszewski
- Language
- eng
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 3 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 688 KB | Adobe Acrobat PDF | View Details Download |