Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.

CONTEXT: In preclinical Alzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy. OBJECTIVE: This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD. DATA SOURCES: A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021. DATA EXTRACTION: Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria. DATA ANALYSIS: All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain. CONCLUSION: MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42019146967.

Association between retinal markers and cognition in older adults: a systematic review.

OBJECTIVES: To appraise the existing literature reporting an association between retinal markers and cognitive impairment in adults aged 65 years and over and to provide directions for future use of retinal scanning as a potential tool for dementia diagnosis. DESIGN: Systematic review of peer-reviewed empirical articles investigating the association of retinal markers in assessing cognitive impairment. DATA SOURCES: Three electronic databases, Medline, PsycINFO and EMBASE were searched from inception until March 2022. ELIGIBILITY CRITERIA: All empirical articles in English investigating the association between retinal markers and cognition in humans aged ≥65 years using various retinal scanning methodologies were included. Studies with no explicit evaluation of retinal scanning and cognitive outcomes were excluded. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. DATA EXTRACTION AND SYNTHESIS: Data extraction was conducted by two authors (VJ, RS) and reviewed by another author (JS). Results were synthesised and described narratively. RESULTS: Sixty-seven eligible studies examining 6815 older adults were included. Majority of studies were cross-sectional (n=60; 89.6%). Optical coherence tomography (OCT) was the most commonly used retinal scanning methodology to measure the thickness of retinal nerve fibre layer, the ganglion cell complex, choroid and macula. 51.1% of cross-sectional studies using OCT reported an association between the thinning of at least one retinal parameter and poor cognition. Longitudinal studies (n=6) using OCT also mostly identified significant reductions in retinal nerve fibre layer thickness with cognitive decline. Study quality was overall moderate. CONCLUSION: Retinal nerve fibre layer thickness is linked with cognitive performance and therefore may have the potential to detect cognitive impairment in older adults. Further longitudinal studies are required to validate our synthesis and understand underlying mechanisms before recommending implementation of OCT as a dementia screening tool in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42020176757.

Plasma metabolites associated with biomarker evidence of neurodegeneration in cognitively normal older adults.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently has no cure. Identifying biochemical changes associated with neurodegeneration prior to symptom onset, will provide insight into the biological mechanisms associated with neurodegenerative processes, that may also aid in identifying potential drug targets. The current study therefore investigated associations between plasma neurofilament light chain (NF-L), a marker of neurodegeneration, with plasma metabolites that are products of various cellular processes. Plasma NF-L, measured by ultrasensitive Single molecule array (Simoa) technology (Quanterix) and plasma metabolites, measured by mass-spectrometry (AbsoluteIDQ® p400HR kit, BIOCRATES), were assessed in the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort comprising 100 cognitively normal older adults. Metabolites belonging to biogenic amine (creatinine, symmetric dimethylarginine, asymmetric dimethylarginine; ADMA, kynurenine, trans-4-hydroxyproline), amino acid (citrulline, proline, arginine, asparagine, phenylalanine, threonine) and acylcarnitine classes were observed to have positive correlations with plasma NF-L, suggesting a link between neurodegeneration and biological pathways associated with neurotransmitter regulation, nitric oxide homoeostasis, inflammation and mitochondrial function. Additionally, after stratifying participants based on low/high brain amyloid-ß load (Aß ±) assessed by positron emission tomography, while creatinine, SDMA and citrulline correlated with NF-L in both Aß- and Aß+ groups, ADMA, proline, arginine, asparagine, phenylalanine and acylcarnitine species correlated with NF-L only in the Aß+ group after adjusting for confounding variables, suggesting that the association of these metabolites with neurodegeneration may be relevant to AD-related neuropathology. Metabolites identified to be associated with plasma NF-L may have the potential to serve as prognostic markers for neurodegenerative diseases, however, further studies are required to validate the current findings in an independent cohort, both cross-sectionally and longitudinally.

Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-ß Load.

BACKGROUND/OBJECTIVE: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer's disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-ß load (NAL). METHODS: Serum hepcidin levels in cognitively normal participants (n = 100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR)<1.35 was classified as low NAL (n = 65) and ≥1.35 (n = 35) was classified as high NAL. RESULTS: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOEɛ4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC = 0.766), but was outperformed when serum hepcidin was added to the base model (AUC = 0.794) and further improved with plasma Aß42/40 ratio (AUC = 0.829). CONCLUSION: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

Food matrix and co-presence of turmeric compounds influence bioavailability of curcumin in healthy humans.

The natural food-derived compound curcumin (from turmeric root) is known for its anti-inflammatory and anti-oxidant effects. However, due to its poor solubility when consumed in isolation, it is poorly bioavailable. In this crossover study we compared the bioavailability of curcumin from a meal containing either curcumin powder, turmeric powder or grated fresh turmeric root, all containing 400 mg of curcumin, along with mashed potatoes and cream. Healthy male participants consumed the meals following overnight fasting, and postprandial blood samples were taken to measure plasma curcuminoids (curcumin, dimethylcurcumin (DMC) and bisdimethylcurcumin (BDMC)). All plasma curcumin values refer to total curcumin (sum of free and conjugated curcumin). The meals were also analysed using confocal laser scanning microscopy to determine the location of curcuminoids. Both of the turmeric meals produced significantly higher amounts (p < 0.05) of plasma curcuminoids at 1-3 hours after the meal was consumed, as compared to the curcumin powder. Plasma curcumin Cmax was 4.9 ng ml-1 95% CI (confidence interval) [2.2, 7.5] for the fresh turmeric meal, 8.4 ng ml-1 95% CI [4.4, 12.48] for the turmeric powder meal and 0.19 ng ml-1 95% [-0.08, 0.47] for the curcumin powder meal. Plasma DMC and BDMC were significantly higher (p < 0.05) following the turmeric powder meal, compared with the fresh turmeric meal and the curcumin powder meal. Microscopy images showed that the curcuminoid particles were mostly confined within curcuminoid cells in the fresh turmeric meal. They were unconfined but in clusters in the turmeric powder meal, while the curcuminoid particles appeared smaller in the curcumin powder meal. Conclusion: curcumin bioavailability is enhanced when consumed as fresh or powdered turmeric, which could be due to the co-presence of other turmeric compounds and/or a turmeric matrix effect.

Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies.

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-ß peptide (also known as Aß or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aß peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aß.

Enhancing Cognitive Functioning in Healthly Older Adults: a Systematic Review of the Clinical Significance of Commercially Available Computerized Cognitive Training in Preventing Cognitive Decline.

Successfully assisting older adults to maintain or improve cognitive function, particularly when they are dealing with neurodegenerative disorders such as Alzheimer's disease (AD), remains a major challenge. Cognitive training may stimulate neuroplasticity thereby increasing cognitive and brain reserve. Commercial brain training programs are computerized, readily-available, easy-to-administer and adaptive but often lack supportive data and their clinical validation literature has not been previously reviewed. Therefore, in this review, we report the characteristics of commercially available brain training programs, critically assess the number and quality of studies evaluating the empirical evidence of these programs for promoting brain health in healthy older adults, and discuss underlying causal mechanisms. We searched PubMed, Google Scholar and each program's website for relevant studies reporting the effects of computerized cognitive training on cognitively healthy older adults. The evidence for each program was assessed via the number and quality (PEDro score) of studies, including Randomized Control Trials (RCTs). Programs with clinical studies were subsequently classified as possessing Level I, II or III evidence. Out of 18 identified programs, 7 programs were investigated in 26 studies including follow-ups. Two programs were identified as possessing Level I evidence, three programs demonstrated Level II evidence and an additional two programs demonstrated Level III evidence. Overall, studies showed generally high methodological quality (average PEDro score = 7.05). Although caution must be taken regarding any potential bias due to selective reporting, current evidence supports that at least some commercially available computerized brain training products can assist in promoting healthy brain aging.