Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aß) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aß, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the ß-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aß, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.

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.

Stress and Coping in Older Australians During COVID-19: Health, Service Utilization, Grandparenting, and Technology Use.

OBJECTIVES: This study examined the impacts of COVID-19 lockdown on health and lifestyle factors for older adults in Sydney, Australia. The study examined demographic differences, social engagement, loneliness, physical activity, emotion regulation, technology use, and grandparenting experiences and their contribution to emotional health and quality of life during lockdown. METHODS: Participants were 201 community-dwelling older adults (60-87 years, M = 70.55, SD = 6.50; 67.8% female) who completed self-report scales measuring physical and emotional health outcomes, quality of life, health service utilization, changes in diet and physical activity, impacts on grandparenting roles, and uptake of new technology. RESULTS: One-third of older adults experienced depression, and 1 in 5 experienced elevated anxiety and/or psychological distress during lockdown. Specific emotion regulation strategies, better social and family engagement, and new technology use were associated with better emotional health and quality of life; 63% of older adults used new technologies to connect with others. CONCLUSIONS: Older adults were adaptable and resilient during lockdown, demonstrating high uptake of new technologies to remain connected to others, while negative emotional health outcomes were linked to loneliness and unhelpful emotion regulation. CLINICAL IMPLICATIONS: Further diversifying use of video technologies may facilitate improved physical and emotional health outcomes.

The acute effect of the menstrual cycle and oral contraceptive cycle on measures of body composition.

PURPOSE: This study aimed to investigate the effect of fluctuating female hormones during the menstrual cycle (MC) and oral contraceptive (OC) cycle on different measures of body composition. METHODS: Twenty-two women with a natural MC and thirty women currently taking combined monophasic OC were assessed over three phases of the menstrual or oral contraceptive cycle. Body weight, skinfolds, bioelectric impedance analysis (BIA), ultrasound, dual-energy X-ray absorptiometry (DXA), and peripheral quantitative computed tomography (pQCT) measurements were performed to assess body composition. Urine specific gravity (USG) was measured as an indication of hydration, and serum oestradiol and progesterone were measured to confirm cycle phases. RESULTS: Five participants with a natural MC were excluded based on the hormone analysis. For the remaining participants, no significant changes over the MC and OC cycle were found for body weight, USG, skinfolds, BIA, ultrasound and pQCT measures. However, DXA body fat percentage and fat mass were lower in the late follicular phase compared to the mid-luteal phase of the MC, while for the OC cycle, DXA body fat percentage was higher and lean mass lower in the early hormone phase compared with the late hormone phase. CONCLUSION: Our findings suggest that assessment of body fat percentage through BIA and skinfolds may be performed without considering the MC or OC cycle. Body adiposity assessment via DXA, however, may be affected by female hormone fluctuations and therefore, it may be advisable to perform repeat testing using DXA during the same phase of the MC or OC cycle.

Long-term relapse rates after cognitive behaviour therapy for anxiety and depressive disorders among older adults: A follow-up study during COVID-19.

OBJECTIVE: This study assessed the long-term symptom relapse rates among older adults previously treated with cognitive behaviour therapy (CBT) for anxiety and/or depression during COVID-19. METHODS: Participants were 37 older adults (M = 75 years, SD = 5; 65% female) previously treated with CBT for anxiety and/or unipolar depression who were re-assessed an average of 5.6 years later, during the first Australian COVID-19 lockdown. RESULTS: On average, there was no significant group-level change in anxiety, depression or quality of life. When assessing change in symptoms based on clinical cut-off points on self-report measures, results suggest only 17%-22% showed a relapse of symptoms by the COVID-19 pandemic. CONCLUSIONS: Findings suggest that CBT may be protective in coping with life stressors many years after treatment ends. However, results warrant replication to attribute continued symptom improvement to CBT given the lack of control group.

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.

Potential of coconut oil and medium chain triglycerides in the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. Currently, there is no effective medication for the prevention or treatment of AD. This has led to the search for alternative therapeutic strategies. Coconut oil(CO) has a unique fatty acid composition that is rich in medium chain fatty acids(MCFA), a major portion of which directly reaches the liver via the portal vein, thereby bypassing the lymphatic system. Given that brain glucose hypometabolism is a major early hallmark of AD, detectable well before the onset of symptoms, ketone bodies from MCFA metabolism can potentially serve as an alternative energy source to compensate for lack of glucose utilisation in the brain. Additionally, neuroprotective antioxidant properties of CO have been attributed to its polyphenolic content. This review discusses how the metabolism of CO and MCFA may aid in compensating the glucose hypometabolism observed in the AD brain. Furthermore, we present the current evidence of the neuroprotective properties of CO on cognition, amyloid-ß pathogenicity, inflammation and oxidative stress. The current review addresses the influence of CO/MCFA on other chronic disorders that are risk factors for AD, and addresses existing gaps in the literature regarding the use of CO/MCFA as a potential treatment for AD.