Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal older carriers.

The precuneus is a site of early amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer's disease (AD) are lacking and the relationship to the Apolipoprotein-E () genotype is unclear.

Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status.

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD.

Locus coeruleus integrity is related to an exploitation-based decision-making bias in older adulthood.

Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity.

Neurobehavioral Mechanisms Influencing the Association Between Generativity, the Desire to Promote Well-Being of Younger Generations, and Purpose in Life in Older Adults at Risk for Alzheimer's Disease.

Objectives: Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults.

Iron Deposition and Distribution Across the Hippocampus Is Associated with Pattern Separation and Pattern Completion in Older Adults at Risk for Alzheimer's Disease.

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD ( = 172, 120 females, 52 males; mean age = 68.8 ± 5.

Midlife physical activity engagement is associated with later-life brain health.

The relationship between midlife physical activity (PA), and cognition and brain health in later life is poorly understood with conflicting results from previous research. Investigating the contribution of midlife PA to later-life cognition and brain health in high-risk populations will propel the development of health guidance for those most in need. The current study examined the association between midlife PA engagement and later-life cognition, grey matter characteristics and resting-state functional connectivity in older individuals at high-risk for Alzheimer's disease.

Resting-state MRI functional connectivity as a neural correlate of multidomain lifestyle adherence in older adults at risk for Alzheimer's disease.

Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer's disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need.

Data and Tools Integration in the Canadian Open Neuroscience Platform.

We present the Canadian Open Neuroscience Platform (CONP) portal to answer the research community's need for flexible data sharing resources and provide advanced tools for search and processing infrastructure capacity. This portal differs from previous data sharing projects as it integrates datasets originating from a number of already existing platforms or databases through DataLad, a file level data integrity and access layer. The portal is also an entry point for searching and accessing a large number of standardized and containerized software and links to a computing infrastructure.

The influence of generativity on purpose in life is mediated by social support and moderated by prefrontal functional connectivity in at-risk older adults.

Objectives: Generativity, the desire and action to improve the well-being of younger generations, is positively associated with purpose in life among older adults. However, the neural basis of generativity and the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults.

INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.

Objective: To evaluate the safety and efficacy of low-dose naproxen for prevention of progression in presymptomatic Alzheimer disease (AD) among cognitively intact persons at risk.

Methods: Investigation of Naproxen Treatment Effects in Pre-symptomatic Alzheimer's Disease (INTREPAD), a 2-year double-masked pharmaco-prevention trial, enrolled 195 AD family history-positive elderly (mean age 63 years) participants screened carefully to exclude cognitive disorder (NCT-02702817). These were randomized 1:1 to naproxen sodium 220 mg twice daily or placebo.

Odor identification as a biomarker of preclinical AD in older adults at risk.

Objective: To assess odor identification (OI) as an indicator of presymptomatic Alzheimer disease (AD) pathogenesis in cognitively normal aging individuals at increased risk of AD dementia.

Methods: In 274 members of the PREVENT-AD cohort of healthy aging persons with a parental or multiple-sibling history of AD dementia, we assessed the cross-sectional association of OI with potential indicators of presymptomatic AD. Some 101 participants donated CSF, thus enabling assessment of AD pathology with the biomarkers total tau (t-tau), phospho-tau (P-tau), and their ratios with β-amyloid (Aβ).

Kinetics of 13C-DHA before and during fish-oil supplementation in healthy older individuals.

Background: Docosahexaenoic acid (DHA) kinetics appear to change with intake, which is an effect that we studied in an older population by using uniformly carbon-13-labeled DHA ((13)C-DHA).

Objective: We evaluated the influence of a fish-oil supplement over 5 mo on the kinetics of (13)C-DHA in older persons.

Design: Thirty-four healthy, cognitively normal participants (12 men, 22 women) aged between 52 and 90 y were recruited.

Effects of vegetable oils on biochemical and biophysical properties of membrane retinal pigment epithelium cells.

The aim of this study was to investigate the effect of vegetable oil enrichment of retinal pigment epithelial (RPE) cells on their biochemical and biophysical properties. For this, RPE cells were incubated with 4 different vegetables oils (olive oil, corn oil, argan oil, and camelina oil). The cytotoxicity of these vegetable oils was assessed in vivo on 8-week-old mice and in vitro by using the neutral red and YO-PRO-1 tests.

Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: estimated potential contribution to brain energy metabolism.

Objective: In humans consuming a normal diet, we investigated 1) the capacity of a medium-chain triacylglycerol (MCT) supplement to stimulate and sustain ketonemia, 2) ¹³C-β-hydroxybutyrate and ¹³C-trioctanoate metabolism, and 3) the theoretical contribution of the degree of ketonemia achieved to brain energy metabolism.

Methods: Eight healthy adults (26 ± 1 y old) were given an MCT supplement for 4 wk (4 times/d; total of 20 g/d for 1 wk followed by 30 g/d for 3 wk). Ketones, glucose, triacylglycerols, cholesterol, free fatty acids, and insulin were measured over 8 h during two separate metabolic study days before and after MCT supplementation.

The ketogenic diet increases brain glucose and ketone uptake in aged rats: a dual tracer PET and volumetric MRI study.

Despite decades of study, it is still unclear whether regional brain glucose uptake is lower in the cognitively healthy elderly. Whether regional brain uptake of ketones (β-hydroxybutyrate and acetoacetate [AcAc]), the main alternative brain fuel to glucose, changes with age is unknown. We used a sequential, dual tracer positron emission tomography (PET) protocol to quantify brain (18)F-fluorodeoxyglucose ((18)F-FDG) and (11)C-AcAc uptake in two studies with healthy, male Sprague-Dawley rats: (i) Aged (21 months; 21M) versus young (4 months; 4M) rats, and (ii) The effect of a 14 day high-fat ketogenic diet (KD) on brain (18)F-FDG and (11)C-AcAc uptake in 24 month old rats (24M).

Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain).

Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats.

Brain glucose and ketone uptake was investigated in Fisher rats subjected to mild experimental ketonemia induced by a ketogenic diet (KD) or by 48 hours fasting (F). Two tracers were used, (11)C-acetoacetate ((11)C-AcAc) for ketones and (18)F-fluorodeoxyglucose for glucose, in a dual-tracer format for each animal. Thus, each animal was its own control, starting first on the normal diet, then undergoing 48 hours F, followed by 2 weeks on the KD.

Bezafibrate mildly stimulates ketogenesis and fatty acid metabolism in hypertriglyceridemic subjects.

Our objective was to determine whether bezafibrate, a hypotriglyceridemic drug and peroxisome proliferator-activated receptor (PPAR)-alpha agonist, is ketogenic and increases fatty acid oxidation in humans. We measured fatty acid metabolism and ketone levels in 13 mildly hypertriglycemic adults (67 +/- 11 years old) during 2 metabolic study days lasting 6 h, 1 day before and 1 day after bezafibrate (400 mg of bezafibrate per day for 12 weeks). beta-Hydroxybutyrate, triglycerides, free fatty acids, fatty acid profiles, insulin, and glucose were measured in plasma, and fatty acid beta-oxidation was measured in breath after an oral 50-mg dose of the fatty acid tracer [U-(13)C]linoleic acid.

Maternal dietary fat determines metabolic profile and the magnitude of endocannabinoid inhibition of the stress response in neonatal rat offspring.

Endocannabinoids (eCBs) are products of phospholipid (PL)-derived arachidonic acid (AA) that regulate hypothalamus-pituitary-adrenal axis activity. We hypothesized that differences in the quality and quantity of maternal dietary fat would modulate the PL AA content in the neonatal brain affecting stress responsiveness via differences in eCB production and activity in stress-activated brain areas. Pregnant rats were fed a 5% [control (C)] or 30% fat [high fat (HF)] diet rich in either n-6 (HF-n-6) or n-3 (HF-n-3) fat during the last week of gestation and lactation.

Ketones and brain function: possible link to polyunsaturated fatty acids and availability of a new brain PET tracer, 11C-acetoacetate.

Changes in the metabolism of polyunsaturated fatty acids (PUFA), both in children on the high fat ketogenic diet (KD) for seizure control and in rats on a KD enriched in PUFA, raise the possibility that increased brain arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) may contribute to better seizure control. Our studies with PUFA and several other reports raise the question of whether persistent ketonemia or elevated brain uptake of ketones are strictly necessary for the clinical effectiveness of the KD in intractable epilepsy. To address this question, we have developed the synthesis of carbon-11 labeled acetoacetate ((11)C-AcAc) for PET studies to investigate brain ketone uptake directly in humans and animals.

Eicosapentaenoic acid decreases postprandial beta-hydroxybutyrate and free fatty acid responses in healthy young and elderly.

Objectives: We investigated whether a dietary supplement rich in eicosapentaenoic acid (EPA) increases fasting plasma ketones or postprandial ketone responses in healthy young and elderly subjects.

Methods: Ten young (22 +/- 1 y old) and 10 elderly (75 +/- 1 y old) subjects were recruited and participated in two identical study days, one before and one 6 wk after providing an EPA-enriched supplement (1.4 g/d of EPA and 0.

Plasma omega-3 fatty acid response to a fish oil supplement in the healthy elderly.

Little information is available concerning whether incorporation of dietary omega-3 fatty acids into plasma lipids changes during healthy aging. Elderly (74 +/- 4 years old) and young (24 +/- 2 years old) adults were given a fish oil supplement for 3 weeks that provided 680 mg/day of docosahexaenoic acid and 320 mg/day of eicosapentaenoic acid, followed by a 2 week wash-out period. Compliance was monitored by spiking the capsules with carbon-13 glucose, the excretion of which was measured in breath CO2.

Unresolved issues in the link between docosahexaenoic acid and Alzheimer's disease.

Lower consumption of docosahexaenoic acid (DHA) is commonly but not always associated with higher risk of cognitive decline and diagnosis of Alzheimer's disease (AD). We review here the available data relating DHA to AD, with emphasis on DHA content of plasma and brain. Our assessment of this literature is that low DHA is not consistently observed in AD plasma or brain.

Flaxseed on cardiovascular disease markers in healthy menopausal women: a randomized, double-blind, placebo-controlled trial.

Objective: Due to its high content of lignans, alpha-linolenic acid and fiber, flaxseed may reduce cardiovascular disease risk in humans. The present study evaluated the effect of flaxseed on markers of cardiovascular disease risk in healthy menopausal women.

Methods: One hundred ninety-nine women were randomly assigned to consume 40 g daily of flaxseed or wheat germ placebo for 12 mo.