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Elevated plasma total homocysteine (tHcy) is associated with the development of Alzheimer's disease and other forms of dementia. In this study, we report the relationship between tHcy and epigenetic age in older adults with mild cognitive impairment from the VITACOG study. Epigenetic age and rate of aging (ROA) were assessed using various epigenetic clocks, including those developed by Horvath and Hannum, DNAmPhenoAge, and with a focus on Index, a new principal component‐based epigenetic clock that, like DNAmPhenoAge, is trained to predict an individual's “PhenoAge.” We identified significant associations between tHcy levels and ROA, suggesting that hyperhomocysteinemic individuals were aging at a faster rate. Moreover, Index revealed a normalization of accelerated epigenetic aging in these individuals following treatment with tHcy‐lowering B‐vitamins. Our results indicate that elevated tHcy is a risk factor for accelerated epigenetic aging, and this can be ameliorated with B‐vitamins. These findings have broad relevance for the sizable proportion of the worldwide population with elevated tHcy. This study uses DNA methylation to evaluate the impact of homocysteine (tHcy) levels on epigenetic age and rate of aging (ROA) in older adults with mild cognitive impairment. Elevated tHcy was associated with faster epigenetic aging, and tHcy‐lowering with B‐vitamins normalized accelerated ROAs in individuals with elevated tHcy.

Background/Objectives: Nutrients such as vitamin B12, folate (B9), and polyunsaturated fatty acids (PUFAs) may independently influence cognitive health, but their combined effects and interactions remain unclear. This study aims to investigate the effects of B12, folate, and PUFAs, including their interactions, on cognitive function in cognitively healthy older adults, considering effect modification by sex and amyloid-beta status. Methods: A cross-sectional analysis was conducted using data from 321 participants aged 60–85 y enrolled in the UK CHARIOT–PRO SubStudy. Dietary intake was assessed using the Scottish Collaborative Group Food Frequency Questionnaire, and cognitive performance was measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Stratified multivariate linear regression models by sex and amyloid-beta status and models with the saturated to unsaturated fatty acid ratio (substituted for PUFAs) as one of the predictors were constructed. Results: Males had lower total RBANS scores with a higher PUFA intake (β = −13.97, p = 0.04) but improved scores with increased folate (β = 9.08, p = 0.04). PUFA × folate revealed contrasting effects to PUFAs alone, with higher cognitive scores in the amyloid-negative group for total RBANS (β = 13.27, 95%: 3.81~22.73, p = 0.01) but lowered scores in the amyloid-positive group. Considering the UFA:SFA ratio, higher delayed memory scores were associated with the combined intake of folate, B12, and PUFAs (β = 7.46, p = 0.02) among females. In the amyloid-positive group, the negative cognitive effects observed with PUFAs were reversed when UFA:SFA was considered. Conclusions: Amyloid status and sex significantly influenced the cognitive effects of nutrient intake, with distinct patterns based on specific cognitive domains and nutrient interactions.

The Galactic Centre contains a supermassive black hole with a mass of four million Suns 1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings 2 . Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts 3 , strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone 4 at Galactic longitude | l | < 0.7 degrees and latitude | b | < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas 5 , a high cosmic-ray ionization rate 6 , unusual gas chemistry, enhanced synchrotron emission 7 , 8 , and a multitude of radio-emitting magnetized filaments 9 , the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 10 52  ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities. Radio observations show a bipolar bubble structure of size 140 parsecs by 430 parsecs both above and below the Galactic Centre.

Dementia prevention in Africa is critically underexplored, despite the continent's high prevalence of modifiable risk factors. With a predominantly young and middle‐aged population, Africa presents a prime opportunity to implement evidence‐based strategies that could significantly reduce future dementia cases and mitigate its economic impact. The multinational Africa‐FINGERS program offers an innovative solution, pioneering culturally sensitive, multidomain interventions tailored to the unique challenges of the region.  Leveraging insights from landmark global studies such as Worldwide‐FINGERS and Alzheimer's Disease Neuroimaging Initiative, the program employs a multideterminant precision prevention framework, grounded in community based systems dynamics. Africa‐FINGERS further integrates cutting‐edge state‐of‐the‐art multimodal biomarker evaluations tailored to regional contexts, with the goal of advancing brain health and establishing a global standard for dementia prevention. This groundbreaking initiative highlights the potential for scalableand sustainable interventions, thus is poised to transform dementia risk reduction efforts across the continent. Highlights Dementia rates are escalating in Africa, largely due to longer life spans and increased prevalence of modifiable risk factors. Yet, few regional interventions have directly targeted lifestyle factors to reduce dementia risk. The multinational Africa‐FINGERS study will address this gap by adapting the successful FINGERS lifestyle intervention to African populations. Africa‐FINGERS will pioneer a culturally informed, multidomain dementia risk reduction intervention in the African region through feasibility dementia prevention trials in rural and urban sites across Kenya and Nigeria in the first instance, enrolling 600 at‐risk adults (≥ 50 years). The program adopts participatory research methods to develop culturally appropriate interventions and build infrastructure to evaluate dementia biomarkers from ante and post mortem samples. A cost‐effectiveness analysis will be conducted to guide the strategic implementation of Africa‐FINGERS into regional health systems. The Africa‐FINGERS strategy aligns with the Worldwide‐FINGERS framework and integrates the global Alzheimer's Disease Neuroimaging Initiative approach, emphasizing multimodal analysis.

Background Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia. Methods MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. Trial registration ClinicalTrials.gov (NCT05109169).

The COVID‐19 pandemic necessitated adaptations to standard operations and management of clinical studies, after lockdown measures put in place by several governments to reduce the spread of SARS‐COV‐2. In this paper, we describe our telehealth strategy developed for transitioning our dementia prevention clinical observational prospective study from face‐to‐face visits to virtual visits, to ensure the ongoing collection of longitudinal data. We share the lessons learned in terms of challenges experienced and solutions implemented to achieve successful administration of study assessments. Our methods will be useful for informing longitudinal observational or interventional studies that require a feasible model for remote data collection, in cognitively unimpaired adults.

Background: Practice effects (PE), after repeated cognitive measurements, may mask cognitive decline and represent a challenge in clinical and research settings. However, an attenuated practice effect may indicate the presence of brain pathologies. This study aimed to evaluate practice effects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scale, and their associations with brain amyloid status and other factors in a cohort of cognitively unimpaired older adults enrolled in the CHARIOT-PRO SubStudy. Methods: 502 cognitively unimpaired participants aged 60-85 years were assessed with RBANS in both screening and baseline clinic visits using alternate versions (median time gap of 3.5 months). We tested PE based on differences between test and retest scores in total scale and domain-specific indices. Multiple linear regressions were used to examine factors influencing PE, after adjusting for age, sex, education level, APOE-ε4 carriage and initial RBANS score. The latter and PE were also evaluated as predictors for amyloid positivity status based on defined thresholds, using logistic regression. Results: Participants’ total scale, immediate memory and delayed memory indices were significantly higher in the second test than in the initial test (Cohen’s dz = 0.48, 0.70 and 0.35, P < 0.001). On the immediate memory index, the PE was significantly lower in the amyloid positive group than the amyloid negative group (P = 0.022). Older participants (≥ 70 years), women, non-APOE-ε4 carriers, and those with worse initial RBANS test performance had larger PE. No associations were found between brain MRI parameters and PE. In addition, attenuated practice effects in immediate or delayed memory index were independent predictors for amyloid positivity (P < 0.05). Conclusion: Significant practice effects on RBANS total scale and memory indices were identified in cognitively unimpaired older adults. The association with amyloid status suggests that practice effects are not simply a source of measurement error but may be informative with regard to underlying neuropathology.

Objectives To quantify the associations between shielding status and loneliness at the start of the COVID-19 pandemic, and physical activity (PA) levels throughout the pandemic. Methods Demographic, health and lifestyle characteristics of 7748 cognitively healthy adults aged >50, and living in London, were surveyed from April 2020 to March 2021. The International Physical Activity Questionnaire (IPAQ) short-form assessed PA before COVID-19 restrictions, and up to 6 times over 11 months. Linear mixed models investigated associations between shielding status and loneliness at the onset of the pandemic, with PA over time. Results Participants who felt 'often lonely' at the outset of the pandemic completed an average of 522 and 547 fewer Metabolic Equivalent of Task (MET) minutes/week during the pandemic (95% CI: -809, -236, p<0.001) (95% CI: -818, -275, p<0.001) than those who felt 'never lonely' in univariable and multivariable models adjusted for demographic factors respectively. Those who felt 'sometimes lonely' completed 112 fewer MET minutes/week (95% CI: -219, -5, p = 0.041) than those who felt 'never lonely' following adjustment for demographic factors. Participants who were shielding at the outset of the pandemic completed an average of 352 fewer MET minutes/week during the pandemic than those who were not (95% CI: -432, -273; p<0.001) in univariable models and 228 fewer MET minutes/week (95% CI: -307, -150, p<0.001) following adjustment for demographic factors. No significant associations were found after further adjustment for health and lifestyle factors. Conclusions Those shielding or lonely at pandemic onset were likely to have completed low levels of PA during the pandemic. These associations are influenced by co-morbidities and health status.

IntroductionThe Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer’s disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline.Methods and analysisCPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60–85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment–Alzheimer’s disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer’s Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required.Ethics and disseminationCPSS received ethical approvals from the London—Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therapeutic strategies to prevent and/or delay cognitive impairment and dementia. Dissemination of results will target the scientific community, research participants, volunteer community, public, industry, regulatory authorities and policymakers. On study completion, and following a predetermined embargo period, CPSS data are planned to be made accessible for analysis to facilitate further research into the determinants of AD pathology, onset of symptomatology and progression.Trial registration numberThe CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry.

ObjectivesPhysical inactivity is more common in older adults, is associated with social isolation and loneliness and contributes to increased morbidity and mortality. We examined the effect of social restrictions to reduce COVID-19 transmission in the UK (lockdown), on physical activity (PA) levels of older adults and the social predictors of any change.DesignBaseline analysis of a survey-based prospective cohort study.SettingAdults enrolled in the Cognitive Health in Ageing Register for Investigational and Observational Trials cohort from general practitioner practices in North West London were invited to participate from April to July 2020.Participants6219 cognitively healthy adults aged 50–92 years completed the survey.Main outcome measuresSelf-reported PA before and after the introduction of lockdown, as measured by metabolic equivalent of task (MET) minutes. Associations of PA with demographic, lifestyle and social factors, mood and frailty.ResultsMean PA was significantly lower following the introduction of lockdown from 3519 to 3185 MET min/week (p<0.001). After adjustment for confounders and prelockdown PA, lower levels of PA after the introduction of lockdown were found in those who were over 85 years old (640 (95% CI 246 to 1034) MET min/week less); were divorced or single (240 (95% CI 120 to 360) MET min/week less); living alone (277 (95% CI 152 to 402) MET min/week less); reported feeling lonely often (306 (95% CI 60 to 552) MET min/week less); and showed symptoms of depression (1007 (95% CI 612 to 1401) MET min/week less) compared with those aged 50–64 years, married, cohabiting and not reporting loneliness or depression, respectively.Conclusions and implicationsMarkers of social isolation, loneliness and depression were associated with lower PA following the introduction of lockdown in the UK. Targeted interventions to increase PA in these groups should be considered.