Treatment and Vaccination for Smallpox and Monkeypox.

The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins.

The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.

Nuclei-specific hypothalamus networks predict a dimensional marker of stress in humans.

The hypothalamus is part of the hypothalamic-pituitary-adrenal axis which activates stress responses through release of cortisol. It is a small but heterogeneous structure comprising multiple nuclei. In vivo human neuroimaging has rarely succeeded in recording signals from individual hypothalamus nuclei. Here we use human resting-state fMRI (n = 498) with high spatial resolution to examine relationships between the functional connectivity of specific hypothalamic nuclei and a dimensional marker of prolonged stress. First, we demonstrate that we can parcellate the human hypothalamus into seven nuclei in vivo. Using the functional connectivity between these nuclei and other subcortical structures including the amygdala, we significantly predict stress scores out-of-sample. Predictions use 0.0015% of all possible brain edges, are specific to stress, and improve when using nucleus-specific compared to whole-hypothalamus connectivity. Thus, stress relates to connectivity changes in precise and functionally meaningful subcortical networks, which may be exploited in future studies using interventions in stress disorders.

Characteristics and outcome of critically ill patients with systemic rheumatic diseases referred to the intensive care unit.

OBJECTIVES: Patients with systemic rheumatic diseases (SRDs) are at risk of admission to the intensive care unit (ICU). Data concerning these critically ill patients are limited to few retrospective studies. METHODS: This is a single-centre retrospective study of patients with SRDs admitted to an ICU at the Vienna General Hospital between 2012 and 2020. Single-predictor and multiple logistic regression analysis was performed to identify potential outcome determinants. RESULTS: A total of 144 patients accounting for 192 ICU admissions were included. Connective tissue diseases (CTDs), vasculitides and rheumatoid arthritis were the most common SRDs requiring ICU admission. Leading causes for ICU admission were respiratory failure and shock, as reflected by a high number of patients requiring mechanical ventilation (60.4%) and vasopressor therapy (72.9%). Overall, 29.2% of admissions were due to SRD-related critical illness. In 70.8% patients, co-existent SRD not responsible for the acute critical illness was documented. When comparing these subgroups, CTDs and vasculitides had a higher frequency in the patients with SRD-related critical illness. In a significantly higher proportion of patients in the SRD-related subgroup, diagnosis of SRD was made at the ICU. ICU and 6-month mortality in the overall population was 20.3% and 38.5%, respectively. Age, glucocorticoid therapy prior to hospital admission and disease severity were associated with poor outcome. CONCLUSIONS: In this study, respiratory failure was the leading cause of ICU admission as reflected by high rates of required mechanical ventilation. Despite considerable severity of critical illness, survival rates were comparable to a general ICU population.

No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy.

Short sleep is held to cause poorer brain health, but is short sleep associated with higher rates of brain structural decline? Analysing 8,153 longitudinal MRIs from 3,893 healthy adults, we found no evidence for an association between sleep duration and brain atrophy. In contrast, cross-sectional analyses (51,295 observations) showed inverse U-shaped relationships, where a duration of 6.5 (95% confidence interval, (5.7, 7.3)) hours was associated with the thickest cortex and largest volumes relative to intracranial volume. This fits converging evidence from research on mortality, health and cognition that points to roughly seven hours being associated with good health. Genome-wide association analyses suggested that genes associated with longer sleep for below-average sleepers were linked to shorter sleep for above-average sleepers. Mendelian randomization did not yield evidence for causal impacts of sleep on brain structure. The combined results challenge the notion that habitual short sleep causes brain atrophy, suggesting that normal brains promote adequate sleep duration-which is shorter than current recommendations.

Dispersion-corrected extracorporeal arterial input functions in PET studies of mice: a comparison to intracorporeal microprobe measurements.

BACKGROUND: Kinetic modelling of dynamic PET typically requires knowledge of the arterial radiotracer concentration (arterial input function, AIF). Its accurate determination is very difficult in mice. AIF measurements in an extracorporeal shunt can be performed; however, this introduces catheter dispersion. We propose a framework for extracorporeal dispersion correction and validated it by comparison to invasively determined intracorporeal AIFs using implanted microprobes. RESULTS: The response of an extracorporeal radiation detector to radioactivity boxcar functions, characterised by a convolution-based dispersion model, gave best fits using double-gamma variate and single-gamma variate kernels compared to mono-exponential kernels for the investigated range of flow rates. Parametric deconvolution with the optimal kernels was performed on 9 mice that were injected with a bolus of 39 ± 25 MBq [18F]F-PSMA-1007 after application of an extracorporeal circulation for three different flow rates in order to correct for dispersion. Comparison with synchronous implantation of microprobes for invasive aortic AIF recordings showed favourable correspondence, with no significant difference in terms of area-under-curve after 300 s and 5000 s. One-tissue and two-tissue compartment model simulations were performed to investigate differences in kinetic parameters between intra- and extracorporeally measured AIFs. Results of the modelling study revealed kinetic parameters close to the chosen simulated values in all compartment models. CONCLUSION: The high correspondence of simultaneously intra- and extracorporeally determined AIFs and resulting model parameters establishes a feasible framework for extracorporeal dispersion correction. This should allow more precise and accurate kinetic modelling in small animal experiments.

Characterising the covariance pattern between lifestyle factors and structural brain measures: a multivariable replication study of two independent ageing cohorts.

Modifiable lifestyle factors have been shown to promote healthy brain ageing. However, studies have typically focused on a single factor at a time. Given that lifestyle factors do not occur in isolation, multivariable analyses provide a more realistic model of the lifestyle-brain relationship. Here, canonical correlation analyses (CCA) examined the relationship between nine lifestyle factors and seven MRI-derived indices of brain structure. The resulting covariance pattern was further explored with Bayesian regressions. CCA analyses were first conducted on a Danish cohort of older adults (n = 251) and then replicated in a British cohort (n = 668). In both cohorts, the latent factors of lifestyle and brain structure were positively correlated (UK: r = .37, p < 0.001; Denmark: r = .27, p < 0.001). In the cross-validation study, the correlation between lifestyle-brain latent factors was r = .10, p = 0.008. However, the pattern of associations differed between datasets. These findings suggest that baseline characterisation and tailoring towards the study sample may be beneficial for achieving targeted lifestyle interventions.

Development and validation of a dementia risk score in the UK Biobank and Whitehall II cohorts.

BACKGROUND: Current dementia risk scores have had limited success in consistently identifying at-risk individuals across different ages and geographical locations. OBJECTIVE: We aimed to develop and validate a novel dementia risk score for a midlife UK population, using two cohorts: the UK Biobank, and UK Whitehall II study. METHODS: We divided the UK Biobank cohort into a training (n=176 611, 80%) and test sample (n=44 151, 20%) and used the Whitehall II cohort (n=2934) for external validation. We used the Cox LASSO regression to select the strongest predictors of incident dementia from 28 candidate predictors and then developed the risk score using competing risk regression. FINDINGS: Our risk score, termed the UK Biobank Dementia Risk Score (UKBDRS), consisted of age, education, parental history of dementia, material deprivation, a history of diabetes, stroke, depression, hypertension, high cholesterol, household occupancy, and sex. The score had a strong discrimination accuracy in the UK Biobank test sample (area under the curve (AUC) 0.8, 95% CI 0.78 to 0.82) and in the Whitehall cohort (AUC 0.77, 95% CI 0.72 to 0.81). The UKBDRS also significantly outperformed three other widely used dementia risk scores originally developed in cohorts in Australia (the Australian National University Alzheimer's Disease Risk Index), Finland (the Cardiovascular Risk Factors, Ageing, and Dementia score), and the UK (Dementia Risk Score). CLINICAL IMPLICATIONS: Our risk score represents an easy-to-use tool to identify individuals at risk for dementia in the UK. Further research is required to determine the validity of this score in other populations.

No moderating influence of education on the association between changes in hippocampus volume and memory performance in aging.

Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.

Lifestyle-related risk factors and their cumulative associations with hippocampal and total grey matter volume across the adult lifespan: A pooled analysis in the European Lifebrain consortium.

BACKGROUND: Lifestyle-related risk factors, such as obesity, physical inactivity, short sleep, smoking and alcohol use, have been associated with low hippocampal and total grey matter volumes (GMV). However, these risk factors have mostly been assessed as separate factors, leaving it unknown if variance explained by these factors is overlapping or additive. We investigated associations of five lifestyle-related factors separately and cumulatively with hippocampal and total GMV, pooled across eight European cohorts. METHODS: We included 3838 participants aged 18-90 years from eight cohorts of the European Lifebrain consortium. Using individual person data, we performed cross-sectional meta-analyses on associations of presence of lifestyle-related risk factors separately (overweight/obesity, physical inactivity, short sleep, smoking, high alcohol use) as well as a cumulative unhealthy lifestyle score (counting the number of present lifestyle-related risk factors) with FreeSurfer-derived hippocampal volume and total GMV. Lifestyle-related risk factors were defined according to public health guidelines. RESULTS: High alcohol use was associated with lower hippocampal volume (r = -0.10, p = 0.021), and overweight/obesity with lower total GMV (r = -0.09, p = 0.001). Other lifestyle-related risk factors were not significantly associated with hippocampal volume or GMV. The cumulative unhealthy lifestyle score was negatively associated with total GMV (r = -0.08, p = 0.001), but not hippocampal volume (r = -0.01, p = 0.625). CONCLUSIONS: This large pooled study confirmed the negative association of some lifestyle-related risk factors with hippocampal volume and GMV, although with small effect sizes. Lifestyle factors should not be seen in isolation as there is evidence that having multiple unhealthy lifestyle factors is associated with a linear reduction in overall brain volume.

Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers.

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems (n = 1742) and participants sleeping the recommended 7-8 h (n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings.SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

Association of gout with brain reserve and vulnerability to neurodegenerative disease.

Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis.

Stakeholder engagement in European brain research: Experiences of the Lifebrain consortium.

INTRODUCTION: Stakeholder engagement remains scarce in basic brain research. However, it can greatly improve the relevance of investigations and accelerate the translation of study findings to policy. The Lifebrain consortium investigated risk and protective factors influencing brain health using cognition, lifestyle and imaging data from European cohorts. Stakeholder activities of Lifebrain-organized in a separate work package-included organizing stakeholder events, investigating public perceptions of brain health and dissemination. Here, we describe the experiences of researchers and stakeholders regarding stakeholder engagement in the Lifebrain project. METHODS: Stakeholder engagement in Lifebrain was evaluated through surveys among researchers and stakeholders and stakeholders' feedback at stakeholder events through evaluation forms. Survey data were analysed using a simple content analysis approach, and results from evaluation forms were summarized after reviewing the frequency of responses. RESULTS: Consortium researchers and stakeholders experienced the engagement activities as meaningful and relevant. Researchers highlighted that it made the research and research processes more visible and contributed to new networks, optimized data collection on brain health perceptions and the production of papers and provided insights into stakeholder views. Stakeholders found research activities conducted in the stakeholder engagement work package to be within their field of interest and research results relevant to their work. Researchers identified barriers to stakeholder engagement, including lack of time, difficulties in identifying relevant stakeholders, and challenges in communicating complex scientific issues in lay language and maintaining relationships with stakeholders over time. Stakeholders identified barriers such as lack of budget, limited resources in their organization, time constraints and insufficient communication between researchers and stakeholders. CONCLUSION: Stakeholder engagement in basic brain research can greatly benefit researchers and stakeholders alike. Its success is conditional on dedicated human and financial resources, clear communication, transparent mutual expectations and clear roles and responsibilities. PUBLIC CONTRIBUTION: Patient organizations, research networks, policymakers and members of the general public were involved in engagement and research activities throughout the project duration.

Metabolites That Confirm Induction and Release of Dormancy Phases in Sweet Cherry Buds.

Here we report on metabolites found in a targeted profiling of 'Summit' flower buds for nine years, which could be indicators for the timing of endodormancy release (t1) and beginning of ontogenetic development (t1*). Investigated metabolites included chrysin, arabonic acid, pentose acid, sucrose, abscisic acid (ABA), and abscisic acid glucose ester (ABA-GE). Chrysin and water content showed an almost parallel course between leaf fall and t1*. After 'swollen bud', water content raised from ~60 to ~80% at open cluster, while chrysin content decreased and lost its function as an acetylcholinesterase inhibitor. Both parameters can be suitable indicators for t1*. Arabonic acid showed a clear increase after t1*. Pentose acid would be a suitable metabolite to identify t1 and t1*, but would not allow describing the ecodormancy phase, because of its continuously low value during this time. Sucrose reached a maximum during ecodormancy and showed a significant correlation with air temperature, which confirms its cryoprotective role in this phase. The ABA content showed maximum values during endodormancy and decreased during ecodormancy, reaching 50% of its content t1 at t1*. It appears to be the key metabolite to define the ecodormancy phase. The ABA-GE was present at all stages and phases and was much higher than the ABA content and is a readily available storage pool in cherry buds.

Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.

BACKGROUND: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. METHODS: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. RESULTS: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. CONCLUSIONS: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.

Individual differences in brain aging: heterogeneity in cortico-hippocampal but not caudate atrophy rates.

It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.

The association of longitudinal diet and waist-to-hip ratio from midlife to old age with hippocampus connectivity and memory in old age: a cohort study.

Epidemiological studies suggest lifestyle factors may reduce the risk of dementia. However, few studies have examined the association of diet and waist-to-hip ratio with hippocampus connectivity. In the Whitehall II Imaging Sub-study, we examined longitudinal changes in diet quality in 512 participants and waist-to-hip ratio in 665 participants. Diet quality was measured using the Alternative Health Eating Index-2010 assessed three times across 11 years between ages 48 and 60 years, and waist-to-hip ratio five times over 21 years between ages 48 and 68 years. Brain imaging and cognitive tests were performed at age 70±5 years. We measured white matter using diffusion tensor imaging and hippocampal functional connectivity using resting-state functional magnetic resonance imaging. In addition to associations of diet and waist-to-hip ratio with brain imaging measures, we tested whether associations between diet, waist-to-hip ratio and cognitive performance were mediated by brain connectivity. We found better diet quality in midlife and improvements in diet over mid-to-late life were associated with higher hippocampal functional connectivity to the occipital lobe and cerebellum, and better white matter integrity as measured by higher fractional anisotropy and lower diffusivity. Higher waist-to-hip ratio in midlife was associated with higher mean and radial diffusivity and lower fractional anisotropy in several tracts including the inferior longitudinal fasciculus and cingulum. Associations between midlife waist-to-hip ratio, working memory and executive function were partially mediated by radial diffusivity. All associations were independent of age, sex, education, and physical activity. Our findings highlight the importance of maintaining a good diet and a healthy waist-to-hip ratio in midlife to maintain brain health in later life. Future interventional studies for the improvement of dietary and metabolic health should target midlife for the prevention of cognitive decline in old age.

Cardiometabolic health across menopausal years is linked to white matter hyperintensities up to a decade later.

Introduction: The menopause transition is associated with several cardiometabolic risk factors. Poor cardiometabolic health is further linked to microvascular brain lesions, which can be detected as white matter hyperintensities (WMHs) using T2-FLAIR magnetic resonance imaging (MRI) scans. Females show higher risk for WMHs post-menopause, but it remains unclear whether changes in cardiometabolic risk factors underlie menopause-related increase in brain pathology. Methods: In this study, we assessed whether cross-sectional measures of cardiometabolic health, including body mass index (BMI) and waist-to-hip ratio (WHR), blood lipids, blood pressure, and long-term blood glucose (HbA1c), as well as longitudinal changes in BMI and WHR, differed according to menopausal status at baseline in 9,882 UK Biobank females (age range 40-70 years, n premenopausal = 3,529, n postmenopausal = 6,353). Furthermore, we examined whether these cardiometabolic factors were associated with WMH outcomes at the follow-up assessment, on average 8.78 years after baseline. Results: Postmenopausal females showed higher levels of baseline blood lipids (HDL ß = 0.14, p < 0.001, LDL ß = 0.20, p < 0.001, triglycerides ß = 0.12, p < 0.001) and HbA1c (ß = 0.24, p < 0.001) compared to premenopausal women, beyond the effects of age. Over time, BMI increased more in the premenopausal compared to the postmenopausal group (ß = -0.08, p < 0.001), while WHR increased to a similar extent in both groups (ß = -0.03, p = 0.102). The change in WHR was however driven by increased waist circumference only in the premenopausal group. While the group level changes in BMI and WHR were in general small, these findings point to distinct anthropometric changes in pre- and postmenopausal females over time. Higher baseline measures of BMI, WHR, triglycerides, blood pressure, and HbA1c, as well as longitudinal increases in BMI and WHR, were associated with larger WMH volumes (ß range = 0.03-0.13, p ≤ 0.002). HDL showed a significant inverse relationship with WMH volume (ß = -0.27, p < 0.001). Discussion: Our findings emphasise the importance of monitoring cardiometabolic risk factors in females from midlife through the menopause transition and into the postmenopausal phase, to ensure improved cerebrovascular outcomes in later years.

Associations between abdominal adipose tissue, reproductive span, and brain characteristics in post-menopausal women.

The menopause transition involves changes in oestrogens and adipose tissue distribution, which may influence female brain health post-menopause. Although increased central fat accumulation is linked to risk of cardiometabolic diseases, adipose tissue also serves as the primary biosynthesis site of oestrogens post-menopause. It is unclear whether different types of adipose tissue play diverging roles in female brain health post-menopause, and whether this depends on lifetime oestrogen exposure, which can have lasting effects on the brain and body even after menopause. Using the UK Biobank sample, we investigated associations between brain characteristics and visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (ASAT) in 10,251 post-menopausal females, and assessed whether the relationships varied depending on length of reproductive span (age at menarche to age at menopause). To parse the effects of common genetic variation, we computed polygenic scores for reproductive span. The results showed that higher VAT and ASAT were both associated with higher grey and white matter brain age, and greater white matter hyperintensity load. The associations varied positively with reproductive span, indicating more prominent associations between adipose tissue and brain measures in females with a longer reproductive span. The effects were in general small, but could not be fully explained by genetic variation or relevant confounders. Our findings indicate that associations between abdominal adipose tissue and brain health post-menopause may partly depend on individual differences in cumulative oestrogen exposure during reproductive years, emphasising the complexity of neural and endocrine ageing processes in females.

People's interest in brain health testing: Findings from an international, online cross-sectional survey.

Brain health entails mental wellbeing and cognitive health in the absence of brain disorders. The past decade has seen an explosion of tests, cognitive and biological, to predict various brain conditions, such as Alzheimer's Disease. In line with these current developments, we investigated people's willingness and reasons to-or not to-take a hypothetical brain health test to learn about risk of developing a brain disease, in a cross-sectional multilanguage online survey. The survey was part of the Global Brain Health Survey, open to the public from 4th June 2019 to 31st August 2020. Respondents were largely recruited via European brain councils and research organizations. 27,590 people responded aged 18 years or older and were predominantly women (71%), middle-aged or older (>40 years; 83%), and highly educated (69%). Responses were analyzed to explore the relationship between demographic variables and responses. Results: We found high public interest in brain health testing: over 91% would definitely or probably take a brain health test and 86% would do so even if it gave information about a disease that cannot be treated or prevented. The main reason for taking a test was the ability to respond if one was found to be at risk of brain disease, such as changing lifestyle, seeking counseling or starting treatment. Higher interest in brain health testing was found in men, respondents with lower education levels and those with poor self-reported cognitive health. Conclusion: High public interest in brain health and brain health testing in certain segments of society, coupled with an increase of commercial tests entering the market, is likely to put pressure on public health systems to inform the public about brain health testing in years to come.