Sex and gender publications in brain health: a mapping review of the Asia-Pacific region.

INTRODUCTION: Reporting of sex and gender analysis in medical research has been shown to improve quality of the science and ensures findings are applicable to women and men. There is conflicting evidence on whether efforts by funding agencies and medical journals to encourage reporting of sex and gender analysis has resulted in tangible improvements. This study mapped the inclusion of sex and gender analysis in stroke and dementia research conducted in the Asia-Pacific region. METHODS: A systematic search for Asia-Pacific stroke and dementia research was conducted in PubMed and papers included from the period 2012 to 2022. Eligible studies were reviewed for inclusion of a primary sex or gender focus and categorized by type of sex and gender analysis. Author gender was determined using an algorithm and its associations with inclusion of sex and gender analysis examined. RESULTS: Total Asia-Pacific publications increased from 109 in 2012 to 313 in 2022, but the rate of studies with a primary sex or gender focus did not increase significantly (R2 = 0.06, F(1,9) = 0.59, p = 0.46). Australia, China, India, Japan and South Korea produced the most publications over the study period and were the only countries with at least 50 publications. The impact of author gender was mixed, with female first authorship associated with inclusion of sex or gender analysis and last female authorship associated with studies having a primary sex or gender focus. CONCLUSIONS: In the Asia-Pacific, brain health research is currently centered around high income countries and efforts are needed to ensure research findings are applicable through out the region. While there was a general increase in brain health publications over the last decade, the rate of sex and gender analysis was unchanged. This demonstrates that even with efforts in some countries in place, there is currently a lack of progress in the Asia-Pacific region to produce more research focusing on sex and gender analysis.

Maximizing utility of neuropsychological measures in sex-specific predictive models of incident Alzheimer's disease in the Framingham Heart Study.

INTRODUCTION: Sex differences in neuropsychological (NP) test performance might have important implications for the diagnosis of Alzheimer's disease (AD). This study investigates sex differences in neuropsychological performance among individuals without dementia at baseline. METHODS: Neuropsychological assessment data, both standard test scores and process coded responses, from Framingham Heart Study participants were analyzed for sex differences using regression model and Cox proportional hazards model. Optimal NP profiles were identified by machine learning methods for men and women. RESULTS: Sex differences were observed in both summary scores and composite process scores of NP tests in terms of adjusted means and their associations with AD incidence. The optimal NP profiles for men and women have 10 and 8 measures, respectively, and achieve 0.76 mean area under the curve for AD prediction. DISCUSSION: These results suggest that NP tests can be leveraged for developing more sensitive, sex-specific indices for the diagnosis of AD.

Walking the talk for dementia: A unique immersive, embodied, and multi-experiential initiative.

Coping with dementia requires an integrated approach encompassing personal, health, research, and community domains. Here we describe "Walking the Talk for Dementia," an immersive initiative aimed at empowering people with dementia, enhancing dementia understanding, and inspiring collaborations. This initiative involved 300 participants from 25 nationalities, including people with dementia, care partners, clinicians, policymakers, researchers, and advocates for a 4-day, 40 km walk through the Camino de Santiago de Compostela, Spain. A 2-day symposium after the journey provided novel transdisciplinary and horizontal structures, deconstructing traditional hierarchies. The innovation of this initiative lies in its ability to merge a physical experience with knowledge exchange for diversifying individuals' understanding of dementia. It showcases the transformative potential of an immersive, embodied, and multi-experiential approach to address the complexities of dementia collaboratively. The initiative offers a scalable model to enhance understanding, decrease stigma, and promote more comprehensive and empathetic dementia care and research.

Sex steroid hormones and epilepsy: Effects of hormonal replacement therapy on seizure frequency of postmenopausal women with epilepsy-A systematic review.

BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

Global estimates on the number of persons across the Alzheimer's disease continuum.

INTRODUCTION: Global estimates on numbers of persons in early stages of Alzheimer's disease (AD), including prodromal and preclinical, are lacking, yet are needed to inform policy decisions on preventive measures and planning for future therapies targeting AD pathology. METHODS: We synthesized the literature on prevalence across the AD continuum and derived a model estimating the number of persons, stratified by 5-year age groups, sex, and disease stage (AD dementia, prodromal AD, and preclinical AD). RESULTS: The global number of persons with AD dementia, prodromal AD, and preclinical AD were estimated at 32, 69, and 315 million, respectively. Together they constituted 416 million across the AD continuum, or 22% of all persons aged 50 and above. DISCUSSION: Considering predementia stages, the number of persons with AD is much larger than conveyed in available literature. Our estimates are uncertain, especially for predementia stages in low- and middle-income regions where biomarker studies are missing.

Early ß-amyloid accumulation in the brain is associated with peripheral T cell alterations.

INTRODUCTION: Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral ß-amyloidosis has raised the question of whether immune markers could be used as proxies for ß-amyloid accumulation in the brain. METHODS: Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies. RESULTS: We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain ß-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. DISCUSSION: Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes.

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience.

BACKGROUND: Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio-cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience. METHODS: We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from (1) literature searches, (2) policy documents and reports by the European Commission and national funding agencies, (3) web-based searches, (4) "Web of Science", and (5) searches of project databases of funding agencies. An informative / non-systematic search was performed for sections on policies and funding, education, basic research, while a systematic literature and database review was conducted forquantitative analysis of research output and funded projects in terms of sex and gender analysis. RESULTS: Our mapping shows that there is a growing interest and attention towards sex and gender consideration in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities. DISCUSSION: We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.

Extravascular CD3+ T Cells in Brains of Alzheimer Disease Patients Correlate with Tau but Not with Amyloid Pathology: An Immunohistochemical Study.

BACKGROUND: Strong genetic and epidemiological evidence points to a crucial role of the immune system in the development of Alzheimer disease (AD). CD3+ T lymphocytes have been described in brains of postmortem AD patients and in transgenic models of AD-like cerebral amyloidosis and tau pathology. However, the occurrence of T cells in AD brains is still controversial; furthermore, the relationship between T cells and hallmarks of AD pathology (amyloid plaques and neurofibrillary tangles) remains to be established. OBJECTIVES: We have studied the occurrence of T cells in postmortem hippocampi and mid frontal gyrus (MFG) samples of AD patients (Braak stage V-VI) and nondemented control subjects and correlated it with amyloid and tau pathology burden. METHODS: Confocal microscopy and bright-field immunohistochemistry were used to identify brain-associated T cells. Extravascular CD3+ T cells were quantified and compared to nondemented controls. In addition, numbers of extravascular CD3+ T cells were correlated with amyloid (6E10 staining) and tau pathology (AT8 staining) in the same sections. RESULTS: Several CD3+, extravascular T cells were observed in the brains of AD patients, mostly of the CD8+ subtype. AD hippocampi harbored significantly increased numbers of extravascular CD3+ T cells compared to nondemented controls. CD3+ T cells significantly correlated with tau pathology but not with amyloid plaques in AD samples. CONCLUSIONS: Our data support the notion of T-cell occurrence in AD brains and suggest that, in advanced stages of AD, T-cell extravasation is driven by tau-related neurodegenerative changes rather than by cerebral amyloidosis. T cells could be crucial for driving the amyloid-independent phase of the AD pathology.

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints.

INTRODUCTION: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. METHODS: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose-positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non-amyloid markers. RESULTS: Men compared with women showed higher anterior cingulate cortex amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower resting-state functional connectivity in the default mode network (P = .024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant. DISCUSSION: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease.

Informant characteristics are associated with the Clinical Dementia Rating Sum of Boxes scores in the Alzheimer's Disease patients participating in the National Alzheimer's Coordinating Center Uniform Data Set.

Background: The Clinical Dementia Rating® Sum of Boxes (CDR®-SB) is used to stage dementia severity; it is one of the most common outcome measurements in Alzheimer's Disease (AD) research and clinical trials. The CDR®-SB requires an informant to provide input to stage a patient's dementia severity. The effect of the informant's characteristics on the CDR®-SB is unknown. We aimed to evaluate the effect of the informant's sex, relationship to the patient, and frequency of contact on the CDR®-SB scores in patients with Alzheimer's Disease with mild cognitive impairment or dementia included in the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Methods: We included all participants from the NACC-UDS that had AD as diagnosis, and information about the Mini-Mental State Examination or Montreal Cognitive Assessment scores, informant sex, relationship to patient and frequency of contact; we also analyzed the possible interaction between these characteristics on the CDR®-SB as the outcome. We performed a multilevel linear regression analysis. Results: We included data from 20636 participants, totalling 47727 visits. Patients' age was 74.0 ± 9.4 years and 54.1% were females. Informant characteristics were mean age of 66.2 ± 13.2 years, 69.1% were females, and the relationship to patients was 60.5% spouse or partner, 26.7% children and 12.8% other relation. The CDR®-SB scores were 0.20 higher (CI 95%: 0.11 to 0.29) when the informant was female. When comparing to informant's relationship with the baseline being spouse or partner, the CDR®-SB was 0.39 higher (CI 95%: 0.25 to 0.53) when the informant was the patient's child and 0.18 lower (CI 95%: -0.35 to -0.01) if relationship was other. Regarding the frequency of contact, CDR®-SB scores were 0.38 higher (CI95%: 0.28 to 0.47) when contact was at least once a week, 0.65 higher (CI95%: 0.52 to 0.78) when contact was daily, and 0.57 higher (CI95%: 0.46 to 0.69) when informant was living with the patient, baseline was a frequency of less than once per week. Finally, the interaction between informant relationships other and female patients showed a 0.24 higher CDR®-SB score (CI95%: 0.03 to 0.46). Conclusions: We found that the CDR®-SB scores are significantly modified by informant characteristics and frequency of contact in the NACC-UDS patients with AD diagnosis. These findings hold clinical significance as informant characteristics ideally should not impact the staging of AD patients, and any such effects could introduce bias into clinical evaluations in clinical trials. Future research endeavours should investigate strategies to address and mitigate the influence of these confounding variables.

National plans and awareness campaigns as priorities for achieving global brain health.

Neurological conditions are the leading cause of death and disability combined. This public health crisis has become a global priority with the introduction of WHO's Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022-2031 (IGAP). 18 months after this plan was adopted, global neurology stakeholders, including representatives of the OneNeurology Partnership (a consortium uniting global neurology organisations), take stock and advocate for urgent acceleration of IGAP implementation. Drawing on lessons from relevant global health contexts, this Health Policy identifies two priority IGAP targets to expedite national delivery of the entire 10-year plan: namely, to update national policies and plans, and to create awareness campaigns and advocacy programmes for neurological conditions and brain health. To ensure rapid attainment of the identified priority targets, six strategic drivers are proposed: universal community awareness, integrated neurology approaches, intersectoral governance, regionally coordinated IGAP domestication, lived experience-informed policy making, and neurological mainstreaming (advocating to embed brain health into broader policy agendas). Contextualised with globally emerging IGAP-directed efforts and key considerations for intersectoral policy design, this novel framework provides actionable recommendations for policy makers and IGAP implementation partners. Timely, synergistic pursuit of the six drivers might aid WHO member states in cultivating public awareness and policy structures required for successful intersectoral roll-out of IGAP by 2031, paving the way towards brain health for all.

Longitudinal progression of choroid plexus enlargement is associated with female sex, cognitive decline and ApoE E4 homozygote status.

Introduction: Choroid plexus (CP)-related mechanisms have been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. In this pilot study, we aimed to elucidate the association between longitudinal changes in CP volume, sex and cognitive impairment. Methods: We assessed longitudinal changes in CP volume in a cohort of n = 613 subjects across n = 2,334 datapoints from ADNI 2 and ADNI-GO, belonging to cognitively unimpaired (CN), stable mild cognitive impairment (MCI), clinically diagnosed Alzheimer's disease dementia (AD) or convertor (to either AD or MCI) subgroups. CP volume was automatically segmented and used as a response variable in linear mixed effect models with random intercept clustered by patient identity. Temporal effects of select variables were assessed by interactions and subgroup analyses. Results: We found an overall significant increase of CP volume in time (14.92 mm3 per year, 95% confidence interval, CI (11.05, 18.77), p < 0.001). Sex-disaggregated results showed an annual rate of increase 9.48 mm3 in males [95% CI (4.08, 14.87), p < 0.001], and 20.43 mm3 in females [95% CI (14.91, 25.93), p < 0.001], indicating more than double the rate of increase in females, which appeared independent of other temporal variables. The only diagnostic group with a significant CP increase as compared to CN was the convertors group, with an increase of 24.88 mm3/year [95% CI (14, 35.82), p < 0.001]. ApoE exhibited a significant temporal effect, with the E4 homozygote group's CP increasing at more than triple the rate of non-carrier or heterozygote groups [40.72, 95% CI (25.97, 55.46), p < 0.001 vs. 12.52, 95% CI (8.02, 17.02), p < 0.001 for ApoE E4 homozygotes and E4 non-carriers, respectively], and may have modified the diagnostic group relationship. Conclusion: Our results contribute to potential mechanisms for sex differences in cognitive impairment with a novel finding of twice the annual choroid plexus enlargement in females and provide putative support for CP-related mechanisms of cognitive deterioration and its relationship to ApoE E4.

Sex and gender considerations in Alzheimer's disease: The Women's Brain Project contribution.

The global population is expected to have about 131.5 million people living with Alzheimer's disease (AD) and other dementias by 2050, posing a severe health crisis. Dementia is a progressive neurodegenerative condition that gradually impairs physical and cognitive functions. Dementia has a variety of causes, symptoms, and heterogeneity concerning the influence of sex on prevalence, risk factors, and outcomes. The proportion of male-to-female prevalence varies based on the type of dementia. Despite some types of dementia being more common in men, women have a greater lifetime risk of developing dementia. AD is the most common form of dementia in which approximately two-thirds of the affected persons are women. Profound sex and gender differences in physiology and pharmacokinetic and pharmacodynamic interactions have increasingly been identified. As a result, new approaches to dementia diagnosis, care, and patient journeys should be considered. In the heart of a rapidly aging worldwide population, the Women's Brain Project (WBP) was born from the necessity to address the sex and gender gap in AD. WBP is now a well-established international non-profit organization with a global multidisciplinary team of experts studying sex and gender determinants in the brain and mental health. WBP works with different stakeholders worldwide to help change perceptions and reduce sex biases in clinical and preclinical research and policy frameworks. With its strong female leadership, WBP is an example of the importance of female professionals' work in the field of dementia research. WBP-led peer-reviewed papers, articles, books, lectures, and various initiatives in the policy and advocacy space have profoundly impacted the community and driven global discussion. WBP is now in the initial phases of establishing the world's first Sex and Gender Precision Medicine Institute. This review highlights the contributions of the WBP team to the field of AD. This review aims to increase awareness of potentially important aspects of basic science, clinical outcomes, digital health, policy framework and provide the research community with potential challenges and research suggestions to leverage sex and gender differences. Finally, at the end of the review, we briefly touch upon our progress and contribution toward sex and gender inclusion beyond Alzheimer's disease.

Global synergistic actions to improve brain health for human development.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology.

BACKGROUND: A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated. METHODS AND RESULTS: To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway. CONCLUSIONS: Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.