Body Composition and Metabolic Syndrome Components in Transgender/Gender Diverse Adolescents and Young Adults.

Purpose: The objective of this study was to examine the association of designated sex at birth, body composition, and gender-affirming hormone treatment (GAHT) with the components of metabolic syndrome (MetS) (overweight/obesity, elevated blood pressure [BP], altered glucose metabolism, and dyslipidemia) in transgender/gender diverse (TGD) adolescents and young adults. Methods: TGD individuals underwent body composition studies by bioelectrical impedance analysis according to designated sex at birth, and their muscle-to-fat ratio (MFR) z-scores were calculated. Generalized estimating equations with binary logistic models (n = 326) were used to explore associations while adjusting for potential confounders. Results: A total of 55 TGD females and 111 TGD males, with mean age of 18 ± 1.9 years and median duration of GAHT of 1.4 years (interquartile range = 0.6-2.5), were enrolled. Overall, 118/166 (71%) of the TGD cohort showed evidence of at least one MetS component, with a significantly higher rate among TGD males compared with TGD females (91.1% vs. 50.9%, p < 0.001). TGD males were at increased odds for overweight/obesity, elevated/hypertensive BP, elevated triglycerides (TGs), and an atherogenic dyslipidemia index (TG/high-density lipoprotein cholesterol [HDL-c], TG:HDL-c). The odds of overweight/obesity increased by 44.9 for each standard deviation decrease in the MFR z-score, while the odds for an elevated TG:HDL-c index increased by 3.7. Psychiatric morbidity increased the odds for overweight/obesity by 2.89. Conclusions: After considering confounding variables, the TGD males on GAHT were found to be at an increased risk for cardiometabolic disease. Our observations support the importance of targeted medical nutrition intervention in this group of individuals.

The association between cannabis use and neuroimaging measures in older adults: findings from the UK biobank.

BACKGROUND: Cannabis use has increased in recent years. However, the long-term implications of cannabis use on brain health remain unknown. We explored the associations of cannabis use with volumetric brain magnetic resonance imaging (MRI) measures in dementia-free older adults. METHODS: This cross-sectional and longitudinal study included dementia-free participants of the UK Biobank aged ≥60 years. Linear regression models were used to evaluate the association of cannabis use and patterns of use with volumetric brain MRI measures. The association between cannabis use and change in brain MRI measures over time was also tested. All models were adjusted for potential confounders. RESULTS: The sample included 19,932 participants (mean age 68 ± 5 years, 48% men), 3,800 (19%) reported lifetime use of cannabis. Cannabis use was associated with smaller total, white, grey and peripheral cortical grey matter volumes (B = -6,690 ± 1,157; P < 0.001, B = -4,396 ± 766; P < 0.001, B = -2,140 ± 690; P = 0.002 and B = -2,451 ± 606; P < 0.001, respectively). Among cannabis users, longer duration of use was associated with smaller total brain, grey and cortical grey matter volumes (B = -7,878 ± 2,396; P = 0.001, B = -5,411 ± 1,430; P < 0.001, B = -5,396 ± 1,254; P < 0.001, respectively), and with increased white matter hyperintensity volume (B = 0.09 ± 0.03; P = 0.008). Additionally, current vs. former users (B = -10,432 ± 4,395; P = 0.020) and frequent versus non-frequent users (B = -2,274 ± 1,125; P = 0.043) had smaller grey and cortical grey matter volumes, respectively. No significant associations were observed between cannabis use and change in brain MRI measures. DISCUSSION: Our findings suggest that cannabis use, particularly longer duration and frequent use, may be related to smaller grey and white matter volumes in older ages, but not to late-life changes in these measures over time.

Association of Neurotrophic Factors at Midlife With In Vivo Measures of ß-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults.

BACKGROUND AND OBJECTIVES: Neurotrophic factors (NTFs) play an important role in Alzheimer disease (AD) pathophysiology. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are important NTFs. However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-ß (Aß) and tau burden remains to be elucidated. We explored the relationship of BDNF and VEGF serum levels with future brain Aß and tau pathology in a cohort of cognitively healthy, predominantly middle-aged adults and tested for possible effect modifications by sex and menopausal status. METHODS: This cross-sectional analysis was conducted using data from the Framingham Heart Study (FHS), a community-based cohort study. The study sample included cognitively healthy participants from the FHS Offspring and Third-generation cohorts. BDNF and VEGF were measured in the third-generation cohort during examination cycles 2 (2005-2008) and 1 (2002-2005), respectively, and in the offspring cohort during examination cycle 7 (1998-2001). Participants underwent 11C-Pittsburgh compound B amyloid and 18F-Flortaucipir tau-PET imaging (2015-2021). Linear regression models were used to assess the relationship of serum BDNF and VEGF levels with regional tau and global Aß, adjusting for potential confounders. Interactions with sex and menopausal status were additionally tested. RESULTS: The sample included 414 individuals (mean age = 41 ± 9 years; 51% female). Continuous measures of BDNF and VEGF were associated with tau signal in the rhinal region after adjustment for potential confounders (ß = -0.15 ± 0.06, p = 0.018 and ß = -0.19 ± 0.09, p = 0.043, respectively). High BDNF (≥32,450 pg/mL) and VEGF (≥488 pg/mL) levels were significantly related to lower rhinal tau (ß = -0.27 ± 0.11, p = 0.016 and ß = -0.40 ± 0.14, p = 0.004, respectively) and inferior temporal tau (ß = -0.24 ± 0.11, p = 0.028 and ß = -0.26 ± 0.13, p = 0.049, respectively). The BDNF-rhinal tau association was observed only among male individuals. Overall, BDNF and VEGF were not associated with global amyloid; however, high VEGF levels were associated with lower amyloid burden in postmenopausal women (ß = -1.96 ± 0.70, p = 0.013, per 1 pg/mL). DISCUSSION: This study demonstrates a robust association between BDNF and VEGF serum levels with in vivo measures of tau almost 2 decades later. These findings add to mounting evidence from preclinical studies suggesting a role of NTFs as valuable blood biomarkers for AD risk prediction.

Impact of dementia status on intravenous thrombolysis and endovascular treatment for acute ischemic stroke: Retrospective study.

INTRODUCTION: Individuals with dementia are underrepresented in interventional studies for acute ischemic stroke (AIS). This research gap creates a bias against their treatment in clinical practice. Our goal was to compare the safety and efficacy of intravenous-thrombolysis (t-PA) and endovascular treatment (EVT) in individuals with or without pre-AIS dementia. METHOD: A retrospective study of AIS patients receiving t-PA or EVT between 2019 and 2022. Patients were classified as dementia on a case-by-case review of baseline assessment. Additional variables included demographic, vascular risk factors, AIS severity and treatment. Outcomes of interest were intracerebral hemorrhage, mortality in 90-days, and the difference in modified rankin scale (mRS) before AIS and in 90-days follow-up. Outcomes were compared across non-matched groups and following propensity-score matching. RESULTS: Altogether, 628 patients were included, of which 68 had pre-AIS dementia. Compared to non-dementia group, dementia group were older, had a higher rate of vascular risk factors, higher pre-stroke mRS and higher baseline NIHSS. Individuals with dementia had higher rates of mortality (25% vs.11%,p < 0.01) on non-matched comparison. All cohort and restricted t-PA EVT matched analysis showed no difference in any outcome. Regression analysis confirmed that AIS severity at presentation and its treatment, not dementia, were the chief contributors to patients' outcomes. DISCUSSION: Our results indicate that pre-AIS dementia does not impact the efficacy or safety of EVT or t-PA for AIS. We thus call for more inclusive research on stroke therapy with regards to baseline cognitive status. Such studies are urgently required to inform stroke guidelines and enhance care.

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration.

BACKGROUND AND PURPOSE: Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. METHODS: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. RESULTS: In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (ß = -3.5, 95% confidence interval [CI] = -5.4 to -1.7), total gray matter (ß = -1.9, 95% CI = -3.4 to -0.3), and total cortical gray matter (ß = -1.9, 95% CI = -3.7 to -0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (ß = -7.3, 95% CI = -11.1 to -3.5). Heterogeneity between studies was low. CONCLUSIONS: NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.

Independent and joint associations of cardiorespiratory fitness and BMI with dementia risk: the Cooper Center Longitudinal Study.

OBJECTIVE: This study aimed to examine the association of midlife fitness and body mass index (BMI) with incident dementia later in life. DESIGN AND PARTICIPANTS: A cohort study of 6428 individuals (mean age 50.9±7.6 years) from the Cooper Center Longitudinal Study. MEASURES: Cardiorespiratory fitness and BMI were assessed twice (1970-1999) during visits to the Cooper Clinic, a preventive medicine clinic in Dallas, Texas. These measures were examined as continuous and categorical variables. As continuous variables, fitness and BMI were examined at baseline (averaged of two examinations) and as absolute change between exams (mean time 2.1±1.8 years). Variables were categorised: unfit versus fit and normal versus overweight/obese. Medicare claims data were used to obtain all-cause dementia incidence (1999-2009). Mean follow-up between midlife examinations and Medicare surveillance was 15.7 ((SD=6.2) years. Multivariable models were used to assess the associations between fitness, BMI and dementia. RESULTS: During 40 773 person years of Medicare surveillance, 632 cases of dementia were identified. After controlling for BMI and covariates, each 1-metabolic equivalent increment in fitness was associated with 5% lower (HR 0.95; 95% CI 0.90 to 0.99) dementia risk. In comparison, after controlling for fitness and covariates, each 1 kg/m2 increment in BMI was associated with a 3.0% (HR 1.03; 95% CI 1.00 to 1.07) higher risk for dementia, yet without significance (p=0.051). Similar findings were observed when the exposures were categorised. Changes in fitness and BMI between examinations were not related to dementia. Jointly, participants who were unfit and overweight/obese had the highest (HR 2.28 95% CI 1.57 to 3.32) dementia risk compared with their fit and normal weight counterparts. CONCLUSION: Lower midlife fitness is a risk marker for dementia irrespective of weight status. Being unfit coupled with overweight/obese status might increase one's risk for dementia even further.

Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia.

Importance: Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested. Objective: To examine the association between adult ADHD and the risk of dementia. Design, Setting, and Participants: This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023. Exposure: Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision); otherwise, absent. Main Outcome and Measures: Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented. Results: At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly (P < .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P < .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P < .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild. Conclusions and Relevance: In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.

The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury.

BACKGROUND: Preclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex. METHODS: This exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer's disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined. RESULTS: Participants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (ß ± SE = - 0.12 ± 0.06, p = 0.034 and ß ± SE = 0.08 ± 0.04, p = 0.026, respectively). CONCLUSIONS: Circulating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer's disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women.

Hospitalizations in older-adults newly diagnosed with dementia: A population-based longitudinal study in Israel.

OBJECTIVES: To compare inpatient burden (i.e. likelihood of hospitalization, number of admissions and length of stay) in persons with newly diagnosed dementia to the general population without dementia. Additionally, to evaluate whether inpatient burden is increased during the years prior to and post dementia diagnosis, and to identify factors associated with increased inpatient burden. METHOD: The Israeli National Dementia Dataset (2016) was cross-linked with the National Hospital Discharge Database of the Israeli Ministry of Health (2014-2018). Dementia definition was based on documented dementia diagnoses and/or the purchase of medications during 2016. Mixed-effects models were applied to identify demographic and health characteristics associated with inpatient burden in the one and 2 years prior to and after dementia diagnosis. RESULTS: The dataset included 11,625 individuals aged ≥65 years, identified as incident dementia cases. Compared to the general population of older-adults without dementia, those with newly diagnosed dementia had a higher age-standardized proportion of hospitalizations (26.4% vs. 40%). The odds for hospitalization were highest during the year preceding dementia diagnosis (OR = 3.19, 95% CI 2.51-4.06) compared to 2 years prior to diagnosis, and remained high (although slightly decreased) after dementia diagnosis. Older age was associated with inpatient burden after, but not prior to dementia diagnosis. CONCLUSIONS: Older persons with dementia are a vulnerable population group with increased utilization of inpatient burden compared to those without dementia, particularly in the years surrounding dementia diagnosis. Sociodemographic risk factors may differ with respect to the time surrounding dementia diagnosis.

Consumption of Ultra-Processed Food and Cognitive Decline among Older Adults With Type-2 Diabetes.

BACKGROUND: Ultra-processed food (UPF) consumption is related to increased morbidity and mortality. However, knowledge on its association with cognitive function is lacking. In this longitudinal study, we examined the associations between UPF intake and cognitive decline in older adults with type-2 diabetes (T2D). METHODS: The sample included initially nondemented T2D older adults (≥65 years), from the Israel Diabetes and Cognitive Decline study, who had complete information on nutrition at baseline and at least 3 cognitive assessments (mean follow-up 5.3 ± 1.5 years). Nutritional intake was evaluated by a validated Food-Frequency Questionnaire, and foods were categorized as UPF based on NOVA classification. Percent of calories from UPF were calculated from total caloric consumption in total and specific food groups. Mixed effect models were used to examine the link between UPF intake (top vs bottom quartiles) and change in cognitive function overall and in specific domains, adjusting for potential confounders. RESULTS: Of the total sample (N = 568; mean age 71.3 ± 4.5 years, 60% men), 141 consumed >31% kcal from UPF (top quartile). Greater intake of ultra-processed meat was associated with a faster decline in executive functions and global cognition (ß = -0.041 ± 0.013; p = .002 and ß = -0.026 ± 0.010; p = .011, respectively). Additionally, consumption of ultra-processed oils/spreads was associated with faster decline in executive functions and global cognition (ß = -0.037 ± 0.014; p = .006 and ß = -0.028 ± 0.010; p = .009, respectively). Total UPF consumption and UPF-derived from dairy products and bread/pastries/starch were not associated with cognitive change. CONCLUSION: This study suggests that a high intake of ultra-processed meat and oils/spreads may be associated with accelerated cognitive decline in older individuals with T2D.

Peripheral sensory nerve function, type 2 diabetes and frailty among men with cardiovascular disease.

OBJECTIVE: To investigated the cross-sectional association between peripheral sensory nerve function and frailty among community-dwelling men, and examine whether type 2 diabetes (T2D) modifies this association. METHODS: A sample of 349 men [mean age = 77.1 ± 6.4 years; 37 % with T2D] who previously (1990-1998) participated in the Bezafibrate Infarction Prevention (BIP) trial, underwent assessment of frailty and legs vibratory thresholds (LVT), a measure of peripheral sensory nerve function, as part of the BIP Neurocognitive study during 2011-2013. LVT was assessed using a graduated tuning fork and frailty was assessed using the Fried criteria. An ordered logistic regression model was used to assess the link between LVT and degrees of frailty and to test for effect modification by T2D. RESULTS: Overall, 117 (33.5 %) of patients were non-frail, 134 (38.4 %) pre-frail, and 98 (28.1 %) frail. A significant interaction between LVT and T2D with regard to frailty was found. Among men with T2D, estimated OR (95%CI) for increasing frailty at the 1st, 2nd, and 3rd as compared to the top LVT quartile were 13.5 (3.4-54.3), 5.9 (1.5-23.5), and 4.4 (1.20-16.0), respectively. Among men without T2D, the estimated ORs for increasing frailty in patients at the 1st, 2nd, and 3rd quartiles compared to the top LVT quartile were 2.8 (1.1-7.4), 1.6 (0.6-4.1), and 2.5 (1.0-6.5), respectively. CONCLUSION: Frailty is significantly associated with worsening peripheral sensory nerve function, particularly among men with T2D.

Physical activity trajectories, autonomic balance and cognitive function: The Coronary Artery Risk Development in Young Adults (CARDIA) study.

Physical activity (PA) plays an important role in cognitive health. However, the underlying mechanisms are not fully understood. Cardiac autonomic balance is influenced by PA and implicated in dementia pathogenesis. We examined whether autonomic balance mediates the association between PA and cognitive function. The sample included 1939 participants from the Coronary Artery Risk Development in Young Adults study who completed cognitive testing after 30-year follow-up (baseline: mean age 25.2 ± 3.5y; 58% women; 43% Black). Moderate to vigorous intensity PA (MVPA) was obtained in 7 consecutive examinations over 20 years (Year 0-Year 20). Cardiac autonomic balance was assessed at Year 20 via resting heart rate (RHR), standard deviation normal to normal (SDNN) and root mean square of successive differences (RMSSD). We used group-based trajectory modeling to identify homogenous MVPA trajectory groups, and formal mediation analysis to test whether autonomic function indices mediate the association between MVPA trajectories and cognition. We identified three distinct PA trajectory patterns: (1) Below MVPA guidelines (n = 1122; 57.9%); (2) Meeting MVPA guidelines (n = 652; 33.6%); and (3) Exceeding MVPA guidelines (n = 165; 8.5%). Meeting and exceeding MVPA guidelines were related to better autonomic balance overall, and to improved semantic fluency performance. Statistically, the association between higher MVPA level and verbal ability was mediated by SDNN and RMSSD, but not by RHR. In our sample of young and middle-aged adults, higher MVPA levels over time were associated with better cardiac autonomic function, which explained some of the associations between PA trajectories and better cognition.

Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium.

Introduction: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection. Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-ß and Tau Pathology in Middle-Aged Adults: The Framingham Study.

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-ß (Aß) and tau pathology. METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aß, adjusting for potential confounders and multiple comparisons. RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aß or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (ß= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (ß= 2.01±0.47, p < 0.001; ß= 1.60±0.53, p = 0.007, and ß= 1.59±0.47, p = 0.003 and ß= 1.60±0.42, p = 0.001, respectively) and to Aß deposition overall and in the inferior temporal and parahippocampal regions (ß= 1.93±0.47, p < 0.001; ß= 1.59±0.38, p < 0.001, and ß= 1.52±0.54, p = 0.008, respectively). CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

Adherence to Mediterranean diet and subsequent cognitive decline in men with cardiovascular disease.

Backgrounds and aims: Evidence from recent years highlighted the importance of the Mediterranean diet for brain health. We investigated the association between adherence to Mediterranean diet and change in cognitive functions two decades later in patients with cardiovascular disease (CVD).Methods: Participants were men with a history of CVD, who previously participated in the Bezafibrate Infarction Prevention (BIP) trial between 1990 and 1997, had a food diary record, and underwent cognitive evaluations 14.6 ± 1.9 years (T1) and 19.9 ± 1.0 years after baseline (T2) as part of the BIP Neurocognitive study (n = 200, mean age at 57.3 ± 6.3 years). Adherence to the Mediterranean diet was determined from the self-administered 4-day food diary record, with patients categorized into high, middle and poor levels of adherence if they received >5, 4-5 and <4 points, respectively. Cognitive function was assessed using the NeuroTrax computerized battery. Linear mixed models were applied.Results: Among the 200 patients, 52 (26%) had poor adherence, 98 (49%) had middle adherence and 50 (25%) had high levels of adherence to the Mediterranean diet. Those categorized to the poor adherence level had poorer cognitive function at T1 compared to the other groups. Additionally, poor vs. high level of adherence was associated with a greater decline in overall cognitive performance [z-score = -0.23 and 95% confidence interval (CI), -0.43;-0.04; p = 0.021] and in visual spatial functions (-0.46 95% CI, -0.86;-0.06; p = 0.023).Conclusion: This study stresses the possible role of the Mediterranean diet in men with a high vascular burden and may set the ground for future intervention to reduce their risk for cognitive decline.

Sitting Time, Physical Activity, and Cognitive Impairment in Midlife and Older Adults.

This study cross-sectionally examines the relations of sitting and physical activity (PA) with cognitive impairment in community-dwelling adults aged 55-87 years (n = 3,780). Multivariable logistic regression assessed independent and joint relations of sitting and PA with Montreal Cognitive Assessment scores adjusting for covariates. Sitting ≥75% of the time and not meeting PA guidelines were related to 60% (95% confidence interval [CI] [1.19, 2.17]) and 27% (95% CI [1.06, 1.53]) higher odds for cognitive impairment, respectively. Stratification by age showed that sitting ≥75% of the time was associated with higher cognitive impairment odds in midlife (odds ratio [OR] = 1.86; 95% CI [1.31, 2.65]), but not older adults (OR = 1.06; 95% CI [0.57, 1.95]). Joint association analysis revealed that, overall, the highest odds for cognitive impairment were in those sitting ≥75% of the time while meeting or not meeting PA guidelines (OR = 1.69, 95% CI [1.13, 2.53]; and OR = 1.66, 95% CI [1.19, 2.32], respectively). In conclusion, prolonged sitting and insufficient PA are independent risk markers for cognitive impairment.

Accelerometer-Measured, Habitual Physical Activity and Circulating Brain-Derived Neurotrophic Factor: A Cross-Sectional Study.

BACKGROUND: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels. OBJECTIVE: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort. METHODS: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement or platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time. RESULTS: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day in moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p > 0.05). We observed a non-linear trend, where 15-50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (ß= -0.049±0.024, p = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (ß= -0.216±0.079, p = 0.01). CONCLUSION: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

Book-Oriented Environment in Childhood and Current Cognitive Performance among Old-Aged Europeans.

INTRODUCTION: Identifying early-life factors that protect against compromised late-life cognition is of great public health interest. We aimed to explore the associations between book-oriented environment in childhood and late-life cognitive performance in the Survey of Health, Ageing and Retirement in Europe (SHARE). METHODS: The sample included 8,239 individuals aged ≥65 years (N = 8,239) free of stroke, Parkinson's disease, or Alzheimer's disease, who participated in both waves 4 (2011) and 5 (2013) of SHARE. Book-oriented environment was assessed by the self-reported home library size during childhood. Cognitive performance was assessed using tests of memory and verbal fluency. Covariates included education and measures of current health, lifestyle, and financial status. Additionally, interactions with age and education were assessed. RESULTS: After controlling for potential confounders, having large home libraries was related to better performance on the immediate and delayed memory (ß = 0.11 ± 0.02, p < 0.001; ß = 0.13 ± 0.02, p < 0.001) and the verbal fluency tests (ß = 0.14 ± 0.06, p < 0.001) and to a lesser decline in these domains (ß = 0.08 ± 0.01, p < 0.001; ß = 0.09 ± 0.02, p < 0.001; and ß = 0.09 ± 0.06, p < 0.001, respectively). Significant interactions were observed between library size and age such that larger home library was more strongly associated with improved immediate memory (p = 0.016), delayed memory (p < 0.001), and verbal fluency (p = 0.003) and with less cognitive decline (p = 0.013, p < 0.001, and p = 0.095, respectively) among the younger-old (<80 years) compared to the oldest-old (≥80 years) participants. No effect modification by education was observed. CONCLUSIONS: These findings suggest that early-life book-oriented environment may be important in shaping cognitive aging.

Autonomic Imbalance and Risk of Dementia and Stroke: The Framingham Study.

Background and Purpose: The autonomic nervous system has been implicated in stroke and dementia pathophysiology. High resting heart rate and low heart rate variability indicate the effect of autonomic imbalance on the heart. We examined the associations of resting heart rate and heart rate variability with incident stroke and dementia in a community-based cohort of middle- and old-aged adults. Methods: The study sample included 1581 participants aged >60 years and 3271 participants aged >45 years evaluated for incident dementia and stroke, respectively, who participated in the Framingham Offspring cohort third (1983­1987) examination and had follow-up for neurology events after the seventh (1998­2001) examination. Heart rate variability was assessed through the standard deviation (SD) of normal-to-normal RR intervals and the root mean square of successive differences between normal heartbeats from 2-hour Holter monitor. Participants were followed-up for stroke and dementia incidence from exam 7 to a maximum of 10 years. Cox regression models were used to assess the link of resting heart rate and heart rate variability with stroke and dementia risk while adjusting for potential confounders, and interactions with age and sex were assessed. Results: Of the dementia (mean age, 55±6 years, 46% men) and stroke (mean age, 48±9 years, 46% men) samples, 133 and 127 developed dementia and stroke, respectively, during the follow-up. Overall, autonomic imbalance was not associated with dementia risk. However, age modified the associations such that SD of normal-to-normal intervals and root mean square of successive differences were associated with dementia risk in older people (hazard ratio [HR] [95% CI] per 1SD, 0.61 [0.38­0.99] and HR [95% CI] per 1SD, 0.34 [0.15­0.74], respectively). High resting heart rate was associated with increased stroke risk (HR [95% CI] per 10 bpm, 1.18 [1.01­1.39]), and high SD of normal-to-normal intervals was associated with lower stroke risk in men (HR [95% CI] per 1SD, 0.46 [0.26­0.79]) but not women (HR [95% CI] per 1SD, 1.25 [0.88­1.79]; P for interaction=0.003). Conclusions: Some measures of cardiac autonomic imbalance may precede dementia and stroke occurrence, particularly in older ages and men, respectively.

Medical cannabis and cognitive performance in middle to old adults treated for chronic pain.

INTRODUCTION AND AIMS: Cannabis exposure is becoming more common in older age but little is known about how it is associated with brain health in this population. This study assesses the relationship between long-term medical cannabis (MC) use and cognitive function in a sample of middle-aged and old chronic pain patients. DESIGN AND METHODS: A cross-sectional study was conducted among chronic pain patients aged 50+ years who had MC licenses (n = 63) and a comparison group who did not have MC licenses (n = 62). CogState computerised brief battery was used to assess cognitive performance of psychomotor reaction, attention, working memory and new learning. Regression models and Bayesian t-tests examined differences in cognitive performance in the two groups. Furthermore, the associations between MC use patterns (dosage, cannabinoid concentrations, length and frequency of use and hours since last use) with cognition were assessed among MC licensed patients. RESULTS: Mean age was 63 ± 6 and 60 ± 5 years in the non-exposed and MC patients, respectively. Groups did not significantly differ in terms of cognitive performance measures. Furthermore, none of the MC use patterns were associated with cognitive performance. DISCUSSION AND CONCLUSIONS: These results suggest that use of whole plant MC does not have a widespread impact on cognition in older chronic pain patients. Considering the increasing use of MC in older populations, this study could be a first step towards a better risk-benefit assessment of MC treatment in this population. Future studies are urgently needed to further clarify the implications of late-life cannabis use for brain health.