Poor cognition is associated with increased abundance of Alistipes and decreased abundance of Clostridium genera in the gut

Background: Brain and gut health are intricately connected via the gut-microbiota-brain axis. Studies have shown that gut dysbiosis is associated with neurodegenerative diseases, including Alzheimer’s disease. However, how cognitive changes affects the gut microbiome structure is currently understudied. We aimed to assess the association between the gut microbiome and global cognitive scores in the Framingham Heart Study (FHS). Method: Our sample included 1,014 participants (mean age 52, 55% female) of the third generation FHS cohort with available stool samples, cognitive assessments, and no history of dementia or stroke (Table 1).We quantified the gut microbiome composition using 16S rRNA sequencing and performed multivariable association and differential abundance analyses, adjusting for age, sex, education, BMI, and other confounders. The global cognitive score (GCS) was built using neuropsychological assessments of four cognitive domains: Executive function (trails-making B); Processing speed (visual reproduction immediate and delayed); Language (similarity test); and Memory (logical memory immediate and delayed). Participants were additionally stratified by GCS with lower and higher scores indicating poor and normal cognition, respectively. Result: Our results (Figure 1) showed that individuals with poor cognition have a decreased abundance of genera Clostridium (OR = 0.69, 95% CI [0.55, 0.86]) and Ruminococcus (0.93, [0.93, 0.94]). Meanwhile, the genus Alistipes, previously connected to anxiety, chronic fatigue syndrome, depression, and hypertension, was more abundant (1.06, [1.05, 1.06]) in the poor cognition group. Moreover, the genus Pseudobutyrivibrio, a butyrate-producing bacteria from the rumen, was also found to be highly abundant (1.12, [1.11, 1.14]) in the poor cognition compared to normal. Finally, there was no difference in alpha and beta diversity between cognitive groups (Figure 2). Conclusion: Our study suggests that the abundance of several genera, including Pseudobutyrivibrio, Alistipes, Ruminococcus, and Clostridium is associated with cognition in middle-age. Clostridium was previously proposed as novel probiotics for human health, and increasing its abundance was viewed as an effective strategy to regulate and maintain the homeostasis of the gut microbiota. As all these bacteria have neuroprotective effects, manipulating their abundance through diet and pre/pro-biotics could be a research path for preserving global cognitive function in the future

Associations between neuropsychiatric symptoms and ADRD serum biomarkers in Mexican American and non-Hispanic white adults with mild cognitive impairment

Background: Mild cognitive impairment (MCI) is a heterogenous diagnostic category with trajectories ranging from reversion to unimpaired cognition to progression to dementia. Neuropsychiatric symptoms such as depression and irritability are common and influence quality of life of patients and caregivers. The role of neuropsychiatric symptoms on disease biology, presentation, and course remains poorly understood. The goal of this study was to evaluate the associations between neuropsychiatric symptoms and serum ADRD biomarkers in Mexican American and non-Hispanic white participants diagnosed with MCI. Method: Participants from the Texas Alzheimer’s Research and Care Consortium underwent a blood draw and clinical evaluation, including psychopathological and cognitive assessments. Diagnoses of MCI were adjudicated in consensus reviews. The presence and severity of neuropsychiatric symptoms were assessed by informant report using the Neuropsychiatric Inventory (NPI). Serum levels of total tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were assessed using Simoa HD-X Analyzer. Associations between NPI total score and individual items with serum biomarker levels were assessed using linear regression adjusted for age and sex. Result: A total of 425 participants (mean age: 71 ± 9 years, 62% female, 74% Mexican American) had a diagnosis of MCI and serum ADRD biomarkers (Table 1). Total NPI score was not associated with total tau (ß=0.002, p=0.609), NfL (ß=0.001, p=0.658), or GFAP (ß=0.001, p=0.777). However, endorsement of appetite changes was associated with higher NfL (ß=0.077, p=0.006) and GFAP (ß=0.088, p=0.002) levels. Stratified analyses indicated associations of appetite changes with serum NfL (ß=0.108, p=0.002) and GFAP (ß=0.095, p=0.003) in Mexican Americans, but not in non-Hispanic whites (NfL: ß=0.022, p=0.633, GFAP: ß=0.102, p=0.066).There were no other significant associations between individual items on the NPI with serum biomarkers (p\u3e0.05, Bonferroni adjustment p±0.003). Conclusion: Within Mexican American adults with MCI, changes in appetite were associated with higher serum NFL and GFAP levels. As elevations in circulating NfL and GFAP levels are associated with ADRD pathology and accelerated disease progression, appetite changes, a non-invasive and easily discernible behavioral phenotype, may predict higher likelihood of worsening cognitive course. Future longitudinal studies will be necessary to confirm predictive utility of appetite changes for disease progression

An innovative model using Promotores or Community Health Workers for home based dementia care

Background: Health disparities and issues with trust building and relationship building are prominent in Hispanic and underserved populations in south Texas. Community health workers can play a bridging role with underserved communities and may be essential in improving the quality and value of health care. The Texas Health and Human Services Commission certifies the training Community Health Workers under the label of “promotores”. Method: Community health workers were integrated into the primary health care team to serve as a bridge between patient/caregiver dyads and the health care team. Result: Community health workers (CHWs) connected patients to social determinants of health resources such as transportation, food pantries and/or social benefits, Medicaid services, and home care provider services. Caregiver education and resources for respite care, caregiver support in person and virtually. Additionally, CHW\u27s provided education on dementia care resources, caregiver support, recruiting and engaging Hispanic underserve participants in research. Our team was able to increase home visits by 229% to homebound patients throughout several underserved zip codes in Bexar County. This is a success as our team was able to increase health care access to persons with dementia that are homebound that may have not been seen by a healthcare provider until they required emergency care. In fact, we saw roughly 11% decrease of inpatient admissions between 2021 and 2022. Conclusion: Trust and familiarity allows the promotores to easily communicate interventions with cultural sensitivity and experiential knowledge of community values, leading to foster rapport with patients and families. The rapport and trust developed with the patients also helped to engage, and recruit Hispanic and underserved participants for research in dementia

Influence of demographic and clinical characteristics on circulating GFAP levels in Mexican American and non-Hispanic white older adults

Background: Circulating levels of glial fibrillary acidic protein (GFAP), an intermediate filament protein of the astrocytic cytoskeleton and putative marker of reactive astrocytosis, increase with cerebral amyloid beta burden and associate with risk of incident all-cause and Alzheimer\u27s disease (AD) dementia. However, further validation in diverse cohorts and evaluation of potential health disparities are necessary for broader generalization. The goal of the present study was to examine the associations between demographics, cardiovascular risk factors, and APOE ε4 status with serum GFAP levels among Mexican American and non-Hispanic white older adults across the continuum from cognitively unimpaired to AD dementia. Method: Participants included 1,156 Mexican American and 587 non-Hispanic white adults, aged 55 years and older, who completed a blood draw, clinical and cognitive evaluations, and dementia consensus reviews as part of the Texas Alzheimer’s Research and Care Consortium. Serum levels of GFAP were assayed using a Simoa HD-1 Analyzer (Quanterix). Associations between demographic and clinical characteristics with serum GFAP levels were evaluated using linear regression. The diagnostic accuracy of serum GFAP was further examined using area under the receiver operating characteristic curves (AUROC) in univariate and adjusted models and optimal cut-points were derived using the maximum Kolmogorov-Smirnov metric. All models were also stratified by ethnicity and disease stage. Result: In the whole sample (Table 1), older age (b=0.588, p Conclusion: The study results highlight the importance of understanding the role of broader demographic and clinical factors on circulating GFAP levels within diverse cohorts in order to enhance precision across clinical, research, and community settings

Blood biomarkers for cognitive decline and clinical progression in a Mexican American cohort

Introduction: The clinical translation of biofluid markers for dementia requires validation in diverse cohorts. The study goal was to evaluate if blood biomarkers reflecting diverse pathophysiological processes predict disease progression in Mexican American adults. Methods: Mexican American adults (n = 745), 50 years of age and older, completed annual assessments over a mean of 4 years. Serum collected at baseline was assayed for total tau, neurofilament light (NFL), ubiquitin carboxyl‐terminal hydrolase LI, glial fibrillary acidic protein (GFAP), soluble cluster of differentiation 14 (sCD14), and chitinase‐3‐like protein 1 (YKL‐40). Results: Higher GFAP and NFL were associated with global cognitive decline. Only GFAP was associated with increased incident dementia risk (hazard ratio: 1.611 (95% confidence interval: 1.204‐2.155)) and inclusion of additional biomarkers did not improve model fit. Discussion: Among a panel of six blood biomarkers previously associated with neurodegenerative disease, only GFAP predicted incident dementia in our cohort. The findings suggest that blood GFAP levels may aid dementia‐risk prediction among Mexican American adults

Covid-19 may have a detrimental impact on sensorimotor function

Background: The long-term impact of COVID-19 on global health is still unknown. Sensorimotor biomarkers may be promising indicators of lasting effects of COVID-19. Although normal aging may cause changes in sensorimotor function, more severe changes may indicate the subsequent impacts of COVID-19 on brain health. The objective of this study was to investigate the association between COVID-19 and sensorimotor markers (grip strength, gait, and smell) in the 7T neuroCOVID consortium, which is comprised of 5 sites: The University of Texas Health Science Center at San Antonio, Houston Methodist Research Institute, The University of Pittsburgh, Massachusetts General Hospital, and Nottingham University (UK). Methods: We studied 101 adult participants (mean age 60.9 ± 8.5 years, range 45-80 years, 51% women) without prior cognitive impairment or cerebrovascular disease from the 7T consortium across 3 US and 1 UK sites. The sample included 77 COVID-19 survivors and 24 healthy controls. Sensorimotor markers were measured for olfaction (n=59; 12-item Brief Smell Identification Test (B-SIT)), grip strength (n=97; measured using a hand dynamometer), and Gait (n=101; 4-meter normal walk time and n=99; 4-meter fast-paced walk time). To assess the association between COVID-19 and sensorimotor outcomes, we performed a series of linear regression models adjusting for age, sex, site, and handedness (grip strength only). Statistical significance was set at a 5% level. Results: As compared to healthy controls, COVID-19 survivors, on average had a significantly reduced hand grip in the right hand (β ± standard error: -0.18 ± 0.07, p=0.006). We also observed associations with reduced gait speed. COVID-19 survivors, on average, had a slower walk time in both normal (0.17 ± 0.06, p=0.004) and fast-paced (0.04 ± 0.02, p=0.022) as compared to healthy controls. We did not observe any statistical associations between COVID-19 survivors and left-hand grip strength or B-SIT. Conclusions: These results highlight that Covid-19 infection may have a detrimental impact on sensorimotor function. Additional analysis with a larger sample size are ongoing, which will allow us to further assess the effect of infection severity. Future studies will look to evaluate the association between sensorimotor markers, cognition, and ultra-high field 7T MRI-based imaging markers

Cognitive performance and normative data between Hispanic and non-Hispanic cohorts: Results from the South Texas Alzheimer’s Disease Research Center (ADRC)

Background: The prevalence of Alzheimer\u27s disease and related dementias (ADRD) in the United States was estimated as 6.5 million people in 2022, with a five-fold increase for the Hispanic/Latinx population expected by 2060. The South Texas Alzheimer\u27s Disease Center (STAC) was designated as a new ADRC in 2021 by the National Institute on Aging (NIA) with a specific aim to serve the growing needs of the local underrepresented Hispanic population. As cultural and linguistic factors can impact performance on cognitive tests, the goal of the study was to compare UDS-3 cognitive test raw scores and normative data in Hispanic and non-Hispanic adults without cognitive impairment residing in South Texas. Method: Participants from the STAC cohort completed the Uniform Data Set (UDS), V.3.0, which includes demographics and neuropsychological battery. All batteries were administered in the participants’ preferred language, English. Normative data was calculated using Weintraub et al. (2018)’s age, sex, and education adjusted regression models for UDSNB 3.0. Mean differences between baseline visit raw scores and normative data were compared using independent sample t-tests among Hispanic and non-Hispanic participants. Result: Thirty-four Hispanic (mean age=70.4, 67.6% female) and thirty-eight non-Hispanic (mean age=71.9, 57.9% female) participants were included. Hispanic participants had fewer years of education relative to non-Hispanic participants [M(SD)] = [14.7(2.5)] to [16.5(2.5)], respectively; (t(70.1)=3.0, p =0.004); although, the groups did not differ in age or sex distribution (p\u3e0.05). Hispanic and non-Hispanic participants generally performed equivalently on the neuropsychological battery. However, Hispanics had lower mean raw scores on the Montreal Cognitive Assessment (MoCA) (t(70.8)= 3.6, p Conclusion: Overall, Hispanic and non-Hispanic participants performed similarly on the UDS-3 neuropsychological battery. However, Hispanics had lower mean raw and normative scores on the MINT, as well as the MoCA which also includes language measures. Our findings highlight the importance of future research validating the sensitivity and specificity of normative data used in underrepresented populations, especially those at higher risk for ADRD

Circulating ceramide ratios and risk of vascular brain aging and dementia

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer\u27s disease (AD) dementia in a large, community-based sample. METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56-0.96) and AD dementia (HR 0.73, 95% CI 0.53-1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57-0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53-1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (-0.05 ± 0.02, P = 0.02; -0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. CONCLUSIONS: Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults

Multi-Vendor and Multisite Evaluation of Cerebrovascular Reactivity Mapping Using Hypercapnia Challenge

Cerebrovascular reactivity (CVR), which measures the ability of cerebral blood vessels to dilate or constrict in response to vasoactive stimuli such as CO2 inhalation, is an important index of the brain\u27s vascular health. Quantification of CVR using BOLD MRI with hypercapnia challenge has shown great promises in research and clinical studies. However, in order for it to be used as a potential imaging biomarker in large-scale and multi-site studies, the reliability of CO2-CVR quantification across different MRI acquisition platforms and researchers/raters must be examined. The goal of this report from the MarkVCID small vessel disease biomarkers consortium is to evaluate the reliability of CO2-CVR quantification in three studies. First, the inter-rater reliability of CO2-CVR data processing was evaluated by having raters from 5 MarkVCID sites process the same 30 CVR datasets using a cloud-based CVR data processing pipeline. Second, the inter-scanner reproducibility of CO2-CVR quantification was assessed in 10 young subjects across two scanners of different vendors. Third, test-retest repeatability was evaluated in 20 elderly subjects from 4 sites with a scan interval of less than 2 weeks. In all studies, the CO2 CVR measurements were performed using the fixed inspiration method, where the subjects wore a nose clip and a mouthpiece and breathed room air and 5% CO2 air contained in a Douglas bag alternatively through their mouth. The results showed that the inter-rater CoV of CVR processing was 0.08 ± 0.08% for whole-brain CVR values and ranged from 0.16% to 0.88% in major brain regions, with ICC of absolute agreement above 0.9959 for all brain regions. Inter-scanner CoV was found to be 6.90 ± 5.08% for whole-brain CVR values, and ranged from 4.69% to 12.71% in major brain regions, which are comparable to intra-session CoVs obtained from the same scanners on the same day. ICC of consistency between the two scanners was 0.8498 for whole-brain CVR and ranged from 0.8052 to 0.9185 across major brain regions. In the test-retest evaluation, test-retest CoV across different days was found to be 18.29 ± 17.12% for whole-brain CVR values, and ranged from 16.58% to 19.52% in major brain regions, with ICC of absolute agreement ranged from 0.6480 to 0.7785. These results demonstrated good inter-rater, inter-scanner, and test-retest reliability in healthy volunteers, and suggested that CO2-CVR has suitable instrumental properties for use as an imaging biomarker of cerebrovascular function in multi-site and longitudinal observational studies and clinical trials

Multi-Tissue Epigenetic analysis Identifies Distinct associations Underlying insulin Resistance and alzheimer\u27s Disease at Cpt1A Locus

BACKGROUND: Insulin resistance (IR) is a major risk factor for Alzheimer\u27s disease (AD) dementia. The mechanisms by which IR predisposes to AD are not well-understood. Epigenetic studies may help identify molecular signatures of IR associated with AD, thus improving our understanding of the biological and regulatory mechanisms linking IR and AD. METHODS: We conducted an epigenome-wide association study of IR, quantified using the homeostatic model assessment of IR (HOMA-IR) and adjusted for body mass index, in 3,167 participants from the Framingham Heart Study (FHS) without type 2 diabetes at the time of blood draw used for methylation measurement. We identified DNA methylation markers associated with IR at the genome-wide level accounting for multiple testing (P \u3c 1.1 × 10 RESULTS: We confirmed the strong association of blood DNA methylation with IR at three loci (cg17901584-DHCR24, cg17058475-CPT1A, cg00574958-CPT1A, and cg06500161-ABCG1). In FHS, higher levels of blood DNA methylation at cg00574958 and cg17058475 were both associated with lower IR (P = 2.4 × 10 CONCLUSIONS: Our results suggest potentially distinct epigenetic regulatory mechanisms between peripheral blood and dorsolateral prefrontal cortex tissues underlying IR and AD at CPT1A locus