Brain Aging Research Research Articles

Abstract P374: Systolic blood pressure burden better predicts tau accumulation than a one-time measurement

In our past work, our group identified a significant relationship between uncontrolled hypertension and greater accumulations of total-tau and phospho-tau181 in cerebrospinal fluid over time. Here, we tested whether blood pressure is related to brain tau deposition assessed using MK-6240 PET. Blood pressure is dynamic in nature, making it difficult to draw conclusions about their risk from a single measurement. To address this issue, different measurement methods have surfaced to better utilize blood pressure as a predictor of disease pathology. Previous studies have found cumulative diastolic blood pressure to increase cardiovascular disease stratification beyond that of a single diastolic blood pressure measurement. In this project, we studied another method of quantifying blood pressure. We examined whether systolic blood pressure (SBP) burden was better related to tau accumulation than a one-time BP measurement taken at the time of PET scan. SBP load was defined as the percentage of SBP values >=140 mmHg taken in the period spanning from 6 months before tau imaging to 6 months after. SUVR (standardized uptake value ratio) was created using the cerebellar gray matter as the reference region. We assessed SUVR in Braak regions 1-6. Pearson correlation was used to test the associations between the variables of interest. We studied cognitively healthy subjects from a brain aging research center (n=72, 40% women, 60% with hypertension). Medians of our group were 72 years of age (interquartile range (IQR) 10.6), education of 18 years (IQR 2), and 8 BP measurements (IQR 14). While one-time SBP measurements and tau were not related, SBP load was progressively correlated with SUVR across Braak stages. In the entire group, the correlations ranged from -0.18 (p = 0.133) in Braak region 1 to 0.19 (p = 0.114) in Braak region 3 to 0.24 (p = 0.042) in Braak region 6. In the hypertensive group, these correlations were stronger and ranged from -0.06 (p = 0.713) in Braak region 1 to 0.38 (p = 0.012) in Braak region 3 to 0.50 (p < 0.001) in Braak region 6. We show that SBP load instead of singular SBP measurements is a stronger predictor of tau accumulation. Furthermore, stronger associations with brain regions known to be affected in more advanced stages suggest that blood pressure control is more critical to tau progression than initial deposition.

Application of proteomics in brain's aging research

Proteomics is one of the commonly used techniques to explore the protein composition or protein modification status in various healthy or diseased brain tissues in the past decades. Aging is an extremely complex biological process including physiological function decline with age increasing. To have a better understanding of protein changes along with aging, proteomics has been applied in aging-associated research trying to uncover protein changes or post-translational modification (PTM) occurs in aging with the advantage of screening proteins on a large scale. In this review, we summarized protein expression differences detected by proteomics in human or animal brains at different age stages. Protein differences among species or brain regions are obvious, which reminds us to carefully consider these factors in brain aging research. Important protein changes have been found in multiple brain regions in the aging process and these differentially expressed proteins are mainly involved in cellular components, activities of metabolism, mitochondria changes, oxidative modification and some specific signaling pathways.

A - 37 Measuring Experiences of Discrimination in Older Adults Enrolled in an Alzheimer's Disease Research Cohort.

Discrimination can affect healthy brain aging and Alzheimer's disease (ad) outcomes. To advance this area of research, we characterized experiences of discrimination in a cohort of older adults, contributing data to a national research sample. An electronic survey was completed by cognitively unimpaired participants (n = 135) in the UPenn ad Research Center clinical cohort. The Everyday Discrimination Scale (EDS) asks 10 questions about lifetime experiences with discrimination. Self-report questionnaires gathered sociodemographic data, including age, race, disability, sex, sexual orientation, and gender identity. Associations between EDS items and sociodemographic characteristics were examined. The sample of 135 older adults averaged 74years old, had 17years of schooling, and were mostly women (61%) and white (71%). Half (49%) reported having discriminatory experiences including receiving less respect (35%), lower quality service (35%), less courtesy (34%), and being treated as inferior (35%) or less smart (22%). The most common reasons for discrimination were race (29%), gender (22%), skin color (18%), age (17%), and ancestry (16%). Black participants comprised the majority who reported receiving lower service (68%), being treated as less smart (60%), and with less courtesy (56%). Our findings suggest older adults enrolled in brain aging research experience many types of discrimination, which disproportionately affect Black individuals. Their experiences make a valuable contribution to ad science, helping researchers to study how discrimination may correspond to ad outcomes. They also highlight the importance of researchers being well-trained to be culturally informed when interacting with individuals who have been, and may continue to be, impacted by discrimination.

Abstract 104: Assessment Of Brain Venous System In Hypertension

With an increasing recognition of the contribution of venous collagenosis to cerebral small vessel disease there is a growing interest in the imaging of brain veins. Some studies showed increased prominence of cerebral veins in animal models of hypertension (HTN) and increased venous visibility in patients with white matter lesions using susceptibility weighted imaging (SWI). Since SWI uses deoxygenated blood as an intrinsic contrast agent, reduced cerebral blood flow (CBF) could result in increased oxygen extraction and thus greater vein prominence. However, others reported that fewer veins visible on SWI correlated with more brain atrophy. We examined whether the number of deep medullary veins (DMVs) was related to HTN and CBF, in a group of cognitively healthy subjects from a brain aging research center (n=351, 220 women, mean age 69.4 ± 7.1). DMVs were assessed by visual inspection on SWI on the level of lateral ventricles, and the number was defined as the average count of both hemispheres. CBF was assessed using arterial spin labeling. The number of DMVs did not differ (p=0.17 after adjusting for age, sex and acquisition type) between normotensive subjects (n=194, <140/90, and no antihypertensive treatment), subjects with controlled HTN (n=74, <140/90, and antihypertensive treatment), and subjects with uncontrolled blood pressure (n=72, ≥ 140/90). It was, however, numerically the lowest in the uncontrolled group (22.8 ± standard error (SE) 1.1, 25.6 ± 1.1 for controlled, and 24.4 ± 0.7 for normotensive individuals). In the entire group there was a negative correlation between CBF and DMVs: r=-0.23, p<0.001. The correlation became progressively stronger across HTN spectrum: r=-0.16, p=0.03 for normotensive subjects, r=-.23, p=0.03 for the controlled group and r=-.038, p=0.001 for the uncontrolled HTN group. At the same time there was a linear trend (p=0.06 after adjusting for age and sex) for CBF decrease from 59.5 ml/100mg/min ± SE 0.4 in normotensive subjects, 58.3±0.7 in controlled and 58.0±0.7 in the uncontrolled group. A greater reliance on oxygen extraction due diminishing perfusion across HTN spectrum may obscure structural changes in cerebral veins previously reported in subjects with vascular disease.

Participant-specific interrogation of population-based data to predict cognitive decline from neuropsychiatric symptoms and neuroimaging biomarkers: A machine learning approach (P12-6.001)

<h3>Objective:</h3> Develop machine learning (ML) models to predict decline in global cognition and attention from neuroimaging biomarkers of Alzheimer’s disease (AD) and neuropsychiatric symptoms (NPS). <h3>Background:</h3> ML is increasingly being used in brain aging research. <h3>Design/Methods:</h3> We developed four ML models (support vector machine, Gaussian process, random forest, Naïve Bayes) to predict z-scored global cognition and attention domain changes between first and last study visits of each participant. We used a stepwise approach to develop the prediction models by: 1) including AD biomarkers (PiB- &amp; FDG-PET), education, and APOE ɛ4 status; followed by 2) adding measures of depression (Beck Depression Inventory-II; BDI-II), and anxiety (Beck Anxiety Inventory; BAI); then 3) adding 12 NPS including NPS severity as measured by Neuropsychiatric Inventory Questionnaire (NPI-Q). <h3>Results:</h3> Data from 777 cognitively unimpaired (CU) participants for the outcome of global cognition z-score, and 795 CU participants for the outcome of attention z-score was available. 80% of the sample was randomly used to train the model, which was blind tested on the remaining 20%. For global cognition, the best model was able to predict 78% of participants with decreasing z-score using AD biomarkers, education, and APOE ɛ4 status. Adding BDI-II and BAI improved the prediction to 87%; and adding 12 NPS further improved the prediction to 96% of participants with decreasing z-scores. Including NPS severity did not improve the model’s performance. For the attention domain, the best model predicted 89% of participants with decreasing z-score using AD biomarkers, education, and APOE ɛ4 status. After adding BDI-II and BAI measurements, the model was able to predict 97% of participants with decreasing z-scores. Adding 12 NPS, and NPI severity only marginally improved the model’s performance to 98%. <h3>Conclusions:</h3> ML has the potential to successfully predict global and domain-specific cognitive decline in community-dwelling persons, with NPS improving prediction compared to AD neuroimaging biomarkers alone. <b>Disclosure:</b> Mr. Shah has nothing to disclose. Jeremy Syrjanen has nothing to disclose. Dr. Krell-Roesch has nothing to disclose. The institution of Walter Kremers has received research support from Biogen. Dr. Vemuri has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Miller Medical Communications Inc.. The institution of Dr. Vemuri has received research support from NIH. The institution of Dr. Vassilaki has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for F. Hoffmann-La Roche Ltd . Dr. Vassilaki has stock in Abbott Laboratories. Dr. Vassilaki has stock in Johnson and Johnson. Dr. Vassilaki has stock in Medtronic. Dr. Vassilaki has stock in Amgen. Dr. Vassilaki has stock in AbbVie. Dr. Vassilaki has stock in Merck. The institution of Dr. Vassilaki has received research support from NIH. The institution of Dr. Vassilaki has received research support from European Union/ St. Anne’s University Hospital Brno, Czech Republic. The institution of an immediate family member of Dr. Vassilaki has received research support from Avobis Bio, LLC. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nestle. Dr. Petersen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech, Inc.. Dr. Petersen has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche, Inc.. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. The institution of Dr. Forzani has received research support from NIH. The institution of Dr. Forzani has received research support from NSF. Dr. Forzani has received intellectual property interests from a discovery or technology relating to health care. Dr. Forzani has received personal compensation in the range of $100,000-$499,999 for serving as a Professor with Arizona State University. Dr. Wu has nothing to disclose. The institution of Dr. Geda has received research support from NIH.

A boot camp translation of Alzheimer's disease in Hispanic/Latino communities.

Hispanics/Latinos (H/Ls) are significantly underrepresented in Alzheimer's disease (AD) research participant samples. This exclusion limits our interpretation of research findings and understanding of the causes of brain health disparities. The Engaging Communities of Hispanics/Latinos for Aging Research (ECHAR) Network was created to engage, educate, and motivate H/Ls for participation in brain aging research by addressing several barriers to inclusion, including health literacy and AD-related communication. We used a novel community-engaged method-Boot Camp Translation (BCT)-to translate medical jargon into action-based, community-relevant messages. H/L community members (n=39) were recruited from three cities to work with local research teams and co-develop culturally responsive AD-related messaging. BCT meetings leveraged various techniques to identify key messages, the target audience for the messages, and methods to disseminate these messages. Themes were constructed collaboratively between BCT facilitators and community members as the group iteratively refined the conceptual framework and language for the main messages, with the goal to make AD messaging accessible for H/L community members. H/L community members showed significant improvements in subjective understanding (Cohen's d=0.75; P<0.001) and objective knowledge of Alzheimer's disease (Cohen's d=0.79; P<0.001) at BCT completion. H/L community members identified key messages that converged for all three cities. These were related to reducing stigma, emphasizing brain health and risk mitigation, and acknowledging the impact of AD on multi-generational families/households. Participants also recommended sharing these messages with H/Ls across the lifespan using multi-media avenues. The collaborative efforts identified culturally responsive and community-relevant messaging that may help address health literacy barriers contributing to AD-related disparities in H/L communities. Hispanics/Latinos are underrepresented in Alzheimer's disease and related dementias (ADRD) research despite increased risk.Limited ADRD health literacy may act as a recruitment barrier.Boot Camp Translation (BCT) is a process that targets health communication.We carried out BCT in three cities to co-develop ADRD messaging.Results highlight regional similarities and differences in ADRD communication.

Characterizing age- and sex-related differences in brain structure among middle-aged and older Hispanic/Latino adults in the study of Latinos- investigation of neurocognitive aging magnetic resonance imaging (SOL-INCA MRI)

Hispanic/Latino adults are a growing segment of the older U.S. population yet are underrepresented in brain aging research. We aimed to characterize brain aging among diverse Hispanic/Latino individuals. Hispanic/Latino individuals (unweighted n = 2273 ages 35–85 years; 56% female) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) population-based study underwent magnetic resonance imaging (MRI) as part of the SOL- Investigation of Neurocognitive Aging MRI (SOL-INCA-MRI) ancillary study (2018–2022). We performed linear regressions to calculate age associations with brain volumes for each outcome (total (global) brain, hippocampal, lateral ventricle, total white matter hyperintensity (WMH), individual cortical lobar, and total cortical gray matter) and tested modification by sex. Older age was associated with smaller gray matter volumes and larger lateral ventricle and WMH volumes. Age-related differences in global brain volumes and gray matter volumes in specific regions (i.e., the hippocampus and temporal and occipital lobes) were less pronounced among women. Our findings warrant further investigation into sex-specific mechanisms of brain aging using longitudinal studies.

A Novel Explainability Approach for Technology-Driven Translational Research on Brain Aging.

Brain aging leads to difficulties in functional independence. Mitigating these difficulties can benefit from technology that predicts, monitors, and modifies brain aging. Translational research prioritizes solutions that can be causally linked to specific pathophysiologies at the same time as demonstrating improvements in impactful real-world outcome measures. This poses a challenge for brain aging technology that needs to address the tension between mechanism-driven precision and clinical relevance. In the current opinion, by synthesizing emerging mechanistic, translational, and clinical research-related frameworks, and our own development of technology-driven brain aging research, we suggest incorporating the appreciation of four desiderata (causality, informativeness, transferability, and fairness) of explainability into early-stage research that designs and tests brain aging technology. We apply a series of work on electrocardiography-based "peripheral" neuroplasticity markers from our work as an illustration of our proposed approach. We believe this novel approach will promote the development and adoption of brain aging technology that links and addresses brain pathophysiology and functional independence in the field of translational research.

Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions

Mammalian models are essential for brain aging research. However, the long lifespan and poor amenability to genetic and pharmacological perturbations have hindered the use of mammals for dissecting aging-regulatory molecular networks and discovering new anti-aging interventions. To circumvent these limitations, we developed an ex vivo model system that faithfully mimics the aging process of the mammalian brain using cultured mouse brain slices. Genome-wide gene expression analyses showed that cultured brain slices spontaneously upregulated senescence-associated genes over time and reproduced many of the transcriptional characteristics of aged brains. Treatment with rapamycin, a classical anti-aging compound, largely abolished the time-dependent transcriptional changes in naturally aged brain slice cultures. Using this model system, we discovered that prions drastically accelerated the development of age-related molecular signatures and the pace of brain aging. We confirmed this finding in mouse models and human victims of Creutzfeldt-Jakob disease. These data establish an innovative, eminently tractable mammalian model of brain aging, and uncover a surprising acceleration of brain aging in prion diseases.

Future trends in brain aging research: Visuo-cognitive functions at stake during mobility and spatial navigation.

Aging leads to a complex pattern of structural and functional changes, gradually affecting sensorimotor, perceptual, and cognitive processes. These multiscale changes can hinder older adults' interaction with their environment, progressively reducing their autonomy in performing tasks relevant to everyday life. Autonomy loss can further be aggravated by the onset and progression of neurodegenerative disorders (e.g., age-related macular degeneration at the sensory input level; and Alzheimer's disease at the cognitive level). In this context, spatial cognition offers a representative case of high-level brain function that involves multimodal sensory processing, postural control, locomotion, spatial orientation, and wayfinding capabilities. Hence, studying spatial behavior and its neural bases can help identify early markers of pathogenic age-related processes. Until now, the neural correlates of spatial cognition have mostly been studied in static conditions thereby disregarding perceptual (other than visual) and motor aspects of natural navigation. In this review, we first demonstrate how visuo-motor integration and the allocation of cognitive resources during locomotion lie at the heart of real-world spatial navigation. Second, we present how technological advances such as immersive virtual reality and mobile neuroimaging solutions can enable researchers to explore the interplay between perception and action. Finally, we argue that the future of brain aging research in spatial navigation demands a widespread shift toward the use of naturalistic, ecologically valid experimental paradigms to address the challenges of mobility and autonomy decline across the lifespan.

Racial differences in AD CSF biomarkers in persons with MCI: Implications and insights

AbstractBackgroundThe implications for potential racial differences in tau CSF biomarkers for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are unclear for standard cutoffs used for determining enrollment criteria into novel clinical trials, and insight into interaction with markers of non‐biological determinants.MethodSetting &amp; Participants‐ Data presented were obtained from baseline assessment of a case control study conducted from March 1, 2016 through January 31, 2019. Participants were 50 years or older adult volunteers recruited from Atlanta, Georgia into the Brain Stress Hypertension and Aging Research Program (B‐SHARP, PI: Hajjar R01AG051633) at the Emory Goizueta Alzheimer’s Disease Research Center. Exposures‐ Self‐reported race and cognitive status per modified Petersen criteria. Outcome measures‐ CSF levels of Aβ1‐42, tau, P‐tau181, ratio of tau or P‐tau181 to Aβ1‐42, and hippocampal volume.Result362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years of age), where 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjusting for multiple determinants, including age, sex, cognitive performance, body mass index (BMI), education, and family history of AD, results suggest Black Americans compared to white individuals with MCI had lower mean (SE) levels of CSF tau (52.4 [5.9] vs. 78.98 [5.02] pg/mL; P=.001) and P‐tau181 (15.42 [2.06] vs. 25.24 [1.75] pg/mL; P=.001). After adjusting for intracranial volume and other covariates in the total sample hippocampal volumes did not differ by race. However, using ROC analyses, AUC comparisons suggest that Aβ1‐42 (0.632 vs 0.779; P=.02) and P‐tau181 (0.638 vs 0.768;P=.03) had lower specificity and sensitivity in Black Americans to distinguish between MCI and normal cognition.ConclusionWe recommend caution in using current biomarker cutoffs to determine enrollment criteria for potential Black American study cohorts. While we hypothesized that these differences could be explained by increased vascular contributors, our supposition was not supported; after adjusting for hypertension and diabetes, racial differences yet remained. Further investigation should clarify the impact of biological factors like vascular disease, interaction with more explicit and well‐defined environmental determinants like education quality and quantity, and their life‐course occurrence.

Development of voice digital biomarkers in AD, their associations with CSF amyloid beta (Aß1‐42) and their underlying neural representations

AbstractBackgroundSubtle changes in connected speech may be detectable years before symptomatic phases of Alzheimer’s disease (AD). In this study we combine machine learning with innovative natural language processing (NLP) and automatic speech recognition (ASR) to develop digital voice biomarkers. We investigate their associations with levels of Ab (1‐42) and map the significant features to underlying brain networks.MethodData for the current case‐control analysis were drawn from participants in the Brain Stress Hypertension and Aging Research Program (B‐SHARP) at Emory University. B‐SHARP participants undergo cognitive assessments, neuroimaging, and lumbar punctures as well as annual audio recordings to capture connected speech. A picture description task was included for NLP analysis In addition, participants were asked to describe the room they were in and to list events they went through from the moment they arrived at the study site. Each audio recording went through 2 NLP pipelines to obtain lexical‐semantics and acoustic features.ResultThe sample included 206 B‐SHARP participants (age=65.1 years, 51% African Americans, 42% with mild cognitive impairment (MCI), 61% women, follow‐up period =2 years). NLP analysis and to a lesser extent acoustic analysis outperformed traditional cognitive screening in identifying MCI status. NLP based analysis outperformed other screening tools of Ab positive status (defined as &lt;250 pg/ml) status especially in the MCI group. Area under the curve (AUC) for identifying MCI, Ab positive , and MCI/Ab positive and NC/Ab positive vs negative. Results are in the Table. We then assessed the association between baseline digital voice biomarkers and disease progression reflected by CDR‐SOB change/2 years. Both NLP‐based scores (Beta= ‐0.18;p=0.0097) and acoustic scores (beta=0.26,p=0.009) were associated with 2‐year change in CDR‐SOB after adjusting for baseline demographics. Finally functional brain connectivity, based on resting state MRI, was associated with digital voice NLP‐based scores in multiple brain networks (Figure).ConclusionA brief voice recording analysis detected cognitive status, increased likelihood of identifying Abeta positivity, and predicted disease progression over 2 years. Our protocol for digital biomarkers had an underlying neural representation in language‐related neural networks. Our study provides multi‐faceted evidence for validity of using voice recording as a tool for biomarker and cognitive screening.

Cornel Iridoid Glycoside Ameliorated Alzheimer's Disease-Like Pathologies and Necroptosis through RIPK1/MLKL Pathway in Young and Aged SAMP8 Mice.

Background Aging is an important risk factor for sporadic Alzheimer's disease (AD) and other neurodegenerative diseases. Senescence-accelerated mouse-prone 8 (SAMP8) is used as an animal model for brain aging and sporadic AD research studies. The aim of the current study was to investigate the pharmacological effects of cornel iridoid glycoside (CIG), an active ingredient of Cornus officinalis, on AD-type pathological changes in young and aged SAMP8 mice. Methods Locomotor activity test was used to detect the aging process of SAMP8 mice. Nissl staining and immunohistochemical staining were applied to detect neurons and myelin basic protein-labelled myelin sheath. Western blotting was used to detect the expression levels of related proteins of synapse, APP processing, and necroptosis. Results The results showed that SAMP8 mice at the age of 6 and 14 months exhibited lower locomotor activity, age-related neuronal loss, demyelination, synaptic damage, and APP amyloidogenic processing. In addition, the increased levels of receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL), and p-MLKL indicating necroptosis were found in the brain of SAMP8 mice. Intragastric administration of CIG for 2 months improved locomotor activity; alleviated neuronal loss and demyelination; increased the expression of synaptophysin, postsynaptic density protein 95, and AMPA receptor subunit 1; elevated the levels of soluble APPα fragment and disintegrin and metalloproteinase 10 (ADAM10); and decreased the levels of RIPK1, p-MLKL, and MLKL in the brain of young and aged SAMP8 mice. Conclusion This study denoted that CIG might be a potential drug for aging-related neurodegenerative diseases such as AD.

Measurements of Brain Age May Help Target Therapy

Measurements of Brain Age May Help Target Therapy

Experiments in macaque monkeys provide critical insights into age-associated changes in cognitive and sensory function

The use of animal models in brain aging research has led to numerous fundamental insights into the neurobiological processes that underlie changes in brain function associated with normative aging. Macaque monkeys have become the predominant nonhuman primate model system in brain aging research due to their striking similarities to humans in their behavioral capacities, sensory processing abilities, and brain architecture. Recent public concern about nonhuman primate research has made it imperative to attempt to clearly articulate the potential benefits to human health that this model enables. The present review will highlight how nonhuman primates provide a critical bridge between experiments conducted in rodents and development of therapeutics for humans. Several studies discussed here exemplify how nonhuman primate research has enriched our understanding of cognitive and sensory decline in the aging brain, as well as how this work has been important for translating mechanistic implications derived from experiments conducted in rodents to human brain aging research.

Racial Disparity in Cerebrospinal Fluid Amyloid and Tau Biomarkers and Associated Cutoffs for Mild Cognitive Impairment

Prior evidence suggests that racial differences exist in tau biomarkers in mild cognitive impairment (MCI) and Alzheimer disease (AD). Whether this reported disparity is associated with a differential level of neurodegeneration and disease stage or with underlying mechanisms separate from amyloid or tau is unclear. To compare cerebrospinal fluid (CSF) biomarkers in African American and white individuals with normal cognition and MCI, to estimate race-based cutoffs for these biomarkers that maximize diagnostic discrimination between normal cognition and MCI, and to study the association of demographic characteristics, cognitive performance, and common vascular risk factors with these differences. This case-control study conducted from March 1, 2016, through January 31, 2019, included participants in the Brain Stress Hypertension and Aging Research Program cohort undergoing baseline assessment. Participants were 50 years or older and recruited from the Atlanta, Georgia, area. Self-reported race and cognitive status categorized using modified Petersen criteria and clinical consensus diagnosis. Levels of β-amyloid 1-42 (Aβ1-42), tau, and phosphorylated tau 181 (pTau181), the ratio of tau or pTau181 to Aβ1-42, and hippocampal volume on magnetic resonance imaging of the brain. Data from 362 study participants were analyzed (mean [SD] age, 65.6 [7.9] years), of whom 152 (42.0%) were African American, 230 (63.5%) were women, and 189 (52.2%) had MCI. After adjustment for demographic characteristics and cognitive performance, lower mean (SE) levels were observed in African American vs white individuals with MCI for tau (52.40 [5.90] vs 78.98 [5.02] pg/mL; P = .001) and pTau181 (15.42 [2.06] vs 25.24 [1.75] pg/mL; P = .001) and a lower pTau181 to Aβ1-42 ratio (0.07 [0.02] vs 0.14 [0.01]; P = .003). There were no racial differences in the normal cognition group or in hippocampal volumes in the MCI group. Cutoffs for CSF biomarkers were higher for Aβ1-42 in African American relative to white individuals (208 [95% CI, 126-321] vs 197 [95% CI, 183-245] pg/mL) and lower for tau (51 [95% CI, 31-59] vs 59 [95% CI, 56-92] pg/mL) and pTau181 (12 [95% CI, 12-19] vs 20 [95% CI, 12-27] pg/mL) levels. Cutoffs for the pTau181 to Aβ1-42 ratio were 0.05 (95% CI, 0.03-0.12) for African American participants and 0.05 (95% CI, 0.05-0.13) for white participants. This study found that African American individuals had lower levels of tau-based biomarkers that were not likely explained by the degree of disease stage or neurodegeneration reflected by hippocampal volumes. This study suggests that race is an important factor when interpreting CSF biomarkers, especially in the clinical diagnosis of prodromal AD. It appears that using the pTau181 to Aβ1-42 ratio may ameliorate these differences.

INSIGHTS FROM AFRICAN AMERICAN OLDER ADULTS ON BRAIN HEALTH RESEARCH ENGAGEMENT: NEED TO SEE THE NEED

Recruitment of African American (AA) participants into clinical research trials in the area of aging and dementia is a major problem facing the field. Although AAs are at a significantly elevated risk of developing Alzheimer’s disease (AD), they are underrepresented in clinical trials and research studies. While previous research has identified a number of barriers to participation, relatively little is known about how to overcome these barriers and engage AA individuals in research. Photovoice may provide a novel approach to advance our understanding of AA perceptions in regards to barriers and strategies to increase AA engagement in brain aging research. The purpose of this project is to add to existing understanding of barriers and facilitators and identify strategies to enhance engagement. Three AA research advocates served as community facilitators to identify and guide groups of AA adults though an 8-10 session photovoice project. Group sessions involved discussions and sharing of images pertaining to various prompts in the area of brain health and research participation. Sessions were audio-taped and transcribed verbatim and photos were uploaded. Participants identified four categories of barriers to AA research participation: Mistrust, the belief that all research involves medication, avoidance and fear of acknowledging problems, and seeing the risks of research but not the need. Participants had various suggestions and approaches for ameliorating each of these barriers. This photovoice community engagement process revealed unique insights into barriers and opportunities for increasing AA engagement in brain aging research.

Neurodevelopment and behavior in neonatal OXYS rats with genetically determined accelerated senescence

Study of the developmental characteristics and mechanisms of senescence is an important field in brain aging research. The OXYS strain was selected from Wistar rats in Novosibirsk, and it serves as a rat model of accelerated aging. Previously, neurodegenerative processes and aberrant behavior were reported in experiments with adult OXYS rats. In our study, neurodevelopmental reflexes, neuronal density in the prefrontal cortex and hippocampus, and global DNA methylation in the hippocampus are compared between OXYS and WAG (Wistar Albino Glaxo) neonatal pups. The development of the righting, forelimb grasp, and cliff avoidance reflexes is delayed, and body weight gain was deferred in neonatal OXYS pups. Neuronal density in the hippocampus does not differ between one-day-old OXYS and WAG pups. On the sixth day, the neuronal density in OXYS pups is reduced in the CA2 hippocampal zone, augmented in CA3 and DG, and unchanged in CA1. Six-day-old OXYS pups have fewer and smaller pyramidal neurons in the prefrontal cortex as compared to WAG controls. Global DNA methylation levels in the hippocampus of OXYS newborns are significantly lower than in the WAG newborn pups. At the age of six days, the global DNA methylation level decreases in WAG pups, but does not change in OXYS pups. Thus, neonatal OXYS rats show delayed neurodevelopment accompanied by changes in the global DNA methylation pattern in the hippocampus and in neuronal density in the hippocampus and the prefrontal cortex. These changes may be related to accelerated senescence in adult OXYS rats.

The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons.

The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double–strand breaks (DSBs) in cultured neurons. We also found that pyridostatin downregulated transcription of the Brca1 gene, a gene that is critical for DSB repair. Importantly, in an in vitro gel shift assay, we discovered that an antibody specific to the G-quadruplex structure binds to a synthetic oligonucleotide, which corresponds to the first putative G-quadruplex in the Brca1 gene promoter. Our results suggest that the G-quadruplex complexes regulate transcription in neurons. Studying the G-quadruplexes could represent a new avenue for neurodegeneration and brain aging research.

Research perspectives of biomedical gerontology and brain aging research: longevity genes in the brain.

Research perspectives of biomedical gerontology and brain aging research: longevity genes in the brain.