Biology subjects

Cohen, R. A.

Publications and source records attributed to Cohen, R. A..

6 recordsLinked to original sources

bioRxiv2025

Your Brain Doesn't Look a Day Past 70! Cross-Sectional Associations with Brain-Predicted Age in the Cognitively-Intact Oldest-Old

The cognitively-intact oldest-old (85+) may be the most-resilient members of their birth cohort; due to survivorship effects (e.g., depletion of susceptibles), risk factors associated with brain aging biomarkers in younger samples may not generalize to the oldest-old. We evaluated associations between established aging-related risk factors and brain-predicted age difference (brainPAD) in a cross-sectional cognitively-intact oldest-old sample. Additionally, we evaluated brainPAD-cognition associations to characterize brain maintenance vs. cognitive reserve in our sample. Oldest-old adults (N = 206; 85-99 years; MoCA > 22 or neurologist evaluation) underwent T1-weighted MRI; brainPAD was generated with brainageR, such that more-positive brainPAD reflected relatively advanced brain aging. Sex, educational attainment, alcohol and smoking history, exercise history, BMI, cardiovascular and metabolic disease history, and anticholinergic medication burden were self-reported. Global cognitive z-score and coefficient of variation were derived from the NACC UDS 3.0 cognitive battery; crystallized-fluid discrepancy was derived from the NIH Toolbox Cognitive Battery. Mean brainPAD was -7.99 (SD: 5.37; range: -24.50, 6.03). Women showed more-delayed brain aging than men (B = -2.35, 95% CI = - 4.28, -0.41, p = 0.018). No other exposures were associated with brainPAD. BrainPAD was not associated with any cognitive variable. These findings suggest that cognitively-intact oldest-old adults may be atypically-resistant to risk factors associated with aging in younger samples, consistent with survivorship effects in aging. Furthermore, brainPAD may have limited explanatory value for cognitive performance in cognitively-intact oldest-old adults, potentially due to high cognitive reserve. Overall, our findings highlight the impact of survivorship effects on brain aging research. HighlightsO_LIBrain-predicted age difference was assessed in cognitively-intact oldest-old ([≥]85) C_LIO_LIMean brain-predicted age corresponded to an 8-year delay in brain aging C_LIO_LIBrain age in oldest-old was not associated with self-reported health history C_LIO_LIBrain age was not associated with cognitive performance C_LI

neuroscience↗

bioRxiv2023

"Surviving and Thriving": Evidence for Cortical GABA Stabilization in Cognitively-Intact Oldest-Old Adults

Cortical GABA levels are reduced in older age; age-related differences in GABA may be associated with age-related cognitive change. The nature of age-related GABA differences in the highest-functioning stratum of the oldest-old (85+) population is not yet known. We extend our previously-reported Individual Participant Data Meta-Analysis of GABA levels (Porges et al., 2021) across the lifespan with four novel datasets sampling the cognitively-intact oldest-old. The slope of age-related GABA differences in cognitively-intact oldest-old adults flattens after roughly age 80. We interpret these findings as an effect of survivorship: inclusion in the study required intact cognition, and too great a reduction of GABA levels may not be compatible with neurophysiological function needed for intact cognition. This work contributes to a growing body of evidence suggesting that successful cognitive aging may require intact GABAergic function, as well as further characterizing successful aging amongst oldest-old adults.

neuroscience↗

bioRxiv2022

Larger and more dentated hippocampal structure is associated with better memory in the oldest-old.

Episodic memory is widely recognized as a critically important aspect of cognition that is often impacted by cognitive and brain aging. Prior work has shown that episodic memory is related to the presence of teeth-like folds on the dentate gyrus, called dentation. We hypothesized that episodic memory performance relates to overall hippocampal structure (i.e., dentation and volume) in an oldest-old cohort. We used data from the McKnight Brain Aging Registry, which consisted of cognitively healthy 85+-year-old adults. We conducted a canonical correlation analysis on 111 participants between a set of episodic memory tests and a set of characterizations of hippocampal structure. The analysis yielded a strong canonical correlation between episodic memory and hippocampal structure (r = 0.491, p = <0.001). The results suggest there is a connection between hippocampal morphology and function in the oldest-old. Our findings suggest that dentation may play an important role in relation to the individual differences observed in episodic memory performance among the oldest old and that hippocampal structure supports healthy cognitive aging. HighlightsO_LIWe characterized hippocampal dentation in a healthy oldest-old sample. C_LIO_LIHippocampal structure is related to episodic memory in healthy oldest-old adults. C_LIO_LIMemory functioning is related to both hippocampal volume and dentation. C_LI

neuroscience↗

bioRxiv2021

Fronto-parietal Network Segregation Predicts Maintained Cognition in the Cognitively Healthy Oldest-old (85+): evidence for dedifferentiation

Functional connections among groups of brain areas give insight into the brains organization. The cognitive effects of aging may relate to the brains large-scale organization. Examining the relationship between individual differences in brain organization and cognitive function in healthy older adults can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry. We found that the segregation of the cortical association system and the segregation of individual networks within that system [the fronto-parietal network (FPN), cingulo-opercular network (CON) and default mode network (DMN)], were strong predictors of overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals experiencing successful cognitive aging.

neuroscience↗

bioRxiv2019

Smaller limbic structures are associated with greater immunosuppression in over 1000 HIV-infected adults across five continents: Findings from the ENIGMA-HIV Working Group

BackgroundHuman immunodeficiency virus type-1 (HIV) infection can be controlled with combination antiretroviral therapy (cART), but neurocognitive impairment remains common even in chronic and treated HIV-infected (HIV+) cohorts. Identifying the neuroanatomical pathways associated with infection has the potential to delineate novel neuropathological processes underlying persisting deficits, yet individual neuroimaging studies have yielded inconsistent findings. The ENIGMA-HIV Working Group was established to harmonize data from diverse studies to identify the common effects of HIV-infection on brain structure.\n\nMethodsData were pooled from 12 independent neuroHIV studies from Africa, Asia, Australia, Europe, and North America. Volume estimates for eight subcortical brain regions were extracted from T1-weighted MRI from 1,044 HIV+ adults (aged 22-81 years; 72.4% on cART; 70.3% male; 41.6% with detectable viral load (dVL)), to identify associations with plasma markers reflecting current immunosuppression (CD4+ T-cell count) or dVL. Follow-up analyses stratified data by cART status and sex. Bonferroni correction was used to determine statistical significance.\n\nFindingsLower current CD4+ count was associated with smaller hippocampal ({beta} = 20.3 mm3 per 100 cells/mm3; p = 0.0001) and thalamic volumes ({beta} = 29.3; p = 0.003); in the subset of participants not on cART, it was associated with smaller putamen volumes ({beta} = 65.1; p = 0.0009). On average, a dVL was associated with smaller hippocampal (Cohens d = 0.24; p = 0.0003) and amygdala volumes (d = 0.18; p = 0.0058).\n\nInterpretationIn HIV+ individuals across five continents, smaller limbic volumes were consistently associated with current plasma markers. As we assessed cohorts with different inclusion/exclusion criteria and demographic distributions, these deficits may represent a generalizable brain-signature of HIV infection in the cART era. Our findings support the importance of achieving viral suppression and immune restoration for maintaining brain health.\n\nFundingThis work was supported, in part, by NIH grant U54 EB020403.\n\nResearch in ContextO_ST_ABSEvidence before this studyC_ST_ABSHIV type-1 infection can be managed with antiretroviral therapy, however neurocognitive impairment persists even in treated HIV+ individuals. Given the challenges associated with standardized cognitive testing, there is a need to identify quantitative markers of central nervous system impairment. A number of neuroimaging studies have reported brain abnormalities in HIV-infected patients; however, prior studies investigating associations between CD4+ T-cell count or HIV viral load and subcortical brain volume report variable effect sizes and regional distributions of effects, limiting the generalizability of the conclusions drawn to date. We have conducted a literature search for reports in English language journals published until June 2019, using the following search terms: HIV AND subcortical AND neuroimaging AND brain AND viral load AND RNA AND CD4. After removing studies that were not applicable, there were 30 studies investigating CD4+ T-cell count and viral load associations with subcortical brain structure.\n\nAdded value of the studyThe aim of the current study was to investigate structural brain associations with two biomarkers universally used to monitor immune function and treatment response, namely plasma RNA viral load and CD4+ T-cell counts. Prior analyses have been performed in smaller, heterogeneous cohorts, but by combining data across cohorts, we can identify consistent associations between brain volume and indicators of HIV infection across cohorts. The ENIGMA-HIV Working Group was established to identify common neurobiological signatures of the HIV-infected brain by harmonizing data analysis from HIV neuroimaging studies worldwide. The value of this dataset is that it is well-powered and representative of many HIV+ people living in the cART era.\n\nImplications of all the available evidenceOur results provide robust evidence that despite demographic and clinical heterogeneity among HIV-infected individuals, brain abnormalities are consistently linked to HIV viral load and immunosuppression. This supports the importance of achieving viral suppression and immune system restoration in maintaining brain health in people living with HIV. The vulnerability of limbic regions, found in this study, extends beyond the classically implicated regions of the basal ganglia; this suggests that these regions remain an important target of cART era HIV research, especially given their heightened vulnerability to age-associated atrophy and neurodegeneration.

neuroscience↗

bioRxiv2017

Bcl11b is a Newly Identified Regulator of Vascular Smooth Muscle Phenotype and Arterial Stiffness

B-cell leukemia 11b (Bcl11b) is a zinc-finger transcription factor known as master regulator of T lymphocytes and neuronal development during embryogenesis. Bcl11b-interacting protein COUP-TFII is required for atrial development and vasculogenesis, however a role of Bcl11b in the adult cardiovascular system is unknown. A genome-wide association study (GWAS) recently showed that a gene desert region downstream of BCL11B and known to function as BCL11B enhancer harbors single nucleotide polymorphisms (SNPs) associated with increased arterial stiffness. Based on these human findings, we sought to examine relations between Bcl11b and arterial function using mice with Bcl11b deletion. We report for the first time that Bcl11b is expressed in vascular smooth muscle (VSM) and transcriptionally regulates the expression of VSM contractile proteins smooth muscle myosin and smooth muscle -actin. Lack of Bcl11b in VSM-specific Bcl11b null mice (BSMKO) resulted in increased expression of Ca++-calmodulin-dependent serine/threonine phosphatase calcineurin in BSMKO VSM cells, cultured in serum-free condition, and in BSMKO aortas, which showed an inverse correlation with levels of phosphorylated VASPS239, a regulator of cytoskeletal actin rearrangements. Moreover, decreased pVASPS239 in BSMKO aortas was associated with increased actin polymerization (F/G actin ratio). Functionally, aortic force, stress and wall tension, measured ex vivo in organ baths, were increased in BSMKO aortas and BSMKO mice had increased pulse wave velocity, the in vivo index of arterial stiffness, compared to WT littermates. Despite having no effect on baseline blood pressure or angiotensin II-induced hypertension, Bcl11b deletion in VSM increased the incidence of aortic aneurysms in BSMKO mice. Aneurysmal aortas from angII-treated BSMKO mice had increased number of apoptotic VSM cells. In conclusion, we identified VSM Bcl11b as a novel and crucial regulator of VSM cell phenotype and vascular structural and functional integrity.

physiology↗