Biology subjects

Alexander, G. E.

Publications and source records attributed to Alexander, G. E..

7 recordsLinked to original sources

bioRxiv2025

Functional assessments of short-term spatial memory in the Dog Aging Project identify strong associations with age that are not moderated by body mass

Companion dogs have emerged as a valuable model in the study of cognitive aging, but assessments of cognitive function in large, diverse, and geographically distributed samples of dogs are challenging to obtain. We developed two novel functional assessments of short-term spatial memory that were administered by community science participants in a sample of 6,753 dogs through the Dog Aging Project. We compared data generated by community scientists to those gathered by research professionals, estimated relationships between age and task performance, and tested the hypothesis that associations between age and cognitive performance vary by dog body mass, as a proxy for expected lifespan. Community scientists generated similar data to research professionals and both cognitive tasks were sensitive to age- related deficits, beginning in midlife. Relationships between age and cognitive function were highly similar across small and large dogs and, for both tasks, comparison of models with and without an interaction between age and body mass yielded decisive evidence for the model without the interaction. Large dogs exhibit accelerated aging across many traits, and so the lack of evidence for accelerated cognitive aging raises the possibility that their large size confers a neuroprotective advantage. We consider possible mechanisms underlying this effect and address how experimental studies of dog cognition using community science methods can support future research on mechanisms of brain and cognitive aging.

animal behavior and cognition↗

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↗

bioRxiv2025

The dynamics of explore-exploit decisions suggest a threshold mechanism for reduced random exploration in older adults

When faced with a choice between exploring an unknown option vs exploiting an option they know well, older adults explore less and exploit more than younger adults. Recent work has suggested that one cause of this age difference in exploration is a reduction in the extent to which older adults use "random exploration" - exploration driven by behavioral variability. Here we investigate potential mechanisms for this age-related difference in random exploration through the lens of a drift diffusion model (DDM) of the explore-exploit choice. In this model, random exploration can be modulated by two mechanisms - the fidelity with which information about the choice is represented in the brain, the "signal-to-noise ratio" (SNR), and the amount of information required to make a decision, the "decision threshold." Reduced random exploration in aging could be caused either by an increase in signal-to-noise ratio or an increase in decision threshold in older adults. By fitting the DDM to choices and response times in a sample of healthy younger and older adults, we found that older adults had a lower SNR and a higher threshold than younger adults. This suggests that reduced random exploration in aging is driven by higher response thresholds in older adults, which may compensate for the reduced signal-to-noise ratio with which decision information is represented in the brain. Author SummaryThe balance of deciding to explore the unknown, versus exploiting the well-known, changes with age. Compared to younger counterparts, healthy older adults have reduced random exploration, in which choices appear uninfluenced by the value of options. To investigate the mechanism of reduced random exploration, reaction time and choices between two slot machines in the Horizon Task were modelled using the drift diffusion model (DDM). In the DDM there is an accumulation of evidence over time, until a boundary threshold for either the explore or exploit option is crossed. The DDM used here can distinguish between two different drivers of random exploration, changes in the signal-to-noise ratio (SNR), with which reward information is represented, and changes in the threshold required to make a decision. We showed that reduced random exploration in older adults results from a higher decision threshold. Whilst older adults had a lower SNR than younger adults, which could lead to more mistakes, older adults actually performed slightly better in the Horizon task than younger adults. Together this suggests that the higher decision threshold could be a healthy aging adaptation, which is overcompensating for the less accurate choices that could result from a lower SNR alone.

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

Associations between physical activity and cognitive dysfunction in older companion dogs: Results from the Dog Aging Project

Canine Cognitive Dysfunction (CCD) is a form of dementia that shares many similarities with Alzheimers disease. Given that physical activity is believed to reduce risk of Alzheimers disease in humans, we explored the association between physical activity and cognitive health in a cohort of companion dogs, aged 6-18 years. We hypothesized that higher levels of physical activity would be associated with lower (i.e., better) scores on a cognitive dysfunction rating instrument and lower prevalence of dementia, and that this association would be robust when controlling for age, comorbidities, and other potential confounders. Our sample included 11,574 companion dogs enrolled through the Dog Aging Project, of whom 287 had scores over the clinical threshold for CCD. In this observational, cross-sectional study, we used owner-reported questionnaire data to quantify dog cognitive health (via a validated scale), physical activity levels, health conditions, training history, and dietary supplements. We fit regression models with measures of cognitive health as the outcome, and physical activity--with several important covariates--as predictors. We found a significant negative relationship between physical activity and current severity of cognitive dysfunction symptoms (estimate = -0.10, 95% CI: -0.11 to - 0.08, p < 0.001), extent of symptom worsening over a 6-month interval (estimate = -0.07, 95% CI: -0.09 to -0.05, p <0.001), and whether a dog reached a clinical level of CCD (odds ratio = 0.53, 95% CI: 0.45 to 0.63, p <0.001). Physical activity was robustly associated with better cognitive outcomes in dogs. Our findings illustrate the value of companion dogs as a model for investigating relationships between physical activity and cognitive aging, including aspects of dementia that may have translational potential for Alzheimers disease. While the current study represents an important first step in identifying a relationship between physical activity and cognitive function, it cannot determine causality. Future studies are needed to rule out reverse causation by following the same dogs prospectively over time, and to evaluate causality by administering physical-activity interventions.

animal behavior and cognition↗

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↗