Hippocampal Subregion Transcriptomic Profiles Reflect Strategy Selection during Cognitive Aging.

Age-related cognitive impairments are associated with differentially expressed genes (DEGs) linked to defined neural systems; however, studies examining multiple regions of the hippocampus fail to find links between behavior and transcription in the dentate gyrus (DG). We hypothesized that use of a task requiring intact DG function would emphasize molecular signals in the DG associated with a decline in performance. We used a water maze beacon discrimination task to characterize young and middle-age male F344 rats, followed by a spatial reference memory probe trial test. Middle-age rats showed increased variability in discriminating two identical beacons. Use of an allocentric strategy and formation of a spatial reference memory were not different between age groups; however, older animals compensated for impaired beacon discrimination through greater reliance on spatial reference memory. mRNA sequencing of hippocampal subregions indicated DEGs in the DG of middle-age rats, linked to synaptic function and neurogenesis, correlated with beacon discrimination performance, suggesting that senescence of the DG underlies the impairment. Few genes correlated with spatial memory across age groups, with a greater number in region CA1. Age-related CA1 DEGs, correlated with spatial memory, were linked to regulation of neural activity. These results indicate that the beacon task is sensitive to impairment in middle age, and distinct gene profiles are observed in neural circuits that underlie beacon discrimination performance and allocentric memory. The use of different strategies in older animals and associated transcriptional profiles could provide an animal model for examining cognitive reserve and neural compensation of aging.SIGNIFICANCE STATEMENT Hippocampal subregions are thought to differentially contribute to memory. We took advantage of age-related variability in performance on a water maze beacon task and next-generation sequencing to test the hypothesis that aging of the dentate gyrus is linked to impaired beacon discrimination and compensatory use of allocentric memory. The dentate gyrus expressed synaptic function and neurogenesis genes correlated with beacon discrimination in middle-age animals. Spatial reference memory was associated with CA1 transcriptional correlates linked to regulation of neural activity and use of an allocentric strategy. This is the first study examining transcriptomes of multiple hippocampal subregions to link age-related impairments associated with discrimination of feature overlap and alternate response strategies to gene expression in specific hippocampal subregions.

Walk with Me Hybrid Virtual/In-Person Walking for Older Adults with Neurodegenerative Disease.

This study presents a protocol for virtual and in-person walking groups for older adults with neurodegenerative diseases and addresses the decline in physical activity and social connectivity during the pandemic. Physical activity, specifically moderate-intensity walking, has been shown to have multiple health benefits for older adults. This methodology was created during the COVID-19 pandemic, contributing to lower physical activity levels and social isolation in older adults. Both the in-person and virtual classes utilize technology such as fitness tracking apps and video platforms. Data are presented from two groups of older adults with neurodegenerative disease: people with prodromal Alzheimer's disease and people with Parkinson's disease. Participants in the virtual classes were screened for balance impairments before the walk, and any person deemed at risk for falls was not eligible to participate virtually. As COVID vaccines became available and restrictions were lifted, in-person walking groups became feasible. Staff and caregivers were trained in balance management, roles/responsibilities, and delivering walking cues. Both walks, virtual and in-person, consisted of a warm up, a walk, and a cool down, and posture, gait, and safety cues were given throughout. Measures of the rate of perceived exertion (RPE) and heart rate (HR) were taken pre-warm up, post-warm up, and at 15 min, 30 min, and 45 min time points. Participants also used a walking application (app) on their phones to record the distance walked and the number of steps taken. The study showed a positive correlation between HR and RPE in both groups. The participants in the virtual group rated the walking group favorably in terms of improving their quality of life during a period of social isolation and contributing to physical, mental, and emotional well-being. The methodology shows a safe and feasible way to implement virtual and in-person walking groups for older adults with neurological diseases.

Parkinson's Disease and Diabetes Mellitus: Individual and Combined Effects on Motor, Cognitive, and Psychosocial Functions.

BACKGROUND/OBJECTIVE: Understanding the effects of multimorbidity on motor and cognitive function is important for tailoring therapies. Individuals with diabetes mellitus (DM) have a greater risk of developing Parkinson's disease (PD). This study investigated if individuals with comorbid PD and DM experienced poorer functional ability compared to individuals with only PD or DM. METHODS: A cross-sectional analysis of 424 individuals: healthy older adults (HOA), n = 170; PD without DM (PD-only), n = 162; DM without PD (DM-only), n = 56; and comorbid PD and DM (PD+DM), n = 36. Motor, motor-cognitive, cognitive, and psychosocial functions and PD motor symptoms were compared among groups using a two-way analyses of covariance with PD and DM as factors. RESULTS: The PD-only and DM-only participants exhibited slower gait, worse balance, reduced strength, and less endurance. Motor-cognitive function was impaired in individuals with PD but not DM. DM-only participants exhibited impaired inhibition. Individuals with comorbid PD+DM had worse PD motor symptoms and exhibited impaired attention compared to the PD-only group. CONCLUSIONS: Having PD or DM was independently associated with poorer physical and mental quality of life, depression, and greater risk for loss of function. Both PD and DM have independent adverse effects on motor function. Comorbid PD+DM further impairs attention compared to the effect of PD-only, suggesting the importance of therapies focusing on attention. Understanding the functional ability levels for motor and cognitive domains will enhance the clinical care for PD, DM, and PD+DM.

Influence of age and sex on microRNA response and recovery in the hippocampus following sepsis.

Sepsis, defined as a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. The excessive host inflammatory response can induce immediate and persistent cognitive decline, which can be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young and old mice of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Expression of hippocampal miR was examined in age- and sex-matched controls at 1 and 4 days post-CLP. Few miR were modified in a similar manner across age or sex and these few miR were generally associated with neuroprotection against inflammation. Similar to previous work examining transcription, young females exhibited a better recovery of the miR profile from day 1 to day 4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day 1 and day 4 and many of the miR upregulated on day 1 and day 4 were linked to neurodegeneration, increased neuroinflammation, and cognitive impairment. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute to susceptibility or resilience to cognitive impairment due to sepsis.

Adulthood systemic inflammation accelerates the trajectory of age-related cognitive decline.

In order to understand the long-term effects of systemic inflammation, it is important to distinguish inflammation-induced changes in baseline cognitive function from changes that interact with aging to influence the trajectory of cognitive decline. Lipopolysaccharide (LPS; 1 mg/kg) or vehicle was administered to young adult (6 months) male rats via intraperitoneal injections, once a week for 7 weeks. Longitudinal effects on cognitive decline were examined 6 and 12 months after the initial injections. Repeated LPS treatment, in adults, resulted in a long-term impairment in memory, examined in aged animals (age 18 months), but not in middle-age (age 12 months). At 12 months following injections, LPS treatment was associated with a decrease in N-methyl-D-aspartate receptor-mediated component of synaptic transmission and altered expression of genes linked to the synapse and to regulation of the response to inflammatory signals. The results of the current study suggest that the history of systemic inflammation is one component of environmental factors that contribute to the resilience or susceptibility to age-related brain changes and associated trajectory of cognitive decline.

The Utility of Cerebrovascular Reactivity MRI in Brain Rehabilitation: A Mechanistic Perspective.

Cerebrovascular control and its integration with other physiological systems play a key role in the effective maintenance of homeostasis in brain functioning. Maintenance, restoration, and promotion of such a balance are one of the paramount goals of brain rehabilitation and intervention programs. Cerebrovascular reactivity (CVR), an index of cerebrovascular reserve, plays an important role in chemo-regulation of cerebral blood flow. Improved vascular reactivity and cerebral blood flow are important factors in brain rehabilitation to facilitate desired cognitive and functional outcomes. It is widely accepted that CVR is impaired in aging, hypertension, and cerebrovascular diseases and possibly in neurodegenerative syndromes. However, a multitude of physiological factors influence CVR, and thus a comprehensive understanding of underlying mechanisms are needed. We are currently underinformed on which rehabilitation method will improve CVR, and how this information can inform on a patient's prognosis and diagnosis. Implementation of targeted rehabilitation regimes would be the first step to elucidate whether such regimes can modulate CVR and in the process may assist in improving our understanding for the underlying vascular pathophysiology. As such, the high spatial resolution along with whole brain coverage offered by MRI has opened the door to exciting recent developments in CVR MRI. Yet, several challenges currently preclude its potential as an effective diagnostic and prognostic tool in treatment planning and guidance. Understanding these knowledge gaps will ultimately facilitate a deeper understanding for cerebrovascular physiology and its role in brain function and rehabilitation. Based on the lessons learned from our group's past and ongoing neurorehabilitation studies, we present a systematic review of physiological mechanisms that lead to impaired CVR in aging and disease, and how CVR imaging and its further development in the context of brain rehabilitation can add value to the clinical settings.

Association between anti-inflammatory interleukin-10 and executive function in African American women at risk for Alzheimer's disease.

INTRODUCTION: African-Americans (AAs) are 64% more likely to be diagnosed with AD than non-Hispanic Whites. AAs with elevated AD biomarkers exhibit greater neurodegeneration in AD signature regions compared to non-Hispanic Whites with elevated AD biomarkers. This pilot trial examined whether normal or elevated plasma levels of interleukin (IL)-10 are associated with changes in executive function and short-term memory in AA women at risk for developing AD due to parental history. METHOD: Observational study comparing groups with elevated and normal plasma IL-10 levels. Study included 31 AA women (age=58.9±8 years) with parental history of AD. Measures included inflammatory blood biomarkers, executive function and visuospatial short-term memory tests. Multivariate linear regression with adjustment for comorbidities, and Bonferroni corrections for multiple comparisons were used to compare groups. Effect sizes (Cohen's d) were generated. Using endpoints with moderate-large effects between groups, Pearson correlations determined associations between biomarker levels and cognitive performance. RESULTS: The elevated IL-10 group performed worse on the Trail-Making Test proportional score ((B-A)/A) (effect size (d =-0.87 (-1.6, -.1)). Moderate effects with large confident intervals were noted in inhibition, set-switching, and body position spatial memory. Significant differences between groups in levels of other inflammatory markers were noted, including IL-7 (p=0.002) and interferon γ (p=0.02). IL-7 remained significant after Bonferroni correction. Correlation matrices revealed moderate-large, significant correlations (yet with wide confidence intervals) between levels of IL-10 and IL-9 with BPST total correct trials, and between interferon γ and delayed recall. CONCLUSIONS: Interleukins may incite inflammation, leading to impaired aspects of executive function and short-term memory in this sample of African American women at risk for developing AD. This research provides effect sizes that will be used to power future research that will further investigate the relationship between inflammation, AD biomarkers, and cognitive function in an understudied population.

Differential Effect of Repeated Lipopolysaccharide Treatment and Aging on Hippocampal Function and Biomarkers of Hippocampal Senescence.

Markers of brain aging and cognitive decline are thought to be influenced by peripheral inflammation. This study compared the effects of repeated lipopolysaccharide (LPS) treatment in young rats to age-related changes in hippocampal-dependent cognition and transcription. Young Fischer 344 X Brown Norway hybrid rats were given intraperitoneal injections once a week for 7 weeks with either LPS or vehicle. Older rats received a similar injection schedule of vehicle. Old vehicle and young LPS rats exhibited a delay-dependent impairment in spatial memory. Further, LPS treatment reduced the hippocampal CA3-CA1 synaptic response. RNA sequencing, performed on CA1, indicated an increase in genes linked to neuroinflammation in old vehicle and young LPS animals. In contrast to an age-related decrease in transcription of synaptic genes, young LPS animals exhibited increased expression of genes that support the growth and maintenance of synapses. We suggest that the increased expression of genes for growth and maintenance of synapses in young animals represents neuronal resilience/recovery in response to acute systemic inflammation. Thus, the results indicate that repeated LPS treatment does not completely recapitulate the aging phenotype for synaptic function, possibly due to the chronic nature of systemic inflammation in aging and resilience of young animals to acute treatments.

Longitudinal Characterization and Biomarkers of Age and Sex Differences in the Decline of Spatial Memory.

The current longitudinal study examined factors (sex, physical function, response to novelty, ability to adapt to a shift in light/dark cycle, brain connectivity), which might predict the emergence of impaired memory during aging. Male and female Fisher 344 rats were tested at 6, 12, and 18 months of age. Impaired spatial memory developed in middle-age (12 months), particularly in males, and the propensity for impairment increased with advanced age. A reduced response to novelty was observed over the course of aging, which is inconsistent with cross-sectional studies. This divergence likely resulted from differences in the history of environmental enrichment/impoverishment for cross-sectional and longitudinal studies. Animals that exhibited lower level exploration of the inner region on the open field test exhibited better memory at 12 months. Furthermore, males that exhibited a longer latency to enter a novel environment at 6 months, exhibited better memory at 12 months. For females, memory at 12 months was correlated with the ability to behaviorally adapt to a shift in light/dark cycle. Functional magnetic resonance imaging of the brain, conducted at 12 months, indicated that the decline in memory was associated with altered functional connectivity within different memory systems, most notably between the hippocampus and multiple regions such as the retrosplenial cortex, thalamus, striatum, and amygdala. Overall, some factors, specifically response to novelty at an early age and the capacity to adapt to shifts in light cycle, predicted spatial memory in middle-age, and spatial memory is associated with corresponding changes in brain connectivity. We discuss similarities and differences related to previous longitudinal and cross-sectional studies, as well as the role of sex differences in providing a theoretical framework to guide future longitudinal research on the trajectory of cognitive decline. In addition to demonstrating the power of longitudinal studies, these data highlight the importance of middle-age for identifying potential predictive indicators of sexual dimorphism in the trajectory in brain and cognitive aging.

The Role of Nutrition and Inflammation on Cognition in a High-Risk Group for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disease. Treatments are necessary to target people at high risk for AD. Inflammation, particularly tumor necrosis factor alpha (TNFα), appears to be an important marker associated with the development of AD pathophysiology. Consuming a high-fat diet induces tissue expression of TNFα. OBJECTIVE: This study investigates the relationship between nutrition, circulating inflammation, and cognition in African American women (age: M = 59.5 (±8.20) [42-73] years) at risk for developing AD. METHODS: Participants were split into high-fat and low-fat groups based on total dietary fat consumption self-reported on the Lower Mississippi Delta Nutrition Intervention Research Initiative Food Frequency Questionnaire (Delta NIRI FFQ). RESULTS: A high-fat diet was associated with increased blood serum TNFα (p = 0.02) compared to the low-fat diet. In addition, global cognition scores were 9.0% better in those who consumed a higher fat diet (p = 0.04). No significant differences across groups were noted for executive function, dual-tasking, and visuospatial performance. CONCLUSION: These results indicate that there may be multiple biological pathways involved in AD development, suggesting the need for more holistic approaches to mitigate AD-development risk.

Age and Sex Influence the Hippocampal Response and Recovery Following Sepsis.

Although in-hospital mortality rates for sepsis have decreased, survivors often experience lasting physical and cognitive deficits. Moreover, older adults are more vulnerable to long-term complications associated with sepsis. We employed a murine model to examine the influence of age and sex on the brain's response and recovery following sepsis. Young (~ 4 months) and old (~ 20 months) mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with restraint stress. The hippocampal transcriptome was examined in age- and sex-matched controls at 1 and 4 days post-CLP. In general, immune- and stress-related genes increased, while neuronal, synaptic, and glial genes decreased 1 day after CLP-induced sepsis. However, specific age and sex differences were observed for the initial responsiveness to sepsis as well as the rate of recovery examined on day 4. Young females exhibited a muted transcriptional response relative to young males and old females. Old females exhibited a robust shift in gene transcription on day 1, and while most genes recovered, genes linked to neurogenesis and myelination continued to be downregulated by day 4. In contrast, old males exhibited a more delayed or prolonged response to sepsis, such that neuronal and synaptic genes continued to decrease while immune response genes continued to increase on day 4. These results suggest that aging is associated with delayed recovery from sepsis, which is particularly evident in males.

Aging in the Brain: New Roles of Epigenetics in Cognitive Decline.

Gene expression in the aging brain depends on transcription signals generated by senescent physiology, interacting with genetic and epigenetic programs. In turn, environmental factors influence epigenetic mechanisms, such that an epigenetic-environmental link may contribute to the accumulation of cellular damage, susceptibility or resilience to stressors, and variability in the trajectory of age-related cognitive decline. Epigenetic mechanisms, DNA methylation and histone modifications, alter chromatin structure and the accessibility of DNA. Furthermore, small non-coding RNA, termed microRNA (miRNA) bind to messenger RNA (mRNA) to regulate translation. In this review, we examine key questions concerning epigenetic mechanisms in regulating the expression of genes associated with brain aging and age-related cognitive decline. In addition, we highlight the interaction of epigenetics with senescent physiology and environmental factors in regulating transcription.