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Homocysteine (Hcy) is a cardiovascular risk factor implicated in cognitive impairment and cerebrovascular disease but has also been associated with Alzheimer's disease. In 160 healthy older adults (mean age = 69.66 ± 9.95 years), we sought to investigate the association of cortical brain volume with white matter hyperintensity (WMH) burden and a previously identified Hcy-related multivariate network pattern showing reductions in subcortical gray matter (SGM) volumes of hippocampus and nucleus accumbens with relative preservation of basal ganglia. We additionally evaluated the potential role of these brain imaging markers as a series of mediators in a vascular brain pathway leading to age-related cognitive dysfunction in healthy aging. We found reductions in parietal lobar gray matter associated with the Hcy-SGM pattern, which was further associated with WMH burden. Mediation analyses revealed that slowed processing speed related to aging, but not executive functioning or memory, was mediated sequentially through increased WMH lesion volume, greater Hcy-SGM pattern expression, and then smaller parietal lobe volume. Together, these findings suggest that volume reductions in parietal gray matter associated with a pattern of Hcy-related SGM volume differences may be indicative of slowed processing speed in cognitive aging, potentially linking cardiovascular risk to an important aspect of cognitive dysfunction in healthy aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Song, Bharadwaj, Raichlen, Habeck, Grilli, Huentelman, Hishaw, Trouard and Alexander.)

Hippocampal volume is particularly sensitive to the accumulation of total brain white matter hyperintensity volume (WMH) in aging, but how the regional distribution of WMH volume differentially impacts the hippocampus has been less studied. In a cohort of 194 healthy older adults ages 50-89, we used a multivariate statistical method, the Scaled Subprofile Model (SSM), to (1) identify patterns of regional WMH differences related to left and right hippocampal volumes, (2) examine associations between the multimodal neuroimaging covariance patterns and demographic characteristics, and (3) investigate the relation of the patterns to subjective and objective memory in healthy aging. We established network covariance patterns of regional WMH volume differences associated with greater left and right hippocampal volumes, which were characterized by reductions in left temporal and right parietal WMH volumes and relative increases in bilateral occipital WMH volumes. Additionally, we observed lower expression of these hippocampal-related regional WMH patterns were significantly associated with increasing age and greater subjective memory complaints, but not objective memory performance in this healthy older adult cohort. Our findings indicate that, in cognitively healthy older adults, left and right hippocampal volume reductions were associated with differences in the regional distribution of WMH volumes, which were exacerbated by advancing age and related to greater subjective memory complaints. Multivariate network analyses, like SSM, may help elucidate important early effects of regional WMH volume on brain and cognitive aging in healthy older adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Van Etten, Bharadwaj, Grilli, Raichlen, Hishaw, Huentelman, Trouard and Alexander.)

Background: Older adults are at a greater risk for contracting and experiencing severe illness from COVID-19 and may be further affected by pandemic-related precautions (e.g., social distancing and isolation in quarantine). However, the longitudinal impact of the COVID-19 pandemic on older adults is unclear. The current study examines changes in health behaviors, psychosocial factors, and cognitive functioning in a large sample of older adults using a pre-pandemic baseline and longitudinal follow-up throughout 9 months of the COVID-19 pandemic. Methods: One hundred and eighty-nine older adults (ages 65-89) were recruited from a multisite clinical trial to complete additional virtual assessments during the COVID-19 pandemic. Mixed effects models evaluated changes in health behaviors, psychosocial factors, and cognitive functioning during the pandemic compared to a pre-pandemic baseline and over the course of the pandemic (i.e., comparing the first and last COVID-19 timepoints). Results: Compared to their pre-pandemic baseline, during the pandemic, older adults reported worsened sleep quality, perceived physical health and functioning, mental health, slight increases in depression and apathy symptoms, reduced social engagement/perceived social support, but demonstrated better performance on objective cognitive tasks of attention and working memory. Throughout the course of the pandemic, these older adults reported continued worsening of perceived physical health and function, fewer depression symptoms, and they demonstrated improved cognitive performance. It is important to note that changes on self-report mood measures and cognitive performance were relatively small regarding clinical significance. Education largely served as a protective factor, such that greater years of education was generally associated with better outcomes across domains. Conclusions: The present study provides insights into the longitudinal impact of the COVID-19 pandemic on health behaviors, psychosocial factors, and cognitive functioning in a population disproportionately affected by the virus. Replicating this study design in a demographically representative older adult sample is warranted to further inform intervention strategies targeting older adults negatively impacted by the COVID-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hausman, Dai, O’Shea, Dominguez, Fillingim, Calfee, Carballo, Hernandez, Perryman, Kraft, Evangelista, Van Etten, Smith, Bharadwaj, Song, Porges, DeKosky, Hishaw, Marsiske, Cohen, Alexander, Wu and Woods.)

Frontal lobe structures decline faster than most other brain regions in older adults. Age-related change in the frontal lobe is associated with poorer executive function (e.g., working memory, switching/set-shifting, and inhibitory control). The effects and presence of frontal lobe white matter hyperintensities (WMH) on executive function in normal aging is relatively unknown. The current study assessed relationships between region-specific frontal WMH load and cognitive performance in healthy older adults using three executive function tasks from the NIH Toolbox (NIHTB) Cognition Battery. A cohort of 279 healthy older adults ages 65-88 completed NIHTB and 3T T1-weighted and FLAIR MRI. Lesion Segmentation Toolbox quantified WMH volume and generated lesion probability maps. Individual lesion maps were registered to the Desikan-Killiany atlas in FreeSurfer 6.0 to define regions of interest (ROI). Independent linear regressions assessed relationships between executive function performance and region-specific WMH in frontal lobe ROIs. All models included age, sex, education, estimated total intracranial volume, multi-site scanner differences, and cardiovascular disease risk using Framingham criteria as covariates. Poorer set-shifting performance was associated with greater WMH load in three frontal ROIs including bilateral superior frontal (left β = -0.18, FDR- p = 0.02; right β = -0.20, FDR- p = 0.01) and right medial orbitofrontal (β = -0.17, FDR- p = 0.02). Poorer inhibitory performance associated with higher WMH load in one frontal ROI, the right superior frontal (right β = -0.21, FDR- p = 0.01). There were no significant associations between working memory and WMH in frontal ROIs. Our study demonstrates that location and pattern of frontal WMH may be important to assess when examining age-related differences in cognitive functions involving switching/set-shifting and inhibition. On the other hand, working memory performance was not related to presence of frontal WMH in this sample. These data suggest that WMH may contribute selectively to age-related declines in executive function. Findings emerged beyond predictors known to be associated with WMH presence, including age and cardiovascular disease risk. The spread of WMH within the frontal lobes may play a key role in the neuropsychological profile of cognitive aging. Further research should explore whether early intervention on modifiable vascular factors or cognitive interventions targeted for executive abilities may help mitigate the effect of frontal WMH on executive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Boutzoukas, O'Shea, Albizu, Evangelista, Hausman, Kraft, Van Etten, Bharadwaj, Smith, Song, Porges, Hishaw, DeKosky, Wu, Marsiske, Alexander, Cohen and Woods.)

Objective : The association between hippocampal volume and memory is continuing to be characterized in healthy older adults. Prior research suggests smaller hippocampal volume in healthy older adults is associated with poorer episodic memory and processing speed, as well as working memory, verbal learning, and executive functioning as measured by the NIH Toolbox Fluid (Fluid Cognition Composite, FCC) and Crystalized Cognition Composites (CCC). This study aimed to replicate these findings and to evaluate the association between: (1) hippocampal asymmetry index and cognition; and (2) independent contributions of the left and right hippocampal volume and cognition in a large sample of healthy older adults. Participants and Methods : One-hundred and eighty-three healthy older adults (M age = 71.72, SD = 5.3) received a T1-weighted sequence on a 3T scanner. Hippocampal subfields were extracted using FreeSurfer 6.0 and combined to provide left, right, and total hippocampal volumes. FCC subtests include Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, List Sorting, Picture Sequence Memory, and Pattern Comparison. CCC subtests include Picture Vocabulary and Oral Reading Recognition. Multiple linear regressions were performed predicting cognition composites from the total, left and right, and asymmetry of hippocampal volume, controlling for sex, education, scanner, and total intracranial volume. Multiple comparisons in primary analyses were corrected using a false discovery rate (FDR) of p < 0.05. Results : FCC scores were positively associated with total ( β = 0.226, FDR q = 0.044) and left ( β = 0.257, FDR q = 0.024) hippocampal volume. Within FCC, Picture Sequence Memory scores positively associated with total ( β = 0.284, p = 0.001) and left ( β = 0.98, p = 0.001) hippocampal volume. List Sorting scores were also positively associated with left hippocampal volume ( β = 0.189, p = 0.029). Conclusions : These results confirm previous research suggesting that bilateral hippocampal volume is associated with FCC, namely episodic memory. The present study also suggests the left hippocampal volume may be more broadly associated with both episodic and working memory. Studies should continue to investigate lateralized hippocampal contributions to aging processes to better identify predictors of cognitive decline., (Copyright © 2020 Hardcastle, O’Shea, Kraft, Albizu, Evangelista, Hausman, Boutzoukas, Van Etten, Bharadwaj, Song, Smith, Porges, Dekosky, Hishaw, Wu, Marsiske, Cohen, Alexander and Woods.)

Cerebral white matter (WM) lesion load, as measured by white matter hyperintensity (WMH) volume with magnetic resonance imaging (MRI), has been associated with increasing age and cardiovascular risk factors, like hypertension. Physical sports activity (PSA) may play an important role in maintaining WM in the context of healthy aging. In 196 healthy older adults, we investigated whether participants reporting high levels of PSA ( n = 36) had reduced total and regional WMH volumes compared to those reporting low levels of PSA ( n = 160). Age group [young-old (YO) = 50-69 years; old-old (OO) = 70-89 years], PSA group, and age by PSA group interaction effects were tested, with sex, hypertension, and body mass index (BMI) as covariates. We found significant main effects for age group and age by PSA group interactions for total, frontal, temporal, and parietal WMH volumes. There were no main effects of PSA group on WMH volumes. The OO group with low PSA had greater total, frontal, temporal, and parietal WMH volumes than the YO with low PSA and OO with high PSA groups. WMH volumes for the YO and OO groups with high PSA were comparable. These findings indicate an age group difference in those with low PSA, with greater WMH volumes in older adults, which was not observed in those with high PSA. The results suggest that engaging in high levels of PSA may be an important lifestyle factor that can help to diminish WMH lesion load in old age, potentially reducing the impact of brain aging., (Copyright © 2020 Franchetti, Bharadwaj, Nguyen, Van Etten, Klimentidis, Hishaw, Trouard, Raichlen and Alexander.)

Speed of processing is a cognitive domain that encompasses the speed at which an individual can perceive a given stimulus, interpret the information, and produce a correct response. Speed of processing has been shown to decline more rapidly than other cognitive domains in an aging population, suggesting that this domain is particularly vulnerable to cognitive aging (Chee et al., 2009). However, given the heterogeneity of neuropsychological measures used to assess the domains underpinning speed of processing, a diffuse pattern of brain regions has been implicated. The current study aims to investigate the structural neural correlates of speed of processing by assessing cortical volume and speed of processing scores on the POSIT Double Decision task within a healthy older adult population ( N = 186; mean age = 71.70 ± 5.32 years). T1-weighted structural images were collected via a 3T Siemens scanner. The current study shows that less cortical thickness in right temporal, posterior frontal, parietal and occipital lobe structures were significantly associated with poorer Double Decision scores. Notably, these include the lateral orbitofrontal gyrus, precentral gyrus, superior, transverse, and inferior temporal gyrus, temporal pole, insula, parahippocampal gyrus, fusiform gyrus, lingual gyrus, superior and inferior parietal gyrus and lateral occipital gyrus. Such findings suggest that speed of processing performance is associated with a wide array of cortical regions that provide unique contributions to performance on the Double Decision task., (Copyright © 2020 Kraft, O’Shea, Albizu, Evangelista, Hausman, Boutzoukas, Nissim, Van Etten, Bharadwaj, Song, Smith, Porges, DeKosky, Hishaw, Wu, Marsiske, Cohen, Alexander and Woods.)

Healthy human aging has been associated with brain atrophy in prefrontal and selective temporal regions, but reductions in other brain areas have been observed. We previously found regional covariance patterns of gray matter with magnetic resonance imaging (MRI) in healthy humans and rhesus macaques, using multivariate network Scaled Subprofile Model (SSM) analysis and voxel-based morphometry (VBM), supporting aging effects including in prefrontal and temporal cortices. This approach has yet to be applied to neuroimaging in rodent models of aging. We investigated 7.0T MRI gray matter covariance in 10 young and 10 aged adult male Fischer 344 rats to identify, using SSM VBM, the age-related regional network gray matter covariance pattern in the rodent. SSM VBM identified a regional pattern that distinguished young from aged rats, characterized by reductions in prefrontal, temporal association/perirhinal, and cerebellar areas with relative increases in somatosensory, thalamic, midbrain, and hippocampal regions. Greater expression of the age-related MRI gray matter pattern was associated with poorer spatial learning in the age groups combined. Aging in the rat is characterized by a regional network pattern of gray matter reductions corresponding to aging effects previously observed in humans and non-human primates. SSM MRI network analyses can advance translational aging neuroscience research, extending from human to small animal models, with potential for evaluating mechanisms and interventions for cognitive aging., (Copyright © 2020 Alexander, Lin, Yoshimaru, Bharadwaj, Bergfield, Hoang, Chawla, Chen, Moeller, Barnes and Trouard.)

Aging is associated with disruptions in the resting-state functional architecture of the brain. Previous studies have primarily focused on age-related declines in the default mode network (DMN) and its implications in Alzheimer's disease. However, due to mixed findings, it is unclear if changes in resting-state network functional connectivity are linked to cognitive decline in healthy older adults. In the present study, we evaluated the influence of intra-network coherence for four higher-order cognitive resting-state networks on a sensitive measure of cognitive aging (i.e., NIH Toolbox Fluid Cognition Battery) in 154 healthy older adults with a mean age of 71 and education ranging between 12 years and 21 years (mean = 16). Only coherence within the cingulo-opercular network (CON) was significantly related to Fluid Cognition Composite scores, explaining more variance in scores than age and education. Furthermore, we mapped CON connectivity onto fluid cognitive subdomains that typically decline in advanced age. Greater CON connectivity was associated with better performance on episodic memory, attention, and executive function tasks. Overall, the present study provides evidence to propose CON coherence as a potential novel neural marker for nonpathological cognitive aging., (Copyright © 2020 Hausman, O’Shea, Kraft, Boutzoukas, Evangelista, Van Etten, Bharadwaj, Smith, Porges, Hishaw, Wu, DeKosky, Alexander, Marsiske, Cohen and Woods.)

Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

Expertise and training in fine motor skills has been associated with changes in brain structure, function, and connectivity. Fewer studies have explored the neural effects of athletic activities that do not seem to rely on precise fine motor control (e.g., distance running). Here, we compared resting-state functional connectivity in a sample of adult male collegiate distance runners ( n = 11; age = 21.3 ± 2.5) and a group of healthy age-matched non-athlete male controls ( n = 11; age = 20.6 ± 1.1), to test the hypothesis that expertise in sustained aerobic motor behaviors affects resting state functional connectivity in young adults. Although generally considered an automated repetitive task, locomotion, especially at an elite level, likely engages multiple cognitive actions including planning, inhibition, monitoring, attentional switching and multi-tasking, and motor control. Here, we examined connectivity in three resting-state networks that link such executive functions with motor control: the default mode network (DMN), the frontoparietal network (FPN), and the motor network (MN). We found two key patterns of significant between-group differences in connectivity that are consistent with the hypothesized cognitive demands of elite endurance running. First, enhanced connectivity between the FPN and brain regions often associated with aspects of working memory and other executive functions (frontal cortex), suggest endurance running may stress executive cognitive functions in ways that increase connectivity in associated networks. Second, we found significant anti-correlations between the DMN and regions associated with motor control (paracentral area), somatosensory functions (post-central region), and visual association abilities (occipital cortex). DMN deactivation with task-positive regions has been shown to be generally beneficial for cognitive performance, suggesting anti-correlated regions observed here are engaged during running. For all between-group differences, there were significant associations between connectivity, self-reported physical activity, and estimates of maximum aerobic capacity, suggesting a dose-response relationship between engagement in endurance running and connectivity strength. Together these results suggest that differences in experience with endurance running are associated with differences in functional brain connectivity. High intensity aerobic activity that requires sustained, repetitive locomotor and navigational skills may stress cognitive domains in ways that lead to altered brain connectivity, which in turn has implications for understanding the beneficial role of exercise for brain and cognitive function over the lifespan.

We present a novel paradigm to identify shared and unique brain regions underlying non-semantic, non-phonological, abstract, audio-visual (AV) memory vs. naming using a longitudinal functional magnetic resonance imaging experiment. Participants were trained to associate novel AV stimulus pairs containing hidden linguistic content. Half of the stimulus pairs were distorted images of animals and sine-wave speech versions of the animal's name. Images and sounds were distorted in such a way as to make their linguistic content easily recognizable only after being made aware of its existence. Memory for the pairings was tested by presenting an AV pair and asking participants to verify if the two stimuli formed a learned pairing. After memory testing, the hidden linguistic content was revealed and participants were tested again on their recollection of the pairings in this linguistically informed state. Once informed, the AV verification task could be performed by naming the picture. There was substantial overlap between the regions involved in recognition of non-linguistic sensory memory and naming, suggesting a strong relation between them. Contrasts between sessions identified left angular gyrus and middle temporal gyrus as key additional players in the naming network. Left inferior frontal regions participated in both naming and non-linguistic AV memory suggesting the region is responsible for AV memory independent of phonological content contrary to previous proposals. Functional connectivity between angular gyrus and left inferior frontal gyrus and left middle temporal gyrus increased when performing the AV task as naming. The results are consistent with the hypothesis that, at the spatial resolution of fMRI, the regions that facilitate non-linguistic AV associations are a subset of those that facilitate naming though reorganized into distinct networks.

With the population of older adults expected to grow rapidly over the next two decades, it has become increasingly important to advance research efforts to elucidate the mechanisms associated with cognitive aging, with the ultimate goal of developing effective interventions and prevention therapies. Although there has been a vast research literature on the use of cognitive tests to evaluate the effects of aging and age-related neurodegenerative disease, the need for a set of standardized measures to characterize the cognitive profiles specific to healthy aging has been widely recognized. Here we present a review of selected methods and approaches that have been applied in human research studies to evaluate the effects of aging on cognition, including executive function, memory, processing speed, language, and visuospatial function. The effects of healthy aging on each of these cognitive domains are discussed with examples from cognitive/experimental and clinical/neuropsychological approaches. Further, we consider those measures that have clear conceptual and methodological links to tasks currently in use for non-human animal studies of aging, as well as those that have the potential for translation to animal aging research. Having a complementary set of measures to assess the cognitive profiles of healthy aging across species provides a unique opportunity to enhance research efforts for cross-sectional, longitudinal, and intervention studies of cognitive aging. Taking a cross-species, translational approach will help to advance cognitive aging research, leading to a greater understanding of associated neurobiological mechanisms with the potential for developing effective interventions and prevention therapies for age-related cognitive decline.

Executive functions supported by prefrontal cortical (PFC) systems provide essential control and planning mechanisms to guide goal-directed behavior. As such, age-related alterations in executive functions can mediate profound and widespread deficits on a diverse array of neurocognitive processes. Many of the critical neuroanatomical and functional characteristics of prefrontal cortex are preserved in rodents, allowing for meaningful cross species comparisons relevant to the study of cognitive aging. In particular, as rodents lend themselves to genetic, cellular and biochemical approaches, rodent models of executive function stand to significantly contribute to our understanding of the critical neurobiological mechanisms that mediate decline of executive processes across the lifespan. Moreover, rodent analogs of executive functions that decline in human aging represent an essential component of a targeted, rational approach for developing and testing effective treatment and prevention therapies for age-related cognitive decline. This paper reviews behavioral approaches used to study executive function in rodents, with a focus on those assays that share a foundation in the psychological and neuroanatomical constructs important for human aging. A particular emphasis is placed on behavioral approaches used to assess working memory and cognitive flexibility, which are sensitive to decline with age across species and for which strong rodent models currently exist. In addition, other approaches in rodent behavior that have potential for providing analogs to functions that reliably decline to human aging (e.g., information processing speed) are discussed.

The gradual decline of cognitive ability with age, even in the absence of overt brain disease, is a growing problem. Although cognitive aging is a common and feared accompaniment of the aging process, its underlying mechanisms are not well understood and there are no highly effective means to prevent it. Additional research on cognitive aging is sorely needed, and methods that enable ready translation between human subjects and animal models stand to provide the most benefit. Here and in the six companion pieces in this special issue, we discuss a variety of challenges and opportunities for studying cognitive aging across species. We identify tests of associative memory, recognition memory, spatial and contextual memory, and working memory and executive function as cognitive domains that are age-sensitive and amenable to testing with parallel means in both humans and animal models. We summarize some of the important challenges in using animal models to test cognition. We describe unique opportunities to study cognitive aging in human subjects, such as those provided by recent large-scale initiatives to characterize cognition in large groups of subjects across the lifespan. Finally, we highlight some of the challenges of studying cognitive aging in human subjects.