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The purpose of this study was to clarify the relationships between glycemia and function of the autonomic nervous system (ANS), assessed via resting-state functional connectivity (FC) and heart-rate variability (HRV). Data for this study were extracted from the Leipzig Study for Mind-Body-Emotion Interactions, including 146 healthy adults (114 young, 32 older). Variables of interest were glycated hemoglobin (HbA1c), resting-state FC in the salience aspect of the central-autonomic (S-CAN) and salience network (SN) and HRV (RMSSD and high-frequency HRV (HF-HRV)). HbA1c was inversely correlated with FC in the S-CAN but not SN. HbA1c was inversely correlated with HRV. Both RMSSD and log(HF-HRV) were correlated with FC in the S-CAN and SN. Age- (not sex-related) differences were observed in the Hb1Ac-FC associations (stronger in older adults) while sex- (not age-related) differences were observed in the HRV-FC (stronger in females). These findings extend the diabetes literature to healthy adults in relating glycemia and brain function. The age- and sex-related differences in these relationships highlight the need to account for the potential effects of age and sex in future investigations. • Glycated hemoglobin inversely related with functional connectivity (FC) in controls. • High heart rate variability (RMSSD) was associated with high FC. • Age- but not sex-related differences found in the association between Hb1Ac and FC. • Sex- but not age-related differences found in the association between HRV and FC. [ABSTRACT FROM AUTHOR]

Some research has shown that older adults benefit more from multisensory information than do young adults. However, more recent evidence has shown that the multisensory age benefit varies considerably across tasks. In the current study, older (65 – 80) and young (18 – 30) adults (N = 191) completed a speeded perceptual discrimination task either online or face-to-face to assess task response speed. We examined whether presenting stimuli in multiple sensory modalities (audio-visual) instead of one (audio-only or visual-only) benefits older adults more than young adults. Across all three experiments, a consistent speeding of response was found in the multisensory condition compared to the unisensory conditions for both young and older adults. Furthermore, race model analysis showed a significant multisensory benefit across a broad temporal interval. Critically, there were no significant differences between young and older adults. Taken together, these findings provide strong evidence in favour of a multisensory benefit that does not differ across age groups, contrasting with prior research. • Multisensory information is responded to faster than unisensory information. • Both young and older adults benefit similarly from multisensory information. • An age-specific multisensory benefit was not replicated from prior research. [ABSTRACT FROM AUTHOR]

This study explores the impact of aging on reinforcement learning in mice, focusing on changes in learning rates and behavioral strategies. A 5-armed bandit task (5-ABT) and a computational Q-learning model were used to evaluate the positive and negative learning rates and the inverse temperature across three age groups (3, 12, and 18 months). Results showed a significant decline in the negative learning rate of 18-month-old mice, which was not observed for the positive learning rate. This suggests that older mice maintain the ability to learn from successful experiences while decreasing the ability to learn from negative outcomes. We also observed a significant age-dependent variation in inverse temperature, reflecting a shift in action selection policy. Middle-aged mice (12 months) exhibited higher inverse temperature, indicating a higher reliance on previous rewarding experiences and reduced exploratory behaviors, when compared to both younger and older mice. This study provides new insights into aging research by demonstrating that there are age-related differences in specific components of reinforcement learning, which exhibit a non-linear pattern. • Compared 3 M, 12 M and 18 M mice groups in a 5-armed bandit task. • 18 M mice retained similar ability to learn from successes as younger groups. • 18 M mice had a reduced capacity to learn from negative experiences. • 12 M mice showed more reliance on exploiting known rewarded options than others. [ABSTRACT FROM AUTHOR]

Prior studies have reported inconsistent results regarding the relationships between the integrity of the fornix and parahippocampal cingulum and both memory performance and longitudinal change in performance. In the present study, we examined associations in a sample of cognitively healthy older adults between free water-corrected fractional anisotropy (FA) metrics derived from the fornix and cingulum, baseline memory performance, and 3-year memory change. Neither fornix nor cingulum FA correlated with memory performance at baseline. By contrast, FA of each tract was predictive of memory change, such that greater FA was associated with less longitudinal decline. These associations remained significant after controlling for FA of other white matter tracts and for performance in other cognitive domains. Furthermore, fornix and cingulum FA explained unique variance in memory change. These results suggest that free water-corrected measures of fornix and parahippocampal cingulum integrity are reliable predictors of future memory change in cognitively healthy older adults. The findings for the fornix in particular highlight the utility of correcting for free water when estimating diffusion tensor imaging metrics of white matter integrity. • Free water-corrected fornix and cingulum FA were unrelated to memory performance. • FA of both fornix and cingulum demonstrated a specific association with memory change. • Fornix and cingulum FA explained unique variance in memory change. [ABSTRACT FROM AUTHOR]

The hypothalamus regulates homeostasis across the lifespan and is emerging as a regulator of aging. In murine models, aging-related changes in the hypothalamus, including microinflammation and gliosis, promote accelerated neurocognitive decline. We investigated relationships between hypothalamic microstructure and features of neurocognitive aging, including cortical thickness and cognition, in a cohort of community-dwelling older adults (age range 65–97 years, n=124). Hypothalamic microstructure was evaluated with two magnetic resonance imaging diffusion metrics: mean diffusivity (MD) and fractional anisotropy (FA), using a novel image processing pipeline. Hypothalamic MD was cross-sectionally positively associated with age and it was negatively associated with cortical thickness. Hypothalamic FA, independent of cortical thickness, was cross-sectionally positively associated with neurocognitive scores. An exploratory analysis of longitudinal neurocognitive performance suggested that lower hypothalamic FA may predict cognitive decline. No associations between hypothalamic MD, age, and cortical thickness were identified in a younger control cohort (age range 18–63 years, n=99). To our knowledge, this is the first study to demonstrate that hypothalamic microstructure is associated with features of neurocognitive aging in humans. • In animal models, aging-related changes in the hypothalamus drive brain aging. • The role of the hypothalamus in neurocognitive aging in humans is unknown. • We show that hypothalamic microstructure is altered with aging in older adults. • Hypothalamic microstructure is associated with cortical thickness and cognition. [ABSTRACT FROM AUTHOR]

Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research. • Reduced PIN1 levels are driven by females in aging and Alzheimer's disease. • PIN1 is negatively correlated with neurofibrillary tangle density in females. • PIN1 levels are negatively correlated with global cognitive function in females. • PIN1 levels are decreased in subjects with mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Age-related episodic memory decline is attributed to functional alternations in the hippocampus. Less clear is how aging affects the functional connections of the hippocampus to the rest of the brain during episodic memory processing. We examined fMRI data from the CamCAN dataset, in which a large cohort of participants watched a movie (N = 643; 18–88 years), a proxy for naturalistic episodic memory encoding. We examined connectivity profiles across the lifespan both within the hippocampus (anterior, posterior), and between the hippocampal subregions and cortical networks. Aging was associated with reductions in contralateral (left, right) but not ipsilateral (anterior, posterior) hippocampal subregion connectivity. Aging was primarily associated with increased coupling between the anterior hippocampus and regions affiliated with Control, Dorsal Attention and Default Mode networks, yet decreased coupling between the posterior hippocampus and a selection of these regions. Differences in age-related hippocampal-cortical, but not within-hippocampus circuitry selectively predicted worse memory performance. Our findings comprehensively characterize hippocampal functional topography in relation to cognition in older age, suggesting that shifts in cortico-hippocampal connectivity may be sensitive markers of age-related episodic memory decline. • Aging alters functional specialization of hippocampal subregions. • Contralateral, not ipsilateral subregion connectivity decreases. • Connectivity patterns shift from posterior to anterior regions. • Cortical, not within subregion connectivity differences predict worse episodic memory. [ABSTRACT FROM AUTHOR]

Age-related neuronal adaptations are known to help maintain function. This study aims to examine gross age-related in vivo retinal functional adaptations (using electroretinography) in young and middle aged C57BL/6J and Thy1-YFPh mice and to relate this to in vivo retinal structure (using optical coherence tomography). Electroretinography responses were generally larger in Thy1-YFPh mice than in C57BL/6J mice, with similar in vivo retinal layer thicknesses except for longer inner/outer photoreceptor segment in Thy1-YFPh mice. Relative to 3-month-old mice, 12-month-old mice showed reduced photoreceptor (C57BL/6J 84.0±2.5 %; Thy1-YFPh 80.2±5.2 %) and bipolar cell (C57BL/6J 75.6±2.3 %; Thy1-YFPh 68.1±5.5 %) function. There was relative preservation of ganglion cell function (C57BL/6J 79.7±3.7 %; Thy1-YFPh 91.7±5.0 %) with age, which was associated with increased b-wave (bipolar cell) sensitivities to light. Ganglion cell function was correlated with both b-wave amplitude and sensitivity. This study shows that there are normal age-related adaptations to preserve functional output. Different mouse strains may have varied age-related adaptation capacity and should be taken into consideration when examining age-related susceptibility to injury. • Photoreceptor and bipolar cell function decline in middle aged mice. • Compensatory increase in bipolar cell sensitivity to light occurs in 12-month-old mice. • Increase inner retinal gain (ganglion cell function) up to 12 months of age. • Age-related functional differences can differ in transgenic mice. [ABSTRACT FROM AUTHOR]

Decline in spatial context memory emerges in midlife, the time when most females transition from pre- to post-menopause. Recent evidence suggests that, among post-menopausal females, advanced age is associated with functional brain alterations and lower spatial context memory. However, it is unknown whether similar effects are evident for white matter (WM) and, moreover, whether such effects contribute to sex differences at midlife. To address this, we conducted a study on 96 cognitively unimpaired middle-aged adults (30 males, 32 pre-menopausal females, 34 post-menopausal females). Spatial context memory was assessed using a face-location memory paradigm, while WM microstructure was assessed using diffusion tensor imaging. Behaviorally, advanced age was associated with lower spatial context memory in post-menopausal females but not pre-menopausal females or males. Additionally, advanced age was associated with microstructural variability in predominantly frontal WM (e.g., anterior corona radiata, genu of corpus callosum), which was related to lower spatial context memory among post-menopausal females. Our findings suggest that post-menopausal status enhances vulnerability to age effects on the brain's WM and episodic memory. • Spatial context memory decline and related neural changes emerge at midlife. • At midlife, most females experience spontaneous menopause. • Little know about menopause/sex and age associations with memory and white matter. • Age was associated with poorer memory in post-menopausal females. • Age-related white matter decline correlated with context memory post-menopause. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid total-tau (t-tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer's disease (AD). In order to adjust for age-related increases in t-tau and NfL, cross-sectional age-adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41–78 years (CN, n = 137). The age-adjusted norms for t-tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD-MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD-MCI, no significant correlation was found for t-tau. The cox proportional hazard models, applied in 429 participants with baseline t-tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age-adjustments (HR = 3.39 for t-tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t-tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age-related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy. • Age adjusted regression norms for CSF t-tau and NfL. • Total tau and neurofilament light chain increased with age in cognitive normal. • Total tau concentrations were not associated with age in mild cognitive impairment. • Age-adjusted norms was not more predictive than models unadjusted for age. [ABSTRACT FROM AUTHOR]

The "structural disconnection" hypothesis of cognitive aging suggests that deterioration of white matter (WM), especially myelin, results in cognitive decline, yet in vivo evidence is inconclusive. We examined age differences in WM microstructure using Myelin Water Imaging and Diffusion Tensor Imaging in 141 healthy participants (age 20–79). We used the Virginia Cognitive Aging Project and the NIH Toolbox® to generate composites for memory, processing speed, and executive function. Voxel-wise analyses showed that lower myelin water fraction (MWF), predominantly in prefrontal WM, genu of the corpus callosum, and posterior limb of the internal capsule was associated with reduced memory performance after controlling for age, sex, and education. In structural equation modeling, MWF in the prefrontal white matter and genu of the corpus callosum significantly mediated the effect of age on memory, whereas fractional anisotropy (FA) did not. Our findings support the disconnection hypothesis, showing that myelin decline contributes to age-related memory loss and opens avenues for interventions targeting myelin health. • Myelin in prefrontal areas predicts memory performance. • Myelin, but not fractional anisotropy, mediates the age-memory relationship. • Myelin-cognition associations persist after adjusting for age. • Fractional anisotropy does not predict memory beyond age. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain. • Long-term CR in aging monkeys reduces oxidative DNA damage in oligodendrocytes. • DNA damage in oligodendrocytes of aging monkeys is primarily within mitochondria. • Long-term CR does not alter baseline DNA damage in microglia. • Long-term CR promotes ramified microglia and reduces hypertrophic / ameboid phenotypes. [ABSTRACT FROM AUTHOR]

Aging is often accompanied by changes in brain structure and executive functions, particularly in tasks involving cognitive flexibility, such as task-switching. However, substantial individual differences in the degree of cognitive impairment indicate that some individuals can cope with brain changes more effectively than others, suggesting higher cognitive reserve (CR). This study identified a neural basis for CR by examining the longitudinal relationship between task-related brain activation, structural brain changes, and changes in cognitive performance during an executive task-switching paradigm including single and dual conditions. Fifty-two older individuals were assessed at baseline and followed up after five years. Structural brain changes related to task-switching performance were analyzed using elastic net regression. Task-related functional brain activation was measured using ordinal trends canonical variate analysis (OrT CVA), capturing patterns of activation increasing from single to dual conditions. A differential task-related expression score (dOrT) was calculated as the difference in pattern expression scores between single and dual conditions at baseline. A linear regression model tested whether dOrT moderated the impact of brain changes on changes in switch cost over five years. Results showed a significant interaction between changes in brain structure and dOrT activation on switch cost change, indicating a moderation effect of task-related activation. Higher dOrT buffered the impact of brain structural decline on switch costs, enabling older adults to better cope with age-related brain structural changes and preserve cognitive flexibility. These findings suggest that these task-related activation patterns represent a neural basis for CR. • Longitudinal study on task activation as neural basis of cognitive reserve in aging. • Functional brain activation moderates effects of structural decline on cognition. • Higher differential activation lessens brain change effects on set-switching ability. [ABSTRACT FROM AUTHOR]

Previously consolidated memories can become temporarily labile upon reactivation. Reactivation-based memory updating is chiefly studied in young subjects, so we aimed to assess this process across the lifespan. To do this, we developed a behavioural paradigm wherein a reactivated object memory is updated with contextual information; 3-month-old and 6-month-old male C57BL/6 mice displayed object memory updating, but 12-month-old mice did not. We found that M1 muscarinic acetylcholine receptor signaling during reactivation was necessary for object memory updating in the young mice. Next, we targeted this mechanism in an attempt to facilitate object memory updating in aging mice. Remarkably, systemic pharmacological M1 receptor activation reversed the age-related deficit. Quantification of cholinergic system markers within perirhinal cortex revealed subtle cellular changes that may contribute to differential performance across age groups. These findings suggest that natural cholinergic change across the lifespan contributes to inflexible memory in the aging brain. • Memory reactivation can signal an opportunity to update previously stored memory. • Muscarinic receptor activity gates post-reactivation object memory updating in mice. • Healthy and moderately aged mice display an object memory updating impairment. • An M1 muscarinic receptor agonist can reverse age-related memory updating deficits. [ABSTRACT FROM AUTHOR]

This study evaluated longitudinal brain iron accumulation in older adults, its association with cognition, and the role of specific nutrients in mitigating iron accumulation. MRI-based, quantitative susceptibility mapping estimates of brain iron concentration were acquired from seventy-two healthy older adults (47 women, ages 60–86) at a baseline timepoint (TP1) and a follow-up timepoint (TP2) 2.5–3.0 years later. Dietary intake was evaluated at baseline using a validated questionnaire. Cognitive performance was assessed at TP2 using the uniform data set (Version 3) neuropsychological tests of episodic memory (MEM) and executive function (EF). Voxel-wise, linear mixed-effects models, adjusted for longitudinal gray matter volume alterations, age, and several non-dietary lifestyle factors revealed brain iron accumulation in multiple subcortical and cortical brain regions, which was negatively associated with both MEM and EF performance at T2. However, consumption of specific dietary nutrients at TP1 was associated with reduced brain iron accumulation. Our study provides a map of brain regions showing iron accumulation in older adults over a short 2.5-year follow-up and indicates that certain dietary nutrients may slow brain iron accumulation. • We observed significant brain iron accumulation over a short, 2.5-year period. • Iron accumulation was detected in multiple cortical and subcortical brain regions. • Iron accumulation was associated with lower cognitive performance. • Consumption of specific nutrients may reduce the rate of brain iron accumulation. [ABSTRACT FROM AUTHOR]

Besides an elevated intraocular pressure (IOP), advanced age is one of the most crucial risk factors for developing glaucoma. βB1-Connective Tissue Growth Factor (βB1-CTGF) high-pressure glaucoma mice were used in this study to assess whether glaucoma mice display more inflammatory and aging processes than age-matched controls. Therefore, 20-month-old βB1-CTGF and corresponding wildtype (WT) controls were examined. After IOP measurements, retinas were processed for (immuno-)histological and quantitative real-time PCR analyses. A significantly higher IOP and diminished retinal ganglion cell numbers were noted in βB1-CTGF mice compared to WT. An enhanced macrogliosis as well as an increased number of microglia/macrophages and microglia was detected in retinas of old glaucoma mice. Interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and transforming growth factor-β2 were upregulated, suggesting an ongoing inflammation. Moreover, βB1-CTGF retinas displayed an increased senescence-associated β-galactosidase staining accompanied by a downregulation of Lmnb1 (laminin-B1) mRNA levels. Our results provide a deeper insight into the association between inflammation and high-pressure glaucoma and thus might help to develop new therapy strategies. • Older βB1-CTGF mice display high intraocular pressure and signs of glaucoma. • Ganglion cell loss is accompanied by macro- and microgliosis. • These old glaucoma mice show a strong pro-inflammatory response in the retina. • Increased senescent markers are expressed in the retina. [ABSTRACT FROM AUTHOR]

Histone acylation plays a pivotal role in modulating gene expression, ensuring proper neurogenesis and responsiveness to various signals. Recently, the evolutionary conserved YAF9, ENL, AF9, TAF41, SAS5 (YEATS) domain found in four human paralogs, has emerged as a new class of histone acylation reader with a preference for the bulkier crotonyl group lysine over acetylation. Despite advancements, the role of either histone crotonylation or its readers in neurons remains unclear. In this study, we employed Drosophila melanogaster to investigate the role of ENL/AF9 (dENL/AF9) in the nervous system. Pan-neuronal dENL/AF9 knockdown not only extended the lifespan of flies but also enhanced their overall fitness during aging, including improved sleep quality and locomotion. Moreover, a decreased activity of dENL/AF9 in neurons led to an up-regulation of catalase gene expression which combined with reduced levels of malondialdehyde (MDA) and an enhanced tolerance to oxidative stress in aging flies. This study unveiled a novel function of histone crotonylation readers in aging with potential implications for understanding age-related conditions in humans. • Knocking down histone reader dENL/AF9 in mature neurons extends Drosophila lifespan. • Aged dENL/AF9 knocked-down flies exhibit a more robust daily rhythm of activities. • Reducing dENL/AF9 boosts CAT expression and enhances oxidative stress tolerance. • dENL/AF9 is identified as a novel epigenetic regulator of aging in Drosophila. [ABSTRACT FROM AUTHOR]

Iron is necessary for many neurobiological mechanisms, but its overaccumulation can be harmful. Factors triggering age-related brain iron accumulation remain largely unknown and longitudinal data are insufficient. We examined associations between brain iron load and accumulation and, blood markers of iron metabolism, cardiovascular health, lifestyle factors (smoking, alcohol use, physical activity, diet), and ApoE status using longitudinal data from the IronAge study (n = 208, age = 20–79, mean follow-up time = 2.75 years). Iron in cortex and basal ganglia was estimated with magnetic resonance imaging using quantitative susceptibility mapping (QSM). Our results showed that (1) higher peripheral iron levels (i.e., composite score of blood iron markers) were related to greater iron load in the basal ganglia; (2) healthier diet was related to higher iron levels in the cortex and basal ganglia, although for the latter the association was significant only in younger adults (age = 20–39); (3) worsening cardiovascular health was related to increased iron accumulation; (4) younger ApoE ε4 carriers accumulated more iron in basal ganglia than younger non-carriers. Our results demonstrate that modifiable factors, including lifestyle, cardiovascular, and physiological ones, are linked to age-related brain iron content and accumulation, contributing novel information on potential targets for interventions in preventing brain iron-overload. • Higher levels of iron blood markers are related to more brain iron content and accumulation. • A healthier diet is related to more iron in basal ganglia in younger adults. • Declining cardiovascular health is related to increased iron accumulation. [ABSTRACT FROM AUTHOR]

Chronic systemic inflammation (CSI) results in neuroinflammation and neurodegeneration. Cofilin1 is a stress protein that activates microglia and induces neuroinflammation, but its role in CSI at different aging stages remains unidentified. Therefore, the study aims to identify cofilin1 and its upstream regulators LIMK1 and SSH1 after CSI in young-, middle-, and advanced-aged mice. CSI was induced by injecting the male and female mice with a sub-lethal dose of Lipopolysaccharide weekly for six weeks. The results showed that normal male mice did not show cofilin pathway dysregulation, but a significant dysregulation was observed in CSI advanced-aged mice. In females, cofilin1 dysregulation was observed in healthy and CSI advanced-aged mice, while significant cofilin1 dysregulation was observed in middle-aged mice during CSI. Furthermore, cofilin1 pathway dysregulations correlated with Alzheimer's disease (AD) biomarkers in the brain and saliva, astrocyte activation, synaptic degeneration, neurobehavioral impairments, gut-microbiota abnormalities, and circulatory inflammation. These results provide new insights into cofilin1 sex and age-dependent mechanistic differences that might help identify targets for modulating neuroinflammation and early onset of AD. • Chronic systemic inflammation (CSI) results in neuroinflammation and neurodegeneration. • Cofilin1 activates microglia and induces neuroinflammation. • Cofilin1 dysregulation was observed in CSI advanced-aged mice. • Cofilin1 dysregulations correlated with AD biomarkers in the brain and saliva. • Gut microbiota and circulatory inflammation co-related with cofilin1 dysregulation. [ABSTRACT FROM AUTHOR]

Glutathione (GSH) is a brain marker for oxidative stress and has previously been associated with cerebral amyloid deposition and memory decline. However, to date, no study has examined the links among GSH, sex, age, amyloid, and Apolipoprotein E (APOE) genotype in a large non-clinical cohort of older adults. We performed APOE genotyping, magnetic resonance spectroscopy (MRS) as well as simultaneous positron emission tomography with the radiotracer Flutemetamol (Amyloid-PET), in a group of older adults. The final analysis set comprised 140 healthy older adults (mean age: 64.7 years) and 49 participants with mild cognitive impairment (mean age: 71.4 years). We recorded metabolites in the posterior cingulate cortex (PCC) by a GSH-edited MEGAPRESS sequence. Structural equation modeling revealed that higher GSH levels were associated with female sex, but neither APOE- epsilon 4 carrier status nor age showed significant associations with GSH. Conversely, older age and the presence of an APOE4 allele, but not sex, are linked to higher global amyloid load. Our results suggest that the PCC shows sex-specific GSH alterations in older adults. • PCC GSH levels may be higher in women than in men. • PCC GSH levels were unrelated to local amyloid load. • PCC GSH levels were unrelated to the presence of an APOE epsilon 4 allele. [ABSTRACT FROM AUTHOR]

Astrocyte heterogeneity and its relation to aging in the normal human brain remain poorly understood. We here analyzed astrocytes in gray and white matter brain tissues obtained from donors ranging in age between the neonatal period to over 100 years. We show that astrocytes are differently distributed with higher density in the white matter. This regional difference in cellular density becomes less prominent with age. Additionally, we confirm the presence of morphologically distinct astrocytes, with gray matter astrocytes being morphologically more complex. Notably, gray matter astrocytes morphologically change with age, while white matter astrocytes remain relatively consistent in morphology. Using regional mass spectrometry-based proteomics, we did, however, identify astrocyte specific proteins with regional differences in abundance, reflecting variation in cellular density or expression level. Importantly, the expression of some astrocyte specific proteins region-dependently decreases with age. Taken together, we provide insights into region- and age-related differences in astrocytes in the human brain. [Display omitted] • White matter astrocyte density becomes less during aging. • Gray matter astrocytes become morphologically more complex during aging. • Region- and age-related differences in astrocyte protein expression. [ABSTRACT FROM AUTHOR]

Aging is associated with a priming of microglia such that they are hypersensitive to further immune challenges. As such high-fat diet during aging can have detrimental effects on cognition that is not seen in the young. However, conflicting findings also suggest that obesity may protect against cognitive decline during aging. Given this uncertainty we aimed here to examine the role of microglia in high-fat, high-sucrose diet (HFSD)-induced changes in cognitive performance in the aging brain. We hypothesised that 8 weeks of HFSD-feeding would alter microglia and the inflammatory milieu in aging and worsen aging-related cognitive deficits in a microglia-dependent manner. We found that both aging and HFSD reduced hippocampal neuron numbers and open field exploration; they also impaired recognition memory. However, the aging-related deficits occurred in the absence of a pro-inflammatory response and the deficits in memory performance persisted after depletion of microglia in the Cx3cr1-Dtr knock-in rat. Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction. • High-fat diet during aging can have detrimental effects on cognition and memory. • However, obesity may also protect against cognitive decline during aging. • Both aging and HFSD impaired recognition memory and hippocampal neuron turnover. • Depletion of microglia did not rescue this effect. • Aging-related dysfunction occurs in the absence of a pro-inflammatory response. [ABSTRACT FROM AUTHOR]

Brain biological age, which measures the aging process in the brain using neuroimaging data, has been used to assess advanced brain aging in neurodegenerative diseases, including Parkinson disease (PD). However, assuming that whole brain degeneration is uniform may not be sufficient for assessing the complex neurodegenerative processes in PD. In this study we constructed a multiscale brain age prediction models based on structural MRI of 1240 healthy participants. To assess the brain aging patterns using the brain age prediction model, 93 PD patients and 91 healthy controls matching for sex and age were included. We found increased global and regional brain age in PD patients. The advanced aging regions were predominantly noted in the frontal and temporal cortices, limbic system, basal ganglia, thalamus, and cerebellum. Furthermore, region-level rather than global brain age in PD patients was associated with disease severity. Our multiscale brain age prediction model could aid in the development of objective image-based biomarkers to detect advanced brain aging in neurodegenerative diseases. • Parkinson's disease patients exhibited increased global and regional brain age. • Region-level brain age is associated with Parkinson's disease severity. • The brain age prediction model assesses brain aging in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Aging is the main risk factor for age-related macular degeneration (AMD), a retinal neurodegenerative disease that leads to irreversible blindness, particularly in people over 60 years old. Retinal pigmented epithelium (RPE) atrophy is an AMD hallmark. Genome-wide chromatin accessibility, DNA methylation, and gene expression studies of AMD and control RPE demonstrate epigenomic/transcriptomic changes occur during AMD onset and progression. However, mechanisms by which molecular alterations of normal aging impair RPE function and contribute to AMD pathogenesis are unclear. Here, we specifically interrogate the RPE translatome with advanced age and across sexes in a novel RPE reporter mouse model. We find differential age- and sex- associated transcript expression with overrepresentation of pathways related to inflammation in the RPE. Concordant with impaired RPE function, the phenotypic changes in the aged translatome suggest that aged RPE becomes immunologically active, in both males and females, with some sex-specific signatures, which supports the need for sex representation for in vivo studies. • The Aldh1l1-NuTRAP model enables cell type-specific studies of the RPE with aging. • Changes in the RPE translatome coincide with functional retina/RPE decline with age. • Gene expression changes with age and sex are represented in inflammatory pathways. • We demonstrate commonalities between mouse RPE aging and human RPE during disease. [ABSTRACT FROM AUTHOR]

Multilingualism has been demonstrated to lead to a more favorable trajectory of neurocognitive aging, yet our understanding of its effect on neurocognition across the lifespan remains limited. We collected resting state EEG recordings from a sample of multilingual individuals across a wide age range. Additionally, we obtained data on participant multilingual language use patterns alongside other known lifestyle enrichment factors. Language experience was operationalized via a modified multilingual diversity (MLD) score. Generalized additive modeling was employed to examine the effects and interactions of age and MLD on resting state oscillatory power and coherence. The data suggest an independent modulatory effect of individualized multilingual engagement on age-related differences in whole brain resting state power across alpha and theta bands, and an interaction between age and MLD on resting state coherence in alpha, theta, and low beta. These results provide evidence of multilingual engagement as an independent correlational factor related to differences in resting state EEG power, consistent with the claim that multilingualism can serve as a protective factor in neurocognitive aging. • We tested the interaction of multilingualism, age and oscillatory activity at rest. • Multilingualism predicts whole brain alpha and theta power with increasing age. • Multilingualism shapes coherence across alpha, low beta, and theta frequency bands. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that aging is associated with impaired endogenous pain modulation, and that this likely underlies the increased transition from acute to chronic pain in older individuals. Resting-state functional connectivity (rsFC) offers a valuable tool to examine the neural mechanisms behind these age-related changes in pain modulation. RsFC studies generally observe decreased within-network connectivity due to aging, but its relevance for pain modulation remains unknown. We compared rsFC within a set of brain regions involved in pain modulation between young and older adults and explored the relationship with the efficacy of distraction from pain. This revealed several age-related increases and decreases in connectivity strength. Importantly, we found a significant association between lower pain relief and decreased strength of three connections in older adults, namely between the periaqueductal gray and right insula, between the anterior cingulate cortex (ACC) and right insula, and between the ACC and left amygdala. These findings suggest that the functional integrity of the pain control system is critical for effective pain modulation, and that its function is compromised by aging. • Older adults showed decreased rsFC within the descending pain control system. • This decrease was associated with lower distraction-related pain relief. • rsFC markers for pain modulation efficacy in aging have clear clinical benefits. [ABSTRACT FROM AUTHOR]

The aging population suffers from memory impairments. Slow-wave activity (SWA) is composed of slow (0.5–1 Hz) and delta (1–4 Hz) oscillations, which play important roles in long-term memory and working memory function respectively. SWA disruptions might lead to memory disturbances often experienced by older adults. We conducted behavioral tests in young and older C57BL/6 J mice. SWA was monitored using wide-field imaging with voltage sensors. Cell-specific calcium imaging was used to monitor the activity of excitatory and inhibitory neurons in these mice. Older mice exhibited impairments in working memory but not memory consolidation. Voltage-sensor imaging revealed aberrant synchronization of neuronal activity in older mice. Notably, we found older mice exhibited no significant alterations in slow oscillations, whereas there was a significant increase in delta power compared to young mice. Calcium imaging revealed hypoactivity in inhibitory neurons of older mice. Combined, these results suggest that neural activity disruptions might correlate with aberrant memory performance in older mice. • Slow wave activity disruptions lead to memory disturbances in older adults. • Older mice show impairments in working memory, but not memory consolidation. • Older mice showed abnormal synchronization of neuronal activity across the cortex. • Older mice exhibited aberrant activity of inhibitory neurons within the circuit. • The neural activity disruptions may be related to memory impairments in Older mice. [ABSTRACT FROM AUTHOR]

Amyloid beta (Aβ) follows a sigmoidal time function with varying accumulation rates. We studied how the position on this function, reflected by different Aβ accumulation phases, influences APOE ɛ4's association with Aβ and cognitive decline in 503 participants without dementia using Aβ-PET imaging over 5.3-years. First, Aβ load and accumulation were analyzed irrespective of phases using linear mixed regression. Generally, ɛ4 carriers displayed a higher Aβ load. Moreover, Aβ normal (Aβ-) ɛ4 carriers demonstrated higher accumulation. Next, we categorized accumulation phases as "decrease", "stable", or "increase" based on trajectory shapes. After excluding the Aβ-/decrease participants from the initial regression, the difference in accumulation attributable to genotype among Aβ- individuals was no longer significant. Further analysis revealed that in increase phases, Aβ accumulation was higher among noncarriers, indicating a genotype-related timeline shift. Finally, cognitive decline was analyzed across phases and was already evident in the Aβ-/increase phase. Our results encourage early interventions for ɛ4 carriers and imply that monitoring accumulating Aβ- individuals might help identify those at risk for cognitive decline. • Understanding amyloid beta trajectories is key for AD therapy trial designs. • APOE ɛ4 modulates onset of amyloid accumulation. • Confirmation of different accumulation phases in individuals without dementia. • Importance of trajectory clustering for patient selection. • Cognitive decline in amyloid normal individuals with high accumulation. [ABSTRACT FROM AUTHOR]

Sequence memory is subject to age-related decline, but the underlying processes are not yet fully understood. We analyzed electroencephalography (EEG) in 21 healthy older (60–80 years) and 26 young participants (20–30 years) and compared time-frequency spectra and theta-gamma phase-amplitude-coupling (PAC) during encoding of the order of visually presented items. In older adults, desynchronization in theta (4–8 Hz) and synchronization in gamma (30–45 Hz) power did not distinguish between subsequently correctly and incorrectly remembered trials, while there was a subsequent memory effect for young adults. Theta-gamma PAC was modulated by item position within a sequence for older but not young adults. Specifically, position within a sequence was coded by higher gamma amplitude for successive theta phases for later correctly remembered trials. Thus, deficient differentiation in theta desynchronization and gamma oscillations during sequence encoding in older adults may reflect neurophysiological correlates of age-related memory decline. Furthermore, our results indicate that sequences are coded by theta-gamma PAC in older adults, but that this mechanism might lose precision in aging. • Sequence memory, an important aspect of episodic memory, declines in healthy aging. • Lower theta and higher gamma activity in encoding of correct trials in young adults. • No subsequent memory effect in oscillatory brain activity in healthy older adults. • Theta phase modulates gamma amplitude to code for item position in older adults. [ABSTRACT FROM AUTHOR]

Through the application of machine learning algorithms to neuroimaging data the brain age methodology was shown to provide a useful individual-level biological age prediction and identify key brain regions responsible for the prediction. In this study, we present the methodology of constructing a rhesus macaque brain age model using a machine learning algorithm and discuss the key predictive brain regions in comparison to the human brain, to shed light on cross-species primate similarities and differences. Structural information of the brain (e.g., parcellated volumes) from brain magnetic resonance imaging of 43 rhesus macaques were used to develop brain atlas-based features to build a brain age model that predicts biological age. The best-performing model used 22 selected features and achieved an R2 of 0.72. We also identified interpretable predictive brain features including Right Fronto-orbital Cortex, Right Frontal Pole, Right Inferior Lateral Parietal Cortex, and Bilateral Posterior Central Operculum. Our findings provide converging evidence of the parallel and comparable brain regions responsible for both non-human primates and human biological age prediction. • Machine-learning based rhesus macaques' Brain age index was developed. • Volume of white and gray matter regions could predict chronological age. • Age-sensitive regions that most contribute to the prediction were identified. • Age-sensitive brain regions in rhesus macaque were comparable to humans. [ABSTRACT FROM AUTHOR]

Exploring the neural basis of age-related decline in working memory is vital in our aging society. Previous electroencephalographic studies suggested that the contralateral delay activity (CDA) may be insensitive to age-related decline in lateralized visual working memory (VWM) performance. Instead, recent evidence indicated that task-induced alpha power lateralization decreases in older age. However, the relationship between alpha power lateralization and age-related decline of VWM performance remains unknown, and recent studies have questioned the validity of these findings due to confounding factors of the aperiodic signal. Using a sample of 134 participants, we replicated the age-related decrease of alpha power lateralization after adjusting for the aperiodic signal. Critically, the link between task performance and alpha power lateralization was found only when correcting for aperiodic signal biases. Functionally, these findings suggest that age-related declines in VWM performance may be related to the decreased ability to prioritize relevant over irrelevant information. Conversely, CDA amplitudes were stable across age groups, suggesting a distinct neural mechanism possibly related to preserved VWM encoding or early maintenance. • Aging is associated with decreased visual working memory performance (VWM). • Contralateral delay activity is insensitive to age-related cognitive decline in VWM. • However, VWM induced alpha power lateralization diminishes in old age. • Alpha power lateralization strength is linked to age-related VWM decline. • Separating (a-)periodic components is crucial to establish link to VWM decline. [ABSTRACT FROM AUTHOR]

Aging affects the scalp-to-cortex distance (SCD) and the comprising tissues. This is crucial for noninvasive neuroimaging and brain stimulation modalities as they rely on traversing from the scalp to the cortex or vice versa. The specific relationship between aging and these tissues has not been comprehensively investigated. We conducted a study on 250 younger and older adults to examine age-related differences in SCD and its constituent tissues. We identified region-specific differences in tissue thicknesses related to age and sex. Older adults exhibit larger SCD in the frontocentral regions compared to younger adults. Men exhibit greater SCD in the inferior scalp regions, while women show similar-to-greater SCD values in regions closer to the vertex compared to men. Younger adults and men have thicker soft tissue layers, whereas women and older adults exhibit thicker compact bone layers. CSF is considerably thicker in older adults, particularly in men. These findings emphasize the need to consider age, sex, and regional differences when interpreting SCD and its implications for noninvasive neuroimaging and brain stimulation. [Display omitted] • Scalp-to-cortex distance (SCD) and the comprising tissues are different across age groups. • Across 19 regions, we examined age and sex effects on the SCD tissues in 250 adults. • Older adults have larger SCD values in frontal and central regions than younger adults. • The comprising tissues show unique age and sex differences, depending on the region. • Considering tissue changes is key for scalp-based neuroimaging and brain stimulation. [ABSTRACT FROM AUTHOR]

Hearing loss and diminished visual acuity are associated with poorer cognition, but the underlying mechanisms are not understood. The apolipoprotein (APOE) ε4 allelic variant may drive the associations. We tested whether APOE -ε4 allele count (0, 1, or 2) was associated with declines in memory, executive function, pure-tone hearing threshold averages, and pinhole-corrected visual acuity among participants in the Canadian Longitudinal Study on Aging (CLSA). Multivariable linear mixed regression models were utilized to assess associations between APOE -ε4 allele count and each of the outcome variables. For each main effects model, interactions between APOE -ε4 and sex and age group (45–54-, 55–64-, 65–74-, and 75–85 years) respectively, were analyzed. Significant associations were not observed in main effects models. Models including APOE- ε4 * age (but not APOE- ε4 * sex) interaction terms better fit the data compared to main effects models. In age group-stratified models, however, there were minimal differences in effect estimates according to allele count. APOE -ε4 allele count does not appear to be a common cause of sensory-cognitive associations in this large cohort. [ABSTRACT FROM AUTHOR]

Greater engagement in cognitively stimulating activities (CSA) during adulthood has been shown to protect against neurocognitive decline, but no studies have investigated whether CSA during childhood protects against effects of brain changes on cognition later in life. The current study tested the moderating role of childhood CSA in the relationships between brain structure and cognitive performance during adulthood. At baseline (N=250) and 5-year follow-up (N=204) healthy adults aged 20–80 underwent MRI to assess four structural brain measures and completed neuropsychological tests to measure three cognitive domains. Participants were categorized into low and high childhood CSA based on self-report questionnaires. Results of multivariable linear regressions analyzing interactions between CSA, brain structure, and cognition showed that higher childhood CSA was associated with a weaker relationship between cortical thickness and memory at baseline, and attenuated the effects of change in cortical thickness and brain volume on decline in processing speed over time. These findings suggest higher CSA during childhood may mitigate the effects of brain structure changes on cognitive function later in life. • Childhood cognitively stimulating activities (CSA) impact adult cognitive function. • Childhood CSA attenuates relationship between cortical thickness and memory. • CSA mitigates effect of cortical thickness and brain volume on speed longitudinally. • Childhood CSA may contribute to cognitive reserve that is protective later in life.. [ABSTRACT FROM AUTHOR]

Hedonic perception deeply changes with aging, significantly impacting health and quality of life in elderly. In young adult mice, an odor hedonic signature is represented along the antero-posterior axis of olfactory bulb, and transferred to the olfactory tubercle and ventral tegmental area, promoting approach behavior. Here, we show that while the perception of unattractive odorants was unchanged in older mice (22 months), the appreciation of some but not all attractive odorants declined. Neural activity in the olfactory bulb and tubercle of older mice was consistently altered when attraction to pleasant odorants was impaired while maintained when the odorants kept their attractivity. Finally, in a self-stimulation paradigm, optogenetic stimulation of the olfactory bulb remained rewarding in older mice even without ventral tegmental area's response to the stimulation. Aging degrades behavioral and neural responses to some pleasant odorants but rewarding properties of olfactory bulb stimulation persisted, providing new insights into developing novel olfactory training strategies to elicit motivation even when the dopaminergic system is altered as observed in normal and/or neurodegenerative aging. • The perception of some pleasant odorants is altered with aging. • Age-related odor depreciation involves the olfactory bulb-olfactory tubercle pathway. • The rewarding properties of olfactory bulb stimulation persist in aged animals. [ABSTRACT FROM AUTHOR]

In a recent proteome-wide study, we identified several candidate proteins for drug discovery whose cortical abundance was associated with cognitive resilience to late-life brain pathologies. This study examines the extent to which these proteins are associated with the brain structures of cognitive resilience in decedents from the Religious Orders Study and Memory and Aging Project. Six proteins were associated with brain morphometric characteristics related to higher resilience (i.e., larger anterior and medial temporal lobe volumes), and five were associated with morphometric characteristics related to lower resilience (i.e., enlarged ventricles). Two synaptic proteins, RPH3A and CPLX1, remained inversely associated with the lower resilience signature, after further controlling for 10 neuropathologic indices. These findings suggest preserved brain structure in periventricular regions as a potential mechanism by which RPH3A and CPLX1 are associated with cognitive resilience. Further work is needed to elucidate other mechanisms by which targeting these proteins can circumvent the effects of pathology on individuals at risk for cognitive decline. • We identified two morphometric brain signatures of cognitive resilience • Larger anterior and medial temporal volumes were associated with higher resilience • Larger ventricles were associated with lower resilience • Six previously identified cortical resilience proteins were linked to the volumes • RPH3A and CPLX1 were related to smaller ventricles beyond neuropathological burden. [ABSTRACT FROM AUTHOR]

Cognitive reserve explains differential susceptibility of cognitive performance to neuropathology. We investigated whether certain personality traits underlie cognitive reserve and are accordingly associated with better cognition and less cognitive decline in the presence of age-related brain changes. We included healthy adults aged 19–80 years for cross-sectional (N=399) and longitudinal (N=273, mean follow-up time=5 years, SD=0.7 years) analyses. Assessment of the BIG5 personality traits openness, conscientiousness, extraversion, agreeableness, and neuroticism was questionnaire-based. Each cognitive domain (perceptual speed, memory, fluid reasoning, vocabulary) was measured with up to six tasks. Cognitive domain-specific brain status variables were obtained by combining 77 structural brain measures into single scores using elastic net regularization. These brain status variables explained up to 43.1% of the variance in cognitive performance. We found that higher openness was associated with higher fluid reasoning and better vocabulary after controlling for brain status, age, and sex. Further, lower brain status was associated with a greater decline in perceptual speed only in individuals with low openness. We conclude that high openness benefits cognitive reserve. • Cognitive reserve explains differential susceptibility of cognition to pathology. • It is crucial to better understand the role of personality in cognitive reserve. • Our results indicate that high openness benefits cognitive reserve. • Neuroticism was not associated with cognitive reserve in our healthy sample. • Implication: openness should be promoted throughout the (adult) lifespan. [ABSTRACT FROM AUTHOR]

Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64–68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging. • 5-year memory decline in older with D2-receptor decline across several brain regions. • Longitudinal associations between working memory and striatal D2 decline. • Older with memory and D2 decline had higher burden of vascular risk factors. • Older with memory and D2 decline showed faster biological pace of aging. [ABSTRACT FROM AUTHOR]

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3380; total N individuals=2322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, greater burden of white matter microlesions, and thinner cortex. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health. • DunedinPACE is a novel epigenetic measure of multi-organ decline. • DunedinPACE associates with worse structural brain integrity in midlife and old age. • Association effect sizes were consistent across three large datasets. • DunedinPACE captures brain-body aging associations using a single blood sample. [ABSTRACT FROM AUTHOR]

We explored neural processing differences associated with aging across four cognitive functions. In addition to ERP analysis, we included task-related microstate analyses, which identified stable states of neural activity across the scalp over time, to explore whole-head neural activation differences. Younger and older adults (YA, OA) completed face perception (N170), word-pair judgment (N400), visual oddball (P3), and flanker (ERN) tasks. Age-related effects differed across tasks. Despite age-related delayed latencies, N170 ERP and microstate analyses indicated no age-related differences in amplitudes or microstates. However, age-related condition differences were found for P3 and N00 amplitudes and scalp topographies: smaller condition differences were found for in OAs as well as broader centroparietal scalp distributions. Age group comparisons for the ERN revealed similar focal frontocentral activation loci, but differential activation patterns. Our findings of differential age effects across tasks are most consistent with the STAC-r framework which proposes that age-related effects differ depending on the resources available and the kinds of processing and cognitive load required of various tasks. • ERP and microstate analyses showed that age effects differed across four tasks. • Microstates with ERPs help distinguish among current theories of neural aging. • Spatial distributions of neural processing phases differ by age across time and task. • Different age-related effects across tasks were most consistent with STAC-r. [ABSTRACT FROM AUTHOR]

In mammals, thick axonal calibers wrapped with heavy myelin sheaths are prevalent in the auditory nervous system. These features are crucial for fast traveling of nerve impulses with minimal attenuation required for sound signal transmission. In particular, the long-range projections from the cochlear nucleus – the axons of globular bush cells (GBCs) – to the medial nucleus of the trapezoid body (MNTB) are tonotopically organized. However, it remains controversial in gerbils and mice whether structural and functional adaptations are present among the GBC axons targeting different MNTB frequency regions. By means of high-throughput volume electron microscopy, we compared the GBC axons in full-tonotopy-ranged MNTB slices from the C57BL/6 mice at different ages. Our quantification reveals distinct caliber diameter and myelin profile of the GBC axons with endings at lateral and medial MNTB, arguing for modulation of functionally heterogeneous axon subgroups. In addition, we reported axon-specific differences in axon caliber, node of Ranvier, and myelin sheath among juvenile, adult, and old mice, indicating the age-related changes of GBC axon morphology over time. These findings provide structural insight into the maturation and degeneration of GBC axons with frequency tuning across the lifespan of mice. [Display omitted] • This study presented a volume EM reconstruction of whole-frequency MNTB in mice. • It revealed distinct caliber diameter and myelin profile of HF and LF-GBC axons. • Changes of Ranvier's node, internode and myelin from GBC axons occur in adult mice. • Diameter of Ranvier's nodes and internodes changes during development and aging. • Myelin thickness of GBC axons increases during development and aging process. [ABSTRACT FROM AUTHOR]

We assessed aging hallmarks in skin, muscle, and adipose in the genetically diverse HET3 mouse, and generated a broad dataset comparing these to individual animal diagnostic SNPs from the 4 founding inbred strains of the HET3 line. For middle- and old-aged HET3 mice, we provided running wheel exercise to ensure our observations were not purely representative of sedentary animals, but age-related phenotypes were not improved with running wheel activity. Adipose tissue fibrosis, peripheral neuropathy, and loss of neuromuscular junction integrity were consistent phenotypes in older-aged HET3 mice regardless of physical activity, but aspects of these phenotypes were moderated by the SNP% contributions of the founding strains for the HET3 line. Taken together, the genetic contribution of founder strain SNPs moderated age-related phenotypes in skin and muscle innervation and were dependent on biological sex and chronological age. However, there was not a single founder strain (BALB/cJ, C57BL/6J, C3H/HeJ, DBA/2J) that appeared to drive more protection or disease-risk across aging in this mouse line, but genetic diversity in general was more protective. [Display omitted] • Genetically diverse HET3 mice are susceptible to age-related neuromuscular decline. • Voluntary exercise was ineffective at preventing age-related neuromuscular decline. • Relative contributions of HET3 founder strain genetics moderated neuropathy onset. [ABSTRACT FROM AUTHOR]

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE -ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE -ε4 status on cross-sectional naming performance (β = −0.002, p = 0.002), and executive function excluding outliers (β = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (β = 0.002, p = 0.05). While cross-sectional models stratified by APOE -ε4 status indicated greater ePVS related to worse cognition mostly in APOE -ε4 carriers, longitudinal models stratified by APOE -ε4 status showed greater ePVS volume related to worse cognition among APOE -ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE- ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE -ε4 non-carriers, possibly due to the deleterious effects of APOE -ε4 on cognition across the lifespan. • ePVS volume interacts with APOE- ε4 status on cognition cross-sectionally. • Greater ePVS relates to worse cognition in APOE -ε4 carriers cross-sectionally. • No interaction between ePVS volume and APOE- ε4 status on cognition longitudinally. [ABSTRACT FROM AUTHOR]

Neural tracking of spoken speech is considered a potential clinical biomarker for speech-processing difficulties, but the reliability of neural speech tracking is unclear. Here, younger and older adults listened to stories in two sessions while electroencephalography was recorded to investigate the reliability and generalizability of neural speech tracking. Speech tracking amplitude was larger for older than younger adults, consistent with an age-related loss of inhibition. The reliability of neural speech tracking was moderate (ICC ∼0.5–0.75) and tended to be higher for older adults. However, reliability was lower for speech tracking than for neural responses to noise bursts (ICC >0.8), which we used as a benchmark for maximum reliability. Neural speech tracking generalized moderately across different stories (ICC ∼0.5–0.6), which appeared greatest for audiobook-like stories spoken by the same person. Hence, a variety of stories could possibly be used for clinical assessments. Overall, the current data are important for developing a biomarker of speech processing but suggest that further work is needed to increase the reliability to meet clinical standards. • Neural speech tracking is a potential EEG biomarker for impaired speech processing. • However, reliability and generalizability of neural speech tracking are unclear. • Younger and older adults show moderate reliability of neural speech tracking. • Neural tracking also moderately generalized across speech materials. • Current results are critical for the development of a biomarker of speech processing. [ABSTRACT FROM AUTHOR]

Episodic memory performance declines with increasing age, and older adults typically show reduced activation of inferior temporo-parietal cortices in functional magnetic resonance imaging (fMRI) studies of episodic memory formation. Given the age-related cortical volume loss, it is conceivable that age-related reduction of memory-related fMRI activity may be partially attributable to reduced grey matter volume (GMV). We performed a voxel-wise multimodal neuroimaging analysis of fMRI correlates of successful memory encoding, using regional GMV as covariate. In a large cohort of healthy adults (106 young, 111 older), older adults showed reduced GMV across the entire neocortex and reduced encoding-related activation of inferior temporal and parieto-occipital cortices compared to young adults. Importantly, these reduced fMRI activations during successful encoding could in part be attributed to lower regional GMV. Our results highlight the importance of controlling for structural MRI differences in fMRI studies in older adults but also demonstrate that age-related differences in memory-related fMRI activity cannot be attributed to structural variability alone. [Display omitted] • Structural differences in distinct age groups may in part explain fMRI differences. • We included voxel-wise GMV into models of the fMRI subsequent memory effect. • Reduced encoding-related activations could in part be attributed to lower local GMV. • Care is advised when modelling fMRI effects for groups with structural differences. • Structural modalities may in part explain alleged differences in function. [ABSTRACT FROM AUTHOR]

We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins. SN DA neurons contained two types of IMPDH structures: cytoplasmic IMPDH filaments and intranuclear IMPDH inclusions. The former were not age-restricted and may represent functional units involved in sustaining purine nucleotide supply in these highly metabolically active cells. The latter showed age-associated changes, including crystallization, features reminiscent of pathological inclusion bodies, and spatial associations with Marinesco bodies; structures previously associated with SN neuron dysfunction and death. We postulate dichotomous roles for these two subcellularly distinct IMPDH structures and propose a nucleus-based model for a novel mechanism of SN senescence that is independent of previously known neurodegeneration-associated proteins. [Display omitted] • Human SN neurons contain inosine monophosphate dehydrogenase (IMPDH) filaments. • SN cytoplasmic IMPDH filaments show contacts with mitochondria. • SN neurons develop nuclear IMPDH inclusion bodies which increase with age. • SN nuclear IMPDH inclusions associate with Marinesco bodies. • Nuclear IMPDH inclusions may contribute to age-related SN neuron loss. [ABSTRACT FROM AUTHOR]

Healthy aging is typically accompanied by cognitive decline. Previous work has shown that engaging in multiple, non-work activities during midlife can have a protective effect on cognition several decades later, rendering it less dependent on brain structural health; the definition of "cognitive reserve". Other work has shown that increasing age is associated with reduced segregation of large-scale brain functional networks. Here we tested the hypothesis that functional segregation (SyS) mediates this effect of middle-aged lifestyle on late-life cognition. We used fMRI data from three tasks in the CamCAN dataset, together with cognitive data on fluid intelligence, episodic memory, and retrospective lifestyle data from the Lifetime of Experiences Questionnaire (LEQ). In all three tasks, we showed that SyS related to fluid intelligence even after adjusting for the (nonlinear) age effects. However, we found no evidence that SyS in late-life mediated the relationship between non-specific (non-occupation) midlife activities and either measure of cognition in late-life. Thus, the brain correlates of cognitive reserve arising from mid-life activities remain to be discovered. • System segregation (SyS) is stable across different brain states. • SyS is negatively associated with age. • Fluid intelligence, but not episodic memory, was robustly predicted by SyS. • Late life SyS was not associated with midlife outside of work activities. [ABSTRACT FROM AUTHOR]

While capacity for motor skill acquisition changes with healthy aging, there has been little consideration of how age-related changes in brain function or baseline brain structure support motor skill acquisition. We examined: (1) age-dependent changes in functional reorganization related to frontoparietal regions during motor skill acquisition, and (2) whether capacity for motor skill acquisition relates to baseline white matter microstructure in frontoparietal tracts. Healthy older and younger adults engaged in 4 weeks of skilled motor practice. Resting-state functional connectivity (rsFC) assessed functional reorganization before and after practice. Diffusion tensor imaging indexed microstructure of a frontoparietal tract at baseline, generated by rsFC seeds. Motor skill acquisition was associated with decreases in rsFC in healthy older adults and increases in rsFC in healthy younger adults. Frontoparietal tract microstructure was lower in healthy older versus younger adults, yet it was negatively associated with rate of skill acquisition regardless of group. Findings indicate that age-dependent alterations in frontoparietal function and baseline structure of a frontoparietal tract reflect capacity for motor skill acquisition. [ABSTRACT FROM AUTHOR]

In the present study we investigated whether hippocampal subfield (cornu ammonis 1–3, dentate gyrus, and subiculum) and anteroposterior hippocampal subregion (head,body, and tail) volumes can predict episodic memory function using high-field high resolution structural magnetic resonance imaging (MRI). We recruited 126 healthy participants (18–85 years). MRI datasets were collected on a 4.7 T system. Participants were administered the Wechsler Memory Scale (WMS–IV) to evaluate episodic memory function. Structural equation modeling was used to test the relationship between studied variables. We found that the volume of the dentate gyrus subfield and posterior hippocampus (body) showed a significant direct effect on visuospatial memory performance; additionally, an indirect effect of age on visuospatial memory mediated through these hippocampal subfield/subregion was significant. Logical and verbal memory were not significantly associated with hippocampal subfield or subregion volumes. [ABSTRACT FROM AUTHOR]

Evidence indicates that dysfunction of older Schwann cells and macrophages contributes to poor regeneration of more mature peripheral nervous system (PNS) neurons after damage. Since the underlying molecular factors are largely unknown, we investigated if CRYAB, a small heat shock protein that is expressed by Schwann cells and axons and whose expression declines with age, impacts prominent deficits in the injured, older PNS including down-regulation of cholesterol biosynthesis enzyme genes, Schwann cell dysfunction, and macrophage persistence. Following sciatic nerve transection injury in 3- and 12-month-old wildtype and CRYAB knockout mice, we found by bulk RNA sequencing and RT-PCR, that while gene expression of cholesterol biosynthesis enzymes is markedly dysregulated in the aging, injured PNS, CRYAB is not involved. However, immunohistochemical staining of crushed sciatic nerves revealed that more macrophages of the pro-inflammatory but not immunosuppressive phenotype persisted in damaged 12-month-old knockout nerves. These pro-inflammatory macrophages were more efficient at engulfing myelin debris. CRYAB thus appears to play a role in resolving pro-inflammatory macrophage responses after damage to the older PNS. [ABSTRACT FROM AUTHOR]