Age-related Brain Alterations Research Articles

Accelerated aging in mice with astrocytic redox imbalance as a consequence of SOD2 deletion.

Aging of the central nervous system (CNS) leads to motoric and cognitive decline and increases the probability for neurodegenerative disease development. Astrocytes fulfill central homeostatic functions in the CNS including regulation of immune responses and metabolic support of neurons and oligodendrocytes. In this study, we investigated the effect of redox imbalance in astrocytes by using a conditional astrocyte-specific SOD2-deficient mouse model (SOD2ako ) and analyzed these animals at different stages of their life. SOD2ako mice did not exhibit any overt phenotype within the first postnatal weeks. However, already as young adults, they displayed progressive motoric impairments. Moreover, as these mice grew older, they exhibited signs of a progeroid phenotype and early death. Histological analysis in moribund SOD2ako mice revealed the presence of age-related brain alterations, neuroinflammation, neuronal damage and myelin impairment in brain and spinal cord. Additionally, transcriptome analysis of primary astrocytes revealed that SOD2 deletion triggered a hypometabolic state and promoted polarization toward A1-neurotoxic status, possibly underlying the neuronal and myelin deficits. Conclusively, our study identifies maintenance of ROS homeostasis in astrocytes as a critical prerequisite for physiological CNS aging.

Novel therapeutic approaches to target neurodegeneration.

Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been considered as causative events in neurodegeneration, several other biological pathways affected by brain ageing also contribute to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism and neuroinflammation in the onset and progression of neurodegenerative disorders. Furthermore, we review the therapeutic strategies currently under development or as future approaches designed to normalize these pathways, which may then increase brain resilience to cope with toxic protein species. In addition to therapies targeting the insoluble protein aggregates specifically associated with each neurodegenerative disorder, these novel pharmacological approaches may be part of combined therapies designed to rescue brain function.

AGING-ASSOCIATED COGNITIVE DECLINE IS REVERSED BY D-SERINE SUPPLEMENTATION.

Brain aging is a natural process that involves structural and functional changes that lead to cognitive decline, even in healthy subjects. This detriment has been associated with NMDA receptor (NMDAR) hypofunction because of a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear whether D-serine supplementation could be used as an intervention to reduce or reverse age-related brain alterations. In the present work, we aimed to analyze the D-serine effect on aging-associated alterations in cellular and large-scale brain systems that could support cognitive flexibility in rats. We found that D-serine supplementation reverts the age-related decline in cognitive flexibility, frontal dendritic spine density, and partially restored large-scale functional connectivity without inducing nephrotoxicity; instead, D-serine restored the thickness of the renal epithelial cells that were affected by age. Our results suggest that D-serine could be used as a therapeutic target to reverse age-related brain alterations.

Design of the Shunyi study on cardiovascular disease and age-related brain changes: a community-based, prospective, cohort study.

BackgroundRapid economic growth and increasing lifespan have contributed to an increasing burden of chronic non-communicable diseases in China. Population-based studies focusing on cardiovascular disease and age-related brain changes, with extensive clinical, genetic, and imaging data as well as a comprehensive evaluation of brain function are lacking in China. The Shunyi cohort study aimed to investigate the determinants and consequences of cardiovascular disease and age-related brain alterations among individuals residing in a rural area of Beijing.MethodsThis prospective, community-based study included individuals aged 35 years and older living in five villages in Shunyi, a rural district located 20 miles from urban Beijing. A total of 1,586 individuals were enrolled between June 2013 and September 2014. Biological samples and brain magnetic resonance images were collected along with baseline clinical data through face-to-face interviews. Whole exome sequencing and quantitative assessments of cognitive and motor function were performed.ResultsAmong the 1,586 participants included, 40% were men, and the mean age of the cohort was 56.7±10.0 years. This population had a relatively low education level. A heavy burden of vascular risk factors with a low control rate was observed in the Shunyi population. Since 2017, the cohort has been followed up annually. As of October 2019, we had failed to obtain the follow-up data of five participants.ConclusionsWith an extensive range of clinical, genetic, and imaging data, the Shunyi cohort study has the potential to contribute significantly towards identifying the causes and consequences of cardiovascular disease and age-related brain changes in older people in China.

IMPROVEMENT THROUGH MOVEMENT: INVESTIGATING FITNESS, FUNCTIONAL CONNECTIVITY, AND COGNITION IN OLDER ADULTS

As the U.S. population has grown older, it has become increasingly crucial to understand age-related brain alterations in an effort to ameliorate and protect against normal, and especially abnormal, decline. Prior research suggests that physical activity acts on and benefits similar cognitive constructs most commonly affected by cognitive aging. PURPOSE: The purpose of this investigation was to advance understanding of functional connectivity as a possible mechanism by which fitness protects and restores brain function. METHODS: Data were collected as a part of the “Fit and Active Seniors Trial” between 2015-2018. We evaluated functional brain changes in participants before and after they took part in an exercise intervention. Seventy-seven older adults that had pre- and post-intervention MRI scans, fitness data, and behavioral data were included. All participants (age range: 60 - 80 years, 69% female) were randomized into either an aerobic walking group (n=34) or active control stretching and toning group (n=43) that met three times a week for six months. RESULTS: Cardiorespiratory fitness (measured by VO2 peak) significantly improved within-groups pre/post (p=.001), but not between-groups (p=.374). Multi-voxel pattern analysis (MVPA) was performed on the resting-state functional MRI scans to detect variability in whole-brain patterns of connectivity. There were no significant between-group differences in functional connectivity at pre-test. However, several significant clusters in the Default Mode Network were identified between-groups at the 6-month post-intervention, including regions of the hippocampus (height threshold p<0.001, cluster threshold p<0.05 corrected for false discovery rate). These MVPA-derived hippocampal voxels were then used for whole-brain seed-to-voxel analysis for post-hoc characterization, and results indicated that increases in between-group functional connectivity were driven by the walking group (p<0.01). CONCLUSION: This research adds to the understanding of the mechanism by which physical activity protects and restores brain function, which ultimately could lead to efforts preventing, minimizing, and improving age-related cognitive decline.

Sex-specific patterns of age-related cerebral atrophy in a nonhuman primate Microcebus murinus

Steadily aging populations result in a growing need for research regarding age-related brain alterations and neurodegenerative pathologies. By allowing a good translation of results to humans, nonhuman primates, such as the gray mouse lemur Microcebus murinus, have gained attention in this field. Our aim was to examine correlations between atrophy-induced brain alterations and age, with special focus on sex differences in mouse lemurs. For cerebral volumetric measurements, in vivo magnetic resonance imaging was performed on 59 animals (28♀♀/31♂♂) aged between 1.0 to 11.9 years. Volumes of different brain regions, cortical thicknesses, and ventricular expansions were evaluated. Analyses revealed significant brain atrophies with increasing age, particularly around the caudate nucleus, the thalamus, and frontal, parietal, and temporo-occipital regions. Especially old females showed a strong decline in cingulate cortex thickness and had higher values of ventricular expansion, whereas cortical thickness of the splenium and occipital regions decreased mainly in males. Our study, thus, provides first evidence for sex-specific, age-related brain alterations in a nonhuman primate, suggesting that mouse lemurs can help elucidating the mechanism underlying sex disparities in cerebral aging, for which there is mixed evidence in humans.

Preserved wake-dependent cortical excitability dynamics predict cognitive fitness beyond age-related brain alterations

Age-related cognitive decline arises from alterations in brain structure as well as in sleep-wake regulation. Here, we investigated whether preserved wake-dependent regulation of cortical function could represent a positive factor for cognitive fitness in aging. We quantified cortical excitability dynamics during prolonged wakefulness as a sensitive marker of age-related alteration in sleep-wake regulation in 60 healthy older individuals (50–69 y; 42 women). Brain structural integrity was assessed with amyloid-beta- and tau-PET, and with MRI. Participants’ cognition was investigated using an extensive neuropsychological task battery. We show that individuals with preserved wake-dependent cortical excitability dynamics exhibit better cognitive performance, particularly in the executive domain which is essential to successful cognitive aging. Critically, this association remained significant after accounting for brain structural integrity measures. Preserved dynamics of basic brain function during wakefulness could therefore be essential to cognitive fitness in aging, independently from age-related brain structural modifications that can ultimately lead to dementia.

Age-related differences in neural spectral power during motor learning

We investigated how older adults preserve the capability to acquire new motor skills in the face of age-related brain alterations. We assessed neural changes associated with learning a bimanual coordination task over 4 days of practice in healthy young (n = 24) and older adults (n = 24). The electroencephalogram was recorded during task performance at the start and end of training. Motor performance improved with practice in both groups, but the amount of learning was lower in the older adults. Beta power (15–30 Hz) in sensorimotor and prefrontal cortices of older adults was reduced with training, indicative of higher neural activity. We also found a functional reorganization after training in beta and alpha (8–12 Hz) bands. Between-session changes in alpha and beta power differed between groups in several cortical areas: young adults exhibited reduced power in the beta band in sensorimotor cortices, whereas older adults displayed a smaller decrease. Our findings indicate a less flexible reorganization of neural activity accompanying learning in older adults compared with young adults.

Sleep-related brain atrophy and disrupted functional connectivity in older adults

Aging associates with sleep dysfunction as well as brain alterations. However, the association between age-related brain alterations and their subjective sleep changes is less understood. To address this issue, we recorded T1 weighted structural and resting-state functional magnetic resonance imaging from both young (n = 62) and older adults (n = 108). In addition, all participants completed a battery of psychometric tests, including the Pittsburg Sleep Quality Index. We found that the age-related atrophy of cerebral gray matter, hippocampal and thalamic volume were associated with subjective sleep decline, and the atrophy of cerebral gray matter mediated the age effect on sleep. In addition, older adults exhibited decreased functional connectivity within the medial temporal lobe subsystem than their young counterparts. Moreover, there is a significant positive association between sleep and functional connectivity in young but not in older adults. In light of our findings, we suggest a neuropathological model in which age-related brain alterations may partially explain the well-documented declines in sleep with aging.

Switching between hands in a serial reaction time task: a comparison between young and old adults.

Healthy aging is associated with a variety of functional and structural brain alterations. These age-related brain alterations have been assumed to negatively impact cognitive and motor performance. Especially important for the execution of everyday activities in older adults (OA) is the ability to perform movements that depend on both hands working together. However, bimanual coordination is typically deteriorated with increasing age. Hence, a deeper understanding of such age-related brain-behavior alterations might offer the opportunity to design future interventional studies in order to delay or even prevent the decline in cognitive and/or motor performance over the lifespan. Here, we examined to what extent the capability to acquire and maintain a novel bimanual motor skill is still preserved in healthy OA as compared to their younger peers (YA). For this purpose, we investigated performance of OA (n = 26) and YA (n = 26) in a bimanual serial reaction time task (B-SRTT), on two experimental sessions, separated by 1 week. We found that even though OA were generally slower in global response times, they showed preserved learning capabilities in the B-SRTT. However, sequence specific learning was more pronounced in YA as compared to OA. Furthermore, we found that switching between hands during B-SRTT learning trials resulted in increased response times (hand switch costs), a phenomenon that was more pronounced in OA. These hand switch costs were reduced in both groups over the time course of learning. More interestingly, there were no group differences in hand switch costs on the second training session. These results provide novel evidence that bimanual motor skill learning is capable of reducing age-related deficits in hand switch costs, a finding that might have important implications to prevent the age-related decline in sensorimotor function.

Augmenting mirror visual feedback‐induced performance improvements in older adults

Previous studies have indicated that age-related behavioral alterations are not irreversible but are subject to amelioration through specific training interventions. Both training paradigms and non-invasive brain stimulation (NIBS) can be used to modulate age-related brain alterations and thereby influence behavior. It has been shown that mirror visual feedback (MVF) during motor skill training improves performance of the trained and untrained hands in young adults. The question remains of whether MVF also improves motor performance in older adults and how performance improvements can be optimised via NIBS. Here, we sought to determine whether anodal transcranial direct current stimulation (a-tDCS) can be used to augment MVF-induced performance improvements in manual dexterity. We found that older adults receiving a-tDCS over the right primary motor cortex (M1) during MVF showed superior performance improvements of the (left) untrained hand relative to sham stimulation. An additional control experiment in participants receiving a-tDCS over the right M1 only (without MVF/motor training of the right hand) revealed no significant behavioral gains in the left (untrained) hand. On the basis of these findings, we propose that combining a-tDCS with MVF might be relevant for future clinical studies that aim to optimise the outcome of neurorehabilitation.

Drinking Hydrogen Water Ameliorated Cognitive Impairment in Senescence-Accelerated Mice

Hydrogen has been reported to have neuron protective effects due to its antioxidant properties, but the effects of hydrogen on cognitive impairment due to senescence-related brain alterations and the underlying mechanisms have not been characterized. In this study, we investigated the efficacies of drinking hydrogen water for prevention of spatial memory decline and age-related brain alterations using senescence-accelerated prone mouse 8 (SAMP8), which exhibits early aging syndromes including declining learning ability and memory. However, treatment with hydrogen water for 30 days prevented age-related declines in cognitive ability seen in SAMP8 as assessed by a water maze test and was associated with increased brain serotonin levels and elevated serum antioxidant activity. In addition, drinking hydrogen water for 18 weeks inhibited neurodegeneration in hippocampus, while marked loss of neurons was noted in control, aged brains of mice receiving regular water. On the basis of our results, hydrogen water merits further investigation for possible therapeutic/preventative use for age-related cognitive disorders.