Aging brain最新文献

Age-related white matter degeneration is characterized by myelin breakdown and neuronal fiber loss that preferentially occur in regions that myelinate later in development. Conventional diffusion MRI (dMRI) has demonstrated age-related increases in diffusivity but provides limited information regarding the tissue-specific changes driving these effects. A recently developed dMRI biophysical modeling technique, Fiber Ball White Matter (FBWM) modeling, offers enhanced biological interpretability by estimating microstructural properties specific to the intra-axonal and extra-axonal spaces. We used FBWM to illustrate the biological mechanisms underlying changes throughout white matter in healthy aging using data from 63 cognitively unimpaired adults ages 45–85 with no radiological evidence of neurodegeneration or incipient Alzheimer’s disease. Conventional dMRI and FBWM metrics were computed for two late-myelinating (genu of the corpus callosum and association tracts) and two early-myelinating regions (splenium of the corpus callosum and projection tracts). We examined the associations between age and these metrics in each region and tested whether age was differentially associated with these metrics in late- vs. early-myelinating regions. We found that conventional metrics replicated patterns of age-related increases in diffusivity in late-myelinating regions. FBWM additionally revealed specific intra- and extra-axonal changes suggestive of myelin breakdown and preferential loss of smaller-diameter axons, yielding in vivo corroboration of findings from histopathological studies of aged brains. These results demonstrate that advanced biophysical modeling approaches, such as FBWM, offer novel information about the microstructure-specific alterations contributing to white matter changes in healthy aging. These tools hold promise as sensitive indicators of early pathological changes related to neurodegenerative disease.

Gray matter networks are altered with amyloid accumulation in the earliest stage of AD, and are associated with decline throughout the AD spectrum. It remains unclear to what extent gray matter network abnormalities are associated with hyperphosphorylated-tau (p-tau). We studied the relationship of cerebrospinal fluid (CSF) p-tau181 with gray matter networks in non-demented participants from the European Prevention of Alzheimer’s Dementia (EPAD) cohort, and studied dependencies on amyloid and cognitive status. Gray matter networks were extracted from baseline structural 3D T1w MRI. P-tau181 and abeta were measured with the Roche cobas Elecsys System. We studied the associations of CSF biomarkers levels with several network’s graph properties. We further studied whether the relationships of p-tau 181 and network measures were dependent on amyloid status and cognitive stage (CDR). We repeated these analyses for network properties at a regional level, where we averaged local network values across cubes within each of 116 areas as defined by the automated anatomical labeling (AAL) atlas. Amyloid positivity was associated with higher network size and betweenness centrality, and lower gamma, clustering and small-world coefficients. Higher CSF p-tau 181 levels were related to lower betweenness centrality, path length and lambda coefficients (all p < 0.01). Three-way interactions between p-tau181, amyloid status and CDR were found for path length, lambda and clustering (all p < 0.05): Cognitively unimpaired amyloid-negative participants showed lower path length and lambda values with higher CSF p-tau181 levels. Amyloid-positive participants with impaired cognition demonstrated lower clustering coefficients in association to higher CSF p-tau181 levels.

Our results suggest that alterations in gray matter network clustering coefficient is an early and specific event in AD.

Age-related sensory decline impacts cognitive performance and exposes individuals to a greater risk of cognitive decline. Integration across the senses also changes with age, yet the link between multisensory perception and cognitive ageing is poorly understood. We explored the relationship between multisensory integration and cognitive function in 2875 adults aged 50 + from The Irish Longitudinal Study on Ageing. Multisensory integration was assessed at several audio-visual temporal asynchronies using the Sound Induced Flash Illusion (SIFI). More precise integration (i.e. less illusion susceptibility with larger temporal asynchronies) was cross-sectionally associated with faster Choice Response Times and Colour Trail Task performance, and fewer errors on the Sustained Attention to Response Task. We then used k-means clustering to identify groups with different 10-year cognitive trajectories on measures available longitudinally; delayed recall, immediate recall and verbal fluency. Across measures, groups with consistently higher performance trajectories had more precise multisensory integration. These findings support broad links between multisensory integration and several cognitive measures, including processing speed, attention and memory, rather than association with any specific subdomain.

Recent reports document sex differences in midlife brain integrity and metabolic health, such that more relationships are detectable between metabolic syndrome (MetS) components and markers of brain health in females than in males. Midlife is characterized by a rapid decrease in endogenous estrogen levels for women which is thought to increase risk for cardiometabolic disease and neurocognitive decline. Our study used network models, designed to explore the interconnectedness and organization of relationships among many variables at once, to compare the influence of endogenous estrogen and chronological age on a network of brain and metabolic health in order to investigate the utility of estrogen as a biomarker for brain vulnerability. Data were analyzed from 82 females (ages 40–62). Networks consisted of known biomarkers of risk for late-life cognitive decline: the five components of MetS; Brain-predicted age difference calculated on gray and white matter volume; white matter hyperintensities; Default Mode Network functional connectivity; cerebral concentrations of N-acetyl aspartate, glutamate and myo-inositol; and serum concentrations of estradiol. A second network replaced estradiol with chronological age. Expected influence (EI) of estradiol on the network was −1.190, relative to chronological age at −0.524, indicating that estradiol had a stronger expected influence over the network than age. A negative expected influence indicates that higher levels of estradiol would be expected to decrease the number of relationships in the model, which is thought to indicate lower risk. Overall, levels of estradiol appear more influential than chronological age at midlife for relationships between brain integrity and metabolic health.

Background

Despite the life-course perspective of popular aging models, few studies on healthy aging to date have examined both younger and older adulthood. The current study examined how cumulative vascular risk factors and self-reported levels of physical, social, and cognitive activity are associated with differences in hippocampal volumes in healthy younger and older adults.

Methods

34 neurologically healthy participants were separated into two age cohorts: a younger adult group (age 25–35, n = 17) and an older adult group (age 65–82, n = 17). Participants underwent a 3 T T1 MRI and completed a series of questionnaires. Voxel-based morphometry examined whole-brain grey matter density differences between groups. Hippocampal volumes were computed. Analyses examined the association between hippocampal volumes, cumulative vascular risk, and self-reported levels of physical, social, and cognitive activity, both within and across groups.

Results

Between-group comparisons revealed greater cortical atrophy in older relative to young adults in regions including the left and right hippocampus and temporal fusiform cortex. Across-group analyses revealed a significant negative association between cardiovascular risk scores and bilateral hippocampal volumes across age groups. A significant negative association was identified between frequency of social activities and bilateral hippocampal volumes in older adults only. No significant associations were found between left or right hippocampal volumes and total, cognitive, or physical activities in both within- and across-group analyses.

Conclusion

Greater cumulative vascular risk is associated with smaller hippocampal volumes across age cohorts. Findings suggest that social activities with low cognitive load may not be beneficial to structural brain outcomes in older age.

Experiencing decline in one’s cognitive abilities is among the most feared aspects of growing old [53]. Age-related cognitive decline carries a huge personal, societal, and financial cost both in pathological ageing (such as dementias) and also within the non-clinical majority of the population. A projected 152 million people worldwide will suffer from dementia by 2050 [3]. The early stages of cognitive decline are much more prevalent than dementia, and can still impose serious limitations of performance on everyday activities, independence, and quality of life in older age [5], [60], [80]. Cognitive decline also predicts poorer health, adherence to medical regimens, and financial decision-making, and can herald dementia, illness, and death [6], [40]. Of course, when seeking to understand why some people experience more severe cognitive ageing than others, researchers have turned to the organ of thinking for clues about the nature, possible mechanisms, and determinants that might underpin more and less successful cognitive agers. However, that organ is relatively inaccessible, a limitation partly alleviated by advances in neuroimaging. Here we discuss lessons for cognitive and brain ageing that have come from neuroimaging research (especially structural brain imaging), what neuroimaging still has left to teach us, and our views on possible ways forward in this multidisciplinary field.

Docosahexaenoic acid (DHA) consumption reduces spatial memory impairment in mice carrying the human apolipoprotein E ε4 (APOE4) allele. The current study evaluated whether astrocyte and microglia morphology contribute to the mechanism of this result. APOE3 and APOE4 mice were fed either a DHA-enriched diet or a control diet from 4 to 12 months of age. Coronal brain sections were immunostained for GFAP, Iba1, and NeuN. Astrocytes from APOE4 mice exhibited signs of reactive astrogliosis compared to APOE3 mice. Consumption of DHA exacerbated reactive astrocyte morphology in APOE4 carriers. Microglia from APOE4-control mice exhibited characteristics of amoeboid morphology and other characteristics of ramified morphology (more processes, greater process complexity, and greater distance between neighboring microglia). DHA enhanced ramified microglia morphology in APOE4 mice. In addition, APOE4 mice fed the DHA diet had lower hippocampal concentrations of interleukin-7, lipopolysaccharide-induced CXC chemokine and monocyte chemoattractant protein 1, and higher concentration of interferon-gamma compared to APOE4-control mice. Our results indicate that a diet rich in DHA enhances reactive astrogliosis and ramified microglia morphology in APOE4 mice.

Brain maintenance has been identified as a major determinant of successful memory aging. However, the extent to which brain maintenance in support of successful memory aging is specific to memory-related brain regions or forms part of a brain-wide phenomenon is unresolved. Here, we used longitudinal brain-wide gray matter MRI volumes in 262 healthy participants aged 55 to 80 years at baseline to investigate separable dimensions of brain atrophy, and explored the links of these dimensions to different dimensions of cognitive change. We statistically adjusted for common causes of change in both brain and cognition to reveal a potentially unique signature of brain maintenance related to successful memory aging. Critically, medial temporal lobe (MTL)/hippocampal change and episodic memory change were characterized by unique, residual variance beyond general factors of change in brain and cognition, and a reliable association between these two residualized variables was established (r = 0.36, p < 0.01). The present study is the first to provide solid evidence for a specific association between changes in (MTL)/hippocampus and episodic memory in normal human aging. We conclude that hippocampus-specific brain maintenance relates to the specific preservation of episodic memory in old age, in line with the notion that brain maintenance operates at both general and domain-specific levels.

Cell cycle proteins play essential roles in regulating embryonic and adult neurogenesis in the mammalian brain. A key example is the Retinoblastoma protein (Rb) whose loss disrupts the whole neurogenic program during brain development, but only results in increased progenitor proliferation in the adult subventricular zone (SVZ) and compromised long-term neuronal survival in the adult olfactory bulb (OB). Whether this holds true of neurogenesis in the aged brain remains unknown. In this study, we find no evidence of irregular proliferation or early commitment defects in the mid-aged (12-month-old) and old-aged (20-month-old) SVZ following tamoxifen-inducible Rb knockout (Rb iKO) in mice. However, we highlight a striking defect in early maturation of Rb-deficient migrating neuroblasts along the rostral migratory stream (RMS), followed by massive decline in neuronal generation inside the aged OB. In the absence of Rb, we also show evidence of incomplete cell cycle re-entry (CCE) along with DNA damage in the young OB, while we find a similar trend towards CCE but no clear signs of DNA damage or neurodegenerative signatures (pTau or Synuclein accumulation) in the aged OB. However, such phenotype could be masked by the severe maturation defect reported above in addition to the natural decline in adult neurogenesis with age. Overall, we show that Rb is required to prevent CCE and DNA damage in adult-born OB neurons, hence maintain neuronal survival. Moreover, while loss of Rb alone is insufficient to trigger seeding of neurotoxic species, this study reveals age-dependent non-monotonic dynamics in regulating neurogenesis by Rb.