Aging brain最新文献

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.

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.

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.

We investigated how the aging brain copes with acoustic and syntactic challenges during spoken language comprehension. Thirty-eight healthy adults aged 54 – 80 years (M = 66 years) participated in an fMRI experiment wherein listeners indicated the gender of an agent in short spoken sentences that varied in syntactic complexity (object-relative vs subject-relative center-embedded clause structures) and acoustic richness (high vs low spectral detail, but all intelligible). We found widespread activity throughout a bilateral frontotemporal network during successful sentence comprehension. Consistent with prior reports, bilateral inferior frontal gyrus and left posterior superior temporal gyrus were more active in response to object-relative sentences than to subject-relative sentences. Moreover, several regions were significantly correlated with individual differences in task performance: Activity in right frontoparietal cortex and left cerebellum (Crus I & II) showed a negative correlation with overall comprehension. By contrast, left frontotemporal areas and right cerebellum (Lobule VII) showed a negative correlation with accuracy specifically for syntactically complex sentences. In addition, laterality analyses confirmed a lack of hemispheric lateralization in activity evoked by sentence stimuli in older adults. Importantly, we found different hemispheric roles, with a left-lateralized core language network supporting syntactic operations, and right-hemisphere regions coming into play to aid in general cognitive demands during spoken sentence processing. Together our findings support the view that high levels of language comprehension in older adults are maintained by a close interplay between a core left hemisphere language network and additional neural resources in the contralateral hemisphere.

Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric—fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO—is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer’s disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.

Alzheimer’s disease (AD) is one of the most persistent and devastating neurodegenerative disorders of old age, and is characterized clinically by an insidious onset and a gradual, progressive deterioration of cognitive abilities, ranging from loss of memory to impairment of judgement and reasoning. Despite years of research, an effective cure is still not available. Autophagy is the cellular ‘garbage’ clearance system which plays fundamental roles in neurogenesis, neuronal development and activity, and brain health, including memory and learning. A selective sub-type of autophagy is mitophagy which recognizes and degrades damaged or superfluous mitochondria to maintain a healthy and necessary cellular mitochondrial pool. However, emerging evidence from animal models and human samples suggests an age-dependent reduction of autophagy and mitophagy, which are also compromised in AD. Upregulation of autophagy/mitophagy slows down memory loss and ameliorates clinical features in animal models of AD. In this review, we give an overview of autophagy and mitophagy and their link to the progression of AD. We also summarize approaches to upregulate autophagy/mitophagy. We hypothesize that age-dependent compromised autophagy/mitophagy is a cause of brain ageing and a risk factor for AD, while restoration of autophagy/mitophagy to more youthful levels could return the brain to health.

Recent evidence suggests that physical activity may influence the functional connectivity of the aging brain. The purpose of this study was to examine the influence of physical activity on the association between executive function and functional connectivity of key brain networks and graph theory metrics in community-dwelling older adults. Participants were 47 older adults (M = 73 years; SD = 5.92) who participated in neuropsychological testing, physical activity measurements, and magnetic resonance imaging (MRI). Seed-to-voxel moderation analyses and graph theory analyses were conducted. Physical activity was significantly positively associated with default mode network functional connectivity (DMN FC; Posterior Cingulate Gyrus, p-FDR = 0.005; Frontal Pole (L), p-FDR = 0.005; Posterior Cingulate Gyrus, p-FDR = 0.006; Superior Frontal Gyrus (L), p-FDR = 0.016) and dorsal attention network functional connectivity (DAN FC; Inferior Frontal Gyrus Pars Opercularis (R), p-FDR = 0.044). The interaction between physical activity and executive function on the DMN FC and DAN FC was analyzed. The interaction between executive function and physical activity was significantly associated with DMN FC. When this significant interaction was probed, the association between physical activity and DMN FC differed between levels of high and low executive function such that the association was only significant at levels of high executive function. These results suggest that greater physical activity in later life is associated with greater DMN and DAN FC and provides evidence for the importance of physical activity in cognitively healthy older adults.

Increase in the brain expression of the 18 kDa translocator protein (TSPO) is considered as a marker of neuroinflammation in the context of brain diseases, such as Alzheimer’s disease (AD). However, in non-demented subjects with Alzheimer’s neuropathology, TSPO accumulation in hippocampus subdivisions has not been fully characterized.

To determine if TSPO is associated with the presence of amyloid β plaques and/or phosphorylated Tau accumulation, we analyzed hippocampal sections using immunohistochemistry of 14 non-demented subjects with positive staining for Aβ and/or phosphorylated Tau. TSPO expression was heterogenous with higher accumulation in the CA2/3 and subiculum subfields of the hippocampus. Its distribution closely resembled that of the microglial IBA1 marker and of the Aβ42 amyloid form. In addition, positive correlations were observed between TSPO and IBA1 densities in CA4, CA2/3 and the subiculum but not with either the astrocyte GFAP marker or the AD-type Aβ and Tau markers. This study sustains the hypothesis that TSPO is mainly associated with microglia and in Aβ42-rich subdivisions in the hippocampus of non-demented elderly individuals.