Aging brain最新文献

It is estimated that short association fibers running immediately beneath the cortex may make up as much as 60 % of the total white matter volume. However, these have been understudied relative to the long-range association, projection, and commissural fibers of the brain. This is largely because of limitations of diffusion MRI fiber tractography, which is the primary methodology used to non-invasively study the white matter connections. Inspired by recent anatomical considerations and methodological improvements in superficial white matter (SWM) tractography, we aim to characterize changes in these fiber systems in cognitively normal aging, which provide insight into the biological foundation of age-related cognitive changes, and a better understanding of how age-related pathology differs from healthy aging. To do this, we used three large, longitudinal and cross-sectional datasets (N = 1293 subjects, 2711 sessions) to quantify microstructural features and length/volume features of several SWM systems. We find that axial, radial, and mean diffusivities show positive associations with age, while fractional anisotropy has negative associations with age in SWM throughout the entire brain. These associations were most pronounced in the frontal, temporal, and temporoparietal regions. Moreover, measures of SWM volume and length decrease with age in a heterogenous manner across the brain, with different rates of change in inter-gyri and intra-gyri SWM, and at slower rates than well-studied long-range white matter pathways. These features, and their variations with age, provide the background for characterizing normal aging, and, in combination with larger association pathways and gray matter microstructural features, may provide insight into fundamental mechanisms associated with aging and cognition.

Prior studies in younger adults showed that reducing the normally high intake of the saturated fatty acid, palmitic acid (PA), in the North American diet by replacing it with the monounsaturated fatty acid, oleic acid (OA), decreased blood concentrations and secretion by peripheral blood mononuclear cells (PBMCs) of interleukin (IL)-1β and IL-6 and changed brain activation in regions of the working memory network. We examined the effects of these fatty acid manipulations in the diet of older adults. Ten subjects, aged 65–75 years, participated in a randomized, cross-over trial comparing 1-week high PA versus low PA/high OA diets. We evaluated functional magnetic resonance imaging (fMRI) using an N-back test of working memory and a resting state scan, cytokine secretion by lipopolysaccharide (LPS)-stimulated PBMCs, and plasma cytokine concentrations. During the low PA compared to the high PA diet, we observed increased activation for the 2-back minus 0-back conditions in the right dorsolateral prefrontal cortex (Broadman Area (BA) 9; p < 0.005), but the effect of diet on working memory performance was not significant (p = 0.09). We observed increased connectivity between anterior regions of the salience network during the low PA/high OA diet (p < 0.001). The concentrations of IL-1β (p = 0.026), IL-8 (p = 0.013), and IL-6 (p = 0.009) in conditioned media from LPS-stimulated PBMCs were lower during the low PA/high OA diet. This study suggests that lowering the dietary intake of PA down-regulated pro-inflammatory cytokine secretion and altered working memory, task-based activation and resting state functional connectivity in older adults.

Habituation is a form of learning characterized by a decrement in responsiveness to a stimulus that is repeated or prolonged. In rodents, habituation to a novel environment is characterized by a decrease in locomotion over time spent in a novel environment. Habituation to a novel environment is dependent on hippocampal function, suggesting that habituation behavior may be a relevant readout for hippocampal-dependent memory deficits that are characteristic of Alzheimer’s disease (AD). Current assays that measure hippocampal-dependent memory in preclinical animal models of AD have not accurately predicted the cognitive protection of novel interventions in human trials. Here, we tested whether a behavioral habituation paradigm could detect age-associated changes in a common preclinical mouse model of AD-like amyloid pathology, the 5XFAD mouse. We exposed 5XFAD mice and age-matched wild-type (WT) littermates at 3, 6, and 9 months of age to a novel environment over two sessions separated by 24 h and measured their locomotion. WT mice habituated to the novel environment over time, while 5XFAD mice displayed age-dependent deficits in behavioral habituation. We replicated our results using publicly available open field data from 5XFAD and late-onset AD mouse models with TREM2*R47H and APOE4 mutations. Overall, we present behavioral habituation as a potentially sensitive task to assess age-associated behavioral deficits in 5XFAD mice and other mouse models of AD that could be used to test the preclinical efficacy of novel AD therapeutics.

Background

To investigate how changes in expression of glial genes relate to a progression of Alzheimer’s disease (AD) pathology, and how anti-Aβ immunotherapy impact these changes, we conducted a transcriptomic analysis for brains from cohorts of 2-, 10-, and 20 month old 3xTg-AD mice, and a cross-sectional study in groups of 20 month-old mice treated with active DNA Aβ42 immunization, passive immunotherapy, untreated, and wild-type (wt) controls.

Methods

Twenty-four Formalin-Fixed Paraffin-Embedded (FFPE) mouse brain sections were used for the gene expression analyses (nanostring). Adjacent sections from these and additional mouse brains were stained for microglia using antibodies detecting IbaI and Gal3. For a semi-quantitative analysis of increased tau and amyloid pathology with aging and disease progression, a comparison of ELISA results from brains of 12 and 20 months old 3xTg-AD mice were shown.

Results

Based on the different comparisons of transcript numbers found the 3xTg-AD age groups with the senescent 20 months old wt control mouse brains, and the 20 months old 3xTg-AD mouse brains with the 20 months old wt control mouse brains, genes were assigned as upregulated due to aging, or due to disease progression, or due to both. The immunohistochemistry of microglia markers revealed that Gal3 might be an important marker for phagocytosing microglia around amyloid plaques. The comparison of the two anti-Aβ immunotherapy approaches showed a differential downregulation of inflammatory glial genes.

Conclusion

These results are relevant for future clinical trials using active anti-amyloid immunotherapy.

Specialized individual circuits in the brain are recruited for specific functions. Interestingly, multiple neural circuitries continuously compete with each other to acquire the specialized function. However, the dominant among them compete and become the central neural network for that particular function. For example, the hippocampal principal neural circuitries are the dominant networks among many which are involved in learning processes. But, in the event of damage to the principal circuitry, many times, less dominant networks compensate for the primary network. This review highlights the psychopathologies of functional loss and the aspects of functional recuperation in the absence of the hippocampus.

Background

The cause of the most common form of dementia, sporadic Alzheimer’s disease (AD), remains unknown. This may reflect insufficiently powered studies to date for this multi-factorial disorder. The UK Biobank dataset presents a unique opportunity to rank known risk factors and determine novel variables.

Methods

A custom machine learning approach for high dimensionality data was applied to explore prospectively associations between AD in a sub-cohort of 156,209 UK Biobank participants aged 60–70 including more than 2,090 who were subsequently diagnosed with AD.

Results

After the possession of the APOE4 allele, the next highest ranked risk factors were other genetic variants within the TOMM40-APOE-APOC1 locus. When stratified by their apolipoprotein $\mathrm{epsilon}$ 4 (APOE4) carrier status, the most prominent risk factors in carriers were AST:ALT ratio, the “number of treatments/ medications” taken as well as “time spent in hospital” while protection was conferred by “Sleeplessness/Insomnia”. In non-APOE carriers, lower socioeconomic status and fewer years of education were highly ranked but effect sizes were small relative to APOE4 carriers.

Conclusions

Possession of the APOE4 allele was confirmed as the most important risk factor in AD. Other TOMM40-APOE-APOC1 locus variants further moderate the risk of AD in APOE4 carriers. Liver pathology is a novel risk factor in APOE4 carriers while “Sleeplessness/Insomnia” is protective in AD irrespective of APOE4 status. Other factors such as “Number of treatments/ medications” suggest that multimorbidity is an important risk factor for AD. Future treatments aimed at co-morbidities, including liver disease, may concomitantly lower the risk of sporadic AD.

There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan. In this cross-sectional study, we used [¹¹C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile positron emission tomography to quantify brain regional serotonin transporter density in 46 normal subjects, ranging from 25 to 84 years of age. Both voxel-based analyses, using sex as a covariate, and volume-of-interest-based analyses were performed. Both analyses revealed age-related declines in [¹¹C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile binding in numerous brain regions, including several neocortical regions, striatum, amygdala, thalamus, dorsal raphe, and other subcortical regions. Similar to some other neurotransmitter systems of subcortical origin, we found evidence of age-related declines in regional serotonin terminal density in both cortical and subcortical regions.

This study evaluated the effect of dietary inclusions of aspartame and sucrose on some selected behavioral and biochemical indices linked with Alzheimer's disease in a transgenic fruit fly (Drosophila melanogaster) model expressing human amyloid precursor protein and secretase. Flies were raised on a diet supplemented with sucrose and aspartame for 14 days. Thereafter, the flies were assessed for their survival rate, learning and memory, as well as locomotor performance, 14 days post-treatment. This was followed by homogenising the fly heads, and the homogenates were assayed for acetylcholinesterase and monoamine oxidase activities, as well as levels of lipid peroxidation, reactive oxygen species, and total thiol. The results showed aspartame at all levels of dietary intake and a high proportion of sucrose significantly aggravated the mortality rate, locomotor deficiency, and impaired biomarkers of oxidative stress and antioxidant status in the transgenic flies, while no significant effect was found on acetylcholinesterase activity or memory function. These findings therefore suggest that while low dietary inclusions of sucrose are tolerable under AD-like phenotypes in the flies, high inclusions of sucrose and all proportions of aspartame tested aggravated mortality rate, locomotion and oxidative stress in the flies.