Aging brain最新文献

Objective

Clusterin is involved in a variety of physiological processes, including proteostasis. Several clusterin polymorphisms were associated with an increased risk of developing Alzheimer’s disease, the world-leading cause of dementia. Herein, the effect of a clusterin polymorphism, aging and dementia in the levels of clusterin in human plasma were analysed in a primary care-based cohort, and the association of this chaperone with fibrillar structures discussed.

Methods

64 individuals with dementia (CDR≥1) and 64 age- and sex-matched Controls from a Portuguese cohort were genotyped for CLU rs1136000 polymorphism, and the plasma levels of clusterin and fibrils were assessed.

Results

An increased prevalence of the CC genotype was observed for the dementia group, although no significant robustness was achieved. CLU rs11136000 SNP did not significantly change plasma clusterin levels in demented individuals. Instead, clusterin levels decreased with aging and even more in individuals with dementia. Importantly, plasma clusterin levels correlated with the presence of fibrillar structures in Control individuals, but not in those with dementia.

Conclusion

This study reveals a significant decrease in plasma clusterin in demented individuals with aging, which related to altered clusterin-fibrils dynamics. Potentially, plasma clusterin and its association with fibrillar structures can be used to monitor dementia progression along aging.

Sleep behavior undergoes significant changes across the lifespan, and aging is associated with marked alterations in sleep amounts and quality. The primary sleep changes in healthy older adults include a shift in sleep timing, reduced slow-wave sleep, and impaired sleep maintenance. However, neurodegenerative and psychiatric disorders are more common among the elderly, which further worsen their sleep health. Irrespective of the cause, insufficient sleep adversely affects various bodily functions including energy metabolism, mood, and cognition. In this review, we will focus on the cognitive changes associated with inadequate sleep during normal aging and the underlying neural mechanisms.

In this article I reprise some selected findings and issues from my previous behavioural work on age-related differences in memory, and relate them to current work on the neural correlates of encoding, retrieval and representation. In particular, I describe the case study of a woman who had persistent experiences of erroneous recollection. I also describe the results of a study showing a double dissociation of implicit and explicit memory in younger and older adults. Finally, I assess recent work on loss of specificity in older adults’ encoding and retrieval processes of episodic events. In all cases I attempt to relate these older findings to current ideas and empirical results in the area of memory, aging, and the brain.

Previous work has suggested unitized pairs behave as a single unit and more critically, are processed neurally different than those of associative memories. The current works examines the neural differences between unitization and non-unitized memory using fMRI and multivoxel analyses. Specifically, we examined the differences across face-occupation pairings as a function of whether the pairing was viewed as a person performing the given job (unitized binding) or a person saying they knew someone who had a particular job (non-unitized binding). The results show that at encoding and retrieval, the angular gyrus can discriminate between unitized and non-unitized target trials. Additionally, during encoding, the medial temporal lobe (hippocampus and perirhinal cortex), frontal parietal regions (angular gyrus and medial frontal gyrus) and visual regions (middle occipital cortex) exhibit distinct neural patterns to recollected unitized and non-unitized targets. Furthermore, the perirhinal cortex and medial frontal gyrus show greater neural similarity within subsequently recollected unitized trials compared to non-unitized trials. We conclude that an encoding based strategy to elicit unitization can produce greater associative memory compared to non-unitized trials in older adults. Additionally, when unitized trials are subsequently recollected in the perirhinal cortex older adults show greater neural similarity within unitized trials compared to non-unitized trials.

Contemporary accounts of factors that may modify the risk for age-related neurocognitive disorders highlight education and its contribution to a cognitive reserve. By this view, individuals with higher educational attainment should show weaker associations between changes in brain and cognition than individuals with lower educational attainment. We tested this prediction in longitudinal data on hippocampus volume and episodic memory from 708 middle-aged and older individuals using local structural equation modeling. This technique does not require categorization of years of education and does not constrain the shape of relationships, thereby maximizing the chances of revealing an effect of education on the hippocampus-memory association. The results showed that the data were plausible under the assumption that there was no influence of education on the association between change in episodic memory and change in hippocampus volume. Restricting the sample to individuals with elevated genetic risk for dementia (APOE ε4 carriers) did not change these results. We conclude that the influence of education on changes in episodic memory and hippocampus volume is inconsistent with predictions by the cognitive reserve theory.

Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] α-syn transgenic mice.

Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated α-syn (pS129 α-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target α-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other α-synucleinopathies.

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.

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.

Knee pain, the most common cause of musculoskeletal pain (MSK), constitutes a severe public health burden. Its neurobiological causes, however, remain poorly understood. Among many possible causes, it has been proposed that sleep problems could lead to an increase in chronic pain symptomatology, which may be driven by central nervous system changes. In fact, we previously found that brain cortical thickness mediated the relationship between sleep qualities and pain severity in older adults with MSK. We also demonstrated a significant difference in a machine-learning-derived brain-aging biomarker between participants with low-and high-impact knee pain. Considering this, we examined whether brain aging was associated with self-reported sleep and pain measures, and whether brain aging mediated the relationship between sleep problems and knee pain. Exploratory Spearman and Pearson partial correlations, controlling for age, sex, race and study site, showed a significant association of brain aging with sleep related impairment and self-reported pain measures. Moreover, mediation analysis showed that brain aging significantly mediated the effect of sleep related impairment on clinical pain and physical symptoms. Our findings extend our prior work demonstrating advanced brain aging among individuals with chronic pain and the mediating role of brain-aging on the association between sleep and pain severity. Future longitudinal studies are needed to further understand whether the brain can be a therapeutic target to reverse the possible effect of sleep problems on chronic pain.