Understanding Brain Aging Research Articles

Genome‐wide association study of brain MRI and other phenotypes in the Tohoku Medical Megabank Organization

AbstractBackgroundThe Tohoku Medical Megabank Organization (ToMMo) is a large cohort study and biobank established in 2013 in the Miyagi Prefecture of Northern Japan following the Great East Japan Earthquake and Tsunami. ToMMo enrolled 150K individuals in a planned longitudinal study aiming to reveal numerous and diverse biological, psychological, and lifestyle characteristics associated with important diseases, and it collects and analyzes a rich set of biological data, including genomics, from participants to support innovative research on these diseases. Importantly, aging and Alzheimer’s disease are key areas of our research agenda, but little is known about common genetic variants that affect quantitative traits related to AD in Japanese people. MRI brain scans and cognitive screening on 12,164 cohort participants were collected at baseline (the TMM Brain‐MRI Study) since 2014 to 2019.MethodThe TMM Brain‐MRI study acquired multiple MRI sequences, including T1‐weighted imaging (T1WI). The ADNI Phantom was used, and each scan’s quality was checked. Following pre‐processing steps, Freesurfer (v7.2.0) was used with the Destrieux or Desikan‐Killiany atlas to parcellate multiple anatomical brain regions and derive cortical thickness data. We conducted a Genome‐Wide Association Study (GWAS) on all Brain‐MRI Study participants who were also genetically profiled with a Japanese‐oriented microarray (Japonica‐Array® v1, v2 and NEO) and WGS.ResultAlong with the other data types, the genotyping data for the TMM Brain‐MRI study participants represented etiological characteristics. The attached Figure shows the age distribution by decile for 7,630 male and female participants who were profiled with the Japonica‐Array® v2. The usable archived volumetric T1WI data demonstrated inverse correlations between brain volume and age, as well as very good agreement with correlations observed in previous clinical studies. We identified nominally genome‐wide significant loci (P < 5×10‐8) associated with imaging phenotypes in this sample consisted of Japanese adults as the discovery stage of the study.ConclusionThe ToMMo MRI and genetic data provide insights into the genetic architecture of the brain that are relevant to understanding brain aging and AD. Our results require some replication stages and meta‐analyses using samples of Japanese individuals in other studies.

Autonomic nervous system flexibility for understanding brain aging.

A recent call was made for autonomic nervous system (ANS) measures as digital health markers for early detection of Alzheimer's disease and related dementia (AD/ADRD). Nevertheless, contradictory or inconclusive findings exist. To help advance understanding of ANS' role in dementia, we draw upon aging and dementia-related literature, and propose a framework that centers on the role of ANS flexibility to guide future work on application of ANS function to differentiating the degree and type of dementia-related brain pathologies. We first provide a brief review of literature within the past 10 years on ANS and dementia-related brain pathologies. Next, we present an ANS flexibility model, describing how the model can be applied to understand these brain pathologies, as well as differentiate or even be leveraged to modify typical brain aging and dementia. Lastly, we briefly discuss the implication of the model for understanding resilience and vulnerability to dementia-related outcomes.

BrainAge of patients with severe late-life depression referred for electroconvulsive therapy

BackgroundSevere depression is associated with accelerated brain aging. BrainAge gap, the difference between predicted and observed BrainAge, was investigated in patients with late-life depression (LLD). We aimed to examine BrainAge gap in LLD and its associations with clinical characteristics indexing LLD chronicity, current severity, prior to electroconvulsive therapy (ECT) and ECT outcome. MethodsData was analyzed from the Mood Disorders in Elderly treated with Electroconvulsive Therapy (MODECT) study. A previously established BrainAge algorithm (BrainAge R by James Cole, (https://github.com/james-cole/brainageR)) was applied to pre-ECT T1-weighted structural MRI-scans of 42 patients who underwent ECT. ResultsA BrainAge gap of 1.8 years (SD = 5.5) was observed, Cohen's d = 0.3. No significant associations between BrainAge gap, number of previous episodes, current episode duration, age of onset, depression severity, psychotic symptoms or ECT outcome were observed. LimitationsLimited sample size. ConclusionsOur initial findings suggest an older BrainAge than chronological age in patients with severe LLD referred for ECT, however with high degree of variability and direction of the gap. No associations were found with clinical measures. Larger samples are needed to better understand brain aging and to evaluate the usability of BrainAge gap as potential biomarker of prognosis an treatment-response in LLD. Trial registrationClinicalTrials.gov identifier: NCT02667353

Preliminary findings of accelerated visual memory decline and baseline brain correlates in middle-age and older adults with autism: The case for hippocampal free-water.

Research aimed at understanding cognitive and brain aging in adults with autism spectrum disorder (ASD) is growing, but critical longitudinal work is scant. Adults with ASD struggle with tasks involving visual memory compared with neurotypical adults (NT). This may be related to differences in size or integrity of the hippocampus and its' primary structural connectivity pathway, the fornix. The aim of this study was to describe preliminary findings of longitudinal aging trajectories in short- and long-term visual memory abilities in middle-age and older adults with ASD, compared with matched NT adults. We then evaluated baseline multi-modal imaging metrics of the hippocampal system, including the relatively novel metric of free-water, as potential correlates of longitudinal memory change in the ASD group. Middle-age and older adults with ASD (n = 25) and matched NT adults (n = 25) between the ages of 40 and 70 years were followed longitudinally at ~2-year intervals (range 2-5 years). Participants completed the Wechsler Memory Scale III Visual Reproduction task. Longitudinal mixed models were utilized to detect group differences in memory change with baseline age and sex as covariates. Hippocampal volume was measured via T1-weighted MRI images with FreeSurfer. Fornix fractional anisotropy and hippocampal and fornix free-water were measured from diffusion tensor imaging scans. Exploratory correlations were run between individual hippocampal system metrics and longitudinal slopes of visual memory change. There was a significant group by time interaction for long-term visual memory, such that middle-age and older adults with ASD declined faster than matched NT adults. There was no group by time interaction for short-term visual memory. Baseline hippocampal free-water was the only hippocampal system metric that correlated with long-term visual memory change in the ASD group. As one of the first longitudinal cognitive and brain aging studies in middle-age and older adults with ASD, our findings suggest vulnerabilities for accelerated long-term visual memory decline, compared to matched NT adults. Further, baseline hippocampal free-water may be a predictor of visual memory change in middle-age and older adults with ASD. These preliminary findings lay the groundwork for future prognostic applications of MRI for cognitive aging in middle-age and older adults with ASD.

Longitudinal Changes in Global Cerebral Blood Flow in Cognitively Normal Older Adults: A Phase-Contrast MRI Study.

Characterization of blood supply changes in older individuals is important in understanding brain aging and diseases. However, prior studies largely focused on cross-sectional design, thus change in cerebral blood flow (CBF) could not be assessed on an individual level. To evaluate longitudinal short-term changes in global CBF in cognitively normal older adults. Prospective, longitudinal, and cohort. One-hundred twenty-seven cognitive-normal participants (mean age 69 ± 7 years, 47 males) underwent serial MRI with an average follow-up time of 2.1 years. 3 T phase-contrast (PC), three-dimensional magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE) and fluid-attenuated inversion recovery (FLAIR) MRI. Total CBF was measured with PC MRI allowing assessment of quantitative flow in four major feeding arteries by a trained radiologist with >3 years' experience (O.K.). Brain volume was obtained from MPRAGE MRI and measured by T1-MultiAtlas MRICloud tool. The ratio between total CBF and brain volume yielded global CBF in mL/100 g/min. White matter hyperintensity (WMH) was measured automatically using a Bayesian probability approach on FLAIR. Linear mixed effect model was used to simultaneously assess cross-sectional age-differences and longitudinal age-changes in CBF. Spearman rank correlation was used to evaluate the relationship between CBF change and WMH progression. A P-value of <0.05 (two-tailed) was considered significant. Global CBF decreased with age at a longitudinal rate of -0.56 mL/100 g/min/year (95% confidence interval [CI]: -1.09, -0.03), compared to a cross-sectional rate of -0.26 mL/100 g/min/year (95% CI: -0.41, -0.11). Changes in CBF were significantly associated with progression of WMH (Spearman rank correlation r=-0.25), as those participants who had a more rapid CBF reduction had greater increases in WMH volumes and the relationship remained significant when adjusting for baseline vascular risk scores. Additionally, age-related changes in whole-brain volume were found to be -0.151%/year (95% CI: -0.186, -0.116). These findings suggest that brain aging in older adults is accompanied by a rapid longitudinal reduction in CBF, the rate of which is associated with white matter damage. 1 TECHNICAL EFFICACY STAGE: 2.

Recent developments in understanding brain aging: sex differences, mechanisms, and implications in diseases

Exemplified by the disproportionate cases of Alzheimer’s disease among women, many diseases show considerable sexual disparity in the aging process. Given that such a sex bias varies significantly in different neurological conditions, considering sex differences is necessary for the diagnosis as well as the treatment of neurological disorders. However, currently, relatively few studies have specifically focused on sex differences in brain aging or the general aging process, which has prevented the development of precision medicine for these sex-different diseases. Here, we summarize age-related disparities relating to cognitive function and dysfunction for males and females from human cross-sectional and longitudinal studies. By discussing potential anatomical and physiological bases underlying such differences, we highlight the importance of sex for aging studies in this review, which may hopefully shed light on understanding the precise causes of different brain diseases.

Neurodegenerative diseases and brain aging

Neurodegenerative diseases such as Alzheimer's, Parkinson's or Amyotrophic Lateral Sclerosis are generally of sporadic origin, but the risk of being affected increases dramatically with age. Progress in understanding brain aging contributes to define precisely the relationships between aging associated physiological and pathological processes. Aging is induced by various stresses, which turn somatic cells to a senescent state. Senescent cells cannot divide but acquire a typical phenotype and release chemicals that trigger inflammation. In the brain, glial cells such as astrocytes or microglia as well as neurons are affected. Dendritic branching declines, resulting in a decrease of synaptic plasticity and cognitive performances, associated with brain aging. Aging alters also glymphatic washing, the process by which brain catabolites are eliminated. The neurodegenerative diseases are proteinopathies resulting from pathological conformations of physiological proteins. Normally washed by the glymphatic flux, these proteins accumulate and aggregate in its absence and then trigger neuron death.

Age effects on white matter microstructure in individuals of self‐identified Indian ancestry from the UK Biobank

AbstractBackgroundThe incidence of dementia in India is 14%, and its prevalence doubles with every five‐year increase in age. Given the lack of ethnic diversity in most brain research to date, it is valuable to study cohorts with diverse genetic and environmental backgrounds, to identify predictors of health and disease that can be generalized to other ethnic groups than the commonly studied populations of European ancestry. To address this gap in the literature, we modeled factors that affect aging patterns in the brain’s white matter in individuals with Indian ancestry using advanced diffusion‐weighted MRI (dMRI).MethodCross‐sectional dMRI data from 123 individuals (males, n=78; females, n=45) of self‐reported Indian ancestry (born in India: 44%; mean age: 60.1±8.3 SD, range: 45‐80) from the UK Biobank were analyzed using diffusion tensor imaging (DTI), the tensor distribution function (TDF), neurite orientation dispersion and density imaging (NODDI) and mean apparent propagator MRI (MAPMRI). Main effects of age, sex, and age‐by‐sex interaction were investigated to characterize trajectories in whole‐brain white matter averages and the corpus callosum (CC), parcellated using the JHU‐ICBM atlas, covarying for years of education, waist/hip ratio, population structure (Figure 1) and the Townsend index. Normative lifespan charts were created to visualize white matter aging trajectories for the major diffusivity metrics.ResultNormative centile curves (Figures 2‐3) show, with increasing age, declining white matter integrity, increased diffusivity, lower white matter density and diffusion restriction at the whole‐brain level and CC (Table 1; Figure 4). There was no detectable effect of sex, nor age‐by‐sex interaction, across whole‐brain metrics. In the CC, a steeper aging trajectory, evidenced by more pronounced white matter changes, was observed in males relative to females (Table 1; Figure 5).ConclusionUsing advanced dMRI modeling, we report diffuse white matter changes with respect to age in a subsample of UK Biobank individuals of self‐reported Indian ancestry. Future studies should include larger sample sizes, comparisons with Indian ancestry individuals residing in India, consider vascular factors, and examine genotype interactions (e.g., with apolipoprotein E genotype), to further characterize risk factors and better understand brain aging in diverse populations with varied genetic and environmental backgrounds.

Expression and function of circular RNAs in the mammalian brain.

Mammalian brain presents extraordinary complexity reflected in the structure, function, and dynamic changes in the biological and physiological processes of development, maturity, and aging. Recent transcriptomic profiles from the brain tissues of distinct species have described a novel class of transcripts with a covalently closed-loop structure, called circular RNAs (circRNAs), which are produced by alternative back-splicing and derived from genes associated with synaptogenesis and neural activities. Brain is a tightly regulated and largely unexplored organ where circRNAs are highly enriched and expressed in the cell type-, spatiotemporal-specific, sex-biased, and age-related manner. Although the biological functions of most of the circRNAs in the brain remain elusive, increased evidence suggests that dynamic changes in circRNA expression are critical for brain function and the maintenance of physiological homeostasis in the brain. Here, we review the latest immense progresses in the understanding of circRNA expression and function in the mammalian brain. We also discuss possibly biological functions of circRNAs in the brain, which may provide new sights of understanding brain development and aging, as well as the pathogenesis of mental diseases.

Complement in Neurologic Disease.

Classic innate immune signaling pathways provide most of the immune response in the brain. This response activates many of the canonical signaling mechanisms identified in peripheral immune cells, despite their relative absence in this immune-privileged tissue. Studies over the past decade have strongly linked complement protein production and activation to age-related functional changes and neurodegeneration. The reactivation of the complement signaling pathway in aging and disease has opened new avenues for understanding brain aging and neurological disease pathogenesis and has implicated cell types such as astrocytes, microglia, endothelial cells, oligodendrocytes, neurons, and even peripheral immune cells in these processes. In this review, we aim to unravel the past decade of research related to complement activation and its numerous consequences in aging and neurological disease.

Brain Lesions in Aging Zoo-Housed Naked Mole-Rats (Heterocephalus glaber).

Naked mole-rats (NMRs) are common in the managed care of zoos and valuable models for aging research. Limited information on NMR neuropathology is available despite many studies regarding their aging physiology. Histologic sections of brain from 27 adult (5-27 years old) NMRs from 2 zoos were reviewed to determine presence or absence of lesions associated with advanced age in humans and other mammals. A majority (23/27; 85%) of NMR brains had cerebral cortical neuronal changes with rounded or angular neurons, cytoplasmic vacuoles containing pale yellow pigment, periodic acid-Schiff (PAS)-positive granules and green autofluorescence, compatible with lipofuscinosis. Less severe lesions were present in cerebellar Purkinje cells, medulla, and hippocampal neurons. The hypothalamic neuropil of all NMRs had scattered variably sized PAS-positive granules and 10 (37%) had larger round bodies consistent with corpora amylacea. The youngest NMRs, 5 to 7 years old, generally had minimal or no cerebrocortical lesions. Further studies will help understand brain aging in this long-lived species.

Automated Cell Counts on Tissue Sections by Deep Learning and Unbiased Stereology

In recent decades stereology-based studies have played a significant role in understanding brain aging and developing novel drug discovery strategies for treatment of neurological disease and mental illness. A major obstacle to further progress in a wide range of neuroscience sub-disciplines remains the lack of high-throughput technology for stereology analyses. Though founded on methodologically unbiased principles, commercially available stereology systems still rely on well-trained humans to manually count hundreds of cells within each region of interest (ROI). Even for a simple study with 10 controls and 10 treated animals, cell counts typically require over a month of tedious labor and high costs. Furthermore, these studies are prone to errors and poor reproducibility due to human factors such as subjectivity, variable training, recognition bias, and fatigue. Here we propose a deep neural network-stereology combination to automatically segment and estimate the total number of immunostained neurons on tissue sections. Our three-step approach consists of (1) creating extended-depth-of-field (EDF) images from z-stacks of images (disector stacks); (2) applying an adaptive segmentation algorithm (ASA) to label stained cells in the EDF images (i.e., create masks) for training a convolutional neural network (CNN); and (3) use the trained CNN model to automatically segment and count the total number of cells in test disector stacks using the optical fractionator method. The automated stereology approach shows less than 2% error and over 5× greater efficiency compared to counts by a trained human, without the subjectivity, tedium, and poor precision associated with conventional stereology.

Recent Developments in Understanding Brain Aging: Implications for Alzheimer's Disease and Vascular Cognitive Impairment.

As the population of the Western world is aging, there is increasing awareness of age-related impairments in cognitive function and a rising interest in finding novel approaches to preserve cerebral health. A special collection of articles in The Journals of Gerontology: Biological Sciences and Medical Sciences brings together information of different aspects of brain aging, from latest developments in the field of neurodegenerative disorders to cerebral microvascular mechanisms of cognitive decline. It is emphasized that although the cellular changes that occur within aging neurons have been widely studied, more research is required as new signaling pathways are discovered that can potentially protect cells. New avenues for research targeting cellular senescence, epigenetics, and endocrine mechanisms of brain aging are also discussed. Based on the current literature it is clear that understanding brain aging and reducing risk for neurological disease with age requires searching for mechanisms and treatment options beyond the age-related changes in neuronal function. Thus, comprehensive approaches need to be developed that address the multiple, interrelated mechanisms of brain aging. Attention is brought to the importance of maintenance of cerebromicrovascular health, restoring neuroendocrine balance, and the pressing need for funding more innovative research into the interactions of neuronal, neuroendocrine, inflammatory and microvascular mechanisms of cognitive impairment, and Alzheimer's disease.

Understanding brain aging and dementia: a life course approach

Understanding brain aging and dementia: a life course approach

Alzheimer’s Research on Black Americans Comes Up Short

Alzheimer’s Research on Black Americans Comes Up Short

Donepezil causes acute increases in regional cerebral blood flow in normal rat

associated to aging and AD. (Kalpouzos 2009, Mosconi, 2007). We focused on the small primate (Microcebus murinus (M.m.), during aging some animals develop cognitive impairments (Picq, 2007), amyloid plaque depositions, and altered Tau protein accumulation associated with cerebral atrophy (Kraska, 2009). Brain atrophy is predictive of cognitive alterations (Picq, 2010). The aim of the current study was to evaluate age-associated evolution of glucose uptake in M.m. by using non-invasive FDG PET. Methods: SeventeenM.m. (1.5 to 9 years) were evaluated by PET with MicroPET Focus220 system (FDG: 900mCurie/100g, i.v.) and 3D-MR images were recorded (PharmaScan Bruker 7T). M.m were anesthetized by isoflurane duringimages acquisition. MR and PET images were co-registered by rigid transformations to define volumes of interest (VOI) in brain and appraise Standard UptakeValues (SUV) as well as relative values as compared to whole brain. Results: MR images didn’t reveal any severe atrophy this study is focused on normal aging. PET study revealed a relationship between age and SUVs in the frontal cortex, the cerebellum, and in the whole brain. However, relative values were not correlated with age. The cohort was split by theM.m.midlife (4.5 years) in two groups, young (1.960.2 years) and old animals (6.460.5 years).This second analyse showed a difference between young and old animals in thewhole brain, frontal cortex and cerebellum (t-test).Conclusions:Anage-associated evolution of glucose uptake as measured by SUVs could bedetected in non-severely atrophied M.m. and resembles evolution of the regionalcerebral metabolic rates for glucose (rCMRGlc) observed in healthy aged humans.This study is a first step toward the characterization of age-associated changesof brain glucose uptake inM.m. and will be useful to understand brain aging inM.m.

Genetic and environmental influences on the size of specific brain regions in midlife: The VETSA MRI study

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51–59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00–0.75) as compared with subcortical and ventricular ROIs (0.48–0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

Estradiol Reverses a Calcium-Related Biomarker of Brain Aging in Female Rats

An increase in L-type voltage-gated calcium channel (LTCC) current is a prominent biomarker of brain aging and is believed to contribute to cognitive decline and vulnerability to neuropathologies. Studies examining age-related changes in LTCCs have focused primarily on males, although estrogen (17beta-estradiol, E2) affects calcium-dependent activities associated with cognition. Therefore, to better understand brain aging in females, the effects of chronic E2 replacement on LTCC current activity in hippocampal neurons of young and aged ovariectomized rats were determined. The zipper slice preparation was used to expose cornu ammonis 1 (CA1) pyramidal neurons for recording LTCC currents using the cell-attached patch-clamp technique. We found that an age-related increase in LTCC current in neurons from control animals was prevented by E2 treatment. In addition, in situ hybridization revealed that within stratum pyramidale of the CA1 area, mRNA expression of the Ca(v)1.2 LTCC subunit, but not the Ca(v)1.3 subunit, was decreased in aged E2-treated rats. Thus, the reported benefits of E2 on cognition and neuronal health may be attributed, at least in part, to its age-related decrease in LTCC current.

Vieillissement cérébral, aspects biologiques et psychosociaux

The world population is aging The frontier between physiological and pathological brain aging is somewhat unclear. Pathological aging can cause both mild cognitive impairments and dementias (vascular and Alzheimer). It is important to understand brain aging in order to identify risk factors and develop protective measures. Proper lifetime brain protection could improve quality of life in old age.

MONOVALENT ELECTROLYTE CONTENT IN VITAMIN E-DEFICIENT RATS: CLUES TO UNDERSTAND BRAIN AGING

MONOVALENT ELECTROLYTE CONTENT IN VITAMIN E-DEFICIENT RATS: CLUES TO UNDERSTAND BRAIN AGING