Human Brain In Aging Research Articles

Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging

The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal’s adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.

An optimized integrated functional genomics toolkit identifies novel role of SORL1 in microglia

AbstractBackgroundRecent genome wide association studies implicated microglia in the pathophysiology of neurodegeneration; however, the translation of these genetic discoveries is hindered by the current lack of a robust human microglia in vitro model system and standardized protocols for functional genomics assessment. Though microglia differentiated from human induced pluripotent stem cells (iMG) could be a promising cellular model, the available differentiation protocols are variable, lengthy and give inefficient, mixed yields, limiting our ability to utilize modern gene editing tools (e.g., CRISPR‐Cas9) in this model for elucidating the functional consequences of disease relevant genes and variants.MethodsIn order to streamline microglia functional genomics, we optimized a highly efficient protocol to differentiate human induced pluripotent stem cells into iMG in two easy steps, offering a significant improvement in purity and time requirement for iMG production. We validated this iMG model system in a robust way through a comprehensive single cell RNA‐sequencing (scRNA‐Seq) study, mass spectrometry‐based proteomics and microglial functional assays. In addition, the iMG differentiation protocol includes sequential iMG harvesting and cell freezing steps, that will allow the researchers to scale up the production of iMG for high‐throughput assays. Furthermore, the toolkit also includes a drug inducible CRISPR‐ON/OFF approach in our newly established microglia model system that enables the investigation of gene function in a temporal fashion. All the data generated as part of the comprehensive validation is publicly available in the form of a searchable online platform (https://jasonchungngo.shinyapps.io/IPSC-derived-Microglia/).ResultsWe used this newly developed integrated microglia functional genomics toolkit, along with human primary microglia freshly purified from dorsolateral prefrontal cortex (DLPFC), to investigate the thus far unidentified role of SORL1, an AD associated gene, in microglia. By combining state‐of‐the art (e.g. single cell RNA‐Seq, proteomics and focused CRISPR‐Cas9 screen) and standard (immunohistochemistry on postmortem human aged brain tissues) approaches we established the molecular mechanisms by which SORL1 shapes the functional phenotypes of human microglia. Most interestingly, we have found divergent roles for SORL1 in microglia when compared to neurons.ConclusionsOur findings highlight the importance of cell type specific functional genomics of susceptibility genes in AD.

Change point detection for high dimensional data via kernel measure with application to human aging brain data.

Identifying the existence and locations of change points has been a broadly encountered task in many statistical application areas. The existing change point detection methods may produce unsatisfactory results for high-dimensional data since certain distributional assumptions are made on data, which are hard to verify in practice. Moreover, some parameters (such as the number of change points) need to be estimated beforehand for some methods, making their powers sensitive to these values. Here, we propose a kernel-based -statistic to identify change points (KUCP) for high dimensional data, which is free of distributional assumptions and sup-parameter estimations. Specifically, we employ a kernel function to describe similarities among the subjects and construct a -statistic to test the existence of change point for a given location. The asymptotic properties of the -statistic are deduced. We also develop a procedure to locate the change points sequentially via a dichotomy algorithm. Extensive simulations demonstrate that KUCP has higher sensitivity in identifying existence of change points and higher accuracy in locating these change points than its counterparts. We further illustrate its practical utility by analyzing a gene expression data of human brain to detect the time point when gene expression profiles begin to change, which has been reported to be closely related with aging brain.

Alternative Splicing Changes in Human Aging Brain Samples

Alternative splicing affects differential isoform generation from genes and may also affect the protein products cellular function. Targeted splicing analysis of exon array analysis of young compared to middle and old post mortem brain samples from 1,234 samples (a total of 10 brain regions) aged from 16 to over 100 allowed me to detect significant alternative splicing changes upon human aging. This kind of data may allow us to better understand the underlying molecular mechanisms.

Chapter 18 - Diurnal and seasonal molecular rhythms in the human brain and their relation to Alzheimer disease

Diurnal and seasonal rhythms influence many aspects of human physiology including brain function. Moreover, altered diurnal and seasonal behavioral and physiological rhythms have been linked to Alzheimer's disease and related dementias (ADRD). Understanding the molecular basis for these links may lead to identification of novel targets to mitigate the negative impact of normal and abnormal diurnal and seasonal rhythms on ADRD or to alleviate the adverse consequences of ADRD on normal diurnal and seasonal rhythms. Diurnally and seasonally rhythmic gene expression and epigenetic modification in the human neocortex may be a key mechanism underlying these links. This chapter will first review the observed epidemiological links between normal and abnormal diurnal and seasonal rhythmicity, cognitive impairment, and ADRD. Then it will review normal diurnal and seasonal rhythms of brain epigenetic modification and gene expression in model organisms. Finally, it will review evidence for diurnal and seasonal rhythms of epigenetic modification and gene expression the human brain in aging, Alzheimer's disease, and other brain disorders.

Aryl Hydrocarbon Receptor in Post-Mortem Hippocampus and in Serum from Young, Elder, and Alzheimer’s Patients

One of the characteristics of the cerebral aging process is the presence of chronic inflammation through glial cells, which is particularly significant in neurodegeneration. On the other hand, it has been demonstrated that the aryl hydrocarbon receptor (AHR) participates in the inflammatory response. Currently, evidence in animal models shows that the hallmarks of aging are associated with changes in the AHR levels. However, there is no information concerning the behavior and participation of AHR in the human aging brain or in Alzheimer’s disease (AD). We evaluated the expression of AHR in human hippocampal post-mortem tissue and its association with reactive astrocytes by immunohistochemistry. Besides this, we analyzed through ELISA the AHR levels in blood serum from young and elder participants, and from AD patients. The levels of AHR and glial fibrillar acid protein were higher in elder than in young post-mortem brain samples. AHR was localized mainly in the cytosol of astrocytes and displayed a pattern that resembles extracellular vesicles; this latter feature was more conspicuous in AD subjects. We found higher serum levels of AHR in AD patients than in the other participants. These results suggest that AHR participates in the aging process, and probably in the development of neurodegenerative diseases like AD.

Neurochemical and Morphological Changes in the Microstructures of the Compact Part of the Substantia Nigra of the Human Brain in Aging and Parkinson’s Disease (Literature Review)

For investigation of pathogenetic patterns of Parkinson's disease, it is important to adequately assess the mechanisms of age-related involution and morphological changes that are formed in the brain during this process. Clinical symptoms, detected in Parkinson's disease (rigidity, hypokinesia, tremor), indicate the involvement in the pathological process of nigrostriate brain formations due to the death of dopamine neurons in the compact part of the substantia nigra. At the same time, the loss of these neurons, as well as the change in the number of neuroglia cells in the substantia nigra of the brain, are detected not only in Parkinson's disease, but also in physiological aging. This review presents and compares data on the morphological changes in the compact part of the substantia nigra of the human brain in physiological aging and Parkinson's disease.

Structural architecture supports functional organization in the human aging brain at a regionwise and network level.

Functional interactions in the brain are constrained by the underlying anatomical architecture, and structural and functional networks share network features such as modularity. Accordingly, age-related changes of structural connectivity (SC) may be paralleled by changes in functional connectivity (FC). We provide a detailed qualitative and quantitative characterization of the SC-FC coupling in human aging as inferred from resting-state blood oxygen-level dependent functional magnetic resonance imaging and diffusion-weighted imaging in a sample of 47 adults with an age range of 18-82. We revealed that SC and FC decrease with age across most parts of the brain and there is a distinct age-dependency of regionwise SC-FC coupling and network-level SC-FC relations. A specific pattern of SC-FC coupling predicts age more reliably than does regionwise SC or FC alone (r = 0.73, 95% CI = [0.7093, 0.8522]). Hence, our data propose that regionwise SC-FC coupling can be used to characterize brain changes in aging. Hum Brain Mapp 37:2645-2661, 2016. © 2016 Wiley Periodicals, Inc.

The effects of an APOE promoter polymorphism on human cortical morphology during nondemented aging.

Apolipoprotein E (APOE) is the best-known susceptibility gene for AD. It has been well demonstrated that the ε4 allele of the APOE gene can affect brain structure/function in nondemented individuals; however, other polymorphisms in the APOE gene have been largely overlooked when assessing the effects of APOE on the neural system. Rs405509 is a newly recognized AD-related polymorphism located in the APOE promoter region that can regulate the transcriptional activity of the APOE gene. To date, it remains unknown whether and how this APOE promoter polymorphism affects the human brain in aging. Here, for the first time, we investigate the effects of the rs405509 genotype (T/T vs G-allele) on human cortical morphology using a large cohort of nondemented elderly subjects (120 subjects in total; aged 52- 81 years). High-resolution structural MRI was performed; cortical thickness and surface area were analyzed separately. Intriguingly, nondemented carriers of the rs405509 T/T genotype showed an accelerated age-related reduction of thickness in the left parahippocampal gyrus compared with the G-allele carriers. Furthermore, the cortical thickness covariance between the left parahippocampal gyrus and left medial cortex, including the left medial superior frontal gyrus, supplementary motor area, and paracentral lobule, was modulated by the interaction of the rs405509 genotype and age. These novel findings suggest an important role for the APOE promoter polymorphism in the human brain and also provide valuable insights into how the rs405509 genotype shapes the neural system to modulate the risk of developing AD.

Analysis of Nonlinear Gene Expression Progression Reveals Extensive Pathway and Age-Specific Transitions in Aging Human Brains

Several recent gene expression studies identified hundreds of genes that are correlated with age in brain and other tissues in human. However, these studies used linear models of age correlation, which are not well equipped to model abrupt changes associated with particular ages. We developed a computational algorithm for age estimation in which the expression of each gene is treated as a dichotomized biomarker for whether the subject is older or younger than a particular age. In addition, for each age-informative gene our algorithm identifies the age threshold with the most drastic change in expression level, which allows us to associate genes with particular age periods. Analysis of human aging brain expression datasets from three frontal cortex regions showed that different pathways undergo transitions at different ages, and the distribution of pathways and age thresholds varies across brain regions. Our study reveals age-correlated expression changes at particular age points and allows one to estimate the age of an individual with better accuracy than previously published methods.

Profiling transcription initiation in human aged brain using deep-CAGE

The genome sequencing projects completed in recent years revealed that the number of protein-coding genes does not change appreciably with increasing complexity of the organisms, and it is now generally accepted that this divergence is largely due to variation at the regulatory level. Mechanisms such as alternative splicing, alternative promoters and antisense transcription allow to both obtain a high number of transcripts from a relatively small number of genes and to fine tune isoforms expression in a cell-specific or developmentally-restricted manner. It is likely that the extensive use of such mechanisms plays a pivotal role in development, adult function and ageing of complex tissues like brain. The aim of this study was to characterize transcription start sites (TSSs) in different areas of human aged brain and correlate expression with methylation and structural genomic variation. Since its ability to profile TSSs at high resolution and at a genome wide level, we used Cap Analysis of Gene Expression (CAGE) combined with high-throughput sequencing (deep-CAGE) to collect exact TSSs and their expression levels. We present here our findings on alternative promoters and antisense transcription. Post-mortem tissue from 5 different brain regions was collected from 5 human donors and used to prepare 25 libraries.

Expression of luteinizing hormone in rat brain

A recent report demonstrated that in human aging brain after menopause/andropause luteinizing hormone (LH) is localized in the cytoplasm of pyramidal neurons and hippocampus and a significant increase of LH is also detected in the cytoplasm of pyramidal neurons and neurofibrillary tangles of Alzheimer's disease brain compared to age-matched control brain. It was suggested that the decreased steroid hormone production and the resulting LH expression in the neurons vulnerable to Alzheimer's disease pathology may have some relevance to the development of Alzheimer's disease. lt is, however, unclear whether the presence of LH in neurons of human aging and Alzheimer's disease brain is due to intracellular LH expression or to LH uptake from extracellular sources since gonadotropins are known to cross the blood brain barrier. Moreover, there is no report by using the brain of an experimental animal that LH is expressed in such neurons as found in the human brain. In the present study, we found that LH immunoreactivity is localized in the pyramidal neurons of cerebral cortex and hippocampus of 12 and 18 months old rats but can not detect any immunoreactivity for LH in the young adult (3-5 months old) rats. To confirm that these LH immunoreactivity results from de novo synthesis in the brain but not the uptake from extracellular space，we performed RT-PCR and found that mRNA for LH is detected in several regions of brain including cerebral cortex and hippocampus. These findings suggest us that LH expression in old rat brain may play an important role in aging process of rat brain.

Walking toward a convergence in aging research

Men ought to know that from nothing else but the brain come joys, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations… And by the same organ we become mad and delirious, and fears and terrors assail us, some by night, and some by day, and dreams and untimely wanderings, and cares that are not suitable, and ignorance of present circumstances, desuetude, and unskilfulness. All these things we endure from the brain, when it is not healthy… —Hippocrates, On the Sacred Disease The brain is responsible for providing everything from the basic involuntary physiological events that allow one to breathe and live, to the conscious actions and thoughts that dictate the very essence of mankind. As such, the preservation of brain function as individuals age is not only crucial to support the ability to live but also the ability to maintain their individuality. Aging is an inevitable process that everyone faces and one that has captivated people's minds since the beginning of our existence. Promises of life extension and immortality have been marketed from alchemists to charlatans and continue to flood popular media even today. The apparent desire to beat the ravages of age often outweighs rigorous thought, and that very popular obsession has sometimes diluted the seriousness of the field. That said, understanding the aging nervous system is a field that has attracted some of the brightest and best clinicians as well as basic scientists whose intellectual ideas and scholarly research bear on the field in an effort to reach an understanding of the fundamental mechanistic events underlying aging. Healthy lifestyles, medical advances in the 20th century, and the coming of age of baby boomers have brought out the reality of living longer, and uncovered the challenges that an aging population brings to human lives, health systems, and communities. In the 21st century, the number of individuals reaching 65 years of age is increasing exponentially. The number has increased 20-fold in the last century such that the spectrum of diseases that affect the population has changed and “aging” itself has become a prevalent condition. Understanding the causes of such age-related problems and the ways in which these problems can be most effectively treated or prevented is a challenge faced by us as a society, a challenge demanding to be addressed in a scientifically rigorous fashion. Over time, numerous theories on aging have been proposed. However, the fundamental link that unites these theories toward a cohesive understanding of aging is still lacking. The dissection of genetics versus environment and the way in which the genetics and the environment interact to affect development and maturation and demise is a pending subject for the research community. Pressing questions that need to be addressed are those concerning mechanisms associated with brain aging vulnerability, and the way in which selective neuronal populations become susceptible to disease as people age. Also, what makes certain individuals maintain incredible mental vitality and lucidity throughout life, and why others lose the essence of their individuality is key to understanding the fundamental layout of not only aging, but also the brain itself. Unfortunately, understanding normal healthy brain function is in its infancy, and while advances in all research disciplines spanning areas as diverse as studying aging genetics in invertebrate or vertebrate models such as zebrafish, or functional neuroimaging in the human aged brain are promising, more often than not understanding the complexity of brain physiology is diminished by reductionist approaches. Such crudeness is only exacerbated by attempts to understand abnormal physiology and pathology. To date, aging neurosciences research is divided across disciplines. The study of age-related molecular switches driving cellular processes from stem cells to mature neurons is, to some extent, studied separately from how the switches are genetically determined, or the process in which environmental factors such as stress, sex-specific events such as menopause, nutrition or even climate affect the blueprints. In addition, the functional manifestations of aging encompassing cognitive, motor, and emotional age-related changes are often studied as separate entities. The challenge, therefore, is to unite the fields into closer approximation to allow a constructive input and open synergetic dialogue between these closely related research entities. Last scene of all that ends this strange, eventful history, is second childishness and mere oblivion. I am sans teeth, sans eyes, sans taste, sans everything. —William Shakespeare, As You Like It

Estrogen receptor-α splice variants in the human brain

In the present review we discuss recent findings showing that, in addition to the canonical estrogen receptor-α (ERα), the level of various ERα splice variants is changed in the human brain in aging and Alzheimer's disease (AD) at both the mRNA and protein level and that they should be considered for the understanding of estrogen effects on the brain and estrogen therapy pitfalls. Indeed, the expression pattern of certain splice forms is brain area-specific. Thus, the major isoform found in the mamillary body (MB) appeared to be del.7 (deletion of exon 7), while in the hippocampus del.4 (exon 4 omitted) was expressed at the highest level. Furthermore, while transcripts missing exons 7 and 2 declined with aging in the MB of patients >60 years old, no age-related alterations were determined for a number of splice variants in the hippocampus. A novel MB1 isoform with a 168-bp deletion within the transactivation function 1 of ERα turned out to accumulate in the histaminergic tuberomamillary nucleus of postmenopausal women. Finally, the level of alternatively spliced ERα may also change in AD in a brain area-specific manner and so affect the sensitivity to estrogen therapy.

Characteristics of Mast Cells in the Choroid Plexus of the Ventricles of the Human Brain in Aging

Characteristics of Mast Cells in the Choroid Plexus of the Ventricles of the Human Brain in Aging

Human aging brain disorders: role of antioxidant enzymes.

In order to investigate the role of two free radical detoxificant enzymes in patients with aging brain disorders, superoxide dismutase (SOD) and catalase (CAT) activities have been measured in blood from male and female human patients of different ages with several types of aging brain disorders. When compared with activities in the normal population, we have detected: 1) SOD and CAT activities are decreased in patients with Parkinson disease. 2) SOD activity seems to be normal and CAT activity is decreased in patients with dementia. 3) In the patients with stroke, SOD activity is normal, while CAT activity is decreased. SOD activity was measured in red blood cells using the Minami and Yoshikawa method. CAT activity was measured in hemolysates by the method of Aebi. We can conclude that SOD and CAT activities in patients with Parkinson disease are decreased.

Changes in the configuration of synaptic membranes of the human brain in aging and vascular pathology

The structure of synapses in the brain of persons who had died of aging and vascular disease was studied by electron microscopy which indicated synaptic contacts with the convex and concave surface of pre- and postsynaptic membranes. There were also synapses with more complicated alterations in the configuration of synaptic membranes. The functional significance of the phenomenon is discussed in the paper. It is assumed that the alterations in the curvature of synaptic membranes are manifestation of plasticity of a synapse and they are of compensatory value.

Critical analysis of the use of computer‐assisted transverse axial tomography to study human brain in aging and dementia of the Alzheimer type

Our purpose is to critically review this literature, relate our conclusions to CT studies performed at the Laboratory of Neurosciences, National Institute on Aging, and to discuss the applicability of CT use in assisting the clinician in the diagnosis of dementia. Finally, a brief discussion of future directions in structural imaging is presented