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Two population-based studies key to advancing knowledge of brain aging are the Honolulu-Asia Aging Study (HAAS) and the Nun Study. Harmonization of their neuropathologic data allows cross comparison, with findings common to both studies likely generalizable, while distinct observations may point to aging brain changes that are dependent on sex, ethnicity, environment, or lifestyle factors. Here, we expanded the neuropathologic evaluation of these 2 studies using revised NIA-Alzheimer's Association guidelines and compared directly the neuropathologic features of resistance and apparent cognitive resilience. There were significant differences in prevalence of Alzheimer disease neuropathologic change, small vessel vascular brain injury, and Lewy body disease between these 2 studies, suggesting that sex, ethnicity, and lifestyle factors may significantly influence resistance to developing brain injury with age. In contrast, hippocampal sclerosis prevalence was very similar, but skewed to poorer cognitive performance, suggesting that hippocampal sclerosis could act sequentially with other diseases to impair cognitive function. Strikingly, despite these observed differences, the proportion of individuals resistant to all 4 diseases of brain or displaying apparent cognitive resilience was virtually identical between HAAS and Nun Study participants. Future in vivo validation of these results awaits comprehensive biomarkers of these 4 brain diseases., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels., Methods: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined., Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy., Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life., (© 2016 American Academy of Neurology.)

Background: Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies., Objective: To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults., Design: Autopsy study., Setting: Community- and population based., Participants: A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN., Main Outcome Measures: Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts., Results: Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies., Conclusions: These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population-based cohorts.

Alzheimer's disease (AD) is a common age-related chronic illness with latent, prodrome, and fully symptomatic dementia stages. Increased free radical injury to regions of brain is one feature of prodrome and dementia stages of AD; however, it also is associated with advancing age. This raises the possibility that age-related free radical injury to brain might be caused in part or in full by latent AD. We quantified free radical injury in the central nervous system with cerebrospinal fluid (CSF) F(2)-isoprostanes (IsoPs) in 421 clinically normal individuals and observed a significant increase over the adult human lifespan (P < 0.001). Using CSF amyloid (A) β(42) and tau, we defined normality using results from 28 clinically normal individuals <50 years old, and then stratified 74 clinically normal subjects ≥60 years into those with CSF that had normal CSF Aβ(42) and tau (n = 37); abnormal CSF Aβ(42) and tau, the biomarker signature of AD (n = 24); decreased Aβ(42) only (n = 4); or increased tau only (n = 9). Increased CSF F(2)-IsoPs were present in clinically normal subjects with the biomarker signature of AD (P < 0.05) and those subjects with increased CSF tau (P < 0.001). Finally, we analyzed the relationship between age and CSF F(2)-IsoPs for those clinically normal adults with normal CSF (n = 37) and those with abnormal CSF Aβ(42) and/or tau (n = 37); only those with normal CSF demonstrated a significant increase with age (P < 0.01). These results show that CSF F(2)-IsoPs increased across the human lifespan and that this age-related increase in free radical injury to brain persisted after culling those with laboratory evidence of latent AD.

Systems biology offers enormous potential to understand the complexity of human brain aging and neurodegenerative diseases. Proteomics has an important role in these investigations because of its unique strengths and because of the potential central pathogenic contribution of pathological protein to several of these diseases. Here we have reviewed the methods and presented some examples of liquid chromatography-electrospray ionization-tandem mass spectrometry-based proteomics, with and without quantification using isotope-coded affinity tags, in the investigation of aging and Alzheimer's disease. As protocols and methods for improved quantitative high-throughput proteomics constantly improve, this approach will likely continue to provide deeper insight into human brain aging and neurodegenerative diseases.

Cerebral oxidative damage is a feature of aging and is increased in a number of neurodegenerative diseases. We pursued the gene-environment interaction of lack of apolipoprotein E (apoE) and modulation of dietary alpha-tocopherol on cerebral oxidative damage in aged male and female mice by quantifying the major isomers of cerebral isoprostanes, derived from arachidonic acid (AA) oxidation, and neuroprostanes, derived from docosahexaenoic acid (DHA) oxidation. Mice fed alpha-tocopherol-deficient, normal, or -supplemented diet had undetectable, 4486 +/- 215, or 6406 +/- 254 ng of alpha-tocopherol per gram of brain tissue (p < 0.0001), respectively. Two factors, male gender and lack of apoE, combined to increase cerebral AA oxidation by 28%, whereas three factors, male gender, lack of apoE, and deficiency in alpha-tocopherol, combined to increase cerebral DHA oxidation by 81%. alpha-Tocopherol supplementation decreased cerebral isoprostanes but not neuroprostanes and enhanced DHA, but not AA, endoperoxide reduction in vivo and in vitro. These results demonstrated that the interaction of gender, inherited susceptibilities, and dietary alpha-tocopherol contributed differently to oxidative damage to cerebral AA and DHA in aged mice.

Methionine oxidation and reduction is a common phenomenon occurring in biological systems under both physiological and oxidative-stress conditions. The levels of methionine sulfoxide (MetO) are dependent on the redox status in the cell or organ, and they are usually elevated under oxidative-stress conditions, aging, inflammation, and oxidative-stress related diseases. MetO modification of proteins may alter their function or cause the accumulation of toxic proteins in the cell/organ. Accordingly, the regulation of the level of MetO is mediated through the ubiquitous and evolutionary conserved methionine sulfoxide reductase (Msr) system and its associated redox molecules. Recent published research has provided new evidence for the involvement of free MetO or protein-bound MetO of specific proteins in several signal transduction pathways that are important for cellular function. In the current review, we will focus on the role of MetO in specific signal transduction pathways of various organisms, with relation to their physiological contexts, and discuss the contribution of the Msr system to the regulation of the observed MetO effect.

Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer’s disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal cortex (EC) and hippocampus CA1 of 6-, 12-, and 21-month-old mice APOE3 or APOE4 knock-in mice expressing GFP under the CX3CR1 promoter. To study microglia surveillance, we imaged microglia baseline motility for 20 min and measured the extension and retraction of processes. We found that APOE4 microglia exhibited significantly less brain surveillance (27%) compared to APOE3 microglia in 6-month-old mice; aging exacerbated this deficit. To measure microglia response to damage, we imaged process motility in response to ATP, an injury-associated signal, for 30 min. We found APOE4 microglia extended their processes significantly slower (0.9 µm/min, p < 0.005) than APOE3 microglia (1.1 μm/min) in 6-month-old animals. APOE-associated alterations in microglia motility were observed in 12- and 21-month-old animals, and this effect was exacerbated with aging in APOE4 microglia. We measured protein and mRNA levels of P2RY12, a core microglial receptor required for process movement in response to damage. We found that APOE4 microglia express significantly less P2RY12 receptors compared to APOE3 microglia despite no changes in P2RY12 transcripts. To examine if the effect of APOE4 on the microglial response to ATP also applied to amyloid β (Aβ), we infused locally Hi-Lyte Fluor 555-labeled Aβ in acute brain slices of 6-month-old mice and imaged microglia movement for 2 h. APOE4 microglia showed a significantly slower (p < 0.0001) process movement toward the Aβ, and less Aβ coverage at early time points after Aβ injection. To test whether P2RY12 is involved in process movement in response to Aβ, we treated acute brain slices with a P2RY12 antagonist before Aβ injection; microglial processes no longer migrated towards Aβ. These results provide mechanistic insights into the impact of APOE4 genotype and aging in dynamic microglial behaviors prior to gross Aβ pathology and could help explain how APOE4 brains are more susceptible to AD pathogenesis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive abilities. A pathological hallmark of AD is a region-specific accumulation of the amyloid-beta protein (Aβ). Here, we explored the association between regional Aβ deposition, sociodemographic, and local biochemical factors. We quantified the Aβ burden in postmortem cortical samples from parietal (PCx) and temporal (TCx) regions of 27 cognitively unimpaired (CU) and 15 AD donors, aged 78–100 + years. Histological images of Aβ immunohistochemistry and local concentrations of pathological and inflammatory proteins were obtained at the "Aging, Dementia and TBI Study" open database. We used the area fraction fractionator stereological methodology to quantify the Aβ burden in the gray and white matter within each cortical region. We found higher Aβ burdens in the TCx of AD octogenarians compared to CU ones. We also found higher Aβ loads in the PCx of AD nonagenarians than in AD octogenarians. Moreover, AD women exhibited increased Aβ deposition compared to CU women. Interestingly, we observed a negative correlation between education years and Aβ burden in the white matter of both cortices in CU samples. In AD brains, the Aβ40, Aβ42, and pTau181 isoforms of Aβ and Tau proteins were positively correlated with the Aβ burden. Additionally, in the TCx of AD donors, the proinflammatory cytokine TNFα showed a positive correlation with the Aβ load. These novel findings contribute to understanding the interplay between sociodemographic characteristics, local inflammatory signaling, and the development of AD-related pathology in the cerebral cortex. [ABSTRACT FROM AUTHOR]

With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is one of the primary chemicals produced by volume worldwide. Extensive literature has raised many concerns about its possible involvement in the pathogenesis of kidney diseases, but its contribution has not been extensively studied. During cellular senescence, the interference of lipofuscin with cellular functions promotes further senescence, causing cellular malfunction. Insulin-like growth factor-1 (IGF-1) plays an important protective role in the setting of kidney injury. The goal of the present work was to evaluate the effects of short-term treatment with low doses of BPA on cellular senescence in adult rat kidneys. Male Wistar rats were injected with vehicle (CONTROL group) or 50 or 500 μg/kg/day of BPA for 1 week (BPA50 and BPA500 groups, respectively). The kidneys were fixed in 4% buffered formaldehyde and embedded in paraffin. Immunohistochemical analyses were performed, and an immunoreactive score (IRS) was calculated. Lipofuscin autofluorescence was used for the study of cellular senescence. The renal cortex showed diffuse autofluorescent lipofuscin signal in the proximal convoluted tubules (PCTs) of males in the BPA50-treated (weak intensity) and BPA500-treated (strong intensity) groups, but not in CONTROL males. Labeling of cortical PCTs with anti-IGF-1 antibodies showed an IRS of 0 in the CONTROL group, but IRSs of 4 and 6 in the BPA50- and BPA500-treated groups, respectively. The present results suggest that low, "safe" doses of BPA induce renal injury, as measured by histological signs of renal changes, increased cellular senescence, and activation of cellular repair systems in PCTs. [ABSTRACT FROM AUTHOR]

The past decade has witnessed increasing evidence for a crucial role played by glial cells, notably astrocytes, in Alzheimer's disease (AD). To provide novel insights into the roles of astrocytes in the pathophysiology of AD, we performed a quantitative ultrastructural characterization of their intracellular contents and parenchymal interactions in an aged mouse model of AD pathology, as aging is considered the main risk factor for developing AD. We compared 20-month-old APP-PS1 and age-matched C57BL/6J male mice, among the ventral hippocampus CA1 strata lacunosum-moleculare and radiatum, two hippocampal layers severely affected by AD pathology. Astrocytes in both layers interacted more with synaptic elements and displayed more ultrastructural markers of increased phagolysosomal activity in APP-PS1 versus C57BL6/J mice. In addition, we investigated the ultrastructural heterogeneity of astrocytes, describing in the two examined layers a dark astrocytic state that we characterized in terms of distribution, interactions with AD hallmarks, and intracellular contents. This electron-dense astrocytic state, termed dark astrocytes, was observed throughout the hippocampal parenchyma, closely associated with the vasculature, and possessed several ultrastructural markers of cellular stress. A case study exploring the hippocampal head of an aged human post-mortem brain sample also revealed the presence of a similar electron-dense, dark astrocytic state. Overall, our study provides the first ultrastructural quantitative analysis of astrocytes among the hippocampus in aged AD pathology, as well as a thorough characterization of a dark astrocytic state conserved from mouse to human. [ABSTRACT FROM AUTHOR]

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience. [ABSTRACT FROM AUTHOR]

Age-related morphological and physiological changes occur in cells, tissues and organs with high metabolic or mitotic activity; these changes decrease their regenerative capacity. One such change is interstitial fibrosis. Mast cells contain basic fibroblast growth factor and have been related to pro-fibrotic activity. We investigated the role of mast cells in physiological aging of the heart and kidney. We analyzed changes in mast cell number and compared the left and right heart ventricles and kidneys of 6- and 12-month-old Wistar rats. We also evaluated the immunohistochemical expression of basic fibroblast growth factor. Finally, we analyzed changes in the extent of interstitial fibrosis and in the glomerular sclerosis index as nonspecific markers of aging and correlated these parameters with of mast cells. Mast cells were visualized by toluidine blue staining and specific immunohistochemical expression of tryptase. The expression of basic fibroblast growth factor was assessed semiquantitatively. The extent of interstitial fibrosis was investigated using Mallory's trichrome staining. Glomerular sclerosis was evaluated using periodic acid-Schiff staining. We found that the number of mast cells increased significantly in the older rats. We also found that the number of mast cells was greatest in the left ventricle followed by the right ventricle, then the kidney. The immunoreactivity of basic fibroblast growth factor also increased in older animals. Correlations between the number of mast cells and immunoreactivity of basic fibroblast growth factor, extent of interstitial fibrosis and glomerular sclerosis index demonstrated the association between mast cells and age-related tissue remodeling of the heart and kidney. [ABSTRACT FROM AUTHOR]

Regulation of gene expression is linked to the organization of the genome. With age, chromatin alterations occur on all levels of genome organization, accompanied by changes in the gene expression profile. However, little is known about the changes in the level of transcriptional regulation. Here, we used a multi‐omics approach and integrated ATAC‐, RNA‐ and NET‐seq to identify age‐related changes in the chromatin landscape of murine liver and to investigate how these are linked to transcriptional regulation. We provide the first systematic inventory of the connection between aging, chromatin accessibility, and transcriptional regulation in a whole tissue. Aging in murine liver is characterized by an increase in chromatin accessibility at promoter regions, but not in an increase in transcriptional output. Instead, aging is accompanied by a decrease in promoter‐proximal pausing of RNA polymerase II (Pol II), while initiation of transcription is not decreased as assessed by RNA polymerase mapping using CUT&RUN. Based on the data reported, we propose that these age‐related changes in transcriptional regulation are due to a reduced stability of the pausing complex. Synopsis: Profiling the chromatin landscape and nascent transcriptome in murine liver reveals an age‐related increase in chromatin accessibility at promoters and enhancers and a decrease in promoter‐proximal pausing of RNA polymerase II due to decreased pausing complex stability. Chromatin accessibility at promoters and enhancers increases with age in murine liver tissue.This increase in chromatin accessibility is not accompanied by major transcriptional alterations, neither at nascent nor steady‐state level.Promoter‐proximal Pol II pausing strongly decreases with age likely due to a decrease in the stability of the pausing complex. [ABSTRACT FROM AUTHOR]

Patients with Alzheimer's disease (AD) often have cerebral white matter (WM) hyperintensities on MRI and microinfarcts of presumed microvascular origin pathologically. Here, we determined if vasodilator dysfunction of WM-penetrating arterioles is associated with pathologically defined WM injury and disturbances in quantitative MRI-defined WM integrity in patients with mixed microvascular and AD pathology. We analyzed tissues from 28 serially collected human brains from research donors diagnosed with varying degrees of AD neuropathologic change (ADNC) with or without cerebral microinfarcts (mVBI). WM-penetrating and pial surface arteriolar responses to the endothelium-dependent agonist bradykinin were quantified ex vivo with videomicroscopy. Vascular endothelial nitric oxide synthase (eNOS) and NAD(P)H-oxidase (Nox1, 2 and 4 isoforms) expression were measured with quantitative PCR. Glial fibrillary acidic protein (GFAP)-labeled astrocytes were quantified by unbiased stereological approaches in regions adjacent to the sites of WM-penetrating vessel collection. Post-mortem diffusion tensor imaging (DTI) was used to measure mean apparent diffusion coefficient (ADC) and fractional anisotropy (FA), quantitative indices of WM integrity. In contrast to pial surface arterioles, white matter-penetrating arterioles from donors diagnosed with high ADNC and mVBI exhibited a significantly reduced dilation in response to bradykinin when compared to the other groups. Expression of eNOS was reduced, whereas Nox1 expression was increased in WM arterioles in AD and mVBI cases. WM astrocyte density was increased in AD and mVBI, which correlated with a reduced vasodilation in WM arterioles. Moreover, in cases with low ADNC, bradykinin-induced WM arteriole dilation correlated with lower ADC and higher FA values. Comorbid ADNC and mVBI appear to synergistically interact to selectively impair bradykinin-induced vasodilation in WM-penetrating arterioles, which may be related to reduced nitric oxide- and excess reactive oxygen species-mediated vascular endothelial dysfunction. WM arteriole vasodilator dysfunction is associated with WM injury, as supported by reactive astrogliosis and MRI-defined disrupted WM microstructural integrity. [ABSTRACT FROM AUTHOR]

The pathogenesis of Alzheimer's disease (AD) is complex. Still it remains unclear, which resulted in all efforts for AD treatments with targeting the pathogenic factors unsuccessful over past decades. It has been evidenced that the innate immune is strongly implicated in the pathogenesis of AD. However, the role of adaptive immune in AD remains mostly unknown and the results obtained were controversial. In the review, we summarized recent studies and showed that the molecular and cellular alterations in AD patients and its animal models involving T cells and B cells as well as immune mediators of adaptive immune occur not only in the peripheral blood but also in the brain and the cerebrospinal fluid. The risk factors that cause AD contribute to AD progress by affecting the adaptive immune, indicating that adaptive immunity proposes a pivotal role in this disease. It may provide a possible basis for applying immunotherapy in AD and further investigates whether the immunotherapies are effective or off-target? [ABSTRACT FROM AUTHOR]

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18F-flortaucipir (FTP) and 11CPittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ1 individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Ab, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aβ, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages. [ABSTRACT FROM AUTHOR]

Background: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer's disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear.Objective: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2-/-) mice, a non-transgenic model of sporadic Alzheimer's disease.Methods: Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2-/- mouse.Results: Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2-/- animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2-/- animals compared to wild-type.Conclusion: With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress. [ABSTRACT FROM AUTHOR]

Background: The Phosphatase and tensin-induced putative kinase 1 (PINK1B9) mutant for Drosophila melanogaster is a key tool that has been used in assessing the pathology of Parkinsonism and its possible remedy. This research was targeted toward determining the effects of ethanolic extract of propolis, with levodopa therapy in the management of Parkinsonism. Method: The PINK1B9 flies were divided into groups and fed with the different treatment doses of ethanoic extract of propolis. The treatment groups were subjected to 21 days of administration of propolis and the levodopa at different doses after which percentage climbing index, antioxidant activity and lifespan studies were done. Results: Propolis alone improved motor activity, antioxidant and lifespan in Drosophila melanogaster than in PINK1 flies. Propolis in combination with levodopa significantly (P<0.05) improved physiological parameters at higher than lower concentrations in Parkinsonism Drosophila melanogaster demonstrating its importance in managing side effects associated with levodopa. Conclusion: Propolis is a novel candidate as an alternative and integrative medicinal option to use in the management of Parkinsonism in both animals and humans at higher concentrations. [ABSTRACT FROM AUTHOR]

A hypothesis is proposed to explain the pathogenesis of neurodegenerative disease and the diversity of its phenotypes. The hypothesis is based on seven main propositions: 1) neurodegenerative disease is associated with multiple risk factors, 2) age is the most important of the risk factors, 3) aging differentially affects neuroanatomical pathways, 4) degeneration of these pathways results in the formation of pathogenic proteins, 5) pathogenic proteins spread along anatomical pathways, 6) the phenotypes of familial and sporadic forms of disease are similar and 7) neurodegenerative disease is characterised by heterogeneity, overlapping phenotypes, and multiple pathology. It is hypothesised that most cases of neurodegenerative disease are multifactorial in which interactions between external environmental and internal genetic risk factors act cumulatively over a lifetime to determine the 'allostatic load' of an individual. The allostatic load determines the rate of neural aging and results in the differential breakdown of neuro-anatomical pathways influenced by their relative use or disuse during life. The consequence is the formation of one or more pathogenic proteins, some of which may exhibit 'prion-like' behaviour and propagate through the brain from initial sites of formation along neuro-anatomical pathways to affect connected brain regions. Variations in the pathological proteins formed and their anatomical spread are ultimately responsible for the clinical and pathological diversity of disease phenotypes. Minimising the factors which contribute to the allostatic load over a lifetime and maximising cognitive and physical exercise may be necessary to reduce the incidence of neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: Current demographic trends point towards an aging society entailing increasing occurrence and burden of neurodegenerative diseases. In this context, understanding physiological aging and its turning point into neurodegeneration is essential for the development of possible biomarkers and future therapeutics of brain disease. Methods: The SENIOR study represents a longitudinal, observational study including cognitively healthy elderlies aged between 50 and 70 years old at the time of inclusion, being followed annually over 10 years. Our multimodal protocol includes structural, diffusion, functional, and sodium magnetic resonance imaging (MRI) at 3 T and 7 T, positron emission tomography (PET), blood samples, genetics, audiometry, and neuropsychological and neurological examinations as well as assessment of neuronal risk factors. Results: One hundred forty-two participants (50% females) were enrolled in the SENIOR cohort with a mean age of 60 (SD 6.3) years at baseline. Baseline results with multiple regression analyses reveal that cerebral white matter lesions can be predicted by cardiovascular and cognitive risk factors and age. Cardiovascular risk factors were strongly associated with juxtacortical and periventricular lesions. Intra-subject across-test variability as a measure of neuropsychological test performance and possible cognitive marker predicts white matter volume and is significantly associated with risk profile. Division of the cohort into subjects with a higher and lower risk profile shows significant differences in intra-subject across-test variability and volumes as well as cortical thickness of brain regions of the temporal lobe. There is no difference between the lower- and higher-risk groups in amyloid load using PET data from a subset of 81 subjects. Conclusions: We here describe the study protocol and baseline findings of the SENIOR observational study which aim is the establishment of integrated, multiparametric maps of normal aging and the identification of early biomarkers for neurodegeneration. We show that intra-subject across-test variability as a marker of neuropsychological test performance as well as age, gender, and combined risk factors influence neuronal decline as represented by decrease in brain volume, cortical thickness, and increase in white matter lesions. Baseline findings will be used as underlying basis for the further implications of aging and neuronal degeneration as well as examination of brain aging under different aspects of brain pathology versus physiological aging. [ABSTRACT FROM AUTHOR]

Introduction: The CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) dementia risk score is based on demographic, genetic, and modifiable risk factors in midlife and has been shown to be predictive of later-life dementia. Objective: To test the predictive capacity of the CAIDE dementia risk score among a cohort of Japanese-American men. Methods: Midlife measures were obtained from a sample of 3,582 Japanese-American men in the Honolulu Heart Program (1965–1968, average age = 53.1 years). A follow-up exam in 1991 (average age = 77.8 years) assessed cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). Severe cognitive impairment was defined as a CASI score <60. Results: In this cohort, the CAIDE dementia risk score demonstrates significant association with later-life severe cognitive impairment (OR = 1.477, 95% CI: 1.39–1.58). However, the area under the receiver-operating characteristic curve c-statistics suggests poor predictive ability (c = 0.645, 95% CI: 0.62–0.67). Using a score cut-point of 10, the accuracy is acceptable (0.82), but the sensitivity is low (0.50). Conclusion: While the CAIDE dementia risk score at midlife is associated with later development of cognitive impairment in Japanese-American men, its predictive capacity in this population is weak. [ABSTRACT FROM AUTHOR]

We conducted a cross-sectional study on 403 participants in the 10-year follow-up examination of the Beaver Dam Offspring Study. The participants included 172 male and 231 female, with age ranging from 33 to 81 years (mean ± SD, 60.7 ± 9.3). The post-illumination pupil response (PIPR) was recorded using binocular infrared pupillometer (Neur-Optics, Inc., Irvine, CA). Cognitive testing consisted of Trail Making Test (TMT) Parts A and B, Rey Auditory Verbal Learning Test (AVLT), Digit Symbol Substitution Test (DSST), and Verbal Fluency Test (VFT) (F, A, and S). Principal component analysis (PCA) was used to calculate an overall cognitive function score. There was a significant reduction in the mean baseline pupil diameter by 0.21 mm for every 5-year increase in age (95% CI: −0.25, −0.17). There was also a significant increase in the PCA cognitive score by 0.20 (linear regression, 95% CI: 0.08, 0.32) for every 0.1 unit increase in the PIPR. The association remained significant after adjusting for age, sex, education, medications, systemic and ocular disease, and short form-12 physical and mental component score. The results of this study demonstrated a modest association between the PIPR and cognitive function, warranting longitudinal studies to evaluate the role of the PIPR in predicting cognitive function in the middle-aged and older adults. [ABSTRACT FROM AUTHOR]

Oxidative stress has been identified as a process which is detrimental to brain health, and associated with age-related cognitive declines. Few studies to-date have examined the relationship between in vivo oxidative stress biomarkers and cognitive performance within healthy elderly populations. The current study investigated the relationship between reaction time and oxidative stress, as measured by blood plasma concentrations of F2-isoprostanes using a sample of 251 healthy, non-demented, elderly volunteers (Male; 111: Female 140) aged 60–75 years from the Australian Research Council Longevity Intervention (ARCLI) study cohort. A Jensen Box was used in conjunction with the Hick paradigm in order to differentiate simple from choice reaction time (two, four and eight-choice conditions) as well as movement (MT) and decision times (DT). MT, but not DT, was found to be significantly slower for participants in the high F2-isoprostane group compared to the low F2-isoprostane group, across all stimulus choices. F2-isoprostanes, age and Wechsler Abbreviated Scale of Intelligence (WASI) full scale intelligence quotient (IQ) were found to be significant predictors of average MT in the sample as a whole. These findings provide preliminary evidence to suggest that higher levels of oxidative stress may be associated with impaired psychomotor speed in the healthy elderly population. [ABSTRACT FROM AUTHOR]

The study of cognition in Parkinson's disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer's disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values < 0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies. [ABSTRACT FROM AUTHOR]

Background: Past research has focused on risk factors for developing dementia, with increasing recognition of "resilient" people who live to old age with intact cognitive function despite pathological features of Alzheimer's disease (AD).Objective: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology.Methods: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors.Results: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01-3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09-0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15-0.78).Conclusion: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience. [ABSTRACT FROM AUTHOR]

Dementia can be empirically described by the latent dementia phenotype "δ" and its various composite "homologs". We have explored δ's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. However, it would be convenient to replicate those associations in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To this end, we have engineered a δ homolog from observed cognitive performance measures common to both projects. Our findings were replicated in randomly selected 50% splits of TARCC data (Group 1, N = 1,747; Group 2, N = 1,755), and then independently in ADNI (N = 1,737). The new δ homolog, i.e., "dT2A" (d-TARCC to ADNI), fit the data of both studies well, and was strongly correlated with dementia severity, as rated by the Clinical Dementia Rating Scale "sum of boxes" (TARCC: r = 0.99, p < 0.001; ADNI: r = 0.96, p < 0.001). dT2A achieved an area under the receiver operating characteristic curve of 0.981 (0.976-0.985) for the discrimination of Alzheimer's disease from normal controls in TARCC, and 0.988 (0.983-0.993) in ADNI. dT2A is the 12th δ homolog published to date, and opens the door to independent replications across these and similar studies. [ABSTRACT FROM AUTHOR]

Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features. [ABSTRACT FROM AUTHOR]

With the implementation of increasingly effective antiretroviral therapy (ART) over the past three decades, individuals infected with HIV live a much longer life. HIV infection is no longer a terminal but rather a chronic disease. However, the lifespan of infected individuals remains shorter than that of their uninfected peers. Even with ART, HIV infection may potentiate “premature” aging. Organ-associated disease and systemic syndromes that occur in treated HIV-infection are like that of older, uninfected individuals. Brain aging may manifest as structural changes or neurocognitive impairment that are beyond the chronological age. The spectrum of neurological, cognitive, and motor deficiencies, currently described as HIV-associated neurocognitive disorders (HAND), may reflect earlier onset of mechanisms common to HIV infection and aging (accelerated aging). HAND could also reflect the neurological impact of HIV infection superimposed on comorbidities linked to age and chronic inflammation, leading to a higher prevalence of neurocognitive impairment across the age span (accentuated aging). In addition, apolipoprotein E (ApoE), one of the most influential host risk factors for developing Alzheimer’s disease, has been implicated in the development of HAND. But studies differ as to whether ApoE is relevant, and whether age and ApoE interact to impair brain function in the HIV-infected patient. What is clear is that HIV-infected individuals are living longer with HIV, and therefore factors related to aging and health need to be examined in the context of current, effective ART. This review addresses the recent evidence for the influence of aging and ApoE on HIV-associated neurocognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI).Objective: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project").Methods: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable.Results: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM.Conclusions: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias. [ABSTRACT FROM AUTHOR]

See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) of the Aβ type is variably present in the brains of patients with Alzheimer's disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n = 18) and Caucasians (n = 19) with end-stage AD. In the combined cohort of 37 subjects, 22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer's Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted. [ABSTRACT FROM AUTHOR]

Background: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI.Objective: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study.Methods: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12).Results: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1.Conclusions: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis. [ABSTRACT FROM AUTHOR]

Background: Approximately 30% of older adults have disrupted gait. It is associated with increased risk of cognitive decline, disability, dementia, and death. Additionally, most older adults present with 1 or more neuropathologies at autopsy. Recently, there has been an effort to investigate the association between subclinical neuropathology and gait. Summary: We reviewed studies that investigated the association between gait and neuropathologies. Although all pathologies reviewed were associated with gait, grey matter atrophy was most consistently linked with poorer gait performance. Studies investigating the association between white matter and gait focused primarily on total white matter. Future research using more parsed regional analysis will provide more insight into this relationship. Evidence from studies investigating neuronal activity and gait suggests that gait disruption is associated with both under- and overactivation. Additional research is needed to delineate these conflicting results. Lastly, early evidence suggests that both amyloid and tau aggregation negatively impact multiple gait parameters, but additional studies are warranted. Overall, there was substantial methodological heterogeneity and a paucity of longitudinal studies. Key Messages: Longitudinal studies mapping changes in different types of neuropathology as they relate to changes in multiple gait parameters are needed to better understand trajectories of pathology and gait. [ABSTRACT FROM AUTHOR]

Background: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly.Objective: We aimed to assess the predictive validity of the MBT for incident aMCI.Methods: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately.Results: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30-4.56, p = 0.005). When varying the prediction window from 4-7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33-3.12, p: 0.0007-0.04).Conclusion: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease. [ABSTRACT FROM AUTHOR]

Life expectancy has increased in most developed countries, which has led to an increase in the proportion of elderly people in the world's population. However, this increase in life expectancy is not accompanied by a lengthening of the health span since aging is characterized with progressive deterioration in cellular and organ functions. The brain is particularly vulnerable to disease, and this is reflected in the onset of age-related neurodegenerative diseases such as Alzheimer's disease. Research shows that dysfunction of two barriers in the central nervous system (CNS), the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB), plays an important role in the progression of these neurodegenerative diseases. The BBB is formed by the endothelial cells of the blood capillaries, whereas the BCSFB is formed by the epithelial cells of the choroid plexus (CP), both of which are affected during aging. Here, we give an overview of how these barriers undergo changes during aging and in Alzheimer's disease, thereby disturbing brain homeostasis. Studying these changes is needed in order to gain a better understanding of the mechanisms of aging at the brain barriers, which might lead to the development of new therapies to lengthen the health span (including mental health) and reduce the chances of developing Alzheimer's disease. [ABSTRACT FROM AUTHOR]

A major problem in elderly patients is the high incidence of multiple pathologies, referred to as multimorbidity, in the aging brain. It has been increasingly recognized that co-occurrence of neurodegenerative proteinopathies and other pathologies including cerebrovascular disorders is a frequent event in the brains of both cognitively intact and impaired aged subjects. Although clinical and neuropathological diagnostic criteria of the major neurodegenerative diseases have been improved, major challenges arise from cerebral multimorbidity, and the thresholds to cause clinical overt dementia are ill defined. More than 80 % of aged human brains show neurodegenerative non-Alzheimer type proteinopathies and other pathologies which, however, frequently have been missed clinically and are even difficult to identify at neuropathological examination. Autopsy studies differ in selection criteria and the applied evaluation methods. Therefore, irrespective of the clinical symptoms, the frequency of cerebral pathologies vary considerably: Alzheimer-related pathology is seen in 19-100 %, with 'pure' Alzheimer's disease (AD) in 17-72 %, Lewy pathology in 6-39 % (AD + Lewy disease 9-28 %), vascular pathologies in 28-93 % (10.7-78 % 'pure' vascular dementia), TDP-43 proteinopathy in 6-39 %, hippocampal sclerosis in 8-1 %, and mixed pathologies in 10-93 %. These data clearly suggest that pathologically deposited proteins in neurodegenerating diseases mutually interact and are influenced by other factors, in particular cardiovascular and cerebrovascular ones, to promote cognitive decline and other clinical symptoms. It is obvious that cognitive and other neuropsychiatric impairment in the aged result from a multimorbid condition in the CNS rather than from a single disease and that the number of complex pathologies progresses with increasing age. These facts have implications for improvement of the clinical diagnosis and prognosis, the development of specific biomarkers, preventive strategies and better treatment of cerebral multimorbidity. [ABSTRACT FROM AUTHOR]

We have employed structural equation models to explicitly distinguish functional status, and therefore 'dementia-relevant' variance in cognitive task performance (i.e., 'δ'). We previously associated δ with cytokines and other serum biomarkers in a well characterized Alzheimer's disease cohort, the Texas Alzheimer's Research and Care Consortium. However, that δ homolog did not exhibit factor equivalence across ethnicity. In this study, we construct a δ homolog that exhibits mean and factor equivalence across ethnicity [i.e., 'd(=)']. d(=) is associated significantly with ten of the twelve previously selected biomarkers. Most of these associations are again specific to Non-Hispanic White participants. These findings have yet to be validated in other cohorts, but may suggest cross-ethnic differences in dementia's pathobiological mechanisms between Hispanic Mexican-Americans and Non-Hispanic Whites. [ABSTRACT FROM AUTHOR]

The innate immune system of the brain is mainly composed of microglial cells, which play a key role in the maintenance of synapses and the protection of neurons against noxious agents or lesions owing to their phagocytic activity. In the healthy brain, microglia are highly motile and strongly interact with neurons either by physical contact, induction of oxidative stress or through specific mediators, such as chemokines and cytokines. In response to inflammatory insult however, microglial cells get activated and produce inflammatory cytokines. The action of cytokines on specific receptors expressed in the brain triggers the development of sickness behavior and altered cognitive and emotional processes. The effects are acute and reversible as normal behavior is restored once the synthesis of inflammatory brain cytokines returns to baseline after a few hours. However, in pathological situations, these cytokines may reach toxic levels and have irreversible consequences such as neuronal death, as observed in neurodegenerative disorders such as Alzheimer's disease. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients and fundamental components of neuronal and glial cell membranes. They accumulate in the brain during the perinatal period in a dietary supply-dependent fashion. Their brain levels may diminish with age, but can be increased by diets enriched in n-3 PUFAs. Changes in the immune profile have been associated with n-3 PUFAs intake in humans and animal models. Therefore, the increasing exposure of the population to diets low in n-3 PUFAs could contribute to the deleterious effects of the chronic activation of microglia in the brain. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 ( ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance ( p = 1.4 × 10), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 ( GRN) and OR = 1.22 rs1990622 ( TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database ( n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology ( p = 0.03). Thus, we describe a novel and targetable dementia risk factor. [ABSTRACT FROM AUTHOR]

Aging is the major risk factor associated with neurodegenerative diseases, including Alzheimer's disease (AD). Until now no clear understanding of the mechanisms of initiation and progression of this dementing disorder exists. Based on the studies that have been conducted so far amyloid β-peptide (Aβ), a protein found in senile plaques, one of the key pathological hallmarks of AD, has been reported to be critical in the pathogenesis of AD. Studies from our laboratory and others showed that Aβ can induce oxidative stress, which leads to oxidative modification of biomolecules, thereby diminishing the normal functions of neuronal cells and eventually leading to loss of neurons and AD. In this review paper, we summarize evidence of oxidative stress in brains of AD and mild cognitive impairment patients, as well as the results from redox proteomics studies. The investigations have provided insights into the downstream effects of oxidative modification of key brain proteins in the pathogenesis of AD. Based on these redox proteomics results, we suggest future areas of research that could be considered to better understand this devastating dementing disorder. [ABSTRACT FROM AUTHOR]

Introduction: A hallmark of Alzheimer's disease (AD) is the presence of senile plaques composed of aggregated amyloid b (Aβ) peptides. Pathological aging (PA) is a postmortem classification that has been used to describe brains with plaque pathology similar in extent to AD, minimal cortical tau pathology, and no accompanying history of cognitive decline in the brain donor prior to death. PA may represent either a prodromal phase of AD, a benign form of Aβ accumulation, or inherent individual resistance to the toxic effects of Aβ accumulation. To attempt to distinguish between these possibilities we have systematically characterized Aβ peptides in a postmortem series of PA, AD and non-demented control (NDC) brains. Methods: Aβ was sequentially extracted with tris buffered saline (TBS), radioimmunoprecipitation buffer (RIPA), 2% sodium dodecyl sulfate (SDS) and 70% formic acid (FA) from the pre-frontal cortex of 16 AD, eight PA, and six NDC patients. These extracts were analyzed by 1) a panel of Aβ sandwich ELISAs, 2) immunoprecipitation followed by mass spectrometry (IP/MS) and 3) western blotting. These studies enabled us to asses Aβ levels and solubility, peptide profiles and oligomeric assemblies. Results: In almost all extracts (TBS, RIPA, 2% SDS and 70% FA) the average levels of Aβ1-40, Aβ1-42, Aβ total, and Aβx-42 were greatest in AD. On average, levels were slightly lower in PA, and there was extensive overlap between Aβ levels in individual PA and AD cases. The profiles of Aβ peptides detected using IP/MS techniques also showed extensive similarity between the PA and AD brain extracts. In select AD brain extracts, we detected more aminoterminally truncated Aβ peptides compared to PA patients, but these peptides represented a minor portion of the Aβ observed. No consistent differences in the Aβ assemblies were observed by western blotting in the PA and AD groups. Conclusions: We found extensive overlap with only subtle quantitative differences between Aβ levels, peptide profiles, solubility, and SDS-stable oligomeric assemblies in the PA and AD brains. These cross-sectional data indicate that Aβ accumulation in PA and AD is remarkably similar. Such data would be consistent with PA representing a prodromal stage of AD or a resistance to the toxic effects of Aβ. [ABSTRACT FROM AUTHOR]

Background/Aims: Hippocampal atrophy has been identified as marker for the development of Alzheimer's dementia (AD). To what extent vascular risk factors and white matter hyperintensities (WMH) affect hippocampal volume (HV) in asymptomatic elderly subjects and thus may impact such a predictive capacity is controversial. Methods: We analysed 287 participants of the Austrian Stroke Prevention Study (mean age 66.6 ± 6.6 years) with a Mini Mental State Examination score ≥27 who were free of neuropsychiatric disease and had undergone MRI including coronal T1-weighted sequences allowing for semi-automatic assessment of HV. Global brain volume (BV) was measured using SIENAX. WMH were rated according to the Fazekas scale and segmented to obtain WMH volumes. Results: Higher age was associated with lower absolute and normalized HV, a lower BV and higher WMH volume. None of the vascular risk factors had an impact on HV except for high-density lipoprotein. This effect disappeared after normalization of HV. WMH severity and volume did not affect HV either. Conclusion: Our data indicate HV loss in parallel with the whole brain and suggest no specific vulnerability towards vascular risk factors or age-related WMH in a cognitively intact normal elderly population. This also supports the utility of HV measurements to identify impending AD. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In neuronal circuits, excitatory synaptic transmission predominantly occurs at postsynaptic protrusions called dendritic spines. Spines are highly plastic structures capable of formation, enlargement, shrinkage, and elimination over time. Individual spine morphology is widely variable, and evidence suggests these differences in morphology are relevant to spine function. Recent reports provide evidence that spine structural plasticity underlies functional synaptic changes, including those seen in animal models of learning and memory plasticity. Conversely, impairments in cognitive functions, such as those commonly seen in aging, have recently been linked to and correlated with alterations in spine density and morphology. In addition, dendritic spine density and morphology also appear to be altered in various transgenic animal models of neurodegenerative diseases. Ultimately, an understanding of the synaptic basis of age- and disease-related cognitive impairments may lead to the development of drug treatments that can restore or protect synaptic profiles in neural circuits that mediate cognition. [ABSTRACT FROM AUTHOR]

The free radical theory of ageing proposes the accumulation of altered, less active and toxic molecules of DNA, RNA, proteins and lipids caused by reactive oxygen species and reactive nitrogen species. Neurodegenerative disorders are characterized by an abnormal accumulation of oxidatively damaged macromolecules inside cells and in the extracellular space. Proteins involved in the formation of aggregates are β-amyloid, tau, α-synuclein, parkin, prion proteins and proteins containing polyglutamine. These abnormal aggregated proteins influence normal cellular metabolism. Additionally, deposition of abnormal proteins induces oxidative stress and proteasomal as well as mitochondrial dysfunction that ultimately lead to neuronal cell death. This review focuses on the impact of oxidative and nitrative stress in the ageing brain and, consequently, on the generation of modified proteins, as these post-translational modifications are assumed to play an important role in the development of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Aberrant protein aggregation is a hallmark of many age-related diseases, yet little is known about whether proteins aggregate with age in a non-disease setting. Using a systematic proteomics approach, we identified several hundred proteins that become more insoluble with age in the multicellular organism Caenorhabditis elegans. These proteins are predicted to be significantly enriched in b-sheets, which promote disease protein aggregation. Strikingly, these insoluble proteins are highly over-represented in aggregates found in human neurodegeneration. We examined several of these proteins in vivo and confirmed their propensity to aggregate with age. Different proteins aggregated in different tissues and cellular compartments. Protein insolubility and aggregation were significantly delayed or even halted by reduced insulin/IGF-1-signaling, which also slows aging. We found a significant overlap between proteins that become insoluble and proteins that influence lifespan and/or polyglutamine-repeat aggregation. Moreover, overexpressing one aggregating protein enhanced polyglutamine-repeat pathology. Together our findings indicate that widespread protein insolubility and aggregation is an inherent part of aging and that it may influence both lifespan and neurodegenerative disease. [ABSTRACT FROM AUTHOR]

The neuropathology underlying dementia syndromes in older populations is complex. The contributions of Alzheimer's and Lewy body pathology are well appreciated. Recent studies with brain autopsies have highlighted the high prevalence of vascular disease as an independent, but often co-morbid contributor to dementia. The Adult Changes in Thought Study is a community-based, longitudinal study of brain aging and cognitive decline which has recently confirmed cerebral microinfarcts as a strong correlate of cognitive impairment and dementia. This study examines correlations between clinical characteristics including extensive, longitudinal medication histories, and longitudinal cognitive testing against structural and biochemical features of disease. [ABSTRACT FROM AUTHOR]

Cholesterol can be detrimental or vital, and must be present in the right place at the right time and in the right amount. This is well known in the heart and the vascular system. However, in the CNS cholesterol is still an enigma, although several of its fundamental functions in the brain have been identified. Brain cholesterol has attracted additional attention owing to its close connection to ApoE, a key polymorphic transporter of extracellular cholesterol in humans. Indeed, both cholesterol and ApoE are so critical to fundamental activities of the brain, that the brain regulates their synthesis autonomously. Yet, similar control mechanisms of ApoE and cholesterol homeostasis may exist on either sides of the blood-brain barrier. One indication is that the APOE ε4 allele is associated with hypercholesterolemia and a proatherogenic profile on the vascular side and with increased risk of Alzheimer's disease on the CNS side. In this review, we draw attention to the association between cholesterol and ApoE in the aging and diseased brain, and to the behavior of the ApoE4 protein at the molecular level. The attempt to correlate in vivo and in vitro observations is challenging but crucial for developing future strategies to address ApoE-related aberrations in cholesterol metabolism selectively in the brain. [ABSTRACT FROM AUTHOR]