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ANRIL is known as a lncRNA that has many linear and circular isoforms and its polymorphisms are observed to be associated with the pathogenesis of many diseases including age-related diseases. Age-related diseases including atherosclerosis, ischemic heart disease, and Alzheimer's and Parkinson's disease are the most common cause of mortality in both developed and undeveloped countries and that is why a better understanding of their pathogenesis and underlying mechanisms is necessary for controlling their healthcare burden.In this review, we aim to gather the data of researches which have investigated the role of ANRIL in aging and its related diseases. The conclusions of this paper might give a new insight for decreasing the mortality rate of these diseases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Age-related cognitive and affective disorders pose significant public health challenges. Notably, emotional and cognitive symptoms co-occur across multiple age-associated conditions like normal aging, Alzheimer's disease (AD), and mood disorders such as depression and anxiety. While the intricate interplay underlying this relationship remains poorly understood, this article highlights the possibility that an imbalance between full-length (TrkB.FL) and truncated (TrkB.T1) isoforms of tyrosine kinase receptor TrkB in the neurotrophic system may significantly affect age-associated emotional and cognitive functions, by altering brain-derived neurotrophic factor (BDNF) signaling, integral to neuronal health, cognitive functions and mood regulation. While the contribution of this imbalance to pathogenesis awaits full elucidation, this review evaluates its potential mediating role, linking emotional and cognitive decline across age-related disorders The interplay between TrkB.T1 and TrkB.FL isoforms may be considered as a pivotal shared regulator underlying this complex relationship. The current review aims to synthesize current knowledge on TrkB isoform imbalance, specifically its contribution to age-related cognitive decline and mood disorders. By examining shared pathogenic pathways between aging, cognitive decline, and mood disorders through the lens of TrkB signaling, this review uncovers potential therapeutic targets not previously considered, offering a fresh perspective on combating age-related mental health issues as well as cognitive deficits., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This Preface introduces the Special Issue entitled, "Energy Substrates and Microbiome Govern Brain Bioenergetics and Cognitive Function with Aging", which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 14th International Conference on Brain Energy Metabolism (ICBEM) held on October 24-27, 2022 in Santa Fe, New Mexico, USA. The conference covered the latest developments in research related to neuronal energetics, emerging roles for glycogen in higher brain functions, the impact of dietary intervention on aging, memory, and Alzheimer's disease, roles of the microbiome in gut-brain signaling, astrocyte-neuron interactions related to cognition and memory, novel roles for mitochondria and their metabolites, and metabolic neuroimaging in aging and neurodegeneration. The special issue contains 25 manuscripts on these topics plus three tributes to outstanding scientists who have made important contributions to brain energy metabolism and participated in numerous ICBEM conferences. In addition, two of the manuscripts describe important directions and the rationale for future research in many thematic areas covered by the conference., (© 2024 International Society for Neurochemistry.)

Aging is a gradual decline of physiological function and tissue homeostasis and, in many instances, is related to increased (neuro)-degeneration, together with inflammation, becoming one of the most important risks for developing neurodegenerative diseases. Certain individual nutrients or foods in combination may counteract aging and associated neurodegenerative diseases by promoting a balance between the pro- and anti-inflammatory responses. Thus, nutrition could represent a powerful modulator of this fine balance, other than a modifiable risk factor to contrast inflammaging. This narrative review explores from a broad perspective the impact of nutrition on the hallmarks of aging and inflammation in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis Syndrome (ALS), starting from nutrients up to single foods and complex dietary patterns., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Dietary interventions can ameliorate age-related neurological decline. Decades of research of in vitro studies, animal models, and clinical trials support their ability and efficacy to improve behavioral outcomes by inducing biochemical and physiological changes that lead to a more resilient brain. Dietary interventions including calorie restriction, alternate day fasting, time restricted feeding, and fasting mimicking diets not only improve normal brain aging but also slow down, or even reverse, the progression of neurological diseases. In this review, we focus on the effects of intermittent and periodic fasting on improving phenotypic outcomes, such as cognitive and motor-coordination decline, in the normal aging brain through an increase in neurogenesis and synaptic plasticity, and decrease in neuroinflammation, mitochondrial dysfunction, and oxidative stress. We summarize the results of various dietary interventions in animal models of age-related neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, and Multiple Sclerosis and discuss the results of clinical trials that explore the feasibility of dietary interventions in the prevention and treatment of these diseases.

Background: Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer's disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology that appear symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging., Methods: The present study examined the impacts of RCAN1 deficiency and overexpression on the photic entrainment, circadian periodicity, intensity and distribution, diurnal patterning, and circadian rhythmicity of wheel running in young (3-6 months old) and aged (9-14 months old) mice of both sexes., Results: We found that daily RCAN1 levels in the hippocampus and suprachiasmatic nucleus (SCN) of light-entrained young mice are generally constant and that balanced RCAN1 expression is necessary for normal circadian locomotor activity rhythms. While the light-entrained diurnal period was unaltered, RCAN1-null and RCAN1-overexpressing mice displayed lengthened endogenous (free-running) circadian periods like mouse models of AD and aging. In light-entrained young mice, RCAN1 deficiency and overexpression also recapitulated the general hypoactivity, diurnal rest-wake pattern fragmentation, and attenuated amplitudes of circadian activity rhythms reported in DS, preclinical and clinical AD, healthily aging individuals, and rodent models thereof. Under constant darkness, RCAN1-null and RCAN1-overexpressing mice displayed altered locomotor behavior indicating circadian clock dysfunction. Using the Dp(16)1Yey/+ (Dp16) mouse model for DS, which expresses three copies of Rcan1, we found reduced wheel running activity and rhythmicity in both light-entrained and free-running young Dp16 mice like young RCAN1-overexpressing mice. Critically, these diurnal and circadian deficits were rescued in part or entirely by restoring Rcan1 to two copies in Dp16 mice. We also found that RCAN1 deficiency but not RCAN1 overexpression altered protein levels of the clock gene Bmal1 in the SCN., Conclusions: Collectively, this study's findings suggest that both loss and aberrant gain of RCAN1 precipitate anomalous light-entrained diurnal and circadian activity patterns emblematic of DS, AD, and possibly aging., (© 2022. The Author(s).)

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The insulin/IGF-1 signaling pathway has a major role in the regulation of longevity both in Caenorhabditis elegans and mammalian species, i.e., reduced activity of this pathway extends lifespan, whereas increased activity accelerates the aging process. The insulin/IGF-1 pathway controls protein and energy metabolism as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. Insulin/IGF-1 signaling also regulates the functions of the innate and adaptive immune systems. The purpose of this review was to elucidate whether insulin/IGF-1 signaling is linked to immunosuppressive STAT3 signaling which is known to promote the aging process., Methods: Original and review articles encompassing the connections between insulin/IGF-1 and STAT3 signaling were examined from major databases including Pubmed, Scopus, and Google Scholar., Results: The activation of insulin/IGF-1 receptors stimulates STAT3 signaling through the JAK and AKT-driven signaling pathways. STAT3 signaling is a major activator of immunosuppressive cells which are able to counteract the chronic low-grade inflammation associated with the aging process. However, the activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which not only inhibit the activity of insulin/IGF-1 receptors but also that of many cytokine receptors. The inhibition of insulin/IGF-1 signaling evokes insulin resistance, a condition known to be increased with aging. STAT3 signaling also triggers the senescence of both non-immune and immune cells, especially through the activation of p53 signaling., Conclusions: Given that cellular senescence, inflammaging, and counteracting immune suppression increase with aging, this might explain why excessive insulin/IGF-1 signaling promotes the aging process., (© 2021. The Author(s).)

Dogs have been used as animal models for human diseases in which there is beta-amyloid (Aβ) deposition in the central nervous system (CNS), such as Alzheimer's and cerebral amyloid angiopathy (CAA). However, many aspects of Aβ deposition in the CNS of dogs still remain unknown. This study aimed to evaluate the deposition of Aβ in different areas of the CNS of aged dogs from different breeds. Aβ was detected in the brains of aged dogs, forming either senile plaques in the neuropil of cortical gray matter or within the walls of parenchymal or leptomeningeal blood vessels. There was a positive correlation between aging and senile plaques or CAA. In dogs older than 8 years, there was no correlation between the area of Aβ plaques and age, with frontal, temporal, and occipital cortices being affected with approximately equal frequency. There was a positive correlation between Aβ deposition in vessel walls and age. Importantly, CAA was associated with the occurrence of microperivascular hemorrhages in the brains of aged dogs. In conclusion, this study demonstrated that Aβ deposition as plaques or within vessel walls are extremely heterogenous in dogs from different breeds and sizes. Although many features of this disease in dogs are similar to those observed in humans, the choice of dog breed and size as a model for human disease will substantially affect the pattern of Aβ deposition., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: N6-methyladenosine (m 6 A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain., Results: We show that m 6 A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m 6 A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m 6 A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m 6 A sites compared to mice. Differential m 6 A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m 6 A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m 6 A methylation in a mouse model of Alzheimer's disease, which is correlated with reduced protein levels., Conclusions: Our results suggest that m 6 A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m 6 A controls protein levels of key genes involved in Alzheimer's disease-associated pathways, suggesting that m 6 A plays an important role in aging and neurodegenerative disease.

Chronic low-grade inflammation is a common hallmark of the aging process and many age-related diseases. There is substantial evidence that persistent inflammation is associated with a compensatory anti-inflammatory response which prevents excessive tissue damage. Interestingly, the inflammatory state encountered with aging, called inflammaging, is associated with the anti-inflammaging process. The age-related activation of immunosuppressive network includes an increase in the numbers of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and macrophages (Mreg/M2c). Immunosuppressive cells secrete several anti-inflammatory cytokines, e.g., TGF-β and IL-10, as well as reactive oxygen and nitrogen species (ROS/RNS). Moreover, immunosuppressive cells suppress the function of effector immune cells by catabolizing L-arginine and tryptophan through the activation of arginase 1 (ARG1) and indoleamine 2,3-dioxygenase (IDO), respectively. Unfortunately, the immunosuppressive armament also induces harmful bystander effects in neighboring cells by impairing host tissue homeostasis. For instance, TGF-β signaling can trigger many age-related degenerative changes, e.g., cellular senescence, fibrosis, osteoporosis, muscle atrophy, and the degeneration of the extracellular matrix. In addition, changes in the levels of ROS, RNS, and the metabolites of the kynurenine pathway can impair tissue homeostasis. This review will examine in detail the harmful effects of the immunosuppressive cells on host tissues. It seems that this age-related immunosuppression prevents inflammatory damage but promotes the tissue degeneration associated with aging and age-related diseases. KEY MESSAGES: • Low-grade inflammation is associated with the aging process and age-related diseases. • Persistent inflammation activates compensatory immunosuppression with aging. • The numbers of immunosuppressive cells increase with aging and age-related diseases. • Immunosuppressive mechanisms evoke harmful bystander effects in host tissues. • Immunosuppression promotes tissue degeneration with aging and age-related diseases.

Alzheimer's disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the illness timecourse. These fMRI correlates of unhealthy aging have been studied in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC alterations associated with AD disrupt the flow of activations between brain regions, leading to aberrant task activations. We apply this activity flow model in a large sample of clinically normal older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) AD risk factors. Modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy (at-risk) aged activations. This enabled reliable prediction of at-risk AD task activations, and these predicted activations were related to individual differences in task behavior. These results support activity flow over altered intrinsic functional connections as a mechanism underlying Alzheimer's-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights, this approach raises clinical potential by enabling prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuronal hyperexcitability has emerged as a potential biomarker of late-onset early-stage Alzheimer's disease (LEAD). We hypothesize that the aging-related posterior cortical hyperexcitability anticipates the loss of excitability with the emergence of impairment in LEAD. To test this hypothesis, we compared the behavioral and neurophysiological responses of young and older (ON) normal adults, and LEAD patients during a visuospatial attentional control task. ONs show frontal cortical signal incoherence and posterior cortical hyper-responsiveness with preserved attentional control. LEADs lose the posterior hyper-responsiveness and fail in the attentional task. Our findings suggest that signal incoherence and cortical hyper-responsiveness in aging may contribute to the development of functional impairment in LEAD., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The gut microbiome is increasingly implicated in modifying susceptibility to and progression of neurodegenerative diseases (NDs). In this review, we discuss roles for the microbiome in aging and in NDs. In particular, we summarize findings from human studies on microbiome alterations in Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We assess animal studies of genetic and environmental models for NDs that investigate how manipulations of the microbiome causally impact the development of behavioral and neuropathological endophenotypes of disease. We additionally evaluate the likely immunological, neuronal, and metabolic mechanisms for how the gut microbiota may modulate risk for NDs. Finally, we speculate on cross-cutting features for microbial influences across multiple NDs and consider the potential for microbiome-targeted interventions for NDs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ageing, genetic, medical and lifestyle factors contribute to the risk of Alzheimer's disease and other dementias. Around a third of dementia cases are attributable to modifiable risk factors such as physical inactivity, smoking and hypertension. With the rising prevalence and lack of neuroprotective drugs, there is renewed focus on dementia prevention strategies across the lifespan. Neurologists encounter many people with risk factors for dementia and are frequently asked whether lifestyle changes may help. Exercise has emerged as a key intervention for influencing cognition positively, including reducing the risk of age-related cognitive decline and dementia. This article focuses on the current evidence for physical inactivity as a modifiable dementia risk factor and aims to support neurologists when discussing risk reduction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The status of vitamin B12 and folate has been implicated in the development and progression of Alzheimer's disease. Methods: The study explored this issue through a retrospective case-control study design, with follow up of the case group for 18 months. The case group ( n  = 136) comprised patients 65 years or older diagnosed with Alzheimer's disease and having a Mini-mental State Examination score (MMSE) of ≤ 27. The control group comprised healthy adults 65 years or older ( n  = 338) with a MMSE score of >27. Results: Vitamin B12 and folate levels were not found to differ between case and control groups. B12 and folate status at baseline was not predictive of disease progression in the case group. Discussion: This lack of association differs from other studies which have shown a protective effect of vitamin B12 and folate on cognitive decline.KEY POINTSThe findings of this study do not confirm evidence suggesting an effect of vitamin B12 and folate levels on development and progression of Alzheimer's disease.Folate and B12 levels were similar in the Alzheimer's group to those of healthy controls.Folate and B12 levels at initial assessment were not predictive of disease progression.

Purpose/Aim : Alzheimer's disease (AD), the primary cause of dementia in the elderly, is one of the leading age-related neurodegenerative diseases worldwide. While AD is notorious for destroying memory and cognition, dementia patients also experience greater incidence of bone loss and skeletal fracture than age-matched neurotypical individuals, greatly impacting their quality of life. Despite the significance of this comorbidity, there is no solid understanding of the mechanisms driving early bone loss in AD. Here, we review studies that have evaluated many of the obvious risk factors shared by dementia and osteoporosis, and illuminate emerging work investigating covert pathophysiological mechanisms shared between the disorders that may have potential as new risk biomarkers or therapeutic targets in AD. Conclusions : Skeletal deficits emerge very early in clinical Alzheimer's progression, and cannot be explained by coincident factors such as aging, female sex, mobility status, falls, or genetics. While research in this area is still in its infancy, studies implicate several potential mechanisms in disrupting skeletal homeostasis that include direct effects of amyloid-beta pathology on bone cells, neurofibrillary tau-induced damage to neural centers regulating skeletal remodeling, and/or systemic Wnt/Beta-catenin signaling deficits. Data from an increasing number of studies substantiate a role for the newly discovered "exercise hormone" irisin and its protein precursor FNDC5 in bone loss and AD-associated neurodegeneration. We conclude that the current status of research on bone loss in AD is insufficient and merits critical attention because this work could uncover novel diagnostic and therapeutic opportunities desperately needed to address AD.

Recent interest in enlarged perivascular spaces (ePVS) in the brain, which can be visualized on MRI and appear isointense to cerebrospinal fluid on all sequence weightings, has resulted in the necessity of reliable algorithms for automated segmentation to allow for whole brain assessment of ePVS burden. However, several publicly available datasets do not contain sequences required for recently published algorithms. This prospective study presents a method for identification of enlarged perivascular spaces (ePVS) in white matter using 3T T 1 and FLAIR MR imaging (MAPS-T 1 ), making the algorithm accessible to groups with valuable sets of limited data. The approach was applied identically to two datasets: 1) a repeated measurement in a dementia-free aged human population (N = 14), and 2) an aged sample of multisite ADNI datasets (N = 30). ePVS segmentation was accomplished by a stepwise local homogeneity search of white matter-masked T 1 -weighted data, constrained by FLAIR hyperintensity, and further constrained by width, volume, and linearity measurements. Pearson's r was employed for statistical testing between visual (gold standard) assessment and repeated measures in cohort one. Visual ePVS counts were significantly correlated with MAPS-T 1 (r = .72, P < .0001). Correlations between repeated measurements in cohort one were significant for both visual and automated methods in the single visually-rated slice (MAPS-T 1 : r = .87, P < .0001, visual: (r = .86, P < .0001) and for whole brain assessment (MAPS-T 1 : r = .77, P = .001). Results from each cohort were manually inspected and found to have positive predictive values of 77.5% and 87.5%, respectively. The approach described in this report is an important tool for detailed assessment of ePVS burden in white matter on routinely acquired MRI sequences., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear "signature" was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF-1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the "pro-longevity" direction. Quantitative network modeling demonstrated that age-regulated ncRNA equaled the contribution of protein-coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with "neuron apoptotic processes" in protein-protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age-related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome-wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Transactive response DNA-binding protein 43 (TDP-43) pathology is common in old age and is strongly associated with cognitive decline and dementia above and beyond contributions from other neuropathologies. TDP-43 pathology in aging typically originates in the amygdala, a brain region also affected by other age-related neuropathologies such as Alzheimer's pathology. The purpose of this study was two-fold: to determine the independent effects of TDP-43 pathology on the volume, as well as shape, of the amygdala in a community cohort of older adults, and to determine the contribution of amygdala volume to the variance of the rate of cognitive decline after accounting for the contributions of neuropathologies and demographics. Cerebral hemispheres from 198 participants of the Rush Memory and Aging Project and the Religious Orders Study were imaged with MRI ex vivo and underwent neuropathologic examination. Measures of amygdala volume and shape were extracted for all participants. Regression models controlling for neuropathologies and demographics showed an independent negative association of TDP-43 with the volume of the amygdala. Shape analysis revealed a unique pattern of amygdala deformation associated with TDP-43 pathology. Finally, mixed-effects models showed that amygdala volume explained an additional portion of the variance of the rate of decline in global cognition, episodic memory, semantic memory, and perceptual speed, above and beyond what was explained by demographics and neuropathologies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The mortality rates of age-related diseases (ARDs) increase exponentially with age. Processes described by the exponential growth function typically involve a branching chain reaction or, more generally, a positive feedback loop. Here I propose that each ARD is mediated by one or several positive feedback loops (vicious cycles). I then identify critical vicious cycles in five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. I also propose that the progression of ARDs can be halted by selectively interrupting the vicious cycles and suggest the most promising targets., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer's disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates - such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.

Significance: Reductionist studies have contributed greatly to our understanding of the basic biology of aging in recent years but we still do not understand fundamental mechanisms for many identified drugs and pathways. Use of systems approaches will help us move forward in our understanding of aging. Recent Advances: Recent work described here has illustrated the power of systems biology to inform our understanding of aging through the study of (i) diet restriction, (ii) neurodegenerative disease, and (iii) biomarkers of aging., Critical Issues: Although we do not understand all of the individual genes and pathways that affect aging, as we continue to uncover more of them, we have now also begun to synthesize existing data using systems-level approaches, often to great effect. The three examples noted here all benefit from computational approaches that were unknown a few years ago, and from biological insights gleaned from multiple model systems, from aging laboratories as well as many other areas of biology., Future Directions: Many new technologies, such as single-cell sequencing, advances in epigenetics beyond the methylome (specifically, assay for transposase-accessible chromatin with high throughput sequencing ), and multiomic network studies, will increase the reach of systems biologists. This suggests that approaches similar to those described here will continue to lead to striking findings, and to interventions that may allow us to delay some of the many age-associated diseases in humans; perhaps sooner that we expect. Antioxid. Redox Signal. 29, 973-984.

The early detection of Alzheimer's disease requires our distinguishing it from cognitive aging. Here, we test whether spatial attentional changes might support that distinction. We engaged young normal (YN), older normal (ON), and patients with early Alzheimer's dementia (EAD) in an attentionally cued, self-movement heading discrimination task while we recorded push-button response times and event related potentials. YNs and ONs show the behavioral effects of attentional shifts from the cue to the target, whereas EAD patients did not (p < 0.001). YNs and ONs also show the shifting lateralization of a newly described attentional event related potentials component, whereas EAD patients did not (p < 0.001). Our findings suggest that spatial inattention in EAD patients may contribute to heading direction processing impairments that distinguish them from ONs and undermine their navigational capacity and driving safety., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) pathogenesis is a multifactorial process that involves numerous pathways within the central nervous system. Thus, interventions that interact with several disease-related pathways may offer an increased opportunity for successful prevention and treatment of AD. Translocator protein 18 kD (TSPO) is a mitochondrial protein that is associated with regulation of many cellular processes including inflammation, steroid synthesis, apoptosis, and mitochondrial respiration. Although TSPO ligands have been shown to be protective in several neurodegenerative paradigms, little work has been done to assess their potential as treatments for AD. Female 3xTg-AD mice were administered the TSPO ligand PK11195 once weekly for 5 weeks beginning at 16 months, an age characterized by extensive β-amyloid pathology and behavioral impairments. Animals treated with PK11195 showed improvements in behavior and modest reductions of in both soluble and deposited β-amyloid. The finding that short-term PK11195 treatment was effective in improving both behavioral and pathological outcomes in a model of late-stage AD supports further investigation of TSPO ligands as potential therapeutics for the treatment of AD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Traditional herbal medicine has provided natural remedies against cancers and many age-related inflammatory diseases for thousands of years. Modern drug discovery techniques have revealed several active ingredients and their medicinal targets have been characterized. Concurrently, there has been great progress in understanding the pathological mechanisms underpinning cancers and inflammatory diseases. These studies have demonstrated that immature myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of cancer cells thus promoting tumor growth. Inflammatory factors stimulate the recruitment, expansion, and activation of MDSCs in tumors and inflamed tissues. The immunosuppression generated by MDSCs has an important role in the resolution of acute inflammation but in chronic inflammatory disorders, the activation of MDSCs suppresses the innate and adaptive immune responses thus aggravating the disease processes in association with tumors, chronic infections, and many degenerative diseases. Currently, MDSCs are important drug discovery targets in cancers and chronic inflammatory diseases. Interestingly, there are promising reports that certain phytochemicals can function as potent inhibitors of the immunosuppressive MDSCs that could partially explain the therapeutic benefits of herbal medicine. We will briefly describe the immune suppressive functions of MDSCs in cancers and age-related inflammatory diseases and then review in detail the chemically characterized phytochemicals of different herbal categories, e.g. flavonoids, terpenoids, retinoids, curcumins, and β-glucans, which possess the MDSC-dependent antitumor and anti-inflammatory properties., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The objective of this study was to examine whether the effects of age-related neuropathologies on cognition change over time. Participants were 1096 deceased persons from two clinical-pathologic studies. All were without dementia at baseline, completed a detailed battery of cognitive tests annually over up to 21 years, died, and underwent detailed neuropathologic examinations to identify Alzheimer's disease pathology, vascular pathologies (i.e. macro- and microscopic infarcts, atherosclerosis, arteriolar sclerosis, and cerebral amyloid angiopathy), Lewy bodies, transactive response DNA-binding protein 43 (TDP-43) pathology, and hippocampal sclerosis. A time-varying effects model was used to flexibly characterize the trajectory of global cognition and assess whether the effects of demographics and each neuropathologic index on cognition changed over time. Results indicated that the mean trajectory of global cognition was characterized by gradual cognitive decline beginning ∼15 years before death and accelerated decline in the last few years. With the exception of microinfarcts and arteriolar sclerosis, all neuropathologies were associated with the cognitive trajectory. However, the nature of their associations varied. Alzheimer's disease pathology, macroscopic infarcts, Lewy bodies, TDP-43 pathology, and hippocampal sclerosis were associated with progressive cognitive decline, with their deleterious effects increasing over time. By contrast, atherosclerosis and cerebral amyloid angiopathy pathology were associated with a lower level of cognition but their effects were relatively stable over time. These results suggest that age-related neuropathologies are differentially related to late life cognitive trajectories. Whereas some contribute to progressive cognitive deterioration, others lower the level of cognition but exert relatively stable effects over time., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Research addressing social class and dementia has largely focused on measures of socioeconomic status as causal risk factors for dementia and in observed differences in diagnosis, treatment and care. This large body of work has produced important insights but also contains numerous problems and weaknesses. Research needs to take account of the ways in which ageing and social class have been transformed in tandem with the economic, social and cultural coordinates of late modernity. These changes have particular consequences for individual identities and social relations. With this in mind this article adopts a critical gaze on research that considers interactions between dementia and social class in three key areas: (i) epidemiological approaches to inequalities in risk (ii) the role of social class in diagnosis and treatment and (iii) class in the framing of care and access to care. Following this, the article considers studies of dementia and social class that focus on lay understandings and biographical accounts. Sociological insights in this field come from the view that dementia and social class are embedded in social relations. Thus, forms of distinction based on class relations may still play an important role in the lived experience of dementia., (© 2017 Foundation for the Sociology of Health & Illness.)

Accompanying the ageing of contemporary ageing societies is an increase in age associated morbidity, with dementia having an important impact. Mental frailty in later life is a source of fear for many and a major policy concern to all those concerned with health and welfare services. This introduction to the special issue on 'Ageing, dementia and the social mind' situates the selected papers within the context of debates about dementia and its social relations. In particular it draws attention to the importance of the social imaginary of the fourth age and what this means for the issue of personhood, care, social representations of dementia and its social contextualisation. The papers illuminating these themes draw on a variety of disciplines and approaches; from the social sciences to the humanities and from the theoretical to the empirical in order to help orientate future researchers to the complexities of dementia and the social and cultural matrix in which it exists. This paper provides an introduction to the potential for a more extended sociology of dementia; one which could combine the insights from medical sociology with the concerns of social gerontology., (© 2017 Foundation for the Sociology of Health & Illness.)

In a previous cross-sectional study, we found that nondemented elderly participants from the Rush Religious Orders Study (RROS) displayed a wide range of Braak neurofibrillary tangle and amyloid plaque pathology similar to that seen in prodromal and frank Alzheimer's disease. Here, we examined longitudinal changes in cognitive domains in subjects from this cohort grouped by Braak stage using linear mixed effects models. We found that the trajectory of episodic memory composite (EMC), executive function composite (EFC), and global cognitive composite scores (GCS: average of EMC and EFC scores) was significantly associated with age at visit over time, but not with Braak stage, apolipoprotein E (APOE) ε4 status or plaque pathology alone. By contrast, the combined effects of Braak stage, APOE status, and age at visit were strongly correlated with the trajectory of EMC, EFC and GCS performance over time. These data suggest that age and APOE ε4 status, rather than Alzheimer's disease-related pathology, play a more prominent role in the trajectory of cognitive decline over time in this elderly nondemented population. However, the findings reported require confirmation in a larger cohort of cases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Synaptic proteomes have evolved a rich and complex diversity to allow the exquisite control of neuronal communication and information transfer. It is therefore not surprising that many neurological disorders are associated with alterations in synaptic function. As technology has advanced, our ability to study the anatomical and physiological function of synapses in greater detail has revealed a critical role for both central and peripheral synapses in neurodegenerative disease. Synapse loss has a devastating effect on cellular communication, leading to wide ranging effects such as network disruption within central neural systems and muscle wastage in the periphery. These devastating effects link synaptic pathology to a diverse range of neurological disorders, spanning Alzheimer's disease to multiple sclerosis. This review will highlight some of the current literature on synaptic integrity in animal models of disease and human post-mortem studies. Synaptic changes in normal brain ageing will also be discussed and finally the current and prospective treatments for neurodegenerative disorders will be summarised., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aging is the strongest known risk factor for Alzheimer's disease (AD). With the discovery of the mechanistic target of rapamycin (mTOR) as a critical pathway controlling the rate of aging in mice, molecules at the interface between the regulation of aging and the mechanisms of specific age-associated diseases can be identified. We will review emerging evidence that mTOR-dependent brain vascular dysfunction, a universal feature of aging, may be one of the mechanisms linking the regulation of the rate of aging to the pathogenesis of Alzheimer's disease. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock., (Published by Elsevier B.V.)

Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology., Methods: Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study cohort. Neurones were isolated from eight cases (four high and four low DDR) by laser capture microdissection and changes in the transcriptome identified by microarray analysis., Results: Two thousand three hundred seventy-eight genes were significantly differentially expressed (1690 up-regulated, 688 down-regulated, P < 0.001) in cases with a high neuronal DDR. Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and Wnt signalling, and up-regulation of glycogen synthase kinase 3β. Candidate genes were validated by quantitative real-time polymerase chain reaction. Cerebrospinal fluid levels of 24(S)-hydroxycholesterol associated with neuronal DDR across all Braak stages (rs  = 0.30, P = 0.03)., Conclusions: A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3β, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain., (© 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Sleep disturbances are a common presenting symptom of older-age adults to their physicians. This article explores normal changes in sleep pattern with aging and primary sleep disorders in the elderly. Behavioral factors and primary psychiatric disorders affecting sleep in this population are reviewed. Further discussion examines sleep changes associated with 2 common forms of neurocognitive disorder: Alzheimer disease and Lewy Body Dementia. Common medical illnesses in the elderly are discussed in relation to sleep symptoms. Nonpharmacological and pharmacologic treatment strategies are summarized, with emphasis placed on risk of side effects in older adults. Future targets are considered., (Published by Elsevier Inc.)

The objective of this work was 2-fold: to generate macrostructural brain signatures of age-related neuropathologies in a community cohort of older adults and to determine the contribution of brain macrostructure to the variation in antemortem cognition after accounting for the contributions of neuropathologies and demographics. Cerebral hemispheres from 165 participants of 2 cohort studies of aging were imaged with magnetic resonance imaging ex vivo (mean age at death = 90 years; standard deviation = 6 years). The volumes of white matter and 42 gray matter regions were measured. The same hemispheres also underwent neuropathologic examination. Alzheimer's disease pathology was negatively associated with volumes of mainly temporal, frontal, and parietal gray matter regions, and with total white matter volume (p < 0.05, false discovery rate-corrected). A negative association was also detected between hippocampal sclerosis and volumes of the hippocampus, as well as other temporal and frontal gray matter regions (p < 0.05, false discovery rate-corrected). The volume of mainly medial temporal lobe regions explained an additional 5%-6% of the variation in antemortem cognition, above and beyond what was explained by neuropathologies and demographics., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Impairments in working memory (WM) can predict the shift from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and the rate at which AD progresses with age. The 3xTg-AD mouse model develops both Aβ plaques and neurofibrillary tangles, the neuro-pathological hallmarks of AD, by 6 months of age, but no research has investigated the age-related changes in WM in these mice. Using a cross-sectional design, we tested male and female 3xTg-AD and wildtype control (B6129SF2/J) mice between 2 and 15 months of age for reference and working memory errors in the 8-arm radial maze. The 3xTg-AD mice had deficits in both working and reference memory across the ages tested, rather than showing the predicted age-related memory deficits. Male 3xTg-AD mice showed more working and reference memory errors than females, but there were no sex differences in wildtype control mice. These results indicate that the 3xTg-AD mouse replicates the impairments in WM found in patients with AD. However, these mice show memory deficits as early as two months of age, suggesting that the genes underlying reference and working memory in these mice cause deficits from an early age. The finding that males were affected more than females suggests that more attention should be paid to sex differences in transgenic AD mice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We investigated whether individuals with impaired glucose tolerance (IGT) in midlife subsequently show regionally specific longitudinal changes in regional cerebral blood flow (rCBF) relative to those with normal glucose tolerance (NGT). Sixty-four cognitively normal participants in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging underwent serial (15)O-water positron emission tomography scans (age at first scan, 69.6 ± 7.5 years) and oral glucose tolerance tests 12 years earlier (age at first oral glucose tolerance test, 57.2 ± 11.1 years). Using voxel-based analysis, we compared changes in rCBF over an 8-year period between 15 participants with IGT in midlife and 49 with NGT. Significant differences were observed in longitudinal change in rCBF between the IGT and NGT groups. The predominant pattern was greater rCBF decline in the IGT group in the frontal, parietal, and temporal cortices. Some brain regions in the frontal and temporal cortices also showed greater longitudinal increments in rCBF in the IGT group. Our findings suggest that IGT in midlife is associated with subsequent longitudinal changes in brain function during aging even in cognitively normal older individuals., (Published by Elsevier Inc.)

Caring for persons with Alzheimer's disease presents neurologists with ethical challenges. Some of these, such as end-of-life care or research participation, are well known and have significant overlap with challenges in other areas of medicine or other neurologic diseases, such as cancer or traumatic brain injury, while others, such as the rise of biomarker-based diagnostics, are more novel and reflect the impact of developments in the science and clinical care of Alzheimer's disease. A thoughtful and systematic approach to these challenges, from the preclinical to the late symptomatic stage of this disease, is required and will help clinicians be better advocates and stewards of their patients. This chapter addresses a number of the most pressing ethical problems facing patients, caregivers, and clinicians during this disease, including early and presymptomatic testing, assessment of decision-making capacity for treatment or research participation, restriction of driving, remote monitoring, assisted suicide, and treatment of disruptive behaviors., (© 2013 Elsevier B.V. All rights reserved.)

The escalating global healthcare challenge posed by Alzheimer's Disease (AD) and compounded by the lack of effective treatments emphasizes the urgent need for innovative approaches to combat this devastating disease. Currently, passive and active immunotherapies remain the most promising strategy for AD. FDA-approved lecanemab significantly reduces Aβ aggregates from the brains of early AD patients administered biweekly with this humanized monoclonal antibody. Although the clinical benefits noted in these trials have been modest, researchers have emphasized the importance of preventive immunotherapy. Importantly, data from immunotherapy studies have shown that antibody concentrations in the periphery of vaccinated people should be sufficient for targeting Aβ in the CNS. To generate relatively high concentrations of antibodies in vaccinated people at risk of AD, we generated a universal vaccine platform, MultiTEP, and, based on it, developed a DNA vaccine, AV-1959D, targeting pathological Aβ, completed IND enabling studies, and initiated a Phase I clinical trial with early AD volunteers. Our current pilot study combined our advanced MultiTEP technology with a novel mRNA approach to develop an mRNA vaccine encapsulated in lipid-based nanoparticles (LNPs), AV-1959LR. Here, we report our initial findings on the immunogenicity of 1959LR in mice and non-human primates, comparing it with the immunogenicity of its DNA counterpart, AV-1959D.

Background: People's wider culture plays a vital role in both dementia care and policy. This study aims to explore the cultural practice and policy influence around caring for People Living with Dementia (PLWD) in Nepal. Methods: An exploratory qualitative study was designed to investigate dementia care in Nepal. The study comprised four in-depth interviews and four focus group discussions with 29 participants, including family members, health care professionals, and other stakeholders. Data were analysed using thematic analysis. Result: Four major themes (each with several sub-themes) were identified: (1) Cultural practice in dementia care; (2) Impact of policy on the dementia care; (3) Service provision; and (4) Education and training. Conclusion: There is a need for community-based awareness raising on dementia and its care, to sensitise all relevant stakeholders to meet the needs of PLWD. In addition, capacity building of health workforce is needed to enhance their knowledge of and skills in providing culturally appropriate dementia care. [ABSTRACT FROM AUTHOR]

Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research. • Reduced PIN1 levels are driven by females in aging and Alzheimer's disease. • PIN1 is negatively correlated with neurofibrillary tangle density in females. • PIN1 levels are negatively correlated with global cognitive function in females. • PIN1 levels are decreased in subjects with mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Abstract Background People’s wider culture plays a vital role in both dementia care and policy. This study aims to explore the cultural practice and policy influence around caring for People Living with Dementia (PLWD) in Nepal. Methods An exploratory qualitative study was designed to investigate dementia care in Nepal. The study comprised four in-depth interviews and four focus group discussions with 29 participants, including family members, health care professionals, and other stakeholders. Data were analysed using thematic analysis. Result Four major themes (each with several sub-themes) were identified: (1) Cultural practice in dementia care; (2) Impact of policy on the dementia care; (3) Service provision; and (4) Education and training. Conclusion There is a need for community-based awareness raising on dementia and its care, to sensitise all relevant stakeholders to meet the needs of PLWD. In addition, capacity building of health workforce is needed to enhance their knowledge of and skills in providing culturally appropriate dementia care.

BACKGROUND: Myostatin, a cytokine produced by skeletal muscle, may influence Alzheimers disease (AD) pathogenesis, but sparse evidence exists in humans. We assessed the association between circulating levels of myostatin at Year 1 and plasma levels of β-amyloid 42/40 at Year 2, a marker of AD pathology, in a biracial cohort of older adults. METHODS: We studied 403 community-dwelling older adults enrolled in the Health, Aging and Body Composition Study from Memphis, Tennessee, and Pittsburgh, PA. Mean age was 73.8 ± 3 years; 54% were female; and 52% were Black. Serum myostatin levels were measured at Year 1, plasma β-amyloid 42/40 levels in Year 2 (higher ratio indicating lower amyloid load). Multivariable linear regression analyses tested the association of serum myostatin with plasma levels of β-amyloid 42/40 adjusted for computed-tomography-derived thigh muscle cross-sectional area, demographics, APOe4 allele, and risk factors for dementia. We tested for 2-way.interactions between myostatin and race or sex; results were stratified by race and sex. RESULTS: In multivariable models, myostatin was positively associated with plasma levels of β-amyloid 42/40 (standardized regression coefficient: 0.145, p = .004). Results were significant for white men and women (0.279, p = .009, and 0.221, p = .035, respectively) but not for Black men or women; interactions by race and gender were not statistically significant. CONCLUSIONS: Higher serum myostatin was associated with lower amyloid burden, independently of APOe4 alleles, muscle area and other established risk factors for dementia. The role of myostatin in AD pathogenesis and the influence of race should be further investigated.

Estrogen exposure during menstrual years has been associated with late-life neuroprotection. We explored the presence of an age-sensitive menarche window for cognition in old age and the impact of socioeconomic status and education. We compared neuropsychological performance of 1082 older women [MeanAGE = 72.69 (5.48)] with menarche in childhood, early-, mid-, and late-adolescence and dementia prevalence, severity, and type, including the effects of education and socioeconomic status. Adjusting for covariates, menarche at 11–14 years of age was associated with better memory, executive and global cognitive functioning in old age, and stronger positive effects of education and socioeconomic status on cognition than those with menarche at 15–17 years. We found a critical age window for the neuroprotective effects of estrogens during early adolescence, putting women with later menarche at higher risk for cognitive decline. Effects of socioeconomic status and education in adulthood should be a focus of future research. [ABSTRACT FROM AUTHOR]

AbstractObjective: Subjective cognitive decline (SCD) is an important part of the aging process and may be a sign of neurodegenerative disease. Current measures of SCD are subject to the limits of retrospective recall of symptoms over a long span of time, which might be addressed by using ecological momentary assessment (EMA) methods. However, there are no currently available measures of SCD validated for use in EMA. Thus, our goal was to develop and pilot test the mobile Everyday Cognition Scale (mECog). Method: 31 community-dwelling older adults completed in lab measures of cognition and mental health symptoms, followed by daily mECog ratings on a smart phone for 28 days. Results: Most participants completed at least 75% of mECog assessments (n = 27, 87%), and the average number of assessments completed was 22. Further, respondents rated the mobile assessment platform and measures as easy to use and non-interfering with daily life. Test-retest reliability of mECog scores was very strong (RKRN = .99), and within-person reliability was moderate (RCN = .41). mECog scores demonstrated strong positive associations with scores from the original ECog (ρ = .62–69, p < .001) and short form ECog (ρ = .63-.69, p < .001) and non-significant associations with demographics (ρ = –0.25–.04, p = .21-.94) and mental health symptoms (ρ = –0.06-.34, p = .08–.99). mECog scores also exhibited small-to-moderate negative correlations with objective cognitive test scores, though these relationships did not reach statistical significance (ρ = –0.32 to −0.22, p = .10–.27). Conclusions: Results suggest that mobile assessment of SCD via the mECog is feasible and acceptable. Further, mECog scores demonstrated good psychometric properties, including evidence of strong reliability, convergent validity, and divergent validity. [ABSTRACT FROM AUTHOR]

Dementia is one of the 10 causes of mortality in the world, which tends to increase with the aging of the population. Alzheimer's disease is characterized by the degeneration of neurons in the hippocampus and cerebral cortex, areas responsible for processing episodic memory and cognitive functions such as learning and attention. Recent epidemiological studies have shown that India, where curcumin is frequently used in the production of meals, has shown a significantly lower incidence of Alzheimer's disease cases when compared to the United States. Research studies and analyzes carried out in an animal model with induction of Alzheimer's disease were used, and the administration of curcumin as a form of prevention and control of signs and symptoms of the disease within the last 10 years. In the electronic search, 94 studies were obtained, of which only 16 were included for analysis because they met the inclusion criteria, 15 clinical trials carried out in an animal model and 1 clinical trial carried out in humans. All clinical trial studies analyzed in this review showed positive effects on cognitive, behavioral and inflammatory parameters of curcumin administration in animal models induced Alzheimer’s disease. Curcumin has also been shown to reduce levels of inflammatory markers in brain tissue and even stimulate antiinflammatory and antioxidant proteins by regulating the process of neuroinflammation. Conclusion: Taken together, the studies showed that curcumin upregulates insulinsignaling proteins in the brain, reduces hyperinsulinemia, and improves glucose levels in rats with Alzheimer’s disease. Results also showed that curcumin administration increased anti-inflammatory proteins with positive effects on cognition and inflammation. [ABSTRACT FROM AUTHOR]

African Americans experience higher incidence and prevalence of Alzheimer's disease (AD). Yet, they continue to be underrepresented in AD research, limiting the ability to generalize findings to the increasingly diverse US population. To reduce AD disparities, targeted efforts are needed to increase the representation of African Americans in AD research. This mini review identified evidence-based strategies that increased research participation among older African Americans. Four recruitment strategies emerged from eight published peer-reviewed studies that directly evaluated the effectiveness of strategies aimed at increasing the number of African American participants in Alzheimer's research. The strategies include community outreach and education, face-to-face discussions, remote access, and referral and partnership with local organizations. Across different locations, these strategies increased the number of African Americans enrolled into AD research, the number of people that signed up to donate their brains for AD research upon death, and the knowledge and perception of AD in the communities. Targeted efforts are effective in increasing AD research participation among older African Americans, especially when combined with approaches that emphasize transparency and mutual trust and involve the community as stakeholders in the research process. [ABSTRACT FROM AUTHOR]