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Aim: Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis., Methods: We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors., Results: Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI., Conclusions: The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD., Competing Interests: Conflict of interest The authors declare no that they have no conflicts of interests with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the extensive knowledge about the effects of chronic stress on cognition, the underlying mechanisms remain unclear. We conducted a cross-sectional moderation analysis on a population-based sample of 596 adults to examine the age- and sex-specific role of emotion regulation (ER) in the relationship between chronic stress and cognitive performance using validated self-report questionnaires. While women showed no direct or moderated relationship between stress and cognition, men displayed a distinct age-related pattern where stress was negatively associated with poorer cognitive performance at older ages, and the onset of this relationship was detected earlier in men with ER problems. These results showed that suppression of emotions and lack of executive control of ER amplify the negative consequences of chronic stress and suggest that there are sex-specific differences in the decline of ability to cope with long-term exposure to stressors., (© 2024. The Author(s).)

Background: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes., Methods: In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively., Results: A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin's abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines., Conclusions: Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs., (© 2024. The Author(s).)

Background: Although several studies have documented the impact of the COVID-19 pandemic on mental health, the long-term effects remain unclear., Aims: To examine longitudinal changes in mental health before and during the consecutive COVID-19 waves in a well-established probability sample., Method: An online survey was completed by the participants of the COVID-19 add-on study at four time points: pre-COVID-19 period (2014-2015, n = 1823), first COVID-19 wave (April to May 2020, n = 788), second COVID-19 wave (August to October 2020, n = 532) and third COVID-19 wave (March to April 2021, n = 383). Data were collected via a set of validated instruments, and analysed with latent growth models., Results: During the pandemic, we observed a significant increase in stress levels (standardised β = 0.473, P < 0.001) and depressive symptoms (standardised β = 1.284, P < 0.001). The rate of increase in depressive symptoms (std. covariance = 0.784, P = 0.014), but not in stress levels (std. covariance = 0.057, P = 0.743), was associated with the pre-pandemic mental health status of the participants. Further analysis showed that secondary stressors played a predominant role in the increase in mental health difficulties. The main secondary stressors were loneliness, negative emotionality associated with the perception of COVID-19 disease, lack of resilience, female gender and younger age., Conclusions: The surge in stress levels and depressive symptoms persisted across all three consecutive COVID-19 waves. This persistence is attributable to the effects of secondary stressors, and particularly to the status of mental health before the COVID-19 pandemic. Our findings reveal mechanisms underlying the surge in mental health difficulties during the COVID-19 waves, with direct implications for strategies promoting mental health during pandemics.

We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion in cultured astrocytes abrogated remodelling of the intermediate filament network and blunted expression of IFN stimulated gene (ISG) products in response to lipopolysaccharide (LPS). Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein (GFAP) observed canonically in astrocytes in response to TBI. Thus, APP represents a molecular inducer and regulator of reactive astrogliosis.

Introduction: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults., Methods: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aβ42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q)., Results: Lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior., Discussion: CSF Aβ42, t-tau/Aβ42, and p-tau/Aβ42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Objective: This study examined associations between physical activity (PA) and neuropsychiatric symptoms (NPS) in older adults free of dementia., Methods: This cross-sectional study included 3,222 individuals ≥70 years of age (1,655 men; mean±SD age=79.2±5.6; cognitively unimpaired, N=2,723; mild cognitive impairment, N=499) from the population-based Mayo Clinic Study of Aging. PA (taken as a presumed predictor) in midlife (i.e., when participants were 50-65 years of age) and late life (i.e., the year prior to assessment) was assessed with a self-reported, validated questionnaire; PA intensity and frequency were used to calculate composite scores. NPS (taken as presumed outcomes) were assessed with the Neuropsychiatric Inventory Questionnaire, Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). Regression analyses included midlife and late-life PA in each model, which were adjusted for age, sex, education, apolipoprotein E ɛ4 status, and medical comorbidity., Results: Higher late-life PA was associated with lower odds of having apathy (OR=0.89, 95% CI=0.84-0.93), appetite changes (OR=0.92, 95% CI=0.87-0.98), nighttime disturbances (OR=0.95, 95% CI=0.91-0.99), depression (OR=0.94, 95% CI=0.90-0.97), irritability (OR=0.93, 95% CI=0.89-0.97), clinical depression (OR=0.92, 95% CI=0.88-0.97), and clinical anxiety (OR=0.90, 95% CI=0.86-0.94), as well as lower BDI-II (β estimate=-0.042, 95% CI=-0.051 to -0.033) and BAI (β estimate=-0.030, 95% CI=-0.040 to -0.021) scores. Higher midlife PA was associated only with higher BDI-II scores (β estimate=0.011, 95% CI=0.004 to 0.019). Sex modified the associations between PA and NPS., Conclusions: Late-life PA was associated with a lower likelihood of clinical depression or anxiety and subclinical NPS. These findings need to be confirmed in a cohort study.

Introduction: Major clinically relevant inflammatory events such as septic shock and severe COVID-19 trigger dynamic changes in the host immune system, presenting promising candidates for new biomarkers to improve precision diagnostics and patient stratification. Hepcidin, a master regulator of iron metabolism, has been intensively studied in many pathologies associated with immune system activation, however these data have never been compared to other clinical settings. Thus, we aimed to reveal the dynamics of iron regulation in various clinical settings and to determine the suitability of hepcidin and/or ferritin levels as biomarkers of inflammatory disease severity., Cohorts: To investigate the overall predictive ability of hepcidin and ferritin, we enrolled the patients suffering with three different diagnoses - in detail 40 patients with COVID-19, 29 patients in septic shock and eight orthopedic patients who were compared to nine healthy donors and all cohorts to each other., Results: We showed that increased hepcidin levels reflect overall immune cell activation driven by intrinsic stimuli, without requiring direct involvement of infection vectors. Contrary to hepcidin, ferritin levels were more strongly boosted by pathogen-induced inflammation - in septic shock more than four-fold and in COVID-19 six-fold in comparison to sterile inflammation. We also defined the predictive capacity of hepcidin-to-ferritin ratio with AUC=0.79 and P = 0.03., Discussion: Our findings confirm that hepcidin is a potent marker of septic shock and other acute inflammation-associated pathologies and demonstrate the utility of the hepcidin-to-ferritin ratio as a predictor of mortality in septic shock, but not in COVID-19., Competing Interests: VO was employed by Intrinsic Lifesciences. GS was employed by Celica BIOMEDICAL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hortová-Kohoutková, Skotáková, Onyango, Slezáková, Panovský, Opatřil, Slanina, De Zuani, Mrkva, Andrejčinová, Lázničková, Dvončová, Mýtniková, Ostland, Šitina, Stokin, Šrámek, Vlková, Helán and Frič.)

Objective: To examine interactions between Neuropsychiatric symptoms (NPS) with Pittsburgh Compound B (PiB) and fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting cognitive trajectories., Methods: We conducted a longitudinal study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, MN, involving 1581 cognitively unimpaired (CU) persons aged ≥50 years (median age 71.83 years, 54.0% males, 27.5% APOE ɛ4 carriers). NPS at baseline were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Brain glucose hypometabolism was defined as a SUVR ≤ 1.47 (measured by FDG-PET) in regions typically affected in Alzheimer's disease. Abnormal cortical amyloid deposition was measured using PiB-PET (SUVR ≥ 1.48). Neuropsychological testing was done approximately every 15 months, and we calculated global and domain-specific (memory, language, attention, and visuospatial skills) cognitive z-scores. We ran linear mixed-effect models to examine the associations and interactions between NPS at baseline and z-scored PiB- and FDG-PET SUVRs in predicting cognitive z-scores adjusted for age, sex, education, and previous cognitive testing., Results: Individuals at the average PiB and without NPS at baseline declined over time on cognitive z-scores. Those with increased PiB at baseline declined faster (two-way interaction), and those with increased PiB and NPS declined even faster (three-way interaction). We observed interactions between time, increased PiB and anxiety or irritability indicating accelerated decline on global z-scores, and between time, increased PiB and several NPS (e.g., agitation) showing faster domain-specific decline, especially on the attention domain., Conclusions: NPS and increased brain amyloid deposition synergistically interact in accelerating global and domain-specific cognitive decline among CU persons at baseline., (© 2023 The Authors. Psychiatric Research and Clinical Practice published by Wiley Periodicals LLC on behalf of American Psychiatric Association.)

Worldwide, depressive disorder is one of the leading determinants of disability-adjusted life years. Although there are benefits associated with a higher physical activity (PA) level, there is a lack of information related to this relationship, especially in countries such as Czechia, where modern approaches to mental health care only recently emerged. The present study aimed to evaluate the association between the level of depression and different PA levels following the World Health Organization (WHO) PA guidelines and according to specific symptoms that indicate depression. Multivariable-adjusted Poisson regression models were used to calculate the prevalence rate (PR) in a sample of 2123 participants (45.3% men, median 48 years). Compared to subjects with insufficient PA, moderate and high PA levels were inversely associated with continuous depression scores (PR = 0.85; 95% CI: 0.75-0.97; and PR = 0.80; 95% CI: 0.70-0.92). Depressed mood and worthlessness were the symptoms associated with moderate and high PA. Tiredness, change in appetite, and concentration problems were related to high PA. The results suggest that reaching the minimum PA target according to the guidelines seems to be effective, and this could stimulate adherence. However, more specific improvements in symptomatology will require a subsequent gradual increase in PA levels.

Introduction: We investigated the longitudinal relationship between cortical amyloid deposition, anxiety, and depression and the risk of incident mild cognitive impairment (MCI)., Methods: We followed 1440 community-dwelling, cognitively unimpaired individuals aged ≥ 50 years for a median of 5.5 years. Clinical anxiety and depression were assessed using Beck Anxiety and Depression Inventories (BAI, BDI-II). Cortical amyloid beta (Aβ) was measured by Pittsburgh compound B positron emission tomography (PiB-PET) and elevated deposition (PiB+) was defined as standardized uptake value ratio ≥ 1.48. We calculated Cox proportional hazards models with age as the time scale, adjusted for sex, education, and medical comorbidity., Results: Cortical Aβ deposition (PiB+) independent of anxiety (BAI ≥ 10) or depression (BDI-II ≥ 13) increased the risk of MCI. There was a significant additive interaction between PiB+ and anxiety (joint effect hazard ratio 6.77; 95% confidence interval 3.58-12.79; P = .031) that is, being PiB+ and having anxiety further amplified the risk of MCI., Discussion: Anxiety modified the association between PiB+ and incident MCI., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Axonal swellings (AS) are one of the neuropathological hallmark of axonal injury in several disorders from trauma to neurodegeneration. Current evidence proposes a role of perturbed Ca 2+ homeostasis in AS formation, involving impaired axonal transport and focal distension of the axons. Mechanisms of AS formation, in particular moments following injury, however, remain unknown. Here we show that AS form independently from intra-axonal Ca 2+ changes, which are required primarily for the persistence of AS in time. We further show that the majority of axonal proteins undergoing de/phosphorylation immediately following injury belong to the cytoskeleton. This correlates with an increase in the distance of the actin/spectrin periodic rings and with microtubule tracks remodeling within AS. Observed cytoskeletal rearrangements support axonal transport without major interruptions. Our results demonstrate that the earliest axonal response to injury consists in physiological adaptations of axonal structure to preserve function rather than in immediate pathological events signaling axonal destruction., (© 2022. The Author(s).)

Axonal homeostasis is maintained by processes that include cytoskeletal regulation, cargo transport, synaptic activity, ionic balance, and energy supply. Several of these processes involve mitochondria to varying degrees. As a transportable powerplant, the mitochondria deliver ATP and Ca 2+ -buffering capabilities and require fusion/fission to maintain proper functioning. Taking into consideration the long distances that need to be covered by mitochondria in the axons, their transport, distribution, fusion/fission, and health are of cardinal importance. However, axonal homeostasis is disrupted in several disorders of the nervous system, or by traumatic brain injury (TBI), where the external insult is translated into physical forces that damage nervous tissue including axons. The degree of damage varies and can disconnect the axon into two segments and/or generate axonal swellings in addition to cytoskeletal changes, membrane leakage, and changes in ionic composition. Cytoskeletal changes and increased intra-axonal Ca 2+ levels are the main factors that challenge mitochondrial homeostasis. On the other hand, a proper function and distribution of mitochondria can determine the recovery or regeneration of the axonal physiological state. Here, we discuss the current knowledge regarding mitochondrial transport, fusion/fission, and Ca 2+ regulation under axonal physiological or pathological conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pozo Devoto, Onyango and Stokin.)

Around half of people with severe COVID-19 requiring intensive care unit (ICU) treatment will survive, but it is unclear how the immune response to SARS-CoV-2 differs between ICU patients that recover and those that do not. We conducted whole-blood immunophenotyping of COVID-19 patients upon admission to ICU and during their treatment and uncovered marked differences in their circulating immune cell subsets. At admission, patients who later succumbed to COVID-19 had significantly lower frequencies of all memory CD8+ T cell subsets, resulting in increased CD4-to-CD8 T cell and neutrophil-to-CD8 T cell ratios. ROC and Kaplan-Meier analyses demonstrated that both CD4-to-CD8 and neutrophil-to-CD8 ratios at admission were strong predictors of in-ICU mortality. Therefore, we propose the use of the CD4-to-CD8 T cell ratio as a marker for the early identification of those individuals likely to require enhanced monitoring and/or pro-active intervention in ICU., (© 2021 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Background: Considering the world's rapidly increasing life expectancy, with people working and maintaining active lifestyles longer than ever before, addressing the effects of aging on cognition is of utmost importance. A greater understanding of cognitive aging may also be critical in distinguishing natural cognitive aging from pre-clinical stages of Alzheimer's disease and related cognitive disorders., Objective: To systematically examine the association between aging and cognitive performance in a cognitively and otherwise healthy probability population-based sample using a computer-based method., Methods: This cross-sectional study enrolled 673 cognitively and otherwise healthy participants aged 25-89 years (mean age 52.3±14.2 years, 52.5% of whom were female) from the Kardiovize study cohort. Mild cognitive impairment and dementia cases were excluded, followed by measurement of cognitive performance with the computer-administered Cogstate Brief Battery. We used ANCOVA and Modified Signed-Likelihood Ratio tests to examine patterns of cognition across age groups., Results: We found a gradual decrease in cognitive performance across the lifespan, which required two decades to demonstrate significant changes. In contrast to attention and learning, psychomotor speed and working memory showed the most significant age-related decrease and variability in performance. The established pattern of cognitive aging was not altered by sex or education., Conclusion: These findings corroborate, validate, and extend the current understanding of natural cognitive aging and pinpoint specific cognitive domains with the most extensive age-related interindividual differences. This will contribute to the development of strategies to preserve cognition with aging and may also serve to improve early diagnostics of cognitive disorders using computer-based methods.

Objective: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors., Methods: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD)., Results: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010)., Conclusions: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes., (Copyright © 2021 by the American Psychosomatic Society.)

We here posit that measurements of midlife cognition can be instructive in understanding cognitive disorders. Even though molecular events signal possible onset of cognitive disorders decades prior to their clinical diagnoses, cognition and its possible early changes in midlife remain poorly understood. We characterize midlife cognition in a cognitively healthy population-based sample using the Cogstate Brief Battery and test for associations with cardiovascular, adiposity-related, lifestyle-associated, and psychosocial variables. Learning and working memory showed significant variability and vulnerability to psychosocial influences in midlife. Furthermore, midlife aging significantly and progressively increased prevalence of suboptimal cognitive performance. Our findings suggest that physiological changes in cognition, measured with simple tests suitable for use in everyday clinical setting, may signal already in midlife the first clinical manifestations of the presymptomatic biologically defined cognitive disorders. This pilot study calls for longitudinal studies investigating midlife cognition to identify clinical correlates of biologically defined cognitive disorders., Competing Interests: The authors report no conflicts of interest., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: The purpose of this study was to test the hypothesis that subcortical β-amyloid (Aβ) deposition was associated with elevated scores on standardized measures of depressive and anxiety symptoms when compared with cortical (Aβ) deposition in persons without dementia., Methods: The authors performed a cross-sectional study, derived from the population-based Mayo Clinic Study of Aging, comprising participants aged ≥70 years (N=1,022; 55% males; 28% apolipoprotein E [APOE] ε4 carriers; without cognitive impairment, N=842; mild cognitive impairment; N=180). To assess Aβ deposition in cortical and subcortical (the amygdala, striatum, and thalamus) regions, participants underwent Pittsburgh Compound B positron emission tomography (PiB-PET) and completed the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). The investigators ran linear regression models to examine the association between PiB-PET standardized uptake value ratios (SUVRs) in the neocortex and subcortical regions and depressive and anxiety symptoms (BDI-II and BAI total scores). Models were adjusted for age, sex, education level, and APOE ε4 carrier status and stratified by cognitive status (without cognitive impairment, mild cognitive impairment)., Results: Cortical PiB-PET SUVRs were associated with depressive symptoms (β=0.57 [SE=0.13], p<0.001) and anxiety symptoms (β=0.34 [SE=0.13], p=0.011). PiB-PET SUVRs in the amygdala were associated only with depressive symptoms (β=0.80 [SE=0.26], p=0.002). PiB-PET SUVRs in the striatum and thalamus were associated with depressive symptoms (striatum: β=0.69 [SE=0.18], p<0.001; thalamus: β=0.61 [SE=0.24], p=0.011) and anxiety symptoms (striatum: β=0.56 [SE=0.18], p=0.002; thalamus: β=0.65 [SE=0.24], p=0.008). In the mild cognitive impairment subsample, Aβ deposition, regardless of neuroanatomic location, was associated with depressive symptoms but not anxiety symptoms., Conclusions: Elevated amyloid deposition in cortical and subcortical brain regions was associated with higher depressive and anxiety symptoms, although these findings did not significantly differ by cortical versus subcortical Aβ deposition. This cross-sectional observation needs to be confirmed by a longitudinal study.

Ideal cardiovascular health (CVH) is defined for the presence of ideal behavioral and health metrics known to prevent cardiovascular disease (CVD). The association of circulatory phospho- and sphingo-lipids to primary reduction in cardiovascular risk is unclear. Our aim was to determine the association of CVH metrics with the circulating lipid profile of a population-based cohort. Serum sphingolipid and phospholipid species were extracted from 461 patients of the randomly selected prospective Kardiovize study based on Brno, Czech Republic. Lipids species were measured by a hyphenated mass spectrometry technique, and were associated with poor CVH scores, as defined by the American Heart Association. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) species were significantly lower in ideal and intermediate scores of health dietary metric, blood pressure, total cholesterol and blood fasting glucose compared to poor scores. Current smokers presented higher levels of PC, PE and LPE individual species compared to non-smokers. Ceramide (Cer) d18:1/14:0 was altered in poor blood pressure, total cholesterol and fasting blood glucose metrics. Poor cardiovascular health metric is associated with a specific phospho- and sphingolipid pattern. Circulatory lipid profiling is a potential biomarker to refine cardiovascular health status in primary prevention strategies.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases., Competing Interests: None

In contrast to the decreasing burden related to cardiovascular disease (CVD), the burden related to dysglycemia and adiposity complications is increasing in Czechia, and local drivers must be identified. A comprehensive literature review was performed to evaluate biological, behavioral, and environmental drivers of dysglycemia and abnormal adiposity in Czechia. Additionally, the structure of the Czech healthcare system was described. The prevalence of obesity in men and diabetes in both sexes has been increasing over the past 30 years. Possible reasons include the Eastern European eating pattern, high prevalence of physical inactivity and health illiteracy, education, and income-related health inequalities. Despite the advanced healthcare system based on the compulsory insurance model with free-for-service healthcare and a wide range of health-promoting initiatives, more effective strategies to tackle the adiposity/dysglycemia are needed. In conclusion, the disease burden related to dysglycemia and adiposity in Czechia remains high but is not translated into greater CVD. This discordant relationship likely depends more on other factors, such as improvements in dyslipidemia and hypertension control. A reconceptualization of abnormal adiposity and dysglycemia into a more actionable cardiometabolic-based chronic disease model is needed to improve the approach to these conditions. This review can serve as a platform to investigate causal mechanisms and secure effective management of cardiometabolic-based chronic disease.

Background: Visceral fat is associated with adiposity-based complications. Bioimpedance measurement allows estimation of visceral fat area (VFA) in an easy manner. However, a validated cut-off value for VFA by bioimpedance associated with cardiometabolic risk is lacking in European population., Aim: To determine cut-off values of VFA measured via bioimpedance associated with cardiometabolic risk., Methods: Random cross-sectional Czech population-based sample of 25-64 years old subjects. Receiver Operating Characteristic (ROC) curves were used and the area under the curve (AUC), sensitivity, and specificity were calculated. The Cardiometabolic Disease Staging System (CMDS) was used to classify cardiometabolic risk: Stage 1 - 1 or 2 metabolic syndrome (MetS) components, without impaired fasting glucose (IFG); Stage 2 - MetS or IFG; Stage 3 - MetS with IFG; Stage 4 - type 2 diabetes and/or cardiovascular disease., Results: 2052 participants (54.5% females, median age 49 years) were included. Median VFA (inter-quartile range) were 82.2 cm 2 (54.8) in men and 89.8 cm 2 (55.6) in women. The best VFA cut-offs associated with Stage 1 in men and women were 71 cm 2 (sensitivity = 0.654; specificity = 0.427) and 83 cm 2 (sensitivity = 0.705; specificity = 0.556) ; Stage 2: 84 cm 2 (sensitivity = 0.673; specificity = 0.551) and 98 cm 2 (sensitivity = 0.702; specificity = 0.628) ; Stage 3: 90 cm 2 (sensitivity = 0.886; specificity = 0.605) and 109 cm 2 (sensitivity = 0.755; specificity = 0.704); Stage 4: 91 cm 2 (sensitivity = 0.625; specificity = 0.611) and 81 cm 2 (sensitivity = 0.695; specificity = 0.448), respectively., Conclusion: A cut-off value of VFA of 71 cm 2 in men and 83 cm 2 in women exhibited the earliest stage of cardiometabolic risk, and 90 cm 2 in men and 109 cm 2 in women showed the best performance to detect risk., (Copyright © 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Objective: Arterial stiffness (ArSt) describes a loss of arterial wall elasticity and is an independent predictor of cardiovascular events. A cardiometabolic-based chronic disease model integrates concepts of adiposity-based chronic disease (ABCD), dysglycemia-based chronic disease (DBCD), and cardiovascular disease. We assessed if ABCD and DBCD models detect more people with high ArSt compared with traditional adiposity and dysglycemia classifiers using the cardio-ankle vascular index (CAVI)., Methods: We evaluated 2070 subjects aged 25 to 64 years from a random population-based sample. Those with type 1 diabetes were excluded. ABCD and DBCD were defined, and ArSt risk was stratified based on the American Association of Clinical Endocrinologists criteria., Results: The highest prevalence of a high CAVI was in stage 2 ABCD (18.5%) and stage 4 DBCD (31.8%), and the lowest prevalence was in stage 0 ABCD (2.2%). In univariate analysis, stage 2 ABCD and all DBCD stages increased the risk of having a high CAVI compared with traditional classifiers. After adjusting for age and gender, only an inverse association between obesity (body mass index ≥30 kg/m 2 ) and CAVI remained significant. Nevertheless, body mass index was responsible for only 0.3% of CAVI variability., Conclusion: The ABCD and DBCD models showed better performance than traditional classifiers to detect subjects with ArSt; however, the variables were not independently associated with age and gender, which might be explained by the complexity and multifactoriality of the relationship of CAVI with the ABCD and DBCD models, mediated by insulin resistance., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

Aims/hypothesis: The need for understanding obesity as a chronic disease, its stigmatization, and the lack of actionability related to it demands a new approach. The adiposity-based chronic disease (ABCD) model is based on adiposity amount, distribution, and function, with a three stage complication-centric rather than a body mass index (BMI)-centric approach. The prevalence rates and associated risk factors are presented., Methods: In total, 2159 participants were randomly selected from Czechia. ABCD was established as BMI ≥ 25 kg/m 2 or high body fat percent, or abdominal obesity and then categorized by their adiposity-based complications: Stage 0: none; Stage 1: mild/moderate; Stage 2: severe., Results: ABCD prevalence was 62.8%. Stage 0 was 2.3%; Stage 1 was 31.4%; Stage 2 was 29.1%. Comparing with other classifiers, participants in Stage 2 were more likely to have diabetes, hypertension, and metabolic syndrome than those with overweight, obesity, abdominal obesity, and increased fat mass. ABCD showed the highest sensitivity and specificity to detect participants with peripheral artery disease, increased intima media, and vascular disease., Conclusion/interpretation: The ABCD model provides a more sensitive approach that facilitates the early detection and stratification of participants at risk compared to traditional classifiers., Competing Interests: Dr. Mechanick has received honoraria for lectures and program development from Abbott Nutrition International. The other authors have not conflict of interest., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Objective: To determine the prevalence rate and associated risk factors for each stage of the Dysglycemia-Based Chronic Disease (DBCD) model, which 4 distinct stages and prompts early prevention to avert Diabetes and cardiometabolic complications., Methods: Subjects between 25 and 64 years old from a random population-based sample were evaluated in Czechia from 2013 to 2014 using a cross-sectional design. DBCD stages were: stage 1 "insulin resistance" (inferred risk from abdominal obesity or a family history of diabetes); stage 2 "prediabetes"(fasting glucose between 5.6 and 6.9 mmol/L); stage 3 "type 2 diabetes (T2D)" (self-report of T2D or fasting glucose ≥7 mmol/L); and stage 4 "vascular complications" (T2D with cardiovascular disease)., Results: A total of 2147 subjects were included (57.8% women) with a median age of 48 years. The prevalence of each DBCD stage were as follows: 54.2% (stage 1); 10.3% (stage 2), 3.7% (stage 3); and 1.2% (stage 4). Stages 2 to 4 were more frequent in men and stage 1 in women (P < .001). Using binary logistic regression analysis adjusting by age/sex, all DBCD stages were strongly associated with abnormal adiposity, hypertension, dyslipidemia, and smoking status. Subjects with lower educational levels and lower income were more likely to present DBCD., Conclusion: Using the new DBCD framework and available metrics, 69.4% of the population had DBCD, identifying far more people at risk than a simple prevalence rate for T2D (9.2% in Czechia, 2013-2014). All stages were associated with traditional cardiometabolic risk factors, implicating common pathophysiologic mechanisms and a potential for early preventive care. The social determinants of health were related with all DBCD stages in alarming proportions and will need to be further studied., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

Objective: The authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction., Methods: About 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status., Results: Participants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ 2  = 11.83, degree of freedom [df] = 1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ 2  = 29.68, df = 1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ 2  = 34.13, df = 1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ 2  = 21.92, df = 1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ 2  = 15.39, df = 1)., Conclusion: Combined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments available for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initiation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mitochondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mitochondrial systems biology. We review evidence for mitochondrial impairments ranging from mitochondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expression, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dynamics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could potentially alter the course of this progressive, heterogeneous Disease while being cognizant that successful future therapeutics may require a combinatorial approach., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Recent reports suggest that the COVID-19 lockdown resulted in changes in mental health, however, potential age-related changes and risk factors remain unknown. We measured COVID-19 lockdown-induced stress levels and the severity of depressive symptoms prior to and during the COVID-19 lockdown in different age groups and then searched for potential risk factors in a well-characterized general population-based sample. A total of 715 participants were tested for mental distress and related risk factors at two time-points, baseline testing prior to COVID-19 and follow-up testing during COVID-19, using a battery of validated psychological tests including the Perceived Stress Scale and the Patient Health Questionnaire. Longitudinal measurements revealed that the prevalence of moderate to high stress and the severity of depressive symptoms increased 1.4- and 5.5-fold, respectively, during the COVID-19 lockdown. This surge in mental distress was more severe in women, but was present in all age groups with the older age group exhibiting, cross-sectionally, the lowest levels of mental distress prior to and during the lockdown. Illness perception, personality characteristics such as a feeling of loneliness, and several lifestyle components were found to be associated with a significant increase in mental distress. The observed changes in mental health and the identified potential risk factors underlying these changes provide critical data justifying timely and public emergency-tailored preventive, diagnostic, and therapeutic mental health interventions, which should be integrated into future public health policies globally., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Novotný, Gonzalez-Rivas, Kunzová, Skladaná, Pospíšilová, Polcrová, Medina-Inojosa, Lopez-Jimenez, Geda and Stokin.)

Objective: To investigate the effect of replacing sitting with standing on cardiovascular risk factors tested in clinical trials., Methods: We searched databases from inception up to August 28, 2019, for studies examining the effect of replacing sitting with standing on fasting blood glucose, fasting insulin, and lipid levels; blood pressure; body fat mass; weight; and waist circumference in healthy adults. Differences in mean ± SD values were used for pooling the data and calculating the mean differences and CIs., Results: The search found 3507 abstracts. Nine clinical trials (8 randomized and 1 nonrandomized) with 877 (64.4% [n=565] women) participants met all inclusion criteria. The mean ± SD age was 45.34±5.41 years; mean follow-up was 3.81 months, and mean difference in standing time between the intervention and control groups was 1.33 hours per day. The follow-up fasting blood glucose and body fat mass values were slightly but significantly lower than baseline records in the intervention groups compared with control groups (-2.53; 95% CI, -4.27 to -0.79 mg/dL; and -0.75; 95% CI, -0.91 to -0.59 kg). The analysis for fasting insulin levels, lipid levels, blood pressure, weight, and waist circumference revealed no significant differences., Conclusion: Replacing sitting with standing can result in very small but statistically significant decreases in fasting blood glucose levels and body fat mass with no significant effect on lipid levels, blood pressure, weight, and waist circumference. Replacing sitting with standing can be used as an adjunctive intervention to decrease the burden of cardiovascular risk factors but cannot be used as an alternative to physical activity to decrease sedentary time., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Existing data have described benefits and drawbacks of alcohol consumption on cardiovascular diseases (CVD), but no research has evaluated its association with the cardiovascular health (CVH) score proposed by the American Heart Association. Here, we conducted a cross-sectional analysis on the Kardiovize cohort (Brno, Czech Republic), to investigate the relationship between alcohol consumption and CVH. We included 1773 subjects (aged 25-64 years; 44.2% men) with no history of CVD. We compared CVD risk factors, CVH metrics (i.e., BMI, healthy diet, physical activity level, smoking status, blood pressure, fasting glucose, and total cholesterol) and CVH score between and within several drinking categories. We found that the relationship between drinking habits and CVH was related to the amount of alcohol consumed, drinking patterns, and beverage choices. Heavy drinkers were more likely to smoke tobacco, and to report diastolic blood pressure, fasting glucose, triglycerides, and low-density lipoprotein (LDL)-cholesterol at higher level than non-drinkers. Among drinkers, however, people who exclusively drank wine exhibited better CVH than those who exclusively drank beer. Although our findings supported the hypothesis that drinking alcohol was related to the CVH in general, further prospective research is needed to understand whether the assessment of CVH should incorporate information on alcohol consumption.

Background: The term arterial stiffness (ArSt) describes structural changes in arterial wall related to the loss of elasticity and is known as an independent predictor of cardiovascular diseases (CVD). The evidence relating to ArSt and triglycerides (TG) shows contradictory results. This paper means to survey the association between high TG and ArSt, utilizing the cardio-ankle vascular index (CAVI)., Methods: Subjects aged between 25 and 64 years from a random population-based sample were evaluated between 2013 and 2016. Data from questionnaires, blood pressure, anthropometric measures, and blood samples were collected and analyzed. CAVI was measured using VaSera VS-1500 N devise. Subjects with a history of CVD or chronic renal disease were excluded., Results: One thousand nine hundred thirty-four participants, 44.7% of males, were included. The median age was 48 (Interquartile Range [IQR] 19) years, TG levels were 1.05 (0.793) mmol/L, and CAVI 7.24 (1.43) points. Prevalence of high CAVI was 10.0% (14.5% in males and 6.4% in females; P <  0.001) and prevalence of hypertriglyceridemia was 20.2% (29.2% in males and 13% in females, P <  0.001). The correlation between TG and CAVI was 0.136 (P <  0.001). High CAVI values were more prevalent among participants with metabolic syndrome (MetS), high blood pressure, dysglycemia, abdominal obesity, high LDL-cholesterol (LDL-c), and high total cholesterol. Using binary regression analysis, high TG were associated with high CAVI, even after adjustment for other MetS components, age, gender, smoking status, LDL-c, and statin treatment (β = 0.474, OR = 1.607, 95% CI = 1.063-2.429, P = 0.024)., Conclusion: TG levels were correlated with ArSt, measured as CAVI. High TG was associated with high CAVI independent of multiple cardiometabolic risk factors. Awareness of the risks and targeted treatment of hypertriglyceridemia could further benefit in reducing the prevalence of CVD and events.

Neuropsychiatric symptoms (NPS) are a risk factor for cognitive impairment and are associated with cortical β-amyloid (Aβ) deposition. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging to examine the frequency of NPS among cognitively unimpaired (CU) and mild cognitive impairment (MCI) participants who either have normal (A-) or abnormal (A+) Aβ deposition. We also investigated whether combined presence of MCI and amyloid positivity (MCI/A+) is associated with greater odds of having NPS as compared to CU/A- (defined as reference group). Participants were 1627 CU and MCI individuals aged ≥ 50 years (54% males; median age 73 years). All participants underwent NPS assessment (Neuropsychiatric Inventory Questionnaire (NPI-Q); Beck Depression Inventory II (BDI-II); Beck Anxiety Inventory (BAI)) and 11 C-PiB-PET. Participants with an SUVR > 1.42 were classified as A+. We conducted multivariable logistic regression analyses adjusted for age, sex, education, and APOE ε4 genotype status. The sample included 997 CU/A-, 446 CU/A+, 78 MCI/A-, and 106 MCI/A+ persons. For most NPS, the highest frequency of NPS was found in MCI/A+ and the lowest in CU/A-. The odds ratios of having NPS, depression (BDI ≥ 13), or anxiety (BAI ≥ 8, ≥ 10) were consistently highest for MCI/A+ participants. In conclusion, MCI with Aβ burden of the brain is associated with an increased risk of having NPS as compared to MCI without Aβ burden. This implies that the underlying Alzheimer's disease biology (i.e., cerebral Aβ amyloidosis) may drive both cognitive and psychiatric symptoms.

Background: Little is known about the association of cortical Aβ with depression and anxiety among cognitively normal (CN) elderly persons., Methods: We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB-) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex., Results: Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00-1.06) and BAI (OR = 1.04; 1.01-1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83-2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.77; 0.97-3.22)., Conclusions: As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.

The authors conducted a cross-sectional study to investigate the association between anxiety symptoms and cortical thickness, as well as amygdalar volume. A total of 1,505 cognitively normal participants, aged ≥70 years, were recruited from the Mayo Clinic Study of Aging in Olmsted County, Minnesota, on whom Beck Anxiety Inventory and 3T brain MRI data were available. Even though the effect sizes were small in this community-dwelling group of participants, anxiety symptoms were associated with reduced global cortical thickness and reduced thickness within the frontal and temporal cortex. However, after additionally adjusting for comorbid depressive symptoms, only the association between anxiety symptoms and reduced insular thickness remained significant.

The etiology of Parkinson's disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.

Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described by a hierarchical model in which elements of Hippo pathway are under the control of focal adhesions (FAs). Here we unveil the molecular mechanism by which cell spreading and RhoA GTPase activity control FA formation through YAP to stabilize the anchorage of the actin cytoskeleton to the cell membrane. This mechanism requires YAP co-transcriptional function and involves the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity leads to the modification of cell mechanics, force development and adhesion strength, and determines cell shape, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify this Hippo effector as the key determinant of cell mechanics in response to ECM cues.

Importance: Cross-sectional associations between engagement in mentally stimulating activities and decreased odds of having mild cognitive impairment (MCI) or Alzheimer disease have been reported. However, little is known about the longitudinal outcome of incident MCI as predicted by late-life (aged ≥70 years) mentally stimulating activities., Objectives: To test the hypothesis of an association between mentally stimulating activities in late life and the risk of incident MCI and to evaluate the influence of the apolipoprotein E (APOE) ε4 genotype., Design, Setting, and Participants: This investigation was a prospective, population-based cohort study of participants in the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Participants 70 years or older who were cognitively normal at baseline were followed up to the outcome of incident MCI. The study dates were April 2006 to June 2016., Main Outcomes and Measures: At baseline, participants provided information about mentally stimulating activities within 1 year before enrollment into the study. Neurocognitive assessment was conducted at baseline, with evaluations at 15-month intervals. Cognitive diagnosis was made by an expert consensus panel based on published criteria. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression models after adjusting for sex, age, and educational level., Results: The final cohort consisted of 1929 cognitively normal persons (median age at baseline, 77 years [interquartile range, 74-82 years]; 50.4% [n = 973] female) who were followed up to the outcome of incident MCI. During a median follow-up period of 4.0 years, it was observed that playing games (HR, 0.78; 95% CI, 0.65-0.95) and engaging in craft activities (HR, 0.72; 95% CI, 0.57-0.90), computer use (HR, 0.70; 95% CI, 0.57-0.85), and social activities (HR, 0.77; 95% CI, 0.63-0.94) were associated with a decreased risk of incident MCI. In a stratified analysis by APOE ε4 carrier status, the data point toward the lowest risk of incident MCI for APOE ɛ4 noncarriers who engage in mentally stimulating activities (eg, computer use: HR, 0.73; 95% CI, 0.58-0.92) and toward the highest risk of incident MCI for APOE ɛ4 carriers who do not engage in mentally stimulating activities (eg, no computer use: HR, 1.74; 95% CI, 1.33-2.27)., Conclusions and Relevance: Cognitively normal elderly individuals who engage in specific mentally stimulating activities even in late life have a decreased risk of incident MCI. The associations may vary by APOE ε4 carrier status.

Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes., Significance Statement: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration., (Copyright © 2017 the authors 0270-6474/17/370059-12$15.00/0.)

Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants (N = 1,507) aged≥70 years. We observed that depressive symptoms were associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants.

Objectives: To investigate the timing (mid- vs late life) of physical activity, apolipoprotein (APO)E ε4, and risk of incident mild cognitive impairment (MCI)., Design: Prospective cohort study., Setting: Mayo Clinic Study of Aging (Olmsted County, MN)., Participants: Cognitively normal elderly adults (N = 1,830, median age 78, 50.2% female)., Measurements: Light, moderate, and vigorous physical activities in mid- and late life were assessed using a validated questionnaire. An expert consensus panel measured MCI based on published criteria. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) with age as a time scale after adjusting for sex, education, medical comorbidity, and depression., Results: Light (HR = 0.58, 95% CI = 0.43-0.79) and vigorous (HR = 0.78, 95% CI = 0.63-0.97) physical activity in midlife were associated with lower risk of incident MCI. The association between moderate activity and incident MCI was not significant (HR = 0.85, 95% CI = 0.67-1.09). In late life, light (HR = 0.75, 95% CI = 0.58-0.97) and moderate (HR = 0.81, 95% CI = 0.66-0.99) but not vigorous physical activity were associated with lower risk of incident MCI. A synergistic interaction was also observed between mid- and late-life activity in reducing risk of incident MCI. Furthermore, APOE ε4 carriers who did not exercise had a higher risk of incident MCI than noncarriers who reported physical activity., Conclusion: Physical activity reduced the risk of incident MCI. Exercising in mid- and late life had an additive synergistic interaction in reducing the risk of MCI., Competing Interests: All other authors do not have any financial or conflict of interest to disclose., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer's disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio < 1.32 in AD-related regions). Abnormal FDG-PET was associated with depression as measured by NPI-Q (OR = 2.12; 1.23-3.64); the point estimate was further elevated for APOE ɛ4 carriers (OR = 2.59; 1.00-6.69), though marginally significant. Additionally, we observed a significant association between abnormal FDG-PET and depressive and anxiety symptoms when treated as continuous measures. These findings indicate that NPS, even in community-based samples, can be an important additional tool to the biomarker-based investigation of presymptomatic AD.

The American Psychiatric Association has recently published the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM-IV category "Dementia, Delirium, Amnestic, and Other Cognitive Disorders" has undergone extensive revision. DSM-5 has renamed this category as "Neurocognitive Disorders" (NCD), which now covers three entities: delirium, major NCD, and mild NCD. The DSM-IV version of mild NCD resembles the DSM-5 version in name only. DSM-IV defined mild NCD based on a single criterion, whereas DSM-5 defines mild NCD by using several cognitive and related criteria. The main difference between mild NCD and the Key International Symposium criteria of mild cognitive impairment (MCI) is that the research work that led to the construct of MCI primarily involved elderly study participants (even though age was not part of the definition of MCI), whereas mild NCD includes acquired cognitive disorders of all age groups. DSM-5 essentially discusses the epidemiology and diagnostic markers of mild NCD by drawing congruence between MCI and mild NCD. The DSM-5 definition of mild NCD is anchored on four criteria and two specifiers. The four criteria refer to cognitive changes, functional activities, and exclusion of delirium and competing mental disorders. The two specifiers are the presumed etiologies of mild NCD and the presence or absence of behavioral problems. While the category "mild NCD" may improve reliability of diagnoses, it has yet to withstand scientific scrutiny to be considered a valid construct. This article reviews the DSM-5 criteria for mild NCD, compares them with the Key International Symposium MCI criteria, and discusses the pros and cons of the mild NCD construct.

The authors compared the risk for subjective cognitive impairment (SCI) between carriers of the apolipoprotein E ε4 (APOE ε4) allele (cases) and APOE ε4 noncarriers (controls). SCI was assessed by a validated self-reported questionnaire. The authors used multivariable logistic regression analyses to compute odds ratios and 95% confidence intervals adjusted for age, sex, education, and marital status. Data were available on 114 participants (83 women; 47 APOE ε4 carriers; mean age, 69 years). The risk for SCI was significantly higher among cases than controls, particularly for those 70 years of age and older. These findings should be considered preliminary until confirmed by a prospective cohort study.