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Alzheimer’s disease is a neurodegenerative disorder characterized clinically by cognitive decline and pathologically by amyloid deposition and neurofibrillary changes. These neuropathological hallmarks are accompanied by reactive events including microglial activation and astrogliosis. The inflammatory response in Alzheimer’s disease brains is distinguished by a pro-inflammatory signature involving amyloid peptides1, inflammasome signaling2 and disrupted blood brain barrier3. Inflammatory changes are observed also in the cerebrospinal fluid in Alzheimer’s disease4,5. It remains unknown, however, whether the choroid plexus which produces cerebrospinal fluid and guards the brain from peripheral inflammatory insults6,7, contributes to the inflammation and pathogenesis of Alzheimer’s disease. Here we show that the choroid plexus in Alzheimer’s disease exhibits a pro-inflammatory signature with aberrant protein accumulations, which contribute to the age-dependent inflammatory changes observed in the cerebrospinal fluid. Magnetic resonance imaging reveals that the choroid plexus in patients with Alzheimer’s disease displays pathological signal and increased volume, which inversely correlates with cognitive decline. Our findings suggest that the choroid plexus, being unable to efficiently resolve inflammatory insults over the lifetime, eventually ignites and drives the aberrant inflammatory response observed in Alzheimer’s disease. These findings advance our understanding of the pathogenesis and open new vistas in the diagnostics and therapeutics of Alzheimer’s disease.

Venezuelans have been living in a humanitarian crisis since 2014 and the effect of this adverse environment on the mental of the population is unknown. This article aims to determinate the prevalence of anxiety and depressive symptoms of adults and factors related during the beginning of the humanitarian crisis of Venezuela. Anxiety and depressive symptoms were determined using the Hospital Anxiety and Depression Scale (HADS). 3,241 adults were evaluated with mean age of 41.1 ± 15.7 years. Anxiety prevalence was 14.7% (women 19.3% and men 9.5%; p

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/m2 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.

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.

OBJECTIVE To assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACE) after adjusting for established cardiovascular disease (CVD) risk factors. PATIENTS AND METHODS We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients aged >30 with a clinical encounter from 1998-2000 with no prior MACE, atrial fibrillation, or heart failure, were followed 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 (AUD), other substance use disorders (SUD), 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 (IQR) follow-up was 16.5 (14.6-17.5) years. 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 (HR: 1.93; 95% CI: 1.43-2.52; P < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, HDL cholesterol, and body mass index (HR: 1.66; 95% CI 1.17-2.28; P = .006), and for AUD, SUD, and MDD (HR: 1.56; 95% CI 1.09-2.14; P = .010). CONCLUSION 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.

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.

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.

Worldwide, depressive disorder is one of the leading determinants of disability-adjusted life years. Although the benefits associated with physical activity (PA), there is a lack of information related to depression, especially in countries like Czechia, where modern approaches to mental health care only recently emerged. The PA levels were associated with aspects of depression such as clinician-diagnosed history; different severities; continuous depression scores; and specific symptoms that characterize the depression. The multivariable-adjusted Poisson regression models were carried out on 2123 participants (45.3% men, median 48 years). Compared to subjects with insufficient PA, the moderate and high PA levels were inversely associated with clinician-diagnosed depression history (respectively, prevalence rate [PR]= 0.84; 95% CI 0.66-0.82 and PR=0.50; 95% CI 0.36-0.67); and with continuous depression scores (PR=0.85; 95% CI 0.75-0.97; and PR=0.79; 95%CI 0.70-0.90).; but only high PA showed association with depression categories (PR=0.75; 95%CI 0.60-0.95). Depressed mood and worthlessness were the symptoms associated with moderate and high PA. Tiredness, change in appetite, and problems with concentration only with high PA. Although only high PA was sufficient for people intending changes among depression categories, the moderate PA may be enough for slight changes in depressive symptoms, and a good strategy when starting.

Background There is wide variability in cardiac rehabilitation (CR) dose (ie, number of sessions) delivered, and no evidence‐based recommendations regarding what dose to prescribe. We aimed to test what CR dose impacts major adverse cardiovascular events (MACEs). Methods and Results This is an historical cohort study of all patients who had coronary artery disease and who initiated supervised CR between 2002 and 2012 from a single major CR center. CR dose was defined as number of visits including exercise and patient education. Follow‐up was performed using record linkage from the Rochester Epidemiology Project. MACEs included acute myocardial infarction, unstable angina, ventricular arrhythmias, stroke, revascularization, or all‐cause mortality. Dose was analyzed in several ways, including tertiles, categories, and as a continuous variable. Cox models were adjusted for factors associated with dose and MACE. The cohort consisted of 2345 patients, who attended a mean of 12.5±11.1 of 36 prescribed sessions. After a mean follow‐up of 6 years, 695 (29.65%) patients had a MACE, including 231 who died. CR dose was inversely associated with MACE (hazard ratio, 0.66 [95% CI]; 0.55–0.91) in those completing ≥20 sessions, when compared with those not exposed to formal exercise sessions (≤1 session; log‐rank P =0.007). We did not find evidence of nonlinearity ( P ≥0.050), suggesting no minimal threshold nor ceiling. Each additional session was associated with a lower rate of MACE (fully adjusted hazard ratio, 0.98 [95% CI, 0.97–0.99]). Greater session frequency was also associated with lower MACE risk (fully adjusted hazard ratio, 0.74 [95% CI, 0.58–0.94]). Conclusions CR reduces MACEs, but the benefit appears to be linear, with greater risk reduction with higher doses, and no upper threshold.

The effect of aging on cognition in cognitively healthy adult populations remains poorly investigated. Given that cognition evolves in time and thus, during aging, and becomes eroded in several disorders, some of which have recently acquired biological definitions, it is imperative to understand the process of cognitive aging. To determine the association of aging with cognitive performance in a cognitively healthy population, we studied cognitive performance in population-based cohort of 673 adults (aged 25-89). We found a gradual decline in cognitive performance across the lifespan, which requires two decades to demonstate significant change. This age-related decline was not significantly altered by either gender or education. These findings contribute to understand cognitive aging and provide essential data on physiological cognition for more precise diagnostics and timely intervention of early changes in cognition.

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 11C-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.

SummaryBackgroundAlthough several studies documented the impact of COVID-19 on mental health, the long-term effects of COVID-19 on mental health remain unclear.AimsTo examine longitudinal changes in mental health prior to and during the consecutive COVID-19 waves in a well-established probability sample.MethodAn online survey was completed by the participants of the COVID-19 add-on study at 4 timepoints (N1=1823, N2=788, N3=532, N4=383): pre-COVID period (2014/2015), 1stCOVID-19 wave (April-May, 2020), 2ndCOVID-19 wave (August-October, 2020) and 3rdCOVID-19 wave (March-April, 2021). Data were collected via a set of validated instruments and analysed using latent growth models.ResultsDuring the pandemic, we observed a significant increase in stress levels (slope=1.127, PConclusionsThe surge in stress levels and depressive symptoms persisted across all three consecutive COVID-19 waves. This surge is attributable to the effect of several risk factors including the status of mental health prior to the COVID-19 pandemic. Our findings have implications for strategies promoting resilience and addressing loneliness to mitigate the mental health impact of COVID-19 pandemic.

We investigated the longitudinal relationship between cortical amyloid deposition, anxiety, and depression and the risk of incident mild cognitive impairment (MCI).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.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.Anxiety modified the association between PiB+ and incident MCI.

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

ObjectiveTo date, cross-sectional surveys reported frequency and distribution of mental health disorders on convenience samples impacted by Covid-19. Longitudinal assessment of mental health during Covid-19 in a representative population-based sample, however, is currently largely missing. The aim of this study was to investigate changes in perceived stress levels and depressive symptoms measured before and during Covid-19 pandemic in a representative population-based sample.MethodsBaseline data on stress levels and depressive symptoms from a well-established population-based sample were compared with those obtained from self-administered e-questionnaires distributed during Covid-19 pandemic. A total of 715 participants completed e-questionnaires. Wilcoxon signed-rank test was used to test repeated-measure differences, while between-group differences were analysed using Mann-Whitney and the Kruskal-Wallis tests.ResultsPerceived stress levels and depressive symptoms increased 1.4 and 5.5 times, respectively, during the Covid-19 pandemic compared to the time prior Covid-19. Changes in stress and depressive symptoms were most significant in females and did not depend on whether one quarantined alone or with others. Feeling of loneliness during Covid-19 pandemic had the greatest impact on increased stress levels and depressive symptoms.ConclusionsThis population-based longitudinal study showed that Covid-19 related measures had significant impact on mental health in a general population with the feeling of loneliness identified as the biggest risk factor. This impact indicates the need of timely and tailored treatment of mental health disorders and integration of preventive mental health measures into global public health policies to protect mental health during future pandemics.

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.

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 P P 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.

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 2013-2016. Data from questionnaires, blood pressure, anthropometric measures, and blood samples were collected and analyzed. CAVI was measured using VaSera VS-1500N devise. Subjects with a history of CVD or chronic renal disease were excluded. Results : 1934 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

Altered cortical thickness has been observed in aging and various neuro-degenerative 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=1507) 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.

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&ndash, 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.

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.

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.

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 atrans-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 STATEMENTThe 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.

OBJECTIVES To investigate the timing (mid- vs late life) of physical activity, apolipoprotein (APO)E e4, 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 e4 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.

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.

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.

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.

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 (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.