Amyloid precursor protein induces reactive astrogliosis.

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.

Swedish Alzheimer's disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways.

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.

Emotion regulation shows an age- and sex-specific moderating effect on the relationship between chronic stress and cognitive performance.

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.

Plectin plays a role in the migration and volume regulation of astrocytes: a potential biomarker of glioblastoma.

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.

The long-term effects of consecutive COVID-19 waves on mental health.

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 ß = 0.473, P < 0.001) and depressive symptoms (standardised ß = 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.

Interactions Between Neuropsychiatric Symptoms and Alzheimer's Disease Neuroimaging Biomarkers in Predicting Longitudinal Cognitive Decline.

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.

Missorting of plasma miRNAs in aging and Alzheimer's disease.

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.

Pathogenesis of Alzheimer's disease: Involvement of the choroid plexus.

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.

Hepcidin and ferritin levels as markers of immune cell activation during septic shock, severe COVID-19 and sterile inflammation.

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.

Association between CSF biomarkers of Alzheimer's disease and neuropsychiatric symptoms: Mayo Clinic Study of Aging.

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 (Aß42), 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 Aß42, and higher t-tau/Aß42 and p-tau/Aß42 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 Aß42, t-tau/Aß42, and p-tau/Aß42 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.

Mid- and Late-Life Physical Activity and Neuropsychiatric Symptoms in Dementia-Free Older Adults: Mayo Clinic Study of Aging.

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 (ß estimate=-0.042, 95% CI=-0.051 to -0.033) and BAI (ß estimate=-0.030, 95% CI=-0.040 to -0.021) scores. Higher midlife PA was associated only with higher BDI-II scores (ß 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.

Amyloid precursor protein induces reactive astrogliosis.

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.

Association of Self-Reported Depression Symptoms with Physical Activity Levels in Czechia.

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.

Unraveling axonal mechanisms of traumatic brain injury.

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 Ca2+ 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 Ca2+ 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.

Mitochondrial behavior when things go wrong in the axon.

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 Ca2+-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 Ca2+ 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 Ca2+ regulation under axonal physiological or pathological conditions.

Natural Pattern of Cognitive Aging.

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.

High CD4-to-CD8 ratio identifies an at-risk population susceptible to lethal COVID-19.

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.

Association of Bipolar Disorder With Major Adverse Cardiovascular Events: A Population-Based Historical Cohort Study.

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.

A longitudinal investigation of Aß, anxiety, depression, and mild cognitive impairment.

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 (Aß) 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 Aß 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.

Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease.

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-ß (Aß) 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 Aß 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.