CRISPR-Powered Aptasensor for Diagnostics of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia, characterized by the accumulation of amyloid beta (Aß) peptides in the brain. Here, we present a simple, rapid, and affordable CRISPR-powered aptasensor for the quantitative detection of Aß40 and Aß42 biomarkers in cerebrospinal fluid (CSF) samples, enabling early and accurate diagnostics of AD patients. The aptasensor couples the high specificity of aptamers for Aß biomarkers with CRISPR-Cas12a-based fluorescence detection. The CRISPR-powered aptasensor enables us to detect Aß40 and Aß42 in CSF samples within 60 min, achieving a detection sensitivity of 1 pg/mL and 0.1 pg/mL, respectively. To validate its clinical utility, we quantitatively detected Aß40 and Aß42 biomarkers in clinical CSF samples. Furthermore, by combining CSF Aß42 levels with the c(Aß42)/c(Aß40) ratio, we achieved an accurate diagnostic classification of AD patients and healthy individuals, showing superior performance over the conventional ELISA method. We believe that our innovative aptasensor approach holds promise for the early diagnostic classification of AD patients.

Abnormal expression of cortical cell cycle regulators underlying anxiety and depressive-like behavior in mice exposed to chronic stress.

Background: The cell cycle is a critical mechanism for proper cellular growth, development and viability. The p16INK4a and p21Waf1/Cip1 are important regulators of the cell cycle progression in response to internal and external stimuli (e.g., stress). Accumulating evidence indicates that the prefrontal cortex (PFC) is particularly vulnerable to stress, where stress induces, among others, molecular and morphological alterations, reflecting behavioral changes. Here, we investigated if the p16INK4a and p21Waf1/Cip1 expression are associated with behavioral outcomes. Methods: Prefrontal cortex mRNA and protein levels of p16INK4A and p21Waf1/Cip1 of mice (six independent groups of C57BL/6J, eight mice/group, 50% female) exposed from 0 to 35 days of chronic restraint stress (CRS) were quantified by qPCR and Western Blot, respectively. Correlation analyses were used to investigate the associations between cyclin-dependent kinase inhibitors (CKIs) expression and anxiety- and depression-like behaviors. Results: Our results showed that the PFC activated the cell cycle regulation pathways mediated by both CKIs p16INK4A and p21Waf1/Cip1 in mice exposed to CRS, with overall decreased mRNA expression and increased protein expression. Moreover, correlation analysis revealed that mRNA and protein levels are statistically significant correlated with anxiety and depressive-like behavior showing a greater effect in males than females. Conclusion: Our present study extends the existing literature providing evidence that PFC cells respond to chronic stress exposure by overexpressing CKIs. Furthermore, our findings indicated that abnormal expression of p16INK4A and p21Waf1/Cip1 may significantly contribute to non-adaptive behavioral responses.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial.

Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.

Telomere shortening in late-life depression: A potential marker of depression severity.

OBJECTIVES: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. METHODS/DESIGN: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. RESULTS: TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21). CONCLUSIONS: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.

The Links between Cardiovascular Diseases and Alzheimer's Disease.

The root cause of non-inherited Alzheimer's disease (AD) remains unknown despite hundreds of research studies performed to attempt to solve this problem. Since proper prophylaxis remains the best strategy, many scientists have studied the risk factors that may affect AD development. There is robust evidence supporting the hypothesis that cardiovascular diseases (CVD) may contribute to AD progression, as the diseases often coexist. Therefore, a lack of well-defined diagnostic criteria makes studying the relationship between AD and CVD complicated. Additionally, inflammation accompanies the pathogenesis of AD and CVD, and is not only a consequence but also implicated as a significant contributor to the course of the diseases. Of note, АроЕε4 is found to be one of the major risk factors affecting both the cardiovascular and nervous systems. According to genome wide association and epidemiological studies, numerous common risk factors have been associated with the development of AD-related pathology. Furthermore, the risk of developing AD and CVDs appears to be increased by a wide range of conditions and lifestyle factors: hypertension, dyslipidemia, hypercholesterolemia, hyperhomocysteinemia, gut/oral microbiota, physical activity, and diet. This review summarizes the literature and provides possible mechanistic links between CVDs and AD.

Education and the moderating roles of age, sex, ethnicity and apolipoprotein epsilon 4 on the risk of cognitive impairment.

BACKGROUND: We examined how the relationship between education and latelife cognitive impairment (defined as a Mini Mental State Examination score below 24) is influenced by age, sex, ethnicity, and Apolipoprotein E epsilon 4 (APOE*4). METHODS: Participants were 30,785 dementia-free individuals aged 55-103 years, from 18 longitudinal cohort studies, with an average follow-up ranging between 2 and 10 years. Pooled hazard ratios were obtained from multilevel parametric survival analyses predicting cognitive impairment (CI) from education and its interactions with baseline age, sex, APOE*4 and ethnicity. In separate models, education was treated as continuous (years) and categorical, with participants assigned to one of four education completion levels: Incomplete Elementary; Elementary; Middle; and High School. RESULTS: Compared to Elementary, Middle (HR = 0.645, P = 0.004) and High School (HR = 0.472, P < 0.001) education were related to reduced CI risk. The decreased risk of CI associated with Middle education weakened with older baseline age (HR = 1.029, P = 0.056) and was stronger in women than men (HR = 1.309, P = 0.001). The association between High School and lowered CI risk, however, was not moderated by sex or baseline age, but was stronger in Asians than Whites (HR = 1.047, P = 0.044), and significant among Asian (HR = 0.34, P < 0.001) and Black (HR = 0.382, P = 0.016), but not White, APOE*4 carriers. CONCLUSION: High School completion may reduce risk of CI associated with advancing age and APOE*4. The observed ethnoregional differences in this effect are potentially due to variations in social, economic, and political outcomes associated with educational attainment, in combination with neurobiological and genetic differences, and warrant further study.

APOE ε4 and the Influence of Sex, Age, Vascular Risk Factors, and Ethnicity on Cognitive Decline.

We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54-103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

Brain-enriched MicroRNA-184 is downregulated in older adults with major depressive disorder: A translational study.

Changes in microRNAs (miRNAs) expression have been described in major depressive disorder in young and middle-aged adults. However, no study has evaluated miRNA expression in older adults with major depression (or late-life depression [LLD]). Our primary aim was to evaluate the expression of miRNAs in subjects with LLD. We first evaluated the miRNA expression using next-generation sequencing (NGS) and then we validated the miRNAs found in NGS in an independent sample of LLD patients, using RT-qPCR. Drosophila melanogaster model was used to evaluate the impact of changes in miRNA expression on behavior. NGS analysis showed that hsa-miR-184 (log2foldchange = -4.21, p = 1.2 × 10-03) and hsa-miR-1-3p (log2foldchange = -3.45, p = 1.3 × 10-02) were significantly downregulated in LLD compared to the control group. RT-qPCR validated the downregulation of hsa-miR-184 (p < 0.001), but not for the hsa-miR-1-3p. The knockout flies of the ortholog of hsa-miR-184 showed significantly reduced locomotor activity at 21-24 d.p.e (p = 0.04) and worse memory retention at 21-24 d.p.e (24h post-stimulus, p = 0.02) compared to control flies. Our results demonstrated that subjects with LLD have significant downregulation of hsa-miR-184. Moreover, the knockout of hsa-miR-184 in flies lead to depressive-like behaviors, being more pronounce in older flies.

The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer's Disease-a Critical Review.

One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the "second brain" and be responsible for neurodegenerative disorders like Alzheimer's disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD.

Epidermal growth factor and fibroblast growth factor-2 circulating levels in elderly with major depressive disorder.

Epidermal growth factor (EGF) and Fibroblast Growth Factor-2 (FGF-2) are growth factors involved neuronal growth and synaptic plasticity. These markers have been implicated in neuropsychiatric disorders, including major depression. However, no particular studies of EGF and FGF-2 have been conducted in older adults with major depressive disorder (MDD). In this study, we aim to investigate the plasma levels of EGF and FGF-2 in elderly with MDD. We included 89 older adults with MDD and 51 older (healthy control, HC) adults. The cognitive performance was evaluated by the Mattis Dementia Rating Scale (MDRS). The EGF and FGF-2 were measured by using multiplex assay for LUMINEX platform. There were also no significant differences between the patient group in terms of plasma levels of EGF and FGF-2 when compared to the HC group. There were not any significant correlations between plasma levels of EGF or FGF2 and MDRS total or individual scores in patient group and HC. There were significant correlations between plasma levels of EGF and FGF2 in both patient group and HC. Further study on plasma levels of EGF and FGF2 should be implemented in larger samples in elderly with MDD.

Depressive symptoms, emotional support and activities of daily living disability onset: 15-year follow-up of the Bambuí (Brazil) Cohort Study of Aging.

Psychosocial factors appear to be associated with increased risk of disability in later life. However, there is a lack of evidence based on long-term longitudinal data from Western low-middle income countries. We investigated whether psychosocial factors at baseline predict new-onset disability in long term in a population-based cohort of older Brazilians adults. We used 15-year follow-up data from 1,014 participants aged 60 years and older of the Bambuí (Brazil) Cohort Study of Aging. Limitations on activities of daily living (ADL) were measured annually, comprising 9,252 measures. Psychosocial factors included depressive symptoms, social support and social network. Potential covariates included sociodemographic characteristics, lifestyle, cognitive function and a physical health score based on 10 self-reported and objectively measured medical conditions. Statistical analysis was based on competitive-risk framework, having death as the competing risk event. Baseline depressive symptoms and emotional support from the closest person were both associated with future ADL disability, independently of potential covariates wide range. The findings showed a clear graded association, in that the risk gradually increased from low emotional support alone (sub-hazard ratio - SHR = 1.11; 95%CI: 1.01; 1.45) to depressive symptoms alone (SHR = 1.52; 95%CI: 1.13; 2.01) and then to both factors combined (SHR = 1.61; 95%CI: 1.18; 2.18). Marital status and social network size were not associated with incident disability. In a population of older Brazilian adults, lower emotional support and depressive symptoms have independent predictive value for subsequent disability in very long term.

Increased reward-oriented impulsivity in older bipolar patients: A preliminary study.

OBJECTIVE: Impulsivity is a well-established trait of bipolar disorder (BD) that persists across mood phases. It is, however, still unknown whether, in BD, impulsivity remains stable or varies in intensity over the lifespan. This cross-sectional study compared impulsive behavior in older euthymic BD patients and healthy individuals using a range of self-rating and behavioral measures of impulsivity. METHODS: 28 BD patients (56.07 ± 4.08 years, 16 women) and 15 healthy controls (HC; 55.1 ± 3.95 years, 6 women) were administered the Barratt Impulsivity Scale (BIS) and selected tasks of the Cambridge Neuropsychological Test Automated Batter (CANTAB) reflecting impulsivity. Multivariate analysis of variance controlled for age compared impulsivity measures across BD and HC. RESULTS: BD patients displayed poor decision making, risk taking, and increased delay aversion. Other measures of impulsivity such as response inhibition, sustained cognitive control, and BIS scores were, overall, comparable between BD and HC. CONCLUSIONS: These preliminary findings suggest that, in BD, aspects of impulsivity related to reward-based decision making persist into late adulthood. Large scale, longitudinal studies are needed to evaluate the relationship of age to impulsivity over time, and explore the link between impulsivity and illness progression in elderly individuals with BD.

Depressive symptoms, emotional support and activities of daily living disability onset: 15-year follow-up of the Bambuí (Brazil) Cohort Study of Aging / Sintomas depressivos, apoio emocional e início do comprometimento das atividades da vida diária: seguimento de 15 anos do Estudo de Coorte de Idosos de Bambuí, Minas Gerais, Brasil / Síntomas depresivos, apoyo emocional y actividades del día a día, conviviendo con la aparición de una discapacidad: seguimiento durante 15 años del Estudio de Cohorte Envejecimiento de Bambuí (Brasil)

Psychosocial factors appear to be associated with increased risk of disability in later life. However, there is a lack of evidence based on long-term longitudinal data from Western low-middle income countries. We investigated whether psychosocial factors at baseline predict new-onset disability in long term in a population-based cohort of older Brazilians adults. We used 15-year follow-up data from 1,014 participants aged 60 years and older of the Bambuí (Brazil) Cohort Study of Aging. Limitations on activities of daily living (ADL) were measured annually, comprising 9,252 measures. Psychosocial factors included depressive symptoms, social support and social network. Potential covariates included sociodemographic characteristics, lifestyle, cognitive function and a physical health score based on 10 self-reported and objectively measured medical conditions. Statistical analysis was based on competitive-risk framework, having death as the competing risk event. Baseline depressive symptoms and emotional support from the closest person were both associated with future ADL disability, independently of potential covariates wide range. The findings showed a clear graded association, in that the risk gradually increased from low emotional support alone (sub-hazard ratio - SHR = 1.11; 95%CI: 1.01; 1.45) to depressive symptoms alone (SHR = 1.52; 95%CI: 1.13; 2.01) and then to both factors combined (SHR = 1.61; 95%CI: 1.18; 2.18). Marital status and social network size were not associated with incident disability. In a population of older Brazilian adults, lower emotional support and depressive symptoms have independent predictive value for subsequent disability in very long term.

Fatores psicossociais parecem estar associados a um aumento do risco de incapacidade em idosos. Entretanto, faltam evidências baseadas em dados longitudinais de longo prazo em países ocidentais de renda baixa e média. Investigamos se os fatores psicossociais presentes na linha de base predizem a incapacidade incidente no longo prazo em uma coorte populacional de idosos brasileiros. Usamos dados do seguimento de 15 anos de 1.014 participantes com 60 anos de idade ou mais do Estudo de Coorte de Idosos de Bambuí, Minas Gerais, Brasil. Foram medidas anualmente as limitações nas atividades de vida diária (AVD), totalizando 9.252 mensurações. Os fatores psicossociais incluíram sintomas depressivos, apoio emocional e rede social. As variáveis independentes incluíram características sociodemográficas, estilo de vida, função cognitiva e uma escala de saúde física com dez condições clínicas autorrelatadas e medidas objetivas. A análise estatística foi baseada em um modelo de risco competitivo, tendo o óbito como evento de risco competitivo. Os sintomas depressivos na linha de base e o apoio emocional da pessoa mais próxima estiveram associados à incapacidade futura nas AVD, independentemente da grande amplitude das variáveis independentes. Os achados mostraram um claro gradiente de associação, onde o risco aumentou progressivamente desde o baixo apoio emocional isoladamente (sub-hazard ratio - SHR = 1,11; IC95%: 1,01; 1,45) para sintomas depressivos isoladamente (SHR = 1,52; IC95%: 1,13; 2,01) até a combinação de ambos os fatores (SHR = 1,61; IC95%: 1,18; 2,18). O estado civil e o tamanho da rede social não mostraram associação com a mortalidade incidente. Em uma população de idosos brasileiros, o apoio emocional baixo e sintomas depressivos apresentam valores preditivos independentes em relação à incapacidade subsequente no prazo muito longo.

Los factores psicosociales parecen que estaban asociados con un aumento del riesgo de sufrir discapacidad más adelante a lo largo de la vida. Sin embargo, existe una falta de evidencias en los datos a largo plazo de carácter longitudinal, procedentes de países occidentales con una renta medio-baja. Investigamos si los factores psicosociales como base de referencia predicen un surgimiento de discapacidad a largo plazo en una cohorte de población, basada en adultos ancianos brasileños. Se realizó un seguimiento durante 15 años con datos de 1.014 participantes con 60 años y de mayor edad en el Estudio de Cohorte Envejecimiento de Bambuí (Brasil). Las limitaciones en las actividades de la vida diaria (ADL por sus siglas en inglés) fueron medidas anualmente, comprendiendo 9.252 medidas. Se trabajó con factores psicosociales, incluidos síntomas depresivos, apoyo social y tejido social. Las covariables potenciales incluyeron características sociodemográficas, estilo de vida, función cognitiva y un marcador de salud física, basado en 10 condiciones médicas autoinformadas y medidas objetivamente. El análisis estadístico estaba basado en un marco de riesgo competitivo, considerando la muerte como riesgo competitivo. Las bases de referencia de los síntomas depresivos y el apoyo emocional de la persona más cercana estuvieron asociadas con una futura discapacidad ADL, independientemente del extenso rango de potenciales covariables. Los resultados muestran un clara asociación graduada, en la que el riesgo gradualmente aumentó desde un bajo apoyo emocional solo (sub-hazard ratio - SHR = 1,11; IC95%: 1,01; 1,45) para síntomas depresivos sólo (SHR = 1.52; IC95%: 1,13; 2,01) y luego para ambos factores combinados (SHR = 1,61; IC95%: 1.18; 2.18). El estado marital y el tamaño del tejido social no estuvieron asociados con la incidencia de discapacidad. En una población de adultos mayores brasileños, un apoyo emocional más bajo y síntomas depresivos poseen un valor predictivo independiente para una consecuente discapacidad a muy largo plazo.

Klotho dysfunction: A pathway linking the aging process to bipolar disorder?

AIM: Although accelerated aging profile has been described in bipolar disorder (BD), the biology linking BD and aging is still largely unknown. Reduced levels and/or activity of a protein named Klotho is associated with decreased life span, premature aging and occurrence of age-related diseases. Therefore, this study was designed to evaluate plasma levels of Klotho in BD patients and controls. METHODS: Forty patients with type 1 BD and 30 controls were enrolled in this study. After clinical evaluation, peripheral blood samples were drawn and plasma levels of Klotho were measured using enzyme-linked immunosorbent assay. RESULTS: Patients with BD and controls presented similar age and sex distribution. The mean ± SD length of illness was 24.00 ± 12.75 years. BD patients presented increased frequency of clinical comorbidities in comparison with controls, mainly arterial hypertension, diabetes mellitus, and hypothyroidism. Both patients with BD in remission and in mania exhibited increased plasma levels of Klotho in comparison with controls. There was no significant difference between patients in mania and patients in remission regarding the levels of Klotho. CONCLUSION: Klotho-related pathway is altered in BD. Contrary to our original hypothesis, our sample of patients with BD presented increased plasma levels of Klotho in comparison with controls. Elevated levels of Klotho in long-term BD patients may be associated with the disorder progression. Further studies are needed to better understand the role of Klotho in BD and other mood disorders.

Enhanced Molecular Aging in Late-Life Depression: the Senescent-Associated Secretory Phenotype.

OBJECTIVE: This study aims to investigate whether a systemic molecular pattern associated with aging (senescent-associated secretory phenotype [SASP]) is elevated in adults with late-life depression (LLD), compared with never-depressed elderly comparison participants. DESIGN: Cross-sectional study. PARTICIPANTS: We included 111 older adults (80 with LLD and 31 comparison participants) in this study. MEASUREMENT: A panel of 22 SASP-related proteins was extracted from a previous multiplex protein panel performed in these participants. We conducted a principal component analysis to create the SASP index based on individual weights of each of protein. RESULTS: Participants with LLD showed a significantly increased SASP index compared with comparison participants, after controlling for age, depressive symptoms, medical comorbidity (CIRS-G) scores, sex, and cognitive performance (F(1,98) = 7.3, p = 0.008). Correlation analyses revealed that the SASP index was positively correlated with age (r = 0.2, p = 0.03) and CIRS score (r = 0.27, p = 0.005), and negatively correlated with information processing speed (r = -0.34, p = 0.001), executive function (r = -0.27, p = 0.004) and global cognitive performance (r = -0.28, p = 0.007). CONCLUSIONS: To the best of our knowledge, this is the first study to show that a set of proteins (i.e., SASP index) primarily associated with cellular aging is abnormally regulated and elevated in LLD. These results suggest that individuals with LLD display enhanced aging-related molecular patterns that are associated with higher medical comorbidity and worse cognitive function. Finally, we provide a set of proteins that can serve as potential therapeutic targets and biomarkers to monitor the effects of therapeutic or preventative interventions in LLD.

Inflammatory Response in the CNS: Friend or Foe?

Inflammatory reactions could be both beneficial and detrimental to the brain, depending on strengths of their activation in various stages of neurodegeneration. Mild activation of microglia and astrocytes usually reveals neuroprotective effects and ameliorates early symptoms of neurodegeneration; for instance, released cytokines help maintain synaptic plasticity and modulate neuronal excitability, and stimulated toll-like receptors (TLRs) promote neurogenesis and neurite outgrowth. However, strong activation of glial cells gives rise to cytokine overexpression/dysregulation, which accelerates neurodegeneration. Altered mutual regulation of p53 protein, a major tumor suppressor, and NF-κB, the major regulator of inflammation, seems to be crucial for the shift from beneficial to detrimental effects of neuroinflammatory reactions in neurodegeneration. Therapeutic intervention in the p53-NF-κB axis and modulation of TLR activity are future challenges to cope with neurodegeneration.

Circulating biosignatures of late-life depression (LLD): Towards a comprehensive, data-driven approach to understanding LLD pathophysiology.

There is scarce information about the pathophysiological processes underlying Late-Life Depression (LLD). We aimed to determine the neurobiological abnormalities related to LLD through a multi-modal biomarker approach combining a large, unbiased peripheral proteomic panel and structural brain imaging. We examined data from 44 LLD and 31 control participants. Plasma proteomic analysis was performed using a multiplex immunoassay. We evaluated the differential protein expression between groups with random intercept models. We carried out enrichment pathway analyses (EPA) to uncover biological pathways and processes related to LLD. Machine learning analysis was applied to the combined dataset to determine the accuracy with which specific proteins could correctly discriminate LLD versus control participants. Sixty-one proteins were differentially expressed in LLD (p < 0.05 and FDR < 0.01). EPA showed that these proteins were related to abnormal immune-inflammatory control, cell survival and proliferation, proteostasis control, lipid metabolism, intracellular signaling. Machine learning analysis showed that a panel of three proteins (C-peptide, FABP-liver, ApoA-IV) discriminated LLD and control participants with 100% accuracy. The plasma proteomic profile in LLD revealed dysregulation in biological processes essential to the maintenance of homeostasis at cellular and systemic levels. These abnormalities increase brain and systemic allostatic load leading to the downstream negative outcomes of LLD, including increased risk of medical comorbidities and dementia. The peripheral biosignature of LLD has predictive power and may suggest novel putative therapeutic targets for prevention, treatment, and neuroprotection in LLD.

Insomnia and risk of dementia in older adults: Systematic review and meta-analysis.

There are cross-sectional evidences of an association between sleep disorders and cognitive impairment on older adults. However, there are no consensus by means of longitudinal studies data on the increased risk of developing dementia related to insomnia. We conduct a systematic review and meta-analysis to evaluate the risk of incident all-cause dementia in individuals with insomnia in population-based prospective cohort studies. Five studies of 5.242 retrieved references were included in the meta-analysis. We used the generic inverse variance method with a random effects model to calculate the pooled risk of dementia in older adults with insomnia. We assessed heterogeneity in the meta-analysis by means of the Q-test and I2 index. Study quality was assessed with the Newcastle-Ottawa Scale The results showed that Insomnia was associated with a significant risk of all-cause dementia (RR = 1.53 CI95% (1.07-2.18), z = 2.36, p = 0.02). There was evidence for significant heterogeneity in the analysis (q-value = 2.4, p < 0.001 I2 = 82%). Insomnia is associated with an increased risk for dementia. This results provide evidences that future studies should investigate dementia prevention among elderly individuals through screening and proper management of insomnia.