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Despite increased advocacy and investments in mental health systems globally, there has been limited progress in reducing mental disorder prevalence. In this paper, we argue that meaningful advancements in population mental health necessitate addressing the fundamental sources of shared distress. Using a systems perspective, economic structures and policies are identified as the potential cause of causes of mental ill-health. Neoliberal ideologies, prioritizing economic optimization and continuous growth, contribute to the promotion of individualism, job insecurity, increasing demands on workers, parental stress, social disconnection and a broad range of manifestations well-recognized to erode mental health. We emphasize the need for mental health researchers and advocates to increasingly engage with the economic policy discourse to draw attention to mental health and well-being implications. We call for a shift towards a well-being economy to better align commercial interests with collective well-being and social prosperity. The involvement of individuals with lived mental ill-health experiences, practitioners and researchers is needed to mobilize communities for change and influence economic policies to safeguard well-being. Additionally, we call for the establishment of national mental wealth observatories to inform coordinated health, social and economic policies and realize the transition to a more sustainable well-being economy that offers promise for progress on population mental health outcomes.
Malgré une meilleure sensibilisation et des investissements accrus dans les systèmes de santé mentale à travers le monde, les progrès en matière de réduction du degré de prévalence des troubles mentaux demeurent très limités. Dans le présent document, nous estimons que, pour réaliser des avancées au niveau de la santé mentale des populations, il est impératif de s'attaquer aux sources de cette détresse collective. En adoptant une perspective systémique, force est de constater que les politiques et structures économiques constituent les causes potentielles d'une mauvaise santé mentale. Les idéologies néolibérales, qui privilégient l'optimisation économique et la croissance ininterrompue, contribuent à promouvoir l'individualisme, l'insécurité professionnelle, la pression pesant sur les travailleurs, le stress parental, l'isolement social et un large éventail de facteurs associés à une dégradation de la santé mentale. Nous insistons sur la nécessité de faire appel à des chercheurs et défenseurs actifs dans ce domaine, afin de jouer un rôle dans la politique économique en attirant l'attention sur les implications pour le bien-être et la santé mentale. Nous plaidons pour une transition vers une économie du bien-être visant à rapprocher les intérêts commerciaux de la prospérité sociale et collective. L'intervention de personnes ayant été confrontées à des troubles mentaux, de praticiens et de chercheurs est nécessaire pour mobiliser les communautés en faveur d'un changement et influencer les politiques économiques pour préserver le bien-être. Par ailleurs, nous militons pour la création d'observatoires nationaux de la santé mentale qui serviront à orienter des politiques économiques, sociales et sanitaires coordonnées, mais aussi à favoriser l'évolution vers une économie du bien-être plus durable, laissant entrevoir une amélioration de la santé mentale au sein de la population.
A pesar del aumento de la promoción y las inversiones en sistemas de salud mental en todo el mundo, los avances en la reducción de la prevalencia de los trastornos mentales han sido limitados. En este documento, sostenemos que para lograr avances significativos en la salud mental de la población es necesario abordar las fuentes fundamentales de la angustia compartida. Mediante una perspectiva sistémica, las estructuras y políticas económicas se identifican como la posible causa de los problemas de salud mental. Las ideologías neoliberales, que priorizan la optimización económica y el crecimiento continuo, contribuyen al fomento del individualismo, la inseguridad laboral, el aumento de las exigencias a los trabajadores, el estrés parental, la desconexión social y una gran variedad de manifestaciones bien reconocidas que perjudican la salud mental. Insistimos en la necesidad de que los investigadores y los defensores de la salud mental se impliquen cada vez más en el discurso de la política económica para atraer la atención sobre las implicaciones para la salud mental y el bienestar. Pedimos un cambio hacia una economía del bienestar para alinear mejor los intereses comerciales con el bienestar colectivo y la prosperidad social. Para movilizar a las comunidades en favor del cambio e influir en las políticas económicas con el fin de salvaguardar el bienestar, es necesaria la participación de personas que han padecido enfermedades mentales, profesionales e investigadores. Además, pedimos la creación de observatorios nacionales de bienestar mental que sirvan de base a las políticas sanitarias, sociales y económicas coordinadas y permitan la transición a una economía del bienestar más sostenible, que ofrezca perspectivas de progreso en los resultados de salud mental de la población.
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Trastornos Mentales , Salud Mental , Medio Social , Humanos , Política PúblicaRESUMEN
OBJECTIVE: Cognitive training may benefit older adults with mild cognitive impairment (MCI), but the prognostic factors are not well-established. METHODS: This study analyzed data from a 78-week trial with 107 participants with MCI, comparing computerized cognitive training (CCT) and computerized crossword puzzle training (CPT). Outcomes were changes in cognitive and functional measures from baseline. Linear mixed-effect models were used to identify prognostic factors for each intervention. RESULTS: Baseline neuropsychological composite z-score was positively associated with cognitive and functional improvements for both interventions in univariable models, retaining significance in the final multivariable model for functional outcome in CPT (P< 0.001). Apolipoprotein E e4 carriers had worse cognitive (P= 0.023) and functional (P= 0.001) outcomes than noncarriers for CPT but not CCT. African Americans showed greater functional improvements than non-African Americans in both CPT (P= 0.001) and CCT (P= 0.010). Better baseline odor identification was correlated with cognitive improvements in CPT (P= 0.006) and functional improvements in CCT (P< 0.001). CONCLUSION: Baseline cognitive test performance, African American background, and odor identification ability are potential prognostic factors for improved outcomes with cognitive interventions in older adults with MCI. Apolipoprotein E e4 is associated with poor outcomes. Replication of these findings may improve the selection of cognitive interventions for individuals with MCI.
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Fructans are commonly used as dietary fibre supplements for their ability to promote the growth of beneficial gut microbes. However, fructan consumption has been associated with various dosage-dependent side effects. We characterised side effects in an exploratory analysis of a randomised trial in healthy adults (n = 40) who consumed 18 g/day inulin or placebo. We found that individuals weighing more or habitually consuming higher fibre exhibited the best tolerance. Furthermore, we identified associations between gut microbiome composition and host tolerance. Specifically, higher levels of Christensenellaceae R-7 group were associated with gastrointestinal discomfort, and a machine-learning-based approach successfully predicted high levels of flatulence, with [Ruminococcus] torques group and (Oscillospiraceae) UCG-002 sp. identified as key predictive taxa. These data reveal trends that can help guide personalised recommendations for initial inulin dosage. Our results support prior ecological findings indicating that fibre supplementation has the greatest impact on individuals whose baseline fibre intake is lowest.
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Fibras de la Dieta , Suplementos Dietéticos , Fructanos , Microbioma Gastrointestinal , Inulina , Humanos , Fibras de la Dieta/farmacología , Masculino , Adulto , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Fructanos/farmacología , Inulina/farmacología , Adulto Joven , Peso Corporal , Persona de Mediana Edad , FlatulenciaRESUMEN
Background PET can be used for amyloid-tau-neurodegeneration (ATN) classification in Alzheimer disease, but incurs considerable cost and exposure to ionizing radiation. MRI currently has limited use in characterizing ATN status. Deep learning techniques can detect complex patterns in MRI data and have potential for noninvasive characterization of ATN status. Purpose To use deep learning to predict PET-determined ATN biomarker status using MRI and readily available diagnostic data. Materials and Methods MRI and PET data were retrospectively collected from the Alzheimer's Disease Imaging Initiative. PET scans were paired with MRI scans acquired within 30 days, from August 2005 to September 2020. Pairs were randomly split into subsets as follows: 70% for training, 10% for validation, and 20% for final testing. A bimodal Gaussian mixture model was used to threshold PET scans into positive and negative labels. MRI data were fed into a convolutional neural network to generate imaging features. These features were combined in a logistic regression model with patient demographics, APOE gene status, cognitive scores, hippocampal volumes, and clinical diagnoses to classify each ATN biomarker component as positive or negative. Area under the receiver operating characteristic curve (AUC) analysis was used for model evaluation. Feature importance was derived from model coefficients and gradients. Results There were 2099 amyloid (mean patient age, 75 years ± 10 [SD]; 1110 male), 557 tau (mean patient age, 75 years ± 7; 280 male), and 2768 FDG PET (mean patient age, 75 years ± 7; 1645 male) and MRI pairs. Model AUCs for the test set were as follows: amyloid, 0.79 (95% CI: 0.74, 0.83); tau, 0.73 (95% CI: 0.58, 0.86); and neurodegeneration, 0.86 (95% CI: 0.83, 0.89). Within the networks, high gradients were present in key temporal, parietal, frontal, and occipital cortical regions. Model coefficients for cognitive scores, hippocampal volumes, and APOE status were highest. Conclusion A deep learning algorithm predicted each component of PET-determined ATN status with acceptable to excellent efficacy using MRI and other available diagnostic data. © RSNA, 2023 Supplemental material is available for this article.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Aprendizaje Profundo , Anciano , Humanos , Masculino , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide , Péptidos beta-Amiloides , Apolipoproteínas E , Biomarcadores , Imagen por Resonancia Magnética/métodos , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Proteínas tau , FemeninoRESUMEN
Background Pathologic evidence of Alzheimer disease (AD) is detectable years before onset of clinical symptoms. Imaging-based identification of structural changes of the brain in people at genetic risk for early-onset AD may provide insights into how genes influence the pathologic cascade that leads to dementia. Purpose To assess structural connectivity differences in cortical networks between cognitively normal autosomal dominant Alzheimer disease (ADAD) mutation carriers versus noncarriers and to determine the cross-sectional relationship of structural connectivity and cortical amyloid burden with estimated years to symptom onset (EYO) of dementia in carriers. Materials and Methods In this exploratory analysis of a prospective trial, all participants enrolled in the Dominantly Inherited Alzheimer Network between January 2009 and July 2014 who had normal cognition at baseline, T1-weighted MRI scans, and diffusion tensor imaging (DTI) were analyzed. Amyloid PET imaging using Pittsburgh compound B was also analyzed for mutation carriers. Areas of the cerebral cortex were parcellated into three cortical networks: the default mode network, frontoparietal control network, and ventral attention network. The structural connectivity of the three networks was calculated from DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship between structural connectivity, amyloid burden, and EYO in mutation carriers. Correlation network analysis was performed to identify clusters of related clinical and imaging markers. Results There were 30 mutation carriers (mean age ± standard deviation, 34 years ± 10; 17 women) and 38 noncarriers (mean age, 37 years ± 10; 20 women). There was lower structural connectivity in the frontoparietal control network in mutation carriers compared with noncarriers (estimated effect of mutation-positive status, -0.0266; P = .04). Among mutation carriers, there was a correlation between EYO and white matter structural connectivity in the frontoparietal control network (estimated effect of EYO, -0.0015, P = .01). There was no significant relationship between cortical global amyloid burden and EYO among mutation carriers (P > .05). Conclusion White matter structural connectivity was lower in autosomal dominant Alzheimer disease mutation carriers compared with noncarriers and correlated with estimated years to symptom onset. Clinical trial registration no. NCT00869817 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by McEvoy in this issue.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Imagen de Difusión Tensora/métodos , Predisposición Genética a la Enfermedad , Tomografía de Emisión de Positrones/métodos , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Cohortes , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
IMPORTANCE: The most common screening tool for depression is the Patient Health Questionnaire-9 (PHQ-9). Despite extensive research on the clinical and behavioral implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and social determinants of health and disease. OBJECTIVE: To assess the relationship between the PHQ-9 at intake and other measurements intended to assess social determinants of health. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of 2502 participants from the Baseline Health Study (BHS), a prospective cohort of adults selected to represent major demographic groups in the US; participants underwent deep phenotyping on demographic, socioeconomic, clinical, laboratory, functional, and imaging findings. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of clinical and socioeconomic status (SES). RESULTS: In addition to a host of clinical and biological factors, higher PHQ-9 scores were associated with female sex, younger participants, people of color, and Hispanic ethnicity. Multiple measures of low SES, including less education, being unmarried, not currently working, and lack of insurance, were also associated with higher PHQ-9 scores across the entire spectrum of PHQ-9 scores. A summative score of SES, which was the 6th most predictive factor, was associated with higher PHQ-9 score after adjusting for 150 clinical, lab testing, and symptomatic characteristics. CONCLUSIONS AND RELEVANCE: Our findings underscore that depression should be considered a comorbidity when social determinants of health are addressed, and both elements should be considered when designing appropriate interventions.
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Depresión , Determinantes Sociales de la Salud , Adulto , Estudios Transversales , Depresión/diagnóstico , Depresión/epidemiología , Femenino , Humanos , Tamizaje Masivo , Estudios ProspectivosRESUMEN
BACKGROUND: Online searches about anxiety and depression are recorded every 3-5 s. As such, information and communication technologies (ICT) have enormous potential to enable or impair help-seeking and patient-professional interactions. Youth studies indicate that ICT searches are undertaken before initial mental health consultations, but no publications have considered how this online activity affects the first steps of the patient journey in youth mental health settings. METHODS: State-of-the-art review using an iterative, evidence mapping approach to identify key literature and expert consensus to synthesize and prioritise clinical and research issues. RESULTS: Adolescents and young adults are more likely to seek health advice via online search engines or social media platforms than from a health professional. Young people not only search user-generated content and social media to obtain advice and support from online communities but increasingly contribute personal information online. CONCLUSIONS: A major clinical challenge is to raise professional awareness of the likely impact of this activity on mental health consultations. Potential strategies range from modifying the structure of clinical consultations to ensure young people are able to disclose ICT activities related to mental health, through to the development and implementation of 'internet prescriptions' and a youth-focused 'toolkit'.
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Salud Mental , Medios de Comunicación Sociales , Adolescente , Trastornos de Ansiedad , Personal de Salud , Humanos , Internet , Adulto JovenAsunto(s)
Política de Salud , Salud Mental , Modelos Teóricos , COVID-19/psicología , Humanos , Pandemias , Salud PúblicaRESUMEN
The advent of tau-targeted PET tracers such as flortaucipir (18F) (flortaucipir, also known as 18F-AV-1451 or 18F-T807) have made it possible to investigate the sequence of development of tau in relationship to age, amyloid-ß, and to the development of cognitive impairment due to Alzheimer's disease. Here we report a multicentre longitudinal evaluation of the relationships between baseline tau, tau change and cognitive change, using flortaucipir PET imaging. A total of 202 participants 50 years old or older, including 57 cognitively normal subjects, 97 clinically defined mild cognitive impairment and 48 possible or probable Alzheimer's disease dementia patients, received flortaucipir PET scans of 20 min in duration beginning 80 min after intravenous administration of 370 MBq flortaucipir (18F). On separate days, subjects also received florbetapir amyloid PET imaging, and underwent a neuropsychological test battery. Follow-up flortaucipir scans and neuropsychological battery assessments were also performed at 9 and 18 months. Fifty-five amyloid-ß+ and 90 amyloid-ß- subjects completed the baseline and 18-month study visits and had valid quantifiable flortaucipir scans at both time points. There was a statistically significant increase in the global estimate of cortical tau burden as measured by standardized uptake value ratio (SUVr) from baseline to 18 months in amyloid-ß+ but not amyloid-ß- subjects (least squared mean change in flortaucipir SUVr : 0.0524 ± 0.0085, P < 0.0001 and 0.0007 ± 0.0024 P = 0.7850, respectively), and a significant association between magnitude of SUVr increase and baseline tau burden. Voxel-wise evaluations further suggested that the regional pattern of change in flortaucipir PET SUVr over the 18-month study period (i.e. which regions exhibited the greatest change) also varied as a function of baseline global estimate of tau burden. In subjects with lower global SUVr, temporal lobe regions showed the greatest flortaucipir retention, whereas in subjects with higher baseline SUVr, parietal and frontal regions were increasingly affected. Finally, baseline flortaucipir and change in flortaucipir SUVr were both significantly (P < 0.0001) associated with changes in cognitive performance. Taken together, these results provide a preliminary characterization of the longitudinal spread of tau in Alzheimer's disease and suggest that the amount and location of tau may have implications both for the spread of tau and the cognitive deterioration that may occur over an 18-month period.
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Envejecimiento , Enfermedad de Alzheimer/patología , Carbolinas , Disfunción Cognitiva/patología , Demencia/patología , Anciano , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Cognición/fisiología , Trastornos del Conocimiento/patología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Proteínas tau/metabolismoRESUMEN
INTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid-ß deposition. METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the "A/T/N" (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aß1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: This is the first study to show serum-based BA metabolites are associated with "A/T/N" AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.
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Enfermedad de Alzheimer/patología , Ácidos y Sales Biliares , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/patología , Neuroimagen , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Disfunción Cognitiva/líquido cefalorraquídeo , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Estudios Prospectivos , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). METHODS: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. RESULTS: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. DISCUSSION: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
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Enfermedad de Alzheimer , Ácidos y Sales Biliares/metabolismo , Disfunción Cognitiva/metabolismo , Microbioma Gastrointestinal , Anciano , Enfermedad de Alzheimer/microbiología , Enfermedad de Alzheimer/fisiopatología , Ácidos y Sales Biliares/sangre , Disbiosis , Femenino , Humanos , Hígado/metabolismo , Masculino , MetabolomaRESUMEN
BACKGROUND: The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression. METHODS AND FINDINGS: Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ [identification and quantification] p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative [ADNI], N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease [EASE-AD]). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio [HR] = 4.430, 95% confidence interval [CI] = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-ß (Aß) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples. CONCLUSIONS: We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
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Enfermedad de Alzheimer/metabolismo , Sangre/metabolismo , Encéfalo/metabolismo , Progresión de la Enfermedad , Metaboloma , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Baltimore , Biomarcadores/sangre , Biomarcadores/metabolismo , Análisis Químico de la Sangre , Encéfalo/patología , Femenino , Humanos , Estudios Longitudinales , MasculinoRESUMEN
BACKGROUND: Amyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively. METHODS: Amyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype. RESULTS: The authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls. CONCLUSIONS: In this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.
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Péptidos beta-Amiloides , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Procedimientos Quirúrgicos Cardíacos/tendencias , Disfunción Cognitiva/diagnóstico por imagen , Glicoles de Etileno , Radioisótopos de Flúor , Tomografía de Emisión de Positrones/métodos , Anciano , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/psicología , Estudios ProspectivosRESUMEN
OBJECTIVE: The classification of mild cognitive impairment (MCI) continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. Our aim was to examine baseline characteristics of DEP-CI patients in the DOTCODE trial, a randomized controlled trial of open antidepressant treatment for 16 weeks followed by add-on donepezil or placebo for 62 weeks. METHODS/DESIGN: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HAM-D) score >14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics. RESULTS: Seventy-nine DEP-CI patients were recruited of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9, and mean HAM-D was 23.0. Late mild cognitive impairment patients had significantly worse ADAS-Cog (P < .001), MMSE (P = .004), Block Design (P = .024), Visual Rep II (P = .006), CFL Animal (P = .006), UPSIT (P = .051), as well as smaller right hippocampal volume (P = .037) compared to EMCI patients. MRI indices of cerebrovascular disease did not differ between EMCI and LMCI patients. CONCLUSIONS: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer's disease.
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Antidepresivos/uso terapéutico , Inhibidores de la Colinesterasa/uso terapéutico , Disfunción Cognitiva , Trastorno Depresivo , Donepezilo/uso terapéutico , Hipocampo/patología , Edad de Inicio , Anciano , Anciano de 80 o más Años , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/psicología , Comorbilidad , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/patología , Trastorno Depresivo/psicología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
OBJECTIVE: The aim of the study was to determine the relationship of lifestyle factors and neurocognitive functioning in older adults with vascular risk factors and cognitive impairment, no dementia (CIND). METHODS: One hundred sixty adults (M [SD] = 65.4 [6.8] years) with CIND completed neurocognitive assessments of executive function, processing speed, and memory. Objective measures of physical activity using accelerometry, aerobic capacity determined by exercise testing, and dietary habits quantified by the Food Frequency Questionnaire and 4-Day Food Diary to assess adherence to the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets were obtained to assess direct effects with neurocognition. Potential indirect associations of high-sensitivity C-reactive protein and the Framingham Stroke Risk Profile also were examined. RESULTS: Greater aerobic capacity (ß = 0.24) and daily physical activity (ß = 0.15) were associated with better executive functioning/processing speed and verbal memory (ßs = 0.24; 0.16). Adherence to the DASH diet was associated with better verbal memory (ß = 0.17). Greater high-sensitivity C-reactive protein (ßs = -0.14; -0.21) and Framingham Stroke Risk Profile (ß = -0.18; -0.18) were associated with poorer executive functioning/processing speed and verbal memory. Greater stroke risk partially mediated the association of aerobic capacity with executive functioning/processing speed, and verbal memory and greater inflammation partially mediated the association of physical activity and aerobic fitness, with verbal memory. CONCLUSIONS: Higher levels of physical activity, aerobic fitness, and adherence to the DASH diet are associated with better neurocognitive performance in adults with CIND. These findings suggest that the adoption of healthy lifestyle habits could reduce the risk of neurocognitive decline in vulnerable older adults. CLINICAL TRIAL REGISTRATION: NCT01573546.
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Envejecimiento/fisiología , Enfermedades Cardiovasculares/fisiopatología , Disfunción Cognitiva/fisiopatología , Dieta Saludable , Función Ejecutiva/fisiología , Ejercicio Físico/fisiología , Estilo de Vida , Memoria/fisiología , Aptitud Física/fisiología , Tiempo de Reacción/fisiología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
AIMS: To evaluate the impact of amyloid PET imaging on diagnosis and patient management in a multicenter, randomized, controlled study. METHODS: Physicians identified patients seeking a diagnosis for mild cognitive impairment or dementia, possibly due to Alzheimer disease (AD), and recorded a working diagnosis and a management plan. The patients underwent florbetapir PET scanning and were randomized to either immediate or delayed (1-year) feedback regarding amyloid status. At the 3-month visit, the physician updated the diagnosis and recorded a summary of the actual patient management since the post-scan visit. The study examined the impact of immediate versus delayed feedback on patient diagnosis/management at 3 and 12 months. RESULTS: A total of 618 subjects were randomized (1:1) to immediate or delayed feedback arms, and 602 subjects completed the 3-month primary endpoint visit. A higher proportion of patients in the immediate feedback arm showed a change in diagnosis compared to the controls (32.6 vs. 6.4%; p = 0.0001). Similarly, a higher proportion of patients receiving immediate feedback had a change in management plan (68 vs. 55.5%; p < 0.002), mainly driven by changes in AD medication. Specifically, acetylcholinesterase inhibitors were prescribed to 67% of the amyloid-positive and 27% of the amyloid-negative subjects in the information group compared with 56 and 43%, respectively, in the control group (p < 0.0001). These between-group differences persisted until the 12-month visit. CONCLUSION: Knowledge of the amyloid status affects the diagnosis and alters patient management.
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Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Disfunción Cognitiva/diagnóstico por imagen , Glicoles de Etileno , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones/métodos , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Amiloide/metabolismo , Proteínas Amiloidogénicas/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/psicología , Retroalimentación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
INTRODUCTION: The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. METHODS: Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. RESULTS: Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aß1-42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease. DISCUSSION: Metabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/complicaciones , Enfermedades Metabólicas/etiología , Redes y Vías Metabólicas/fisiología , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Aminoácidos/sangre , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina/metabolismo , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Estudios de Cohortes , Estudios Transversales , Ayuno , Femenino , Humanos , Masculino , Enfermedades Metabólicas/sangre , Enfermedades Metabólicas/líquido cefalorraquídeo , Enfermedades Metabólicas/diagnóstico por imagen , Metabolómica/métodos , Fragmentos de Péptidos/metabolismo , Fosfatidilcolinas/sangre , Fosfatidilcolinas/metabolismo , Esfingomielinas/sangre , Tiazoles/metabolismo , Proteínas tau/líquido cefalorraquídeoRESUMEN
PURPOSE: To evaluate differences in the structural connectome among patients with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer disease (AD) and to determine associations between the structural connectome and cortical amyloid deposition. MATERIALS AND METHODS: Patients enrolled in a multicenter biomarker study (Alzheimer's Disease Neuroimaging Initiative [ADNI] 2) who had both baseline diffusion-tensor (DT) and florbetapir positron emission tomography (PET) data at the time of data analyses in November 2012 were studied. All institutions received institutional review board approval. There were 102 patients in ADNI 2 who met criteria for analysis. Patients' T1-weighted images were automatically parcellated into cortical regions of interest. Standardized uptake value ratio (SUVr) was calculated from florbetapir PET images for composite cortical regions (frontal, cingulate, parietal, and temporal). Structural connectome graphs were created from DT images, and connectome topology was analyzed in each region by using graph theoretical metrics. Analysis of variance of structural connectome metrics and florbetapir SUVr across diagnostic group was performed. Linear mixed-effects models were fit to analyze the effect of florbetapir SUVr on structural connectome metrics. RESULTS: Diagnostic group (NC, MCI, or AD) was associated with changes in weighted structural connectome metrics, with decreases from the NC group to the MCI group to the AD group shown for (a) strength in the bilateral frontal, right parietal, and bilateral temporal regions (P < .05); (b) weighted local efficiency in the left temporal region (P < .05); and (c) weighted clustering coefficient in the bilateral frontal and left temporal regions (P < .05). Increased cortical florbetapir SUVr was associated with decreases in weighted structural connectome metrics; namely, strength (P = .00001), weighted local efficiency (P = .00001), and weighted clustering coefficient (P = .0006), independent of brain region. For every 0.1-unit increase in florbetapir SUVr, there was a 14% decrease in strength, an 11% decrease in weighted local efficiency, and a 9% decrease in weighted clustering coefficient, regardless of the analyzed cortical region or, in the case of weighted local efficiency and clustering coefficient, diagnostic group. CONCLUSION: Increased amyloid burden, as measured with florbetapir PET imaging, is related to changes in the topology of the large-scale cortical network architecture of the brain, as measured with graph theoretical metrics of DTI tractography, even in the preclinical stages of AD. Online supplemental material is available for this article.
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Enfermedad de Alzheimer/patología , Conectoma/métodos , Imagen de Difusión Tensora , Placa Amiloide/patología , Tomografía de Emisión de Positrones , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Biomarcadores , Femenino , Humanos , Masculino , América del Norte , Placa Amiloide/diagnóstico por imagenRESUMEN
OBJECTIVE: To compare differences in gray matter volumes, white matter and subcortical gray matter hyperintensities, neuropsychological factors, and treatment outcome between early- and late-onset late-life depressed (LLD) subjects. METHODS: We conducted a prospective, nonrandomized, controlled trial at the outpatient clinics at Washington University and Duke University on 126 subjects, aged 60 years or older, who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received neuropsychological testing and magnetic resonance imaging. Subjects were excluded for cognitive impairment or severe medical disorders. After 12 weeks of sertraline treatment, subjects' MADRS scores over time and neuropsychological factors were studied. RESULTS: Left anterior cingulate thickness was significantly smaller in the late-onset depressed group than in the early-onset LLD subjects. The late-onset group also had more hyperintensities than the early-onset LLD subjects. No differences were found in neuropsychological factor scores or treatment outcome between early-onset and late-onset LLD subjects. CONCLUSION: Age at onset of depressive symptoms in LLD subjects are associated with differences in cortical thickness and white matter and subcortical gray matter hyperintensities, but age at onset did not affect neuropsychological factors or treatment outcome.