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Circular RNAs (circRNAs) are noncoding RNAs abundant in brain tissue, and many are derived from activity-dependent, linear mRNAs encoding for synaptic proteins, suggesting that circRNAs may directly or indirectly play a role in regulating synaptic development, plasticity, and function. However, it is unclear if the circular forms of these RNAs are similarly regulated by activity and what role these circRNAs play in developmental plasticity. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent linear forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following MD. Knockdown of circHomer1 prevented the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown led to a reduction in average dendritic spine size prior to MD, but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 regulates plasticity through mechanisms of activity-dependent AMPA receptor endocytosis. Thus, activity-dependent circRNAs regulate developmental synaptic plasticity, and our findings highlight the essential role of circHomer1 in V1 plasticity induced by short-term MD.
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INTRODUCTION: Current physical activity guidelines recommend 150 min of moderate-to-vigorous physical activity (MVPA) for health benefits, regardless of the pattern of MVPA. However, MVPA that occurs in sessions (MVPA-S) may have different health implications compared to MVPA that is not accumulated in sessions (MVPA-nonS). This study aimed to investigate the associations of MVPA-S and MVPA-nonS with mortality. METHODS: We conducted a cohort study of the National Health and Nutrition Examination Survey 2003-2006 (n = 5,658) with accelerometer-measured physical activity at baseline and mortality followed through December 31, 2019. A session was defined as a time window of 30 min or longer where the average intensity was at or above 2020 counts/minute. MVPA accumulated within such sessions was quantified as MVPA-S, while MVPA accumulated outside the sessions was quantified as MVPA-nonS. We examined the joint association of MVPA-S and MVPA-nonS by classifying the participants into four groups (both < 75 min/week [referent], MVPA-S ≥ 75 and MVPA-nonS < 75, MVPA-S < 75 and MVPA-nonS ≥ 75, and both ≥ 75). We used 75 min as the cut-point because it is half of the guideline-recommended MVPA volume where a strong MVPA-mortality association has been observed in previous studies, and because it was close to the median of MVPA-nonS (75 min/week was the 54th percentile), allowing a sufficient sample size in each group for testing statistical significance. The hazard ratios and 95% confidence intervals were estimated with adjustment for important confounders. RESULTS: During 13.9 years of follow-up (74,988 person-years), there were 1,424 deaths, out of which 472 were related to cardiovascular diseases (CVD). Compared to the referent combination (both < 75), the hazard ratios in the other three combinations were 0.48 (0.33-0.69), 0.85 (0.71-1.01), and 0.45 (0.30-0.67) for all-cause mortality; and were 0.34 (0.17-0.70), 0.96 (0.69-1.33), and 0.40 (0.17-0.90) for CVD mortality, respectively. Results were largely consistent in the spline-based models, age- and sex-stratified analyses, complete-case analysis, competing risk analysis, and the analysis excluding deaths within two years of follow-up. CONCLUSION: In conclusion, MVPA accumulated in sessions that lasted at least 30 min was associated with significant reductions in all-cause and CVD-specific mortality risks. The health implications of MVPA that were not accumulated in such sessions warrant further investigation.
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Acelerometria , Exercício Físico , Inquéritos Nutricionais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Mortalidade , Estudos de Coortes , Idoso , Fatores de TempoRESUMO
INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. HIGHLIGHTS: We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Transcriptoma , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , BiomarcadoresRESUMO
INTRODUCTION: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited. METHODS: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations. RESULTS: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression. DISCUSSION: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine. HIGHLIGHTS: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Etnicidade , Biomarcadores , Peptídeos beta-Amiloides , Proteínas tau , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologiaRESUMO
BACKGROUND: Patients with type 2 diabetes (T2D) are at high risk of developing multiple complications, affecting their health-related quality of life (HRQoL). Existing studies only considered impact of complication on HRQoL in the year of occurrence but not its residual impacts in subsequent years. We investigated temporal impacts of diabetes-related complications on HRQoL in a 12-year prospective cohort of ambulatory Chinese patients with T2D enrolled in the clinic-based Joint Asia Diabetes Evaluation (JADE) Register. METHODS: HRQoL utility measures were derived from EuroQol five-dimensional three-level questionnaire (EQ-5D-3L) questionnaires completed by 19 322 patients with T2D in Hong Kong (2007-2018). Temporal EQ-5D utility decrements associated with subtypes of cardiovascular-renal events were estimated using generalized linear regression model after stepwise selection of covariates with p < .01 as cutoff. RESULTS: In this cohort (mean ± SD age:61.2 ± 11.5 years, 55.3% men, median [interquartile range] duration of diabetes:10.1 [3.0-15.0] years, glycated hemoglobin [HbA1C ] 7.5 ± 1.5%), EQ-5D utility was 0.860 ± 0.163. The largest HRQoL decrements were observed in year of occurrence of hemorrhagic stroke (-0.230), followed by ischemic stroke (-0.165), peripheral vascular disease (-0.117), lower extremity amputation (-0.093), chronic kidney disease (CKD) G5 without renal replacement therapy (RRT) (-0.079), congestive heart failure (CHF) (-0.061), and CKD G3-G4 without RRT (-0.042). Residual impacts on HRQoL persisted for 2 years after occurrence of CHF or ischemic stroke and 1 year after hemorrhagic stroke or CKD G3-G4 without RRT. CONCLUSION: This is the first comprehensive report on temporal associations of HRQoL decrements with subtypes of diabetes-related complications in ambulatory Asian patients with T2D. These data will improve the accuracy of cost-effectiveness analysis of diabetes interventions at an individual level in an Asian setting.
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In this issue of Neuron, Essayan-Perez and Südhof1 demonstrate roles for γ-secretase in the regulation of synaptic functions in human neurons. Chronic attenuation of γ-secretase activity increases synapse formation but decreases neurotransmission (i.e., the probability of presynaptic release), likely due to impairment of cholesterol metabolism.
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Secretases da Proteína Precursora do Amiloide , Neurônios , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Neurônios/metabolismo , Transmissão Sináptica/fisiologia , Homeostase , Colesterol/metabolismo , Sinapses/metabolismoRESUMO
In Alzheimer's disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aß) plaque-associated ApoE, and leads to Aß clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aß-directed migration. Functional screening identified that VCAM1 directs microglial Aß chemotaxis by sensing Aß plaque-associated ApoE. Moreover, we found that disrupting VCAM1-ApoE interaction abolishes microglial Aß chemotaxis, resulting in decreased microglial clearance of Aß. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aß chemotaxis. Together, our findings demonstrate that promoting VCAM1-ApoE-dependent microglial functions ameliorates AD pathology.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Microglia/metabolismo , Interleucina-33/metabolismo , Quimiotaxia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismoRESUMO
Microglia maintain brain homeostasis through their ability to survey and phagocytose danger-associated molecular patterns (DAMPs). In Alzheimer's disease (AD), microglial phagocytic clearance regulates the turnover of neurotoxic DAMPs including amyloid beta (Aß) and hyperphosphorylated tau. To mediate DAMP clearance, microglia express a repertoire of surface receptors to sense DAMPs; the activation of these receptors subsequently triggers a chemotaxis-to-phagocytosis functional transition in microglia. Therefore, the interaction between microglial receptors and DAMPs plays a critical role in controlling microglial DAMP clearance and AD pathogenesis. However, there is no comprehensive overview on how microglial sensome receptors interact with DAMPs and regulate various microglial functions, including chemotaxis and phagocytosis. In this review, we discuss the important axes of receptor-ligand interaction that control different microglial functions and their roles in AD pathogenesis. First, we summarize how the accumulation and structural changes of DAMPs trigger microglial functional impairment, including impaired DAMP clearance and aberrant synaptic pruning, in AD. Then, we discuss the important receptor-ligand axes that restore microglial DAMP clearance in AD and aging. These findings suggest that targeting microglial chemotaxis-the first critical step of the microglial chemotaxis-to-phagocytosis state transition-can promote microglial DAMP clearance in AD. Thus, our review highlights the importance of microglial chemotaxis in promoting microglial clearance activity in AD. Further detailed investigations are essential to identify the molecular machinery that controls microglial chemotaxis in AD.
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Doença de Alzheimer , Humanos , Microglia , Peptídeos beta-Amiloides , Quimiotaxia , LigantesRESUMO
BACKGROUND: The polygenic nature of Alzheimer's disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual's genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Because of the complexity of genomic data, current statistical analyses cannot comprehensively capture the polygenic risk of AD, resulting in unsatisfactory disease risk prediction. However, deep learning methods, which capture nonlinearity within high-dimensional genomic data, may enable more accurate disease risk prediction and improve our understanding of AD etiology. Accordingly, we developed deep learning neural network models for modeling AD polygenic risk. METHODS: We constructed neural network models to model AD polygenic risk and compared them with the widely used weighted polygenic risk score and lasso models. We conducted robust linear regression analysis to investigate the relationship between the AD polygenic risk derived from deep learning methods and AD endophenotypes (i.e., plasma biomarkers and individual cognitive performance). We stratified individuals by applying unsupervised clustering to the outputs from the hidden layers of the neural network model. RESULTS: The deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms. CONCLUSION: Our results suggest that deep learning methods are effective for modeling the genetic risks of AD and other diseases, classifying disease risks, and uncovering disease mechanisms.
Polygenic diseases, such as Alzheimer's disease (AD), are those caused by the interplay between multiple genetic risk factors. Statistical models can be used to predict disease risk based on a person's genetic profile. However, there are limitations to existing methods, while emerging methods such as deep learning may improve risk prediction. Deep learning involves computer-based software learning from patterns in data to perform a certain task, e.g. predict disease risk. Here, we test whether deep learning models can help to predict AD risk. Our models not only outperformed existing methods in modeling AD risk, they also allow us to estimate an individual's risk of AD and determine the biological processes that may be involved in AD. With further testing and optimization, deep learning may be a useful tool to help accurately predict risk of AD and other diseases.
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Background: In Asia, diabetes-associated death due to cardiorenal diseases were 2-3 times higher in women than men which might be due to gender disparity in quality of care and health habits. Methods: Adults with type 2 diabetes (T2D) from 11 Asian countries/areas were assessed using the same protocol (2007-2015). We compared treatment target attainment (HbA1c < 7%, blood pressure [BP] < 130/80 mmHg, risk-based LDL-cholesterol, lack of central obesity [waist circumference <90 cm in men or <80 cm in women), use of cardiorenal-protective drugs (renin-angiotensin system [RAS] inhibitors, statins), and self-reported health habits including self-monitoring blood glucose (SMBG) by gender. Analyses were stratified by countries/areas, age of natural menopause (<50 vs. ≥50 years), and comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure, kidney impairment [eGFR < 60 mL/min/1.73 m2]). Findings: Among 106,376 patients (53.2% men; median (interquartile range) diabetes duration: 6.0 (2.0-12.0) years; mean ± SD HbA1c 8.0 ± 1.9%; 27% insulin-treated), women were older and less likely to receive college education than men (28.9% vs. 48.8%). Women were less likely to smoke/drink alcohol and were physically less active than men. Women had lower BP (<130/80 mmHg: 29.4% vs. 25.7%), less general obesity (54.8% vs. 57.8%) but more central obesity than men (77.5% vs. 57.3%). Women were less likely to have ASCVD (12.8% vs. 17.0%) or heart failure (1.3% vs. 2.3%), but more likely to have kidney impairment (22.3% vs. 17.6%) and any-site cancer than men (2.5% vs. 1.6%). In most countries/areas, more men attained HbA1c <7% and risk-based LDL-cholesterol level than women. After adjusting for potential confounders including countries and centres, men had 1.63 odds ratio (95% CI 1.51, 1.74) of attaining ≥3 treatment targets than women. Interpretation: Asian women with T2D had worse quality of care than men especially in middle-income countries/areas, calling for targeted implementation programs to close these care gaps. Sponsor: Asia Diabetes Foundation. Funding: Nil.
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Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a global burden, while the renoprotective effects of metformin remain controversial. In a population-based cohort (2002-2018) including 96,643 patients with T2D observed for 0.7 million person-years, we estimated the risk association of metformin and its dose-relationship with ESKD in a propensity-score overlap-weighting (PS-OW) cohort by eGFR categories. Amongst 96,643, 83,881 (86.8%) had eGFR-G1/G2 (≥60 mL/min/1.73 m2), 8762 (9.1%) had eGFR-G3a (≥45-60 mL/min/1.73 m2), 3051 (3.2%) had eGFR-G3b (≥30-45 mL/min/1.73 m2), and 949 (1.0%) had eGFR-G4 (≥15-30 mL/min/1.73 m2). The respective proportions of metformin users in these eGFR categories were 95.1%, 81.9%, 53.8%, and 20.8%. In the PS-OW cohort with 88,771 new-metformin and 7872 other oral glucose-lowering-drugs (OGLDs) users, the respective incidence rates of ESKD were 2.8 versus 22.4/1000 person-years. Metformin use associated with reduced risk of ESKD (hazard ratio (HR) = 0.43 [95% CI: 0.35-0.52] in eGFR-G1/G2, 0.64 [0.52-0.79] in eGFR-G3a, 0.67 [0.56-0.80] in eGFR-G3b, and 0.63 [0.48-0.83] in eGFR-G4). Metformin use was associated with reduced or neutral risk of major adverse cardiovascular events (MACE) (7.2 versus 16.0/1000 person-years) and all-cause mortality (14.6 versus 65.1/1000 person-years). Time-weighted mean daily metformin dose was 1000 mg in eGFR-G1/G2, 850 mg in eGFR-G3a, 650 mg in eGFR-G3b, and 500 mg in eGFR-G4. In a subcohort of 14,766 patients observed for 0.1 million person-years, the respective incidence rates of lactic acidosis and HR in metformin users and non-users were 42.5 versus 226.4 events/100,000 person-years (p = 0.03) for eGFR-G1/G2 (HR = 0.57, 0.25-1.30) and 54.5 versus 300.6 events/100,000 person-years (p = 0.01) for eGFR-G3/G4 (HR = 0.49, 0.19-1.30). These real-world data underscore the major benefits and low risk of lactic acidosis with metformin use down to an eGFR of 30 mL/min/1.73 m2 and possibly even 15 mL/min/1.73 m2, while reinforcing the importance of dose adjustment and frequent monitoring of eGFR.
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OBJECTIVE: To compare the effect of ultrasound (US)-guided dry needling (DN) with traditional DN in the treatment of pain and dysfunction for patients with knee osteoarthritis (KOA). DESIGN: A double-blind, randomized controlled trial. METHODS: Patients (25 male and 65 female), age 50-80 years diagnosed with KOA were recruited and randomly assigned to one of three groups in a 1:1:1 ratio for intervention: real US-guided DN with exercise therapy (G1), placebo US-guided DN with exercise therapy (G2), and exercise therapy solely (G3). G1 and G2 were blinded to the application of real or placebo US guidance by turning the monitor of US imaging out-of-view from participants' vantage points. The effectiveness of blinding was evaluated by asking the participants whether they had received real-US guided DN. The responses were assessed by Chi-square test. Visual Analogue Scale (VAS), Knee injury, and Osteoarthritis Outcome Score (KOOS) subscales (KOOS-pain, KOOS-symptoms, KOOS-quality-of-life (QoL)) were collected at baseline, 4 weeks, and 8 weeks by a blinded assessor. Data were analyzed by mixed model analysis of variance (ANOVA) with Bonferroni correction. RESULTS: Eighty-four participants (61.26±5.57 years) completed the study. G1 achieved significant improvement in VAS at 8 weeks compared to G2 and G3 (G1 vs. G2: MD = -15.61, 95% CI [-25.49, -5.51], p = 0.001; G1 vs. G3: MD = -19.90, 95% CI [-29.71, -10.08], p< 0.001). G1 achieved significant improvement in KOOS-pain at 8 weeks compared to G2 and G3 (G1 vs. G2: MD = 9.76, 95% CI [2.38, 17.14], p = 0.006; G1 vs. G3: MD = 9.48, 95% CI [2.31, 16.66], p = 0.010). KOOS-symptoms and KOOS-QoL were not statistically significant between groups. G2 had no significant difference of the perceptions as G1 with p = 0.128. G2 were successfully blinded to placebo US-guided DN. CONCLUSION: US-guided DN with exercise therapy may be more effective than traditional DN with exercise therapy or exercise therapy alone in reduce pain of KOA.
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Agulhamento Seco , Osteoartrite do Joelho , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/terapia , Dor , Qualidade de Vida , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
BACKGROUND: Family history (FamH) of type 2 diabetes might indicate shared genotypes, environments, and/or behaviors. We hypothesize that FamH interacts with unhealthy behaviors to increase the risk of early onset of diabetes and poor cardiometabolic control. METHODS: In a cross-sectional analysis of the prospective Joint Asia Diabetes Evaluation Register including patients from 427 clinics in 11 Asian countries/regions in 2007-2021, we defined positive FamH as affected parents/siblings and self-management as (1) healthy lifestyles (balanced diet, non-use of alcohol and tobacco, regular physical activity) and (2) regular self-monitoring of blood glucose (SMBG). RESULTS: Among 86,931 patients with type 2 diabetes (mean±SD age: 56.6±11.6 years; age at diagnosis of diabetes: 49.8±10.5 years), the prevalence of FamH ranged from 39.1% to 85.3% in different areas with FamH affecting mother being most common (32.5%). The FamH group (n=51,705; 59.5%) was diagnosed 4.6 years earlier than the non-FamH group [mean (95% CI): 47.9 (47.8-48.0) vs. 52.5 (52.4-52.6), logrank p<0.001]. In the FamH group, patients with both parents affected had the earliest age at diagnosis [44.6 (44.5-44.8)], followed by affected single parent [47.7 (47.6-47.8)] and affected siblings only [51.5 (51.3-51.7), logrank p<0.001]. The FamH plus ≥2 healthy lifestyle group had similar age at diagnosis [48.2 (48.1-48.3)] as the non-FamH plus <2 healthy lifestyle group [50.1 (49.8-50.5)]. The FamH group with affected parents had higher odds of hyperglycemia, hypertension, and dyslipidemia than the FamH group with affected siblings, with the lowest odds in the non-FamH group. Self-management (healthy lifestyles plus SMBG) was associated with higher odds of attaining HbA1c<7%, blood pressure<130/80mmHg, and LDL-C<2.6 mmol/L especially in the FamH group (FamH×self-management, pinteraction=0.050-0.001). CONCLUSIONS: In Asia, FamH was common and associated with young age of diagnosis which might be delayed by healthy lifestyle while self management was associated with better control of cardiometabolic risk factors especially in those with FamH.
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Diabetes Mellitus Tipo 2 , Hipertensão , Autogestão , Idoso , Ásia/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipertensão/complicações , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Recent multi-omics analyses paved the way for a comprehensive understanding of pathological processes. However, only few studies have explored Alzheimer's disease (AD) despite the possibility of biological subtypes within these patients. For this study, unsupervised classification of four datasets (genetics, miRNA transcriptomics, proteomics, and blood-based biomarkers) using Multi-Omics Factor Analysis+ (MOFA+), along with systems-biological approaches following various downstream analyses are performed. New subgroups within 170 patients with cerebral amyloid pathology (Aß+) are revealed and the features of them are identified based on the top-rated targets constructing multi-omics factors of both whole (M-TPAD) and immune-focused models (M-IPAD). The authors explored the characteristics of subtypes and possible key-drivers for AD pathogenesis. Further in-depth studies showed that these subtypes are associated with longitudinal brain changes and autophagy pathways are main contributors. The significance of autophagy or clustering tendency is validated in peripheral blood mononuclear cells (PBMCs; n = 120 including 30 Aß- and 90 Aß+), induced pluripotent stem cell-derived human brain organoids/microglia (n = 12 including 5 Aß-, 5 Aß+, and CRISPR-Cas9 apolipoprotein isogenic lines), and human brain transcriptome (n = 78). Collectively, this study provides a strategy for precision medicine therapy and drug development for AD using integrative multi-omics analysis and network modelling.
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Doença de Alzheimer , Amiloidose , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Autofagia/genética , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Microglia/metabolismo , Microglia/patologiaRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. OBJECTIVE: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. METHODS: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care of the Hospital Authority between January 1, 2007 and December 31, 2017. RESULTS: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for >â1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. CONCLUSION: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases.
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Doença de Alzheimer , Antipsicóticos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/epidemiologia , Antipsicóticos/uso terapêutico , Estudos de Coortes , Demografia , Feminino , Hong Kong/epidemiologia , Humanos , MasculinoRESUMO
Importance: Diabetic kidney disease (DKD) and its comorbidities can be prevented by treating multiple targets. Technology-assisted team-based care with regular feedback and patient empowerment can improve the attainment of multiple targets and clinical outcomes in patients with type 2 diabetes, but the effects of this intervention on patients with DKD are unclear. Objective: To evaluate the effect of the Joint Asia Diabetes Evaluation (JADE) web portal, nurse reminders, and team-based care on multiple risk factors in patients with DKD. Design, Setting, and Participants: This 12-month multinational, open-label randomized clinical trial was conducted between June 27, 2014, and February 19, 2019, at 13 hospital-based diabetes centers in 8 countries or regions in Asia. All patients who participated had DKD. The intention-to-treat data analysis was performed from April 7 to June 30, 2020. Interventions: Patients were randomized in a 1:1:1 ratio at each site to usual care, empowered care, or team-based empowered care. All patients underwent a JADE web portal-guided structured assessment at baseline and month 12. Patients in the usual care and empowered care groups received a medical follow-up. Patients in the empowered care group also received a personalized JADE report and nurse telephone calls every 3 months. Patients in the team-based empowered care group received additional face-to-face reviews every 3 months from a physician-nurse team. Main Outcomes and Measures: The primary outcome was the proportion of patients who attained multiple treatment targets (defined as ≥3 of 5 targets: HbA1c level <7.0% [53 mmol/mol], blood pressure <130/80 mm Hg, low-density lipoprotein cholesterol level <1.8 mmol/L, triglyceride level <1.7 mmol/L, and/or persistent use of renin-angiotensin-aldosterone system inhibitors). Results: A total of 2393 patients (mean [SD] age, 67.7 [9.8] years; 1267 men [52.9%]) were randomized to the usual care group (n = 795), empowered care group (n = 802), and team-based empowered care group (n = 796). At baseline, 34.7% patients (n = 830) were on 3 treatment targets. On intention-to-treat analysis, the team-based empowered care group had the highest proportion of patients who had further increase in attainment of multiple treatment targets (within-group differences: usual care group, 3.9% [95% CI, 0.0%-7.8%]; empowered care group, 1.3% [95% CI, -2.8% to 5.4%]; team-based empowered care group, 9.1% [95% CI, 4.7%-13.5%]). The team-based empowered care group was more likely to attain multiple treatment targets than the usual care group (risk ratio [RR], 1.17; 95% CI, 1.00-1.37) and the empowered care group (RR, 1.25; 95% CI, 1.06-1.48) after adjustment for site. Compared with the group that did not attain multiple treatment targets, the group that attained multiple treatment targets reported a lower incidence of cardiovascular, kidney, and cancer events (8.4% [n = 51] vs 14.5% [n = 134]; P = .004). Analysis of the per-protocol population yielded similar results. Conclusions and Relevance: This trial found that technology-assisted team-based care for 12 months improved the attainment of multiple treatment targets as well as empowerment in patients with DKD. Trial Registration: ClinicalTrials.gov Identifier: NCT02176278.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/terapia , Humanos , Internet , Masculino , Fatores de RiscoRESUMO
BACKGROUND: Genetic studies reveal that single-nucleotide polymorphisms (SNPs) of SPI1 are associated with Alzheimer's disease (AD), while their effects in the Chinese population remain unclear. OBJECTIVE: We aimed to examine the AD-association of SPI1 SNPs in the Chinese population and investigate the underlying mechanisms of these SNPs in modulating AD risk. METHODS: We conducted a genetic analysis of three SPI1 SNPs (i.e., rs1057233, rs3740688, and rs78245530) in a Chinese cohort (nâ=â333 patients with AD, nâ=â721 normal controls). We also probed public European-descent AD cohorts and gene expression datasets to investigate the putative functions of those SNPs. RESULTS: We showed that SPI1 SNP rs3740688 is significantly associated with AD in the Chinese population (odds ratio [OR]â=â0.72 [0.58-0.89]) and identified AD-protective SPI1 haplotypes ß (tagged by rs1057233 and rs3740688) and γ (tagged by rs3740688 and rs78245530). Specifically, haplotypes ß and γ are associated with decreased SPI1 gene expression level in the blood and brain tissues, respectively. The regulatory roles of these haplotypes are potentially mediated by changes in miRNA binding and the epigenetic landscape. Our results suggest that the AD-protective SPI1 haplotypes regulate pathways involved in immune and neuronal functions. CONCLUSION: This study is the first to report a significant association of SPI1 with AD in the Chinese population. It also identifies SPI1 haplotypes that are associated with SPI1 gene expression and decreased AD risk.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/genética , China , Expressão Gênica , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas , TransativadoresRESUMO
Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aß) pathology through the modulation of microglial activation and Aß clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.
Assuntos
Doença de Alzheimer , Humanos , Feminino , Animais , Camundongos , Doença de Alzheimer/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Estudo de Associação Genômica Ampla , Apolipoproteína E4/genética , Peptídeos beta-Amiloides/genéticaRESUMO
The pathology of familial Alzheimer's disease, which is caused by dominant mutations in the gene that encodes amyloid-beta precursor protein (APP) and in those that encode presenilin 1 and presenilin 2, is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles in multiple brain regions. Here we show that the brain-wide selective disruption of a mutated APP allele in transgenic mouse models carrying the human APP Swedish mutation alleviates amyloid-beta-associated pathologies for at least six months after a single intrahippocampal administration of an adeno-associated virus that encodes both Cas9 and a single-guide RNA that targets the mutation. We also show that the deposition of amyloid-beta, as well as microgliosis, neurite dystrophy and the impairment of cognitive performance, can all be ameliorated when the CRISPR-Cas9 construct is delivered intravenously via a modified adeno-associated virus that can cross the blood-brain barrier. Brain-wide disease-modifying genome editing could represent a viable strategy for the treatment of familial Alzheimer's disease and other monogenic diseases that affect multiple brain regions.