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1.
J Alzheimers Dis ; 98(3): 1133-1143, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38578896

RESUMO

Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p = 2.828×10-2) and poorer cognition (CM-MMSE: p = 1.539×10-5, MoCA-b: p = 4.552×10-6). Additionally, no discernible correlation surfaced between ICVD and amyloid-ß (Aß) 42 (p = 6.910×10-1) or phosphorylated tau (p-tau) (p = 4.324×10-1). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Ataque Isquêmico Transitório , AVC Isquêmico , Humanos , Masculino , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Doença de Alzheimer/psicologia
2.
J Affect Disord ; 353: 90-98, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38452935

RESUMO

BACKGROUND: Reversion from mild cognitive impairment (MCI) to normal cognition (NC) is not uncommon and indicates a better cognitive trajectory. This study aims to identify predictors of MCI reversion and develop a predicting model. METHOD: A total of 391 MCI subjects (mean age = 74.3 years, female = 61 %) who had baseline data of magnetic resonance imaging, clinical, and neuropsychological measurements were followed for two years. Multivariate logistic analyses were used to identify the predictors of MCI reversion after adjusting for age and sex. A stepwise backward logistic regression model was used to construct a predictive nomogram for MCI reversion. The nomogram was validated by internal bootstrapping and in an independent cohort. RESULT: In the training cohort, the 2-year reversion rate was 19.95 %. Predictors associated with reversion to NC were higher education level (p = 0.004), absence of APOE4 allele (p = 0.001), larger brain volume (p < 0.005), better neuropsychological measurements performance (p < 0.001), higher glomerular filtration rate (p = 0.035), and lower mean arterial pressure (p = 0.060). The nomogram incorporating five predictors (education, hippocampus volume, the Alzheimer's Disease Assessment Scale-Cognitive score, the Rey Auditory Verbal Learning Test-immediate score, and mean arterial pressure) achieved good C-indexes of 0.892 (95 % confidence interval [CI], 0.859-0.926) and 0.806 (95 % CI, 0.709-0.902) for the training and validation cohort. LIMITATION: Observational duration is relatively short; The predicting model warrant further validation in larger samples. CONCLUSION: This prediction model could facilitate risk stratification and early management for the MCI population.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Feminino , Idoso , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Cognição , Imageamento por Ressonância Magnética , Hipocampo/patologia , Testes Neuropsicológicos , Doença de Alzheimer/diagnóstico por imagem , Progressão da Doença
3.
J Alzheimers Dis ; 98(2): 629-642, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427482

RESUMO

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.


Assuntos
Doença de Alzheimer , Apatia , Disfunção Cognitiva , Fragilidade , Humanos , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Estudos Longitudinais , Fragilidade/complicações , Disfunção Cognitiva/psicologia , Testes Neuropsicológicos
4.
Alzheimers Res Ther ; 16(1): 65, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38532501

RESUMO

BACKGROUND: It has been reported that the risk of Alzheimer's disease (AD) could be predicted by the Australian National University Alzheimer Disease Risk Index (ANU-ADRI) scores. However, among non-demented Chinese adults, the correlations of ANU-ADRI scores with cerebrospinal fluid (CSF) core biomarkers and cognition remain unclear. METHODS: Individuals from the Chinese Alzheimer's Biomarker and LifestyLE (CABLE) study were grouped into three groups (low/intermediate/high risk groups) based on their ANU-ADRI scores. The multiple linear regression models were conducted to investigate the correlations of ANU-ADRI scores with several biomarkers of AD pathology. Mediation model and structural equation model (SEM) were conducted to investigate the mediators of the correlation between ANU-ADRI scores and cognition. RESULTS: A total of 1078 non-demented elders were included in our study, with a mean age of 62.58 (standard deviation [SD] 10.06) years as well as a female proportion of 44.16% (n = 476). ANU-ADRI scores were found to be significantly related with MMSE (ß = -0.264, P < 0.001) and MoCA (ß = -0.393, P < 0.001), as well as CSF t-tau (ß = 0.236, P < 0.001), p-tau (ß = 0.183, P < 0.001), and t-tau/Aß42 (ß = 0.094, P = 0.005). Mediation analyses indicated that the relationships of ANU-ADRI scores with cognitive scores were mediated by CSF t-tau or p-tau (mediating proportions ranging from 4.45% to 10.50%). SEM did not reveal that ANU-ADRI scores affected cognition by tau-related pathology and level of CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2). CONCLUSION: ANU-ADRI scores were associated with cognition and tau pathology. We also revealed a potential pathological mechanism underlying the impact of ANU-ADRI scores on cognition.


Assuntos
Doença de Alzheimer , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Austrália , Biomarcadores/líquido cefalorraquidiano , Cognição , Estilo de Vida , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Masculino
5.
J Neurochem ; 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38533619

RESUMO

Though previous studies revealed the potential associations of elevated levels of plasma fibrinogen with dementia, there is still limited understanding regarding the influence of Alzheimer's disease (AD) biomarkers on these associations. We sought to investigate the interrelationships among fibrinogen, cerebrospinal fluid (CSF) AD biomarkers, and cognition in non-demented adults. We included 1996 non-demented adults from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study and 337 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The associations of fibrinogen with AD biomarkers and cognition were explored using multiple linear regression models. The mediation analyses with 10 000 bootstrapped iterations were conducted to explore the mediating effects of AD biomarkers on cognition. In addition, interaction analyses and subgroup analyses were conducted to assess the influence of covariates on the relationships between fibrinogen and AD biomarkers. Participants exhibiting low Aß42 were designated as A+, while those demonstrating high phosphorylated tau (P-tau) and total tau (Tau) were labeled as T+ and N+, respectively. Individuals with normal measures of Aß42 and P-tau were categorized as the A-T- group, and those with abnormal levels of both Aß42 and P-tau were grouped under A+T+. Fibrinogen was higher in the A+ subgroup compared to that in the A- subgroup (p = 0.026). Fibrinogen was higher in the A+T+ subgroup compared to that in the A-T- subgroup (p = 0.011). Higher fibrinogen was associated with worse cognition and Aß pathology (all p < 0.05). Additionally, the associations between fibrinogen and cognition were partially mediated by Aß pathology (mediation proportion range 8%-28%). Interaction analyses and subgroup analyses showed that age and ApoE ε4 affect the relationships between fibrinogen and Aß pathology. Fibrinogen was associated with both cognition and Aß pathology. Aß pathology may be a critical mediator for impacts of fibrinogen on cognition.

6.
Alzheimers Res Ther ; 16(1): 28, 2024 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321520

RESUMO

BACKGROUND: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD. METHODS: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed. RESULTS: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: ß = 0.165, P = 0.037) and neuronal injury (CSF T-tau: ß = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aß42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses. CONCLUSIONS: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.


Assuntos
Doença de Alzheimer , Diabetes Mellitus , Hipertensão , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Apolipoproteína E4/líquido cefalorraquidiano , Multimorbidade , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano
7.
J Alzheimers Dis ; 97(4): 1913-1922, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38339928

RESUMO

Background: Cerebral microbleeds (CMB) play an important role in neurodegenerative pathology. Objective: The present study aims to test whether cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) level is linked to CMBs in elderly people. Methods: A total of 750 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had measurements of GAP-43 and CMBs were included in the study. According to the presence and extent of CMBs, participants were stratified into different groups. Regression analyses were used to assess cross-sectional and longitudinal associations between GAP-43 and CMBs. Results: Participants with CMB were slightly older and had higher concentrations of CSF GAP43. In multivariable adjusted analyses for age, gender, APOEɛ4 status, and cognitive diagnoses, higher CSF GAP-43 concentrations were modestly associated with CMB presence (OR = 1.169, 95% CI = 1.001-1.365) and number (ß= 0.020, SE = 0.009, p = 0.027). Similarly, higher CSF GAP43 concentrations were accrual of CMB lesions, associated with higher CMB progression (OR = 1.231, 95% CI = 1.044-1.448) and number (ß= 0.017, SE = 0.005, p = 0.001) in the follow up scan. In stratified analyses, slightly stronger associations were noted in male participants, those 65 years and older, carriers of APOEɛ4 alleles, and with more advanced cognitive disorders. Conclusions: CSF GAP-43 was cross-sectionally associated with the presence and extent of CMBs. GAP-43 might be used as a biomarker to track the dynamic changes of CMBs in elderly persons.


Assuntos
Hemorragia Cerebral , Imageamento por Ressonância Magnética , Humanos , Masculino , Idoso , Proteína GAP-43 , Hemorragia Cerebral/líquido cefalorraquidiano , Estudos Longitudinais , Estudos Transversais , Imageamento por Ressonância Magnética/métodos
8.
Neurobiol Aging ; 137: 55-61, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38422799

RESUMO

This study explored the associations between peripheral immunity with cerebral small vessel diseases. Older adults without dementia from the Alzheimer's Disease Neuroimaging Initiative were investigated. Peripheral blood was obtained, and magnetic resonance imaging was performed to measure cerebral microbleeds (CMB), lacunar infarctions (LI), and white matter hyperintensities (WMH). Multivariable-adjusted regression models, linear mixed-effects models, and the Spearman correlations were used to evaluate the associations. At baseline, individuals with greater neutrophils (odds ratio [OR] =1.10, 95% confidence interval [CI] 1.00-1.20, p=0.042) and monocytes (OR=1.12, 95% CI 1.02-1.22, p=0.016) had higher WMH volume. On the contrary, a higher lymphocyte-to-monocyte ratio (LMR) was related to lower WMH volume (OR=0.91, 95% CI 0.82-1.00, p=0.041). Longitudinally, higher neutrophils (ρ=0.084, p=0.049) and NLR (ρ=0.111, p=0.009) predicted accelerated progression of WMH volume, while a greater LMR (ρ=-0.101, p=0.018) was linked to slower growth of WMH volume. Nevertheless, associations between peripheral immunity with CMB or LI were not observed at baseline and follow-up. Our study found that peripheral immune indexes could serve as convenient noninvasive biomarkers of WMH.


Assuntos
Doenças de Pequenos Vasos Cerebrais , Demência , Substância Branca , Humanos , Idoso , Estudos Longitudinais , Doenças de Pequenos Vasos Cerebrais/patologia , Imageamento por Ressonância Magnética , Neuroimagem , Demência/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
9.
J Neurol ; 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38265471

RESUMO

BACKGROUND: Muscle weakness is a prominent feature of Parkinson's disease, but whether the occurrence of this deficit in healthy adults is associated with subsequent PD diagnosis remains unclear. OBJECTIVE: This study sought to examine the relationship between muscle strength, represented by grip strength and walking pace, and the risk of incident PD. METHODS: A total of 422,531 participants from the UK biobank were included in this study. Longitudinal associations of grip strength and walking pace with the risk of incident PD were investigated by Cox proportional hazard models adjusting for several well-established risk factors. Subgroup and sensitivity analyses were also conducted for further validation. RESULTS: After a median follow-up of 9.23 years, 2,118 (0.5%) individuals developed incident PD. For per 5 kg increment of absolute grip strength, there was a significant 10.2% reduction in the risk of incident PD (HR = 0.898, 95% CI [0.872-0.924], P < 0.001). Similarly, per 0.05 kg/kg increment of relative grip strength was related to a 9.2% reduced risk of incident PD (HR = 0.908, 95% CI [0.887-0.929], P < 0.001). Notably, the associations remained consistent when grip strength was calculated as quintiles. Moreover, participants with a slower walking pace demonstrated an elevated risk of incident PD (HR = 1.231, 95%CI [1.075-1.409], P = 0.003). Subgroup and sensitivity analyses further validated the robustness of the observed associations. CONCLUSION: Our findings showed a negative association of grip strength and walking pace with the risk of incident PD independent of important confounding factors. These results hold potential implications for the early screening of people at high-risk of PD.

10.
NPJ Parkinsons Dis ; 10(1): 23, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38233432

RESUMO

Inconsistent findings exist regarding the potential association between polluted air and Parkinson's disease (PD), with unclear insights into the role of inherited sensitivity. This study sought to explore the potential link between various air pollutants and PD risk, investigating whether genetic susceptibility modulates these associations. The population-based study involved 312,009 initially PD-free participants with complete genotyping data. Annual mean concentrations of PM2.5, PM10, NO2, and NOx were estimated, and a polygenic risk score (PRS) was computed to assess individual genetic risks for PD. Cox proportional risk models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between ambient air pollutants, genetic risk, and incident PD. Over a median 12.07-year follow-up, 2356 PD cases (0.76%) were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs and 95% CIs of 1.247 (1.089-1.427) and 1.201 (1.052-1.373) for PD incidence, respectively. Each 10 µg/m3 increase in NO2 and PM10 yielded elevated HRs and 95% CIs for PD of 1.089 (1.026-1.155) and 1.363 (1.043-1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145-3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912-3.048). Findings suggest that exposure to air contaminants heightens PD risk, particularly in individuals genetically predisposed to high susceptibility.

11.
J Affect Disord ; 349: 201-209, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38199419

RESUMO

BACKGROUND: Antipsychotics (APs) are among the most widely prescribed medications, and have been shown to cause cognitive decline. But previous studies on their effects on dementia risk are controversial and scarce. We aimed to examine the relationships of APs exposure with the risk of dementia. METHODS: Data were obtained from a prospective cohort of 415,100 UK Biobank (UKB) participants. We investigated the effects of APs exposure and their various classes on dementia risk by using multivariable Cox proportional hazard models and further the dose-response effects of oral APs. RESULTS: After a mean follow-up of 8.64 years, 5235 (1.3 %) participants developed all-cause dementia (ACD), among whom 2313 (0.6 %) developed Alzheimer's disease (AD), and 1213 (0.3 %) developed vascular dementia (VaD). Exposure to any APs conferred increased risks of ACD (HR: 1.33, 95 % CI = 1.17-1.51, P < 0.001) and VaD (HR: 1.90, 95 % CI = 1.51-2.40, P < 0.001), but not AD (HR: 1.22, 95 % CI = 1.00-1.48, P = 0.051). Cumulative dose-response relationships of oral APs with the risks of ACD and VaD were observed (P for trend, P < 0.05). LIMITATIONS: Our study is observational and does not show evidence of causality. Since there are relatively few cases of dementia in the UKB, APs exposure may be higher than estimated in our study. CONCLUSIONS: APs exposure increased the risk of developing dementia. Dose-response relationships were found between oral APs and dementia risk. Efforts to raise awareness of doctors and patients about this potential drug-related risk are critical to reducing APs use.


Assuntos
Doença de Alzheimer , Antipsicóticos , Disfunção Cognitiva , Demência Vascular , Humanos , Estudos Prospectivos , Antipsicóticos/efeitos adversos , Doença de Alzheimer/complicações , Demência Vascular/induzido quimicamente , Demência Vascular/epidemiologia , Disfunção Cognitiva/complicações , Fatores de Risco
12.
Alzheimers Res Ther ; 16(1): 12, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38238858

RESUMO

BACKGROUND: Cerebrospinal fluid (CSF) complement activation is a key part of neuroinflammation that occurs in the early stages of Alzheimer's disease (AD). However, the associations of CSF complement proteins with AD pathology, cognition, and structural neuroimaging biomarkers for AD have been rarely investigated. METHODS: A total of 210 participants (125 mild cognitive impairment [MCI] patients and 85 normal controls) were included from Alzheimer's Disease Neuroimaging Initiative (ADNI) database who measured AD pathology, cognition, and neuroimaging at baseline and every 12 months. The mixed-effect linear models were utilized to investigate longitudinal associations of CSF complement proteins with AD pathology, cognition, and neuroimaging in cognitively normal (CN) and mild cognitive impairment (MCI) subjects. Causal mediation analyses were conducted to explore the potential mediators between CSF complement proteins and cognitive changes. RESULTS: We found that the subjects with low CSF complement protein levels at baseline had worse outcomes in AD pathology, indicated by their lowest concentrations observed in A + and A + T + individuals. The reduced CSF complement proteins were associated with faster accumulation of tau among CN subjects and with cognitive decline and greater brain atrophy of specific regions among MCI subjects. Furthermore, mediation analyses showed that the effects of CSF complement proteins on cognitive performance were partially mediated by regional brain structures (mediation proportions range from 19.78 to 94.92%; p < 0.05). CONCLUSIONS: This study demonstrated that CSF complement proteins were involved in the early progression of AD. Our results indicated that regional brain atrophy might be a plausible way to connect CSF complement protein levels and cognition.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cognição , Disfunção Cognitiva/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Atrofia/patologia , Proteínas do Sistema Complemento , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano
13.
Nat Hum Behav ; 8(1): 164-180, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37857874

RESUMO

The cerebral ventricles are recognized as windows into brain development and disease, yet their genetic architectures, underlying neural mechanisms and utility in maintaining brain health remain elusive. Here we aggregated genetic and neuroimaging data from 61,974 participants (age range, 9 to 98 years) in five cohorts to elucidate the genetic basis of ventricular morphology and examined their overlap with neuropsychiatric traits. Genome-wide association analysis in a discovery sample of 31,880 individuals identified 62 unique loci and 785 candidate genes associated with ventricular morphology. We replicated over 80% of loci in a well-matched cohort of lateral ventricular volume. Gene set analysis revealed enrichment of ventricular-trait-associated genes in biological processes and disease pathogenesis during both early brain development and degeneration. We explored the age-dependent genetic associations in cohorts of different age groups to investigate the possible roles of ventricular-trait-associated loci in neurodevelopmental and neurodegenerative processes. We describe the genetic overlap between ventricular and neuropsychiatric traits through comprehensive integrative approaches under correlative and causal assumptions. We propose the volume of the inferior lateral ventricles as a heritable endophenotype to predict the risk of Alzheimer's disease, which might be a consequence of prodromal Alzheimer's disease. Our study provides an advance in understanding the genetics of the cerebral ventricles and demonstrates the potential utility of ventricular measurements in tracking brain disorders and maintaining brain health across the lifespan.


Assuntos
Doença de Alzheimer , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Estudo de Associação Genômica Ampla , Fenótipo , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia
14.
Neurobiol Aging ; 134: 106-114, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38056216

RESUMO

Based on the 'AT(N)' system, individuals with normal amyloid biomarkers but abnormal tauopathy or neurodegeneration biomarkers are classified as non-Alzheimer's disease (AD) pathologic change. This study aimed to assess the long-term clinical and cognitive trajectories of individuals with non-AD pathologic change among older adults without dementia, comparing them to those with normal AD biomarkers and AD pathophysiology. Analyzing Alzheimer's Disease Neuroimaging Initiative data, we evaluated clinical outcomes and conversion risk longitudinally using mixed effects models and multivariate Cox proportional hazard models. We found that compared to individuals with A-T-N-, those with abnormal tauopathy or neurodegeneration biomarkers (A-T + N-, A-T-N + , and A-T + N + ) had a faster rate of cognitive decline and disease progression. Individuals with A-T + N + had a faster rate of decline than those with A-T + N-. Additionally, in individuals with the same baseline tauopathy and neurodegeneration biomarker status, the presence of baseline amyloid could accelerate cognitive decline and clinical progression. These findings provide a foundation for future studies on non-AD pathologic change and its comparison with AD pathophysiology.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Humanos , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Estudos Longitudinais , Peptídeos beta-Amiloides , Disfunção Cognitiva/psicologia , Biomarcadores , Progressão da Doença , Proteínas tau
15.
Neurobiol Aging ; 134: 1-8, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37950963

RESUMO

Studies have shown that multimorbidity may be associated with the Alzheimer's disease (AD) stages, but it has not been fully characterized in patients without dementia. A total of 1402 Han Chinese older adults without dementia from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were included and grouped according to their multimorbidity patterns, defined by the number of chronic disorders and cluster analysis. Multivariable linear regression models were used to detect the associations with AD-related cerebrospinal fluid (CSF) biomarkers. Multimorbidity and severe multimorbidity (≥4 chronic conditions) were significantly associated with CSF amyloid and tau levels (pFDR < 0.05). Metabolic patterns were significantly associated with higher levels of CSF Aß40 (ß = 0.159, pFDR = 0.036) and tau (P-tau: ß = 0.132, pFDR = 0.035; T-tau: ß = 0.126, pFDR = 0.035). The above associations were only significant in the cognitively normal (CN) group. Multimorbidity was associated with brain AD pathology before any symptomatic evidence of cognitive impairment. Identifying such high-risk groups might allow tailored interventions for AD prevention.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/diagnóstico , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Multimorbidade , Disfunção Cognitiva/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Estilo de Vida , Fragmentos de Peptídeos/líquido cefalorraquidiano
16.
Geroscience ; 46(2): 2265-2279, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37926784

RESUMO

Healthy lifestyle might alleviate the socioeconomic inequities in health, but the extent of the joint and interactive effects of these two factors on dementia are unclear. This study aimed to detect the joint and interactive associations of socioeconomic status (SES) and lifestyle factors with incident dementia risk, and the underlying brain imaging alterations. Cox proportional hazards analysis was performed to test the joint and interactive associations. Partial correlation analysis was performed to reflect the brain imaging alterations. A total of 276,730 participants with a mean age of 55.9 (±8.0) years old from UK biobank were included. Over 8.5 (±2.6) years of follow-up, 3013 participants were diagnosed with dementia. Participants with high SES and most healthy lifestyle had a significantly lower risk of incident dementia (HR=0.19, 95% CI=0.14 to 0.26, P<2×10-16), Alzheimer's disease (AD, HR=0.19, 95% CI=0.13 to 0.29, P=8.94×10-15), and vascular dementia (HR=0.24, 95% CI=0.12 to 0.48, P=7.57×10-05) compared with participants with low SES and an unhealthy lifestyle. Significant interactions were found between SES and lifestyle on dementia (P=0.002) and AD (P=0.001) risks; the association between lifestyle and dementia was stronger among those of high SES. The combination of high SES and healthy lifestyle was positively associated with higher volumes in brain regions vulnerable to dementia-related atrophy. These findings suggest that SES and lifestyle significantly interact and influence dementia with its related brain structure phenotypes.


Assuntos
Doença de Alzheimer , Humanos , Estudos Prospectivos , Estilo de Vida , Classe Social , Encéfalo
17.
J Neurochem ; 168(1): 39-51, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38055867

RESUMO

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Globulinas , Humanos , Doença de Alzheimer/patologia , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Albuminas , Fígado , Fragmentos de Peptídeos/líquido cefalorraquidiano
18.
J Neurochem ; 168(1): 26-38, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37830502

RESUMO

The relationship between liver dysfunction and dementia has been researched extensively but remains poorly understood. In this study, we investigate the longitudinal and cross-sectional associations between liver function and liver diseases and risk of incident dementia, impaired cognition, and brain structure abnormalities using Cox proportion hazard model and linear regression model. 431 699 participants with a mean of 8.65 (standard deviation [SD] 2.61) years of follow-up were included from the UK Biobank; 5542 all-cause dementia (ACD), 2427 Alzheimer's disease (AD), and 1282 vascular dementia (VaD) cases were documented. We observed that per SD decreases in alanine transaminase (ALT; hazard ratio [HR], 0.917; PFDR <0.001) and per SD increases in aspartate aminotransferase (AST; HR, 1.048; PFDR = 0.010), AST to ALT ratio (HR, 1.195; PFDR <0.001), gamma-glutamyl transpeptidase (GGT; HR, 1.066; PFDR <0.001), alcoholic liver disease (ALD; HR, 2.872; PFDR <0.001), and fibrosis and cirrhosis of liver (HR, 2.285; PFDR = 0.002), being significantly associated with a higher risk of incident ACD. Restricted cubic spline models identified a strong U-shaped association between Alb and AST and incident ACD (Pnonlinear <0.05). Worse cognition was positively correlated with AST, AST to ALT ratio, direct bilirubin (DBil), and GGT; negatively correlated with ALT, Alb, and total bilirubin (TBil); and ALD and fibrosis and cirrhosis of liver (PFDR <0.05). Moreover, changes in ALT, GGT, AST to ALT ratio, and ALD were significantly associated with altered cortical and subcortical regions, including hippocampus, amygdala, thalamus, pallidum, and fusiform (PFDR <0.05). In sensitivity analysis, metabolic dysfunction-associated steatotic liver disease (MASLD) was associated with the risk of ACD and brain subcortical changes. Our findings provide substantial evidence that liver dysfunction may be an important factor for incident dementia. Early intervention in the unhealthy liver may help prevent cognitive impairment and dementia incidence.


Assuntos
Demência , Hepatopatias , Adulto , Humanos , Estudos Prospectivos , Estudos Transversais , Hepatopatias/epidemiologia , Fígado , Cognição , Bilirrubina , Encéfalo , Cirrose Hepática , Demência/epidemiologia , Aspartato Aminotransferases
19.
J Alzheimers Dis ; 97(1): 471-484, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38143362

RESUMO

BACKGROUND: The associations between neuropsychiatric symptoms (NPSs) and Alzheimer's disease (AD) have been well-studied, yet gaps remain. OBJECTIVE: We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies. METHODS: Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration. RESULTS: We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-ß (Aß) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aß deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aß, the mediation percentage varied from 6.05% to 17.51% (p < 0.05). CONCLUSIONS: NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aß.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Masculino , Humanos , Idoso , Feminino , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Estudos Transversais , Biomarcadores , Disfunção Cognitiva/diagnóstico por imagem , Peptídeos beta-Amiloides , Amiloide , Proteínas tau
20.
J Alzheimers Dis ; 96(4): 1813-1825, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38073392

RESUMO

BACKGROUND: The APOE genotype has emerged as the major genetic factor for AD but differs among different alleles. OBJECTIVE: To investigate the discrepant effects of APOE genotype on AD cerebrospinal fluid (CSF) biomarkers. METHODS: A total of 989 non-demented ADNI participants were included. The associations of APOEɛ2 and APOEɛ4 with CSF biomarkers were investigated using linear regression models. Interaction and subgroup analyses were used to investigate the effects of sex and age on these associations. Furthermore, we used mediation analyses to assess whether Aß mediated the associations between APOE genotypes and tau. RESULTS: APOEɛ2 carriers only showed higher Aß levels (ß [95% CI] = 0.07 [0.01, 0.13], p = 0.026). Conversely, APOEɛ4 carriers exhibited lower Aß concentration (ß [95% CI] = -0.27 [-0.31, -0.24], p < 0.001), higher t-Tau (ß [95% CI] = 0.25 [0.08, 0.18], p < 0.001) and higher p-Tau (ß [95% CI] = 0.31 [0.25, 0.37], p < 0.001). Subgroup analysis showed that APOE ɛ2 was significantly positively associated with Aß only in females (ß [95% CI] = 0.12 [0.04, 0.21], p = 0.005) and older people (ß [95% CI] = 0.06 [0.001, 0.12], p = 0.048). But the effects of APOE ɛ4 were independent of gender and age. Besides, the associations of APOE ɛ4 with t-Tau and p-Tau were both mediated by baseline Aß. CONCLUSIONS: Our data suggested that APOEɛ2 could promote Aß clearance, while the process could be modified by sex and age. However, APOEɛ4 might cause the accumulation of Aß and tau pathology independent of sex and age.


Assuntos
Doença de Alzheimer , Feminino , Humanos , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Genótipo , Biomarcadores/líquido cefalorraquidiano
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