Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 112
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-34655218

RESUMO

OBJECTIVE: The cognitive reserve hypothesis has been proposed as a key mechanism explaining the link between social networks and cognitive function but has rarely been empirically tested using neuroimaging data. This study examines whether social network attributes moderate the association between amygdalar volume and cognitive function. METHODS: Data were from the Social Networks in Alzheimer Disease study (N=154) and Indiana Alzheimer's Disease Research Center. Social networks were measured using the PhenX Social Network Battery. Regional data from MRI (amygdalar volume; AV) were analyzed using FreeSurfer software. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and consensus diagnosis. Linear regression analyses were conducted to test the moderating role of social networks on the association between AV and cognitive function. RESULTS: Participants with greater ability to span multiple social roles and subgroups within their networks scored higher on the MoCA after adjusting for sociodemographic variables, depression, frequency of contact, and AV. Social networks moderated the association between AV and cognitive function. CONCLUSIONS: Among participants who engaged in diverse and loosely connected social networks, the expected adverse cognitive effects of brain volume in regions implicated in socioemotional processing were attenuated. These findings suggest that cognitive stimulation achieved through social interaction with a diverse array of social relationships across multiple contexts may help promote cognitive reserve.

2.
Alzheimers Dement (Amst) ; 13(1): e12230, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34466653

RESUMO

Introduction: Head injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important. Methods: Cognition and tau deposition were compared between 752 individuals with (impaired, n = 302) or without cognitive impairment (CN, n = 450) with amyloid and [18F]flortaucipir positron emission tomography, HI history information, and cognitive testing from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study. Results: Sixty-three (38 CN, 25 impaired) reported a history of HI. Higher neuropsychiatric scores and poorer memory were observed in those with a history of HI. Tau was higher in individuals with a history of HI, especially those who experienced a loss of consciousness (LOC). Results were driven by impaired individuals, especially amyloid beta-positive individuals with history of HI with LOC. Discussion: These findings suggest biological changes, such as greater tau, are associated with HI in individuals with cognitive impairment. Small effect sizes were observed; thus, further studies should replicate and extend these results.

3.
Alzheimers Dement ; 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482619

RESUMO

Research suggests social connectedness may help older adults with dementia maintain cognitive functionality and quality of life. However, little is known about its specific social and biological mechanisms. This paper proposes two pathways through social bridging (i.e., cognitive enrichment through expansive social networks) and bonding (i.e., neuroendocrine benefits of integration in cohesive social networks). We provide preliminary evidence for these pathways using neuroimaging, cognitive, and egocentric social network data from the Social Networks and Alzheimer's Disease (SNAD) study (N = 280). We found that network size, density, and presence of weak ties (i.e., social bridging) moderated the association between brain atrophy and cognitive function, while marriage/cohabitation (i.e., social bonding) moderated the association between perceived stress and cognitive function. We argue that social connectedness may have downstream implications for multiple pathophysiological processes in cognitive aging, even negating existing structural damage to the brain, making it a strong candidate for clinical or policy intervention.

4.
Front Aging Neurosci ; 13: 705889, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489676

RESUMO

Background: Neurocognitive disorder (NCD) is common after stroke, with major NCD appearing in about 10% of survivors of a first-ever stroke. We aimed to classify clinical- and imaging factors related to rapid development of major NCD 3 months after a stroke, so as to examine the optimal composition of factors for predicting rapid development of the disorder. We hypothesized that the prediction would mainly be driven by neurodegenerative as opposed to vascular brain changes. Methods: Stroke survivors from five Norwegian hospitals were included from the "Norwegian COgnitive Impairment After STroke" (Nor-COAST) study. A support vector machine (SVM) classifier was trained to distinguish between patients who developed major NCD 3 months after the stroke and those who did not. Potential predictor factors were based on previous literature and included both vascular and neurodegenerative factors from clinical and structural magnetic resonance imaging findings. Cortical thickness was obtained via FreeSurfer segmentations, and volumes of white matter hyperintensities (WMH) and stroke lesions were semi-automatically gathered using FSL BIANCA and ITK-SNAP, respectively. The predictive value of the classifier was measured, compared between classifier models and cross-validated. Results: Findings from 227 stroke survivors [age = 71.7 (11.3), males = (56.4%), stroke severity NIHSS = 3.8 (4.8)] were included. The best predictive accuracy (AUC = 0.876) was achieved by an SVM classifier with 19 features. The model with the fewest number of features that achieved statistically comparable accuracy (AUC = 0.850) was the 8-feature model. These features ranked by their weighting were; stroke lesion volume, WMH volume, left occipital and temporal cortical thickness, right cingulate cortical thickness, stroke severity (NIHSS), antiplatelet medication intake, and education. Conclusion: The rapid (<3 months) development of major NCD after stroke is possible to predict with an 87.6% accuracy and seems dependent on both neurodegenerative and vascular factors, as well as aspects of the stroke itself. In contrast to previous literature, we also found that vascular changes are more important than neurodegenerative ones. Although possible to predict with relatively high accuracy, our findings indicate that the development of rapid onset post-stroke NCD may be more complex than earlier suggested.

5.
Neuroimage Clin ; 31: 102726, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34153687

RESUMO

Understanding the interrelationships of clinical manifestations of Alzheimer's disease (AD) and functional connectivity (FC) as the disease progresses is necessary for use of FC as a potential neuroimaging biomarker. Degradation of resting-state networks in AD has been observed when FC is estimated over the entire scan, however, the temporal dynamics of these networks are less studied. We implemented a novel approach to investigate the modular structure of static (sFC) and time-varying (tvFC) connectivity along the AD spectrum in a two-sample Discovery/Validation design (n = 80 and 81, respectively). Cortical FC networks were estimated across 4 diagnostic groups (cognitively normal, subjective cognitive decline, mild cognitive impairment, and AD) for whole scan (sFC) and with sliding window correlation (tvFC). Modularity quality (across a range of spatial scales) did not differ in either sFC or tvFC. For tvFC, group differences in temporal stability within and between multiple resting state networks were observed; however, these differences were not consistent between samples. Correlation analyses identified a relationship between global cognition and temporal stability of the ventral attention network, which was reproduced in both samples. While the ventral attention system has been predominantly studied in task-evoked designs, the relationship between its intrinsic dynamics at-rest and general cognition along the AD spectrum highlights its relevance regarding clinical manifestation of the disease.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Descanso
6.
Alzheimers Res Ther ; 13(1): 113, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127075

RESUMO

BACKGROUND: Although few studies have shown that risk factors for Alzheimer's disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset < 65 years of age) versus late-onset AD (LOAD). Therefore, we evaluated whether the impact of Alzheimer's disease (AD) risk factors on cognitive trajectories differ in EOAD and LOAD. METHODS: We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories. RESULTS: APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD. CONCLUSIONS: Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.


Assuntos
Doença de Alzheimer , Idade de Início , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Cognição , Humanos , Memória , Fatores de Risco
7.
Hum Brain Mapp ; 42(11): 3500-3516, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33949732

RESUMO

Functional connectivity, as estimated using resting state functional MRI, has shown potential in bridging the gap between pathophysiology and cognition. However, clinical use of functional connectivity biomarkers is impeded by unreliable estimates of individual functional connectomes and lack of generalizability of models predicting cognitive outcomes from connectivity. To address these issues, we combine the frameworks of connectome predictive modeling and differential identifiability. Using the combined framework, we show that enhancing the individual fingerprint of resting state functional connectomes leads to robust identification of functional networks associated to cognitive outcomes and also improves prediction of cognitive outcomes from functional connectomes. Using a comprehensive spectrum of cognitive outcomes associated to Alzheimer's disease (AD), we identify and characterize functional networks associated to specific cognitive deficits exhibited in AD. This combined framework is an important step in making individual level predictions of cognition from resting state functional connectomes and in understanding the relationship between cognition and connectivity.

8.
Alzheimers Dement ; 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34018654

RESUMO

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aß)-positive EOAD, 200 Aß-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

9.
N Engl J Med ; 384(18): 1691-1704, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33720637

RESUMO

BACKGROUND: A hallmark of Alzheimer's disease is the accumulation of amyloid-ß (Aß) peptide. Donanemab, an antibody that targets a modified form of deposited Aß, is being investigated for the treatment of early Alzheimer's disease. METHODS: We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog13), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET. RESULTS: A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab. CONCLUSIONS: In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Placa Amiloide/tratamento farmacológico , Atividades Cotidianas , Administração Intravenosa , Idoso , Edema Encefálico/induzido quimicamente , Cognição/efeitos dos fármacos , Progressão da Doença , Método Duplo-Cego , Epitopos , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Ácido Pirrolidonocarboxílico/antagonistas & inibidores , Índice de Gravidade de Doença
10.
Lancet Neurol ; 20(3): 222-234, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33609479

RESUMO

Most patients with Alzheimer's disease present with amnestic problems; however, a substantial proportion, over-represented in young-onset cases, have atypical phenotypes including predominant visual, language, executive, behavioural, or motor dysfunction. In the past, these individuals often received a late diagnosis; however, availability of CSF and PET biomarkers of Alzheimer's disease pathologies and incorporation of atypical forms of Alzheimer's disease into new diagnostic criteria increasingly allows them to be more confidently diagnosed early in their illness. This early diagnosis in turn allows patients to be offered tailored information, appropriate care and support, and individualised treatment plans. These advances will provide improved access to clinical trials, which often exclude atypical phenotypes. Research into atypical Alzheimer's disease has revealed previously unrecognised neuropathological heterogeneity across the Alzheimer's disease spectrum. Neuroimaging, genetic, biomarker, and basic science studies are providing key insights into the factors that might drive selective vulnerability of differing brain networks, with potential mechanistic implications for understanding typical late-onset Alzheimer's disease.


Assuntos
Doença de Alzheimer/diagnóstico , Biomarcadores , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/classificação , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos
11.
Heart Lung ; 50(1): 51-58, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32703621

RESUMO

BACKGROUND: Apolipoprotein E (APOE) ε2, ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles have been associated with cognition. Associations of these alleles with cognition in heart failure (HF) and influences of HF across the cognitive spectrum (i.e., cognitively normal to Alzheimer's dementia [AD]) remain unexplored. OBJECTIVES: To investigate influences of APOE ε2, ε4, BDNF Met and HF on cognition among participants across the cognitive spectrum. METHODS: Genetic association study using national databases (N = 7,166). RESULTS: APOE ε2 frequencies were similar across the cognitive spectrum among participants with HF. APOE ε4 frequency was lower among participants with HF and AD than non-HF participants with AD. BDNF Met frequencies did not differ across the spectrum. HF was associated with worse attention and language. In the HF subsample, ε4 was associated with worse memory. CONCLUSION: Associations between APOE and cognition may differ in HF but need to be tested in a larger sample.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Insuficiência Cardíaca , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Cognição , Insuficiência Cardíaca/genética , Humanos
12.
Neuroimage ; 226: 117560, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33189932

RESUMO

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model - neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-ß PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Degeneração Neural/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Estudos Transversais , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Tomografia por Emissão de Pósitrons , Substância Branca/metabolismo , Substância Branca/patologia
13.
Alzheimers Res Ther ; 12(1): 93, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758274

RESUMO

BACKGROUND: A substantial number of patients clinically diagnosed with Alzheimer's disease do not harbor amyloid pathology. We analyzed the presence and extent of tau deposition and neurodegeneration in amyloid-positive (AD) and amyloid-negative (nonAD) ADNI subjects while also taking into account age of onset (< or > 65 years) as we expected that the emerging patterns could vary by age and presence or absence of brain amyloidosis. METHODS: One hundred and ten early-onset AD (EOAD), 121 EOnonAD, 364 late-onset AD (LOAD), and 175 LOnonAD mild cognitive impairment (MCI) and dementia (DEM) subjects were compared to 291 ADNI amyloid-negative control subjects using voxel-wise regression in SPM12 with cluster-level family-wise error correction at pFWE < 0.05). A subset of these subjects also received 18F-flortaucipir scans and allowed for analysis of global tau burden. RESULTS: As expected, relative to LOAD, EOAD subjects showed more extensive neurodegeneration and tau deposition in AD-relevant regions. EOnonADMCI showed no significant neurodegeneration, while EOnonADDEM showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonADMCI and LOnonADDEM showed diffuse brain atrophy and a fronto-temporo-parietal hypometabolic pattern. LOnonAD and EOnonAD subjects failed to show significant tau binding. CONCLUSIONS: LOnonAD subjects show a fronto-temporal neurodegenerative pattern in the absence of tau binding, which may represent underlying hippocampal sclerosis with TDP-43, also known as limbic-predominant age-related TDP-43 encephalopathy (LATE). The hypometabolic pattern observed in EOnonADDEM seems similar to the one observed in EOADMCI. Further investigation into the underlying etiology of EOnonAD is warranted.


Assuntos
Doença de Alzheimer , Amiloidose , Disfunção Cognitiva , Idoso , Peptídeos beta-Amiloides/metabolismo , Amiloidose/complicações , Amiloidose/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
14.
Alzheimers Dement ; 16(9): 1213-1223, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32755048

RESUMO

INTRODUCTION: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aß) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aß deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aß1-42 . DISCUSSION: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.

15.
Clin Epigenetics ; 12(1): 84, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539856

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants. RESULTS: In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 × 10-5 to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex). CONCLUSIONS: Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Metilação de DNA/genética , Neuroimagem/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Diagnóstico Diferencial , Progressão da Doença , Diagnóstico Precoce , Epigenômica/métodos , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência/normas , Fenótipo , Transcriptoma/genética
16.
J Alzheimers Dis ; 75(3): 959-969, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32390626

RESUMO

BACKGROUND: Aberrant angiogenesis may play a role in the development of Alzheimer's disease and related dementia. OBJECTIVE: To explore the relationship between angiogenesis activity and evidence of neurodegeneration among older adults. METHODS: Cross-sectional study of 49 older adults clinically characterized as cognitively normal, mild cognitive impairment, or early Alzheimer's disease. In addition to neuroimaging, we completed assays on peripheral blood, including: vascular endothelial growth factor, tumor necrosis factor, fibroblast growth factor, and amyloid-ß peptide 40. We used advanced polychromatic flow cytometry to phenotype circulating mononuclear cells to assess angiogenesis activity. RESULTS: Although we documented differences in cognitive performance, structural changes on neuroimaging, and burden of amyloid and tau on positron emission tomography, angiogenesis activity did not vary by group. Interestingly, VEGF levels were shown to be increased among subjects with mild cognitive impairment. In ANCOVA models controlling for age, sex, intracranial volume, and monocyte subpopulations, angiogenesis activity was correlated with increased white matter hyperintensities. CONCLUSION: We demonstrate a significant association between angiogenesis activity and cerebrovascular disease. To better understand the potential of angiogenesis as an intervention target, longitudinal studies are needed.


Assuntos
Encéfalo/patologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Demência/diagnóstico , Demência/patologia , Neovascularização Patológica/diagnóstico , Idoso , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/sangue , Disfunção Cognitiva/complicações , Estudos Transversais , Demência/sangue , Demência/complicações , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neovascularização Patológica/sangue , Neovascularização Patológica/complicações , Tomografia por Emissão de Pósitrons
17.
Brain Commun ; 2(1): fcaa019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32309804

RESUMO

Visual deficits are common in neurodegenerative diseases including Alzheimer's disease. We sought to determine the association between visual contrast sensitivity and neuroimaging measures of Alzheimer's disease-related pathophysiology, including cerebral amyloid and tau deposition and neurodegeneration. A total of 74 participants (7 Alzheimer's disease, 16 mild cognitive impairment, 20 subjective cognitive decline, 31 cognitively normal older adults) underwent the frequency doubling technology 24-2 examination, a structural MRI scan and amyloid PET imaging for the assessment of visual contrast sensitivity. Of these participants, 46 participants (2 Alzheimer's disease, 9 mild cognitive impairment, 12 subjective cognitive decline, 23 cognitively normal older adults) also underwent tau PET imaging with [18F]flortaucipir. The relationships between visual contrast sensitivity and cerebral amyloid and tau, as well as neurodegeneration, were assessed using partial Pearson correlations, covaried for age, sex and race and ethnicity. Voxel-wise associations were also evaluated for amyloid and tau. The ability of visual contrast sensitivity to predict amyloid and tau positivity were assessed using forward conditional logistic regression and receiver operating curve analysis. All analyses first were done in the full sample and then in the non-demented at-risk individuals (subjective cognitive decline and mild cognitive impairment) only. Significant associations between visual contrast sensitivity and regional amyloid and tau deposition were observed across the full sample and within subjective cognitive decline and mild cognitive impairment only. Voxel-wise analysis demonstrated strong associations of visual contrast sensitivity with amyloid and tau, primarily in temporal, parietal and occipital brain regions. Finally, visual contrast sensitivity accurately predicted amyloid and tau positivity. Alterations in visual contrast sensitivity were related to cerebral deposition of amyloid and tau, suggesting that this measure may be a good biomarker for detecting Alzheimer's disease-related pathophysiology. Future studies in larger patient samples are needed, but these findings support the power of these measures of visual contrast sensitivity as a potential novel, inexpensive and easy-to-administer biomarker for Alzheimer's disease-related pathology in older adults at risk for cognitive decline.

18.
J Alzheimers Dis ; 73(4): 1305-1311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929164

RESUMO

BACKGROUND: Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-ß (Aß) accumulation and accelerates Alzheimer's disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established. OBJECTIVE: We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies. METHODS: This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer's Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders. RESULTS: HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype. CONCLUSION: This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/patologia , Hipercolesterolemia/complicações , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Autopsia , Feminino , Genótipo , Humanos , Masculino , Neuritos/patologia , Placa Amiloide/patologia , Estados Unidos
19.
BMJ Open ; 9(12): e031947, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31857304

RESUMO

OBJECTIVE: To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline. METHODS: 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer's disease dementia subjects from the Alzheimer's Disease Neuroimaging Initiative received (18F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher's exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status. RESULTS: No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects. CONCLUSIONS: Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia.


Assuntos
Doença de Alzheimer/patologia , Amiloidose/patologia , Sintomas Comportamentais/etiologia , Disfunção Cognitiva/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Amiloidose/diagnóstico por imagem , Amiloidose/psicologia , Sintomas Comportamentais/diagnóstico , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/psicologia , Progressão da Doença , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Fatores de Risco , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...