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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 1100-1103, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018178

RESUMO

Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia. Early stage ß-amyloid oligomers (AßOs) and late stage Aß plaques are the pathological hallmarks of AD brains. AßOs are known to be more neurotoxic and contribute to neuronal damage. Most current approaches are focused on detecting Aß plaques, which occurs at the late stage of AD, and are limited by poor sensitivity and/or contrast agent toxicity. In previous studies, we developed a new curcumin-conjugated magnetic nanoparticle (Cur-MNPs) to target the Aß pathologies. In this study, we investigate the in vivo feasibility of this novel Cur-MNPs to detect Aß pathologies at the early and late stages of AD in transgenic AD mice and perform immunohistochemical examinations to validate the specific targeting of various form of Aß pathologies.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides , Animais , Diagnóstico Precoce , Imagem por Ressonância Magnética , Camundongos , Placa Amiloide/diagnóstico por imagem
2.
Neurology ; 95(19): e2648-e2657, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913020

RESUMO

OBJECTIVE: To investigate the association between discordant ß-amyloid (Aß) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later. METHODS: We included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aß42 available. Aß CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aß) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aß CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET- participants who during follow-up (1) progressed to Aß CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET. RESULTS: Aß CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET- (n = 80) participants were overall similar to the CSF-/PET- (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET- group (1.20 ± 0.13) did not differ from CSF-/PET- (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET- participants, 21/64 (33%) progressed to Aß CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET. CONCLUSIONS: Aß load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aß levels on both PET and CSF, the CSF+/PET- group has a distinctly better prognosis.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Fragmentos de Peptídeos/líquido cefalorraquidiano , Placa Amiloide/diagnóstico por imagem , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Encéfalo/metabolismo , Carbolinas , Estudos de Casos e Controles , Disfunção Cognitiva/fisiopatologia , Meios de Contraste , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos
3.
Neurology ; 95(19): e2622-e2634, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-32732300

RESUMO

OBJECTIVE: To determine whether vascular and neurodegenerative factors influence cognition before clinically relevant Alzheimer disease pathology, we analyzed MRI measures and amyloid imaging in an ethnoracially diverse cohort of cognitively normal individuals older than 60 years. METHODS: Participants (n = 154; mean age 74.15 ± 6.94; 50% female; 54% Caucasian, 22.1% Hispanic, 14.9% African American) were recruited from the University of California, Davis Alzheimer's Disease Research Center, who were cognitively normal at baseline, time of PET, and MRI, and received yearly cognitive assessment for 6.23 ± 4.16 years. Mixed model regression with random slope and intercept was calculated for episodic memory and executive function, adjusting for age, sex, education, and ethnicity. RESULTS: Vascular burden score was associated with total white matter hyperintensity (WMH) volume (ß, 0.171; 95% confidence interval [CI], 0.024-0.318). WMH volume was associated with low baseline executive function (-0.115; -0.226 to -0.003) and rate of change in memory (-0.029; -0.045 to -0.012). Hippocampal volume was associated with the rate of change in memory (0.040; 0.021-0.059) and executive function (0.024; 0.008-0.039). Continuous measures of amyloid status influenced change in memory (-0.026; -0.044 to -0.008) and executive function (-0.033; -0.046 to -0.021) independently of MRI measures. CONCLUSION: Vascular brain injury and neurodegeneration are associated with baseline cognitive performance and the rate of longitudinal change independent of amyloid status among community-dwelling, ethnicity diverse cognitively normal individuals, supporting the role of vascular diseases as risk factors for later-life dementia.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Hipocampo/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Encéfalo/metabolismo , Cognição/fisiologia , Progressão da Doença , Função Executiva/fisiologia , Feminino , Hipocampo/patologia , Humanos , Vida Independente , Imagem por Ressonância Magnética , Masculino , Transtornos da Memória/fisiopatologia , Memória Episódica , Testes Neuropsicológicos , Tamanho do Órgão , Tomografia por Emissão de Pósitrons , Tiazóis , Substância Branca/patologia
4.
Rev. esp. med. nucl. imagen mol. (Ed. impr.) ; 39(4): 254-266, jul.-ago. 2020. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-198286

RESUMO

La amiloidosis cardíaca relacionada con el depósito de transtirretina (ATTR) ha sido tradicionalmente considerada como una enfermedad rara, de difícil diagnóstico y sin tratamiento. Sin embargo, en la actualidad sabemos que su prevalencia es mayor de la considerada, disponemos de métodos diagnósticos no invasivos y están apareciendo tratamientos eficaces. En este contexto, la gammagrafía cardíaca (GC) con difosfonatos marcados con 99mTc ha alcanzado un inusitado interés al mostrar alta sensibilidad y especificidad para el diagnóstico no invasivo y fiable de la ATTR. Este artículo, a modo de guía, pretende identificar los componentes críticos en la realización de la GC que resulten de utilidad en la práctica clínica diaria y, así, ayudar a los especialistas a utilizar los radiofármacos idóneos, obtener las imágenes más adecuadas, interpretar los resultados de estas y conocer los escenarios clínicos en los que resulta apropiado realizar la GC


Transthyretin cardiac amyloidosis (ATTR) has traditionally been considered a rare, difficult-to-diagnose and untreatable disease. However, its prevalence is known to be greater than what was previously thought, non-invasive diagnostic methods are available, and that effective treatments are emerging. In this context, cardiac scintigraphy (CS) with 99mTc-labelled diphosphonates has aroused a noticeable surge in interest by demonstrating high sensitivity and specificity for the reliable, non-invasive diagnosis of ATTR. By way of a guide, this article aims to identify the critical components in the performance of CS that are useful in everyday clinical practice and, thus, help specialists use optimal radiopharmaceuticals, obtain the most appropriate images, interpret the results thereof, and acquaint themselves with those clinical scenarios in which it is convenient to perform CS


Assuntos
Humanos , Cintilografia/métodos , Pré-Albumina/análise , Placa Amiloide/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Difosfonatos/administração & dosagem , Tecnécio/administração & dosagem , Marcação por Isótopo/métodos
5.
AJNR Am J Neuroradiol ; 41(6): 980-986, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32499247

RESUMO

BACKGROUND AND PURPOSE: Cortical amyloid quantification on PET by using the standardized uptake value ratio is valuable for research studies and clinical trials in Alzheimer disease. However, it is resource intensive, requiring co-registered MR imaging data and specialized segmentation software. We investigated the use of deep learning to automatically quantify standardized uptake value ratio and used this for classification. MATERIALS AND METHODS: Using the Alzheimer's Disease Neuroimaging Initiative dataset, we identified 2582 18F-florbetapir PET scans, which were separated into positive and negative cases by using a standardized uptake value ratio threshold of 1.1. We trained convolutional neural networks (ResNet-50 and ResNet-152) to predict standardized uptake value ratio and classify amyloid status. We assessed performance based on network depth, number of PET input slices, and use of ImageNet pretraining. We also assessed human performance with 3 readers in a subset of 100 randomly selected cases. RESULTS: We have found that 48% of cases were amyloid positive. The best performance was seen for ResNet-50 by using regression before classification, 3 input PET slices, and pretraining, with a standardized uptake value ratio root-mean-square error of 0.054, corresponding to 95.1% correct amyloid status prediction. Using more than 3 slices did not improve performance, but ImageNet initialization did. The best trained network was more accurate than humans (96% versus a mean of 88%, respectively). CONCLUSIONS: Deep learning algorithms can estimate standardized uptake value ratio and use this to classify 18F-florbetapir PET scans. Such methods have promise to automate this laborious calculation, enabling quantitative measurements rapidly and in settings without extensive image processing manpower and expertise.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Aprendizado Profundo , Neuroimagem/métodos , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Idoso , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Etilenoglicóis , Feminino , Radioisótopos de Flúor , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Compostos Radiofarmacêuticos
6.
Clin Chem ; 66(4): 587-597, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087019

RESUMO

BACKGROUND: Cerebrospinal fluid (CSF) amyloid-ß1-42 (Aß42) reliably detects brain amyloidosis based on its high concordance with plaque burden at autopsy and with amyloid positron emission tomography (PET) ligand retention observed in several studies. Low CSF Aß42 concentrations in normal aging and dementia are associated with the presence of fibrillary Aß across brain regions detected by amyloid PET imaging. METHODS: An LC-MS/MS reference method for Aß42, modified by adding Aß40 and Aß38 peptides to calibrators, was used to analyze 1445 CSF samples from ADNIGO/2 participants. Seventy runs were completed using 2 different lots of calibrators. For preparation of Aß42 calibrators and controls spiking solution, reference Aß42 standard with certified concentration was obtained from EC-JRC-IRMM (Belgium). Aß40 and Aß38 standards were purchased from rPeptide. Aß42 calibrators' accuracy was established using CSF-based Aß42 Certified Reference Materials (CRM). RESULTS: CRM-adjusted Aß42 calibrator concentrations were calculated using the regression equation Y (CRM-adjusted) = 0.89X (calibrators) + 32.6. Control samples and CSF pools yielded imprecision ranging from 6.5 to 10.2% (Aß42) and 2.2 to 7.0% (Aß40). None of the CSF pools showed statistically significant differences in Aß42 concentrations across 2 different calibrator lots. Comparison of Aß42 with Aß42/Aß40 showed that the ratio improved concordance with concurrent [18F]-florbetapir PET as a measure of fibrillar Aß (n = 766) from 81 to 88%. CONCLUSIONS: Long-term performance assessment substantiates our modified LC-MS/MS reference method for 3 Aß peptides. The improved diagnostic performance of the CSF ratio Aß42/Aß40 suggests that Aß42 and Aß40 should be measured together and supports the need for an Aß40 CRM.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Placa Amiloide/líquido cefalorraquidiano , Placa Amiloide/diagnóstico por imagem , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Biomarcadores/líquido cefalorraquidiano , Calibragem , Estudos de Casos e Controles , Cromatografia Líquida/métodos , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico por imagem , Etilenoglicóis , Humanos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons/métodos , Padrões de Referência , Reprodutibilidade dos Testes
7.
Brain ; 143(1): 320-335, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31886494

RESUMO

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-ß and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Encéfalo/metabolismo , Radioisótopos de Carbono , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Feminino , Radioisótopos de Flúor , Humanos , Isoquinolinas , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Testes Neuropsicológicos , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Tiazóis , Proteínas tau/metabolismo
8.
Alzheimer Dis Assoc Disord ; 34(1): 1-9, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31414990

RESUMO

OBJECTIVE: To evaluate determinants of willingness to accept a treatment to return memory to normal among persons with cognitive impairment who received an amyloid positron emission tomography (PET) scan and their care partner and discordance in risk taking. METHODS: Using data from CARE-IDEAS (n=1872 dyads), a supplement of the Imaging Dementia-Evidence for Amyloid Scanning study, we predicted scan recipient's willingness to accept a risky treatment, the risk care partners believed their care recipient would accept, and discordance in these perceptions. RESULTS: Scan recipients were willing to accept a treatment with a 27.94% (SD=34.36) risk of death. Care partners believed their care recipient would accept a 29.68% (SD=33.74) risk of death; thus, overestimating risk acceptance by 1.74 (SD=41.88) percentage points. A positive amyloid PET scan was associated with willingness to accept greater risk. Poorer functioning of the care recipient was associated with care partners believing their care recipient would accept more risk. The amyloid PET scan result was not significantly associated with discordance, but poorer functioning of the care recipient resulted in care partners overestimating risk. CONCLUSIONS: Scan recipients were willing to accept a treatment with a high risk of death. Discordance was affected by scan recipient's having poorer functioning.


Assuntos
Disfunção Cognitiva/terapia , Demência/terapia , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Assunção de Riscos , Idoso , Encéfalo , Cuidadores/psicologia , Morte , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos
9.
J Histochem Cytochem ; 68(1): 9-23, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31385742

RESUMO

Ultrastructural analysis of healthy, diseased, or experimental tissues is essential in diagnostic and investigative pathology. Evaluation of large tissue areas with suborganelle resolution is challenging because biological structures ranging from several millimeters to nanometers in size need to be identified and imaged while maintaining context over multiple scales. Imaging with field emission scanning electron microscopes (FE-SEMs) is uniquely suited for this task. We describe an efficient workflow for the preparation and unobstructed multiscale imaging of tissue sections with backscattered electron scanning electron microscopy (BSE-SEM) for applications in ultrastructural pathology. We demonstrate that a diverse range of tissues, processed by conventional electron microscopy protocols and avoiding the use of mordanting agents, can be imaged on standard glass slides over multiple scales, from the histological to the ultrastructural level, without any visual obstructions. Our workflow takes advantage of the very large scan fields possible with modern FE-SEMs that allow for the acquisition of wide-field overview images which can be explored at the ultrastructural level by digitally zooming into the images. Examples from applications in pulmonary research and neuropathology demonstrate the versatility and efficiency of this method. This BSE-SEM-based multiscale imaging procedure promises to substantially simplify and accelerate ultrastructural tissue analysis in pathology.


Assuntos
Microscopia Eletrônica de Varredura , Patologia/métodos , Animais , Glomérulos Renais/diagnóstico por imagem , Glomérulos Renais/patologia , Glomérulos Renais/ultraestrutura , Pulmão/diagnóstico por imagem , Pulmão/patologia , Camundongos , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologia , Placa Amiloide/ultraestrutura , Ratos
10.
Alzheimers Res Ther ; 11(1): 101, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831056

RESUMO

BACKGROUND: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-ß by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-ß plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD). METHODS: A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-ß plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. RESULTS: Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-ß plaque levels below the amyloid-ß positivity threshold. CONCLUSION: Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-ß plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-ß plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Encéfalo/diagnóstico por imagem , Placa Amiloide/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Anticorpos Monoclonais Humanizados/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Resultado do Tratamento
11.
Curr Alzheimer Res ; 16(11): 1055-1062, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31724513

RESUMO

BACKGROUND: Visuospatial dysfunction is one predominant symptom in many atypical Alzheimer's disease (AD) patients, however, until now its neural correlates still remain unclear. For the accumulation of intracellular hyperphosphorylated tau proteins is a major pathogenic factor in neurodegeneration of AD, the distributional pattern of tau could highlight the affected brain regions associated with specific cognitive deficits. OBJECTIVE: We investigated the brain regions particularly affected by tau accumulation in patients with visuospatial dysfunction to explore its neural correlates. METHODS: Using 18F-AV-1451 tau positron emission tomography (PET), voxel-wise two-sample t-tests were performed between AD patients with obvious visuospatial dysfunction (VS-AD) and cognitively normal subjects, AD patients with little-to-no visuospatial dysfunction (non VS-AD) and cognitively normal subjects, respectively. RESULTS: Results showed increased tau accumulations mainly located in occipitoparietal cortex, posterior cingulate cortex, precuneus, inferior and medial temporal cortex in VS-AD patients, while increased tau accumulations mainly occurred in the inferior and medial temporal cortex in non VS-AD patients. CONCLUSION: These findings suggested that occipitoparietal cortex, posterior cingulate cortex and precuneus, which were particularly affected by increased tau accumulation in VS-AD patients, may associate with visuospatial dysfunction of AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Proteínas tau/análise , Idoso , Doença de Alzheimer/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/patologia , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons
12.
Curr Alzheimer Res ; 16(12): 1132-1142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31670622

RESUMO

BACKGROUND: Alzheimer's Disease (AD) is the most common neurodegenerative disorder, and it is still incurable. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. Mounting evidence indicates that the neurotoxic effects might be attributed to Soluble ß-Amyloid Oligomers (SAßO). The SAßO are believed to be neurotoxic peptides more predominant than Aß plaques in the early stage, and their key role in AD is self-evident. Unfortunately, identification of SAßO proves to be difficult due to their heterogeneous and transient nature. In spite of many obstacles, multiple techniques have recently been developed to target SAßO effectively. This review focuses on the recent progress in the approaches towards SAßO detection in order to shed some light on the future development of SAßO assays. METHODS: Literatures were obtained from the following libraries: Web of Science, PubMed, EPO, SIPO, USPTO. Articles were critically reviewed based on their titles, abstracts, and contents. RESULTS: A total of 85 papers are referenced in the review. Results are divided into three categories based on the types of detection methods: small molecule fluorescence probes, oligomer-specific antibodies and electrochemical biosensors. Finally, the improvements and challenges of these approaches applied in the early diagnosis of AD were discussed. CONCLUSION: This review article covers three kinds of strategies that could be translated into clinic practice and lead to earlier diagnosis and therapeutic interventions of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Corantes Fluorescentes/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Diagnóstico Precoce , Humanos , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo
13.
J Prev Alzheimers Dis ; 6(4): 228-231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686093

RESUMO

The engineered fusion protein NPT088 targets amyloid in vitro and in animal models of Alzheimer's disease. Previous studies showed that NPT088 treatment reduced ß-amyloid plaque and tau aggregate loads in mouse disease models. Here, we present the results from an initial clinical study of NPT088 in patients with mild to moderate Alzheimer's disease. Patients were treated with 4 dose levels of NPT088 for 6 months to evaluate its safety and tolerability. Exploratory measurements included measurement of change in ß-amyloid plaque and tau burden utilizing Positron Emission Tomography imaging as well as measures of Alzheimer's disease symptoms. At endpoint NPT088 was generally safe and well-tolerated with the most prominent finding being infusion reactions in a minority of patients. No effect of NPT088 on brain plaques, tau aggregates or Alzheimer's disease symptoms was observed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Bacteriófago M13/genética , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Etilenoglicóis , Feminino , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Masculino , Pessoa de Meia-Idade , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
14.
J Alzheimers Dis ; 72(2): 455-465, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31594223

RESUMO

Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer's disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis (p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aß positive MCI cases from Aß negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aß positive SCD and control cases from Aß negative controls. These findings suggest that in prodromal stages of AD, such as in Aß positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aß positive SCD and control cases.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/diagnóstico , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Estudos de Coortes , Imagem de Tensor de Difusão , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/patologia , Masculino , Pessoa de Meia-Idade , Placa Amiloide/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Substância Branca/patologia
15.
Analyst ; 144(23): 7049-7056, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31657367

RESUMO

The global prevalence of Alzheimer's disease (AD) points to endemic levels, especially considering the increase of average life expectancy worldwide. AD diagnosis based on early biomarkers and better knowledge of related pathophysiology are both crucial in the search for medical interventions that are able to modify AD progression. In this study we used unsupervised spectral unmixing statistical techniques to identify the vibrational spectral signature of amyloid ß aggregation in neural tissues, as early biomarkers of AD in an animal model. We analyzed spectral images composed of a total of 55 051 Raman spectra obtained from the frontal cortex and hippocampus of five bitransgenic APPswePS1ΔE9 mice, and colocalized amyloid ß plaques by other fluorescence techniques. The Raman signatures provided a multifrequency fingerprint consistent with the results of synthesized amyloid ß fibrils. The fingerprint obtained from unmixed analysis in neural tissues is shown to provide a detailed image of amyloid plaques in the brain, with the potential to be used as biomarkers for non-invasive early diagnosis and pathophysiology studies in AD on the retina.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/análise , Placa Amiloide/diagnóstico por imagem , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Animais , Lobo Frontal/patologia , Hipocampo/patologia , Camundongos Transgênicos , Presenilina-1/genética , Análise Espectral Raman/métodos
16.
Orv Hetil ; 160(33): 1289-1295, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31401858

RESUMO

The ever-growing average age of the society significantly increases the occurrence of Alzheimer's disease. The increased prevalence represents considerable social and economic burden, which urges the development of diagnostic and therapeutic methods in the field. The most common cause of dementia is Alzheimer's disease, the typical histopathological abnormality of which are well known. The detection of functional changes results in the early diagnosis of the disease, which precedes the morphological changes by years. Positron-emission tomography plays an important role in the demonstration of metabolic changes. The glucose metabolic pattern differs significantly in each clinical form of dementia. The most important ß-amyloid-binding radiopharmaceuticals that should be highlighted are [11C]Pittsburgh compound B that is widely used in the research and [18F]florbetapir that is commonly approved in diagnostics. Tracers visualising neurofibrillary tangles consisting of tau protein appeared most recently. The development continues; newer and newer radiopharmaceuticals appear. These tracers play an important role in both the research and the diagnostics. Orv Hetil. 2019; 160(33): 1289-1295.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Imagem Molecular , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Placa Amiloide/patologia
17.
Eur J Med Chem ; 181: 111585, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404860

RESUMO

Brain amyloid deposits have been identified as the main neuropathological hallmarks of Alzheimer's diseases (AD) and intensive efforts have been devoted to develop aggregation inhibitors preventing the formation of toxic oligomeric Aß for therapeutic. In addition, evidence indicates that the formation and accumulation of ß-amyloid plaques probably precede clinical symptoms by around 20 years and imaging of such plaques would be beneficial for early-stage AD detection. In this study, we investigated phenothiazine-based compounds as novel promising theranostic agents for AD. These multifunctional agents exhibited BBB permeability, low neurotoxicity, good bio-stability as well as strong turn-on fluorescence with a Stokes shift upon binding to Aß aggregates. They had metal-chelating property which could delay Aß aggregation and displayed high binding affinity for ß-amyloid aggregates. Moreover, they have been simultaneously applied to perform in vivo near-infrared fluorescence imaging of ß-amyloid plaques in double transgenic AD mouse model, to prevent self-aggregation of Aß monomer from forming toxic oligomers and to protect human neuroblastoma SH-SY5Y cells against Aß-induced toxicity and oxidative stress.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/análise , Fármacos Neuroprotetores/uso terapêutico , Fenotiazinas/uso terapêutico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Imagem Óptica , Fenotiazinas/química , Fenotiazinas/farmacocinética , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/tratamento farmacológico , Agregação Patológica de Proteínas/diagnóstico por imagem , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/prevenção & controle , Nanomedicina Teranóstica
18.
Ann Clin Transl Neurol ; 6(9): 1815-1824, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31464088

RESUMO

OBJECTIVE: To determine the cutoffs that optimized the agreement between 18 F-Florbetapir positron emission tomography (PET) and Aß1-42, Aß1-40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available 18 F-Florbetapir imaging. METHODS: Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of Aß1-42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with 18 F-Florbetapir PET and evaluated concordance between markers of the amyloid category. RESULTS: Aß1-42, tTau and pTau (but not Aß1-40) and the ratios with Aß1-42 had good diagnostic agreement with 18 F-Florbetapir PET. As a marker of amyloid pathology, the Aß1-42/Aß1-40 ratio had higher agreement and better correlation with amyloid PET than Aß1-42 alone. INTERPRETATION: CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of Aß1-42 with Aß1-40 increases the agreement between markers of amyloid pathology.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Placa Amiloide/diagnóstico por imagem , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/metabolismo , Demência/líquido cefalorraquidiano , Demência/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons
19.
Medicine (Baltimore) ; 98(29): e16509, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335725

RESUMO

To evaluate the use of amyloid-positron emission tomography (PET) in routine clinical practice, in a selected population with cognitive impairment that meets appropriate use criteria (AUC).A multicenter, observational, prospective case-series study of 211patients from 2 level-3 hospitals who fulfilled clinical AUC for amyloid-PET scan in a naturalistic setting. Certainty degree was evaluated using a 5-point Likert scale: 0 (very low probability); 1 (low probability); 2 (intermediate probability); 3 (high probability); and 4 (practically sure), before and after amyloid PET. The treatment plan was considered as cognition-specific or noncognition-specific.Amyloid-PET was positive in 118 patients (55.9%) and negative in 93 patients (44.1%). Diagnostic prescan confidence according amyloid-PET results showed that in both, negative and positive-PET subgroup, the most frequent category was intermediate probability (45.7% and 55.1%, respectively). After the amyloid-PET, the diagnostic confidence showed a very different distribution, that was, in the negative-PET group the most frequent categories are very unlikely (70.7%) and unlikely (29.3%), while in the positive-PET group were very probable (57.6%) and practically sure (39%). Only in 14/211 patients (6.6%) the result of the amyloid-PET did not influence the diagnostic confidence, while in 194 patients (93.4%), the diagnostic confidence improved significantly after amyloid-PET results. The therapeutic intention was modified in 93 patients (44.1%). Specific treatment for Alzheimer disease was started, before amyloid-PET, in 80 patients (37.9%).This naturalistic study provides evidence that the implementation of amyloid-PET is associated with a significant improvement in diagnostic confidence and has a high impact on the therapeutic management of patients with mild cognitive impairment fulfilled clinical AUC.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Idoso , Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
20.
J Alzheimers Dis ; 71(4): 1071-1079, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31322563

RESUMO

As calls for transparency in human subjects research grow, investigators conducting Alzheimer's disease (AD) biomarker research are increasingly required to consider their ethical obligations regarding the return of AD biomarker test results to research participants. When disclosing these test results to potentially vulnerable participants, investigators may face unique challenges to identify adverse events, particularly psychological events. The purpose of this paper is to describe our research team's experience with developing and implementing a process for enhanced adverse event monitoring following the return of amyloid-ß (Aß) imaging results to research participants with mild cognitive impairment (MCI). Ethical and logistical considerations are presented along with preliminary findings from an ongoing randomized controlled trial of Aß imaging results disclosure in MCI. Following receipt of amyloid imaging results, participants underwent 14 days of adverse event monitoring using ecological momentary assessment (EMA), a strategy to capture health, behaviors, and mood as they occur in participants' natural settings in real time. EMA telephone calls were placed at random during waking hours to screen for mood changes. Investigators were alerted for positive depression, anxiety, suicidal ideation screenings, or for two days of failed call attempts. Preliminary feasibility of twenty-four participants with MCI who participated in EMA mood assessments was successfully completed 83% (SD = 0.4) of the time over 14 days with no alerts for anxiety or depression screening items. EMA, when used with standard adverse event monitoring, is a promising and novel approach to maximize early detection of negative psychological reactions following AD biomarker results disclosed in research settings.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Avaliação Momentânea Ecológica , Placa Amiloide/diagnóstico por imagem , Revelação da Verdade/ética , Afeto , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Ética em Pesquisa , Humanos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/psicologia , Prognóstico , Ideação Suicida
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