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1.
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
2.
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
4.
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
5.
Geriatr Psychol Neuropsychiatr Vieil ; 17(2): 211-220, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162121

RESUMO

The biomarkers of Alzheimer's disease (AD) have enabled the identification of its pathological features, many years before the onset of clinical symptoms. Positon emission tomography (PET) using radiotracers binding the amyloid plaques has, indeed, paved the way for new perspectives. However, these biomarkers have only been studies in small populations so far, with limited follow-up. The objectives of this work were to assess the interest of amyloid PET in elderly but also to study the relationship of amyloid deposition to Instrumental Activities of Daily Living (IADL) performance. METHODS: Our population included 271 participants from the MAPT trial aged 70 and over, without major cognitive impairment, who performed amyloid PET examination. In a cross-sectional study we examined the association between brain amyloid load and IADL abilities. Moreover, in a longitudinal analysis, we studied the changes in IADL performance between amyloid positive and amyloid negative participants over the 3-year follow-up without and with adjustments for confounding factors (age, randomization group, ApoE genotyping, timespan between baseline and PET examination). RESULTS: Amyloid positive subjects showed poorer abilities in IADL compared to their amyloid negative counterparts, despite similar cognitive performance. Brain amyloid load also impacted the daily functioning of individuals over time, taking in consideration confounding factors. The difference after 3 years between the amyloid positive and negative participants was not significant (p=0.08; in adjusted models p=0.06). Amyloid negative individuals also improved in memory-related instrumental activities (p<0.001) throughout the study, unlike amyloid positive participants. CONCLUSION: These findings confirmed the relationship of brain amyloid deposition with subtle changes in IADL abilities, even in the absence of cognitive impairment. Yet, the absence of disease modifying agents as well as uncertainties regarding the long-term evolution of asymptomatic individuals showing a positive biomarker are still to be determined.


Assuntos
Encéfalo/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/psicologia , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Cognição , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons
6.
Magn Reson Imaging ; 62: 87-93, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31247251

RESUMO

PURPOSE: Simultaneous Non-Contrast Angiography and Intraplaque Hemorrhage (SNAP) was developed for improved imaging of intraplaque hemorrhage (IPH). Its signal polarity also allows for non-contrast time-of-flight MR angiography (TOF). This study sought to compare SNAP and TOF in delineating carotid lumen using contrast-enhanced MRA (CE-MRA) as the reference standard. MATERIALS AND METHODS: Two hundred and eighty-nine matched slices from 15 arteries among 11 subjects (9 males and 2 females, mean age of 72.1 ±â€¯8.6 years) with luminal stenosis on CE-MRA were studied. Cross-sectional slices centered around the carotid bifurcation were matched between the three MRA techniques (SNAP, TOF, and CE-MRA) and classified as slices with or without plaque (focal wall thickness ≥ 1.5 mm) by additional black-blood vessel wall MRI. Lumen area was measured using a Sobel gradient map for TOF and CE-MRA (magnitude images) and a polarity map for SNAP. Agreement between techniques for measuring lumen area and percent stenosis was evaluated using intraclass correlation coefficient (ICC) and paired t-test. RESULTS: Among the 289 matched slices, SNAP showed a higher agreement with CE-MRA than TOF for measuring lumen area (ICC: 0.93 vs. 0.83; p = 0.03). Agreement with CE-MRA was high for both SNAP and TOF in slices without plaque (ICC: 0.91 vs. 0.89; p > 0.05) but favored SNAP over TOF in slices with plaque (ICC: 0.93 vs. 0.80; p = 0.02). CONCLUSION: SNAP, assisted by signal polarity information, demonstrated a higher agreement with CE-MRA in delineating carotid lumen compared to TOF, particularly in slices with plaque where flow conditions may be more complex.


Assuntos
Artérias Carótidas/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Meios de Contraste/farmacologia , Angiografia por Ressonância Magnética , Idoso , Idoso de 80 Anos ou mais , Constrição Patológica/diagnóstico por imagem , Estudos Transversais , Feminino , Hemorragia , Humanos , Processamento de Imagem Assistida por Computador , Imagem Tridimensional , Masculino , Pessoa de Meia-Idade , Placa Amiloide/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Padrões de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos
7.
Neurology ; 92(23): e2699-e2705, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31068481

RESUMO

OBJECTIVE: To identify potential predictors for outcome in individuals with mild cognitive impairment (MCI) who have reverted to normal cognition (NC). METHODS: We selected individuals with MCI, who reverted at follow-up to NC, with follow-up after reversion from Alzheimer's Disease Neuroimaging Initiative. Common clinical markers, Alzheimer disease (AD) biomarkers, and neurodegeneration imaging markers were used to compare MCI reverters based on subsequent clinical outcome (i.e., subsequent decline or stable reversion). For independent comparison, findings of the clinical Amsterdam Dementia Cohort are presented. RESULTS: Seventy-seven (10%) out of 757 individuals with MCI reverted to NC and 61 of these individuals had follow-up data available. After 3.2 ± 2.2 years, 16 (24%) progressed to MCI, and 3 (5%) to dementia. Those who declined were older and had a higher amyloid PET burden and higher CSF tau levels. CONCLUSION: In MCI reverters, abnormal biomarkers for AD pathology are associated with subsequent decline. AD biomarkers may aid in the prognosis of reverting MCI.


Assuntos
Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/epidemiologia , Placa Amiloide/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Biomarcadores , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/epidemiologia , Progressão da Doença , Etilenoglicóis , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Prognóstico , Recidiva , Remissão Espontânea , Medição de Risco , Tiazóis , Proteínas tau/líquido cefalorraquidiano
8.
Eur J Med Chem ; 175: 149-161, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078865

RESUMO

Six novel 2-arylimidazo[2,1-b]benzothiazole (IBT) derivatives were synthesized as potential tridentate radiotracers for AD imaging purposes. Two of these ligands (6a,b) were successfully labeled with 99mTc radionuclide at high radiochemical purity using fac-[99mTc(CO)3(H2O)3]+ synthon. [99mTc]7a and [99mTc]7b were evaluated as single photon emission computed tomography (SPECT) imaging agents for Aß plaque in AD. [99mTc]7a and [99mTc]7b exhibited suitable affinity toward Aß aggregates with IC50 values of 33.2 and 102.5 nM, respectively. The IC50 value of these radiotracers depends on the length of the spacer (alkyl chain). In biodistribution study, these complexes showed good initial brain uptakes (0.78 and 0.86% ID/g at 2 min post-injection) and fast blood clearance. Autoradiography results confirmed that these small 99mTc complexes (Mw about 600 Da) can bind to Aß plaques in the brain sections of the rat AD model. Histopathological staining with Congo red approved the presence of Aß plaques in these brain sections.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Benzotiazóis/metabolismo , Imidazóis/química , Compostos de Organotecnécio/metabolismo , Placa Amiloide/diagnóstico por imagem , Compostos Radiofarmacêuticos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Doença de Alzheimer/metabolismo , Animais , Benzotiazóis/química , Benzotiazóis/farmacocinética , Barreira Hematoencefálica , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual
9.
Clin Nucl Med ; 44(7): 587-588, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31135517

RESUMO

Previous studies have reported increased Pittsburgh compound-B (PiB) uptake in meningiomas; however, histological correlation to elucidate the underlying mechanism has not yet been done. We report a case of an 82-year-old woman with an incidental intracranial tumor that showed focal increased PiB uptake. Because of tumor growth, surgical resection was performed, yielding a histological diagnosis of meningioma. Any special and immunochemical staining for amyloid did not reveal amyloid deposition in the tumor. Our findings suggest that increased PiB uptake was not associated with amyloid in this instance.


Assuntos
Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Idoso de 80 Anos ou mais , Compostos de Anilina , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética , Neoplasias Meníngeas/patologia , Meningioma/patologia , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tiazóis
10.
JAMA ; 321(13): 1286-1294, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30938796

RESUMO

Importance: Amyloid positron emission tomography (PET) detects amyloid plaques in the brain, a core neuropathological feature of Alzheimer disease. Objective: To determine if amyloid PET is associated with subsequent changes in the management of patients with mild cognitive impairment (MCI) or dementia of uncertain etiology. Design, Setting, and Participants: The Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study was a single-group, multisite longitudinal study that assessed the association between amyloid PET and subsequent changes in clinical management for Medicare beneficiaries with MCI or dementia. Participants were required to meet published appropriate use criteria stating that etiology of cognitive impairment was unknown, Alzheimer disease was a diagnostic consideration, and knowledge of PET results was expected to change diagnosis and management. A total of 946 dementia specialists at 595 US sites enrolled 16 008 patients between February 2016 and September 2017. Patients were followed up through January 2018. Dementia specialists documented their diagnosis and management plan before PET and again 90 (±30) days after PET. Exposures: Participants underwent amyloid PET at 343 imaging centers. Main Outcomes and Measures: The primary end point was change in management between the pre- and post-PET visits, as assessed by a composite outcome that included Alzheimer disease drug therapy, other drug therapy, and counseling about safety and future planning. The study was powered to detect a 30% or greater change in the MCI and dementia groups. One of 2 secondary end points is reported: the proportion of changes in diagnosis (from Alzheimer disease to non-Alzheimer disease and vice versa) between pre- and post-PET visits. Results: Among 16 008 registered participants, 11 409 (71.3%) completed study procedures and were included in the analysis (median age, 75 years [interquartile range, 71-80]; 50.9% women; 60.5% with MCI). Amyloid PET results were positive in 3817 patients with MCI (55.3%) and 3154 patients with dementia (70.1%). The composite end point changed in 4159 of 6905 patients with MCI (60.2% [95% CI, 59.1%-61.4%]) and 2859 of 4504 patients with dementia (63.5% [95% CI, 62.1%-64.9%]), significantly exceeding the 30% threshold in each group (P < .001, 1-sided). The etiologic diagnosis changed from Alzheimer disease to non-Alzheimer disease in 2860 of 11 409 patients (25.1% [95% CI, 24.3%-25.9%]) and from non-Alzheimer disease to Alzheimer disease in 1201 of 11 409 (10.5% [95% CI, 10.0%-11.1%]). Conclusions and Relevance: Among Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, the use of amyloid PET was associated with changes in clinical management within 90 days. Further research is needed to determine whether amyloid PET is associated with improved clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02420756.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Demência/diagnóstico por imagem , Nootrópicos/uso terapêutico , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/tratamento farmacológico , Amiloide , Disfunção Cognitiva/terapia , Demência/etiologia , Demência/terapia , Diagnóstico Diferencial , Feminino , Humanos , Estudos Longitudinais , Masculino , Medicare , Estados Unidos
11.
N Engl J Med ; 380(15): 1408-1420, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970186

RESUMO

BACKGROUND: Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered ß-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aß). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. RESULTS: The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, NCT01953601.).


Assuntos
Doença de Alzheimer/prevenção & controle , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Disfunção Cognitiva/tratamento farmacológico , Óxidos S-Cíclicos/uso terapêutico , Tiadiazinas/uso terapêutico , Idoso , Peptídeos beta-Amiloides/análise , Química Encefálica , Disfunção Cognitiva/patologia , Óxidos S-Cíclicos/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Hipocampo/patologia , Humanos , Análise de Intenção de Tratamento , Imagem por Ressonância Magnética , Masculino , Tamanho do Órgão , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Tiadiazinas/efeitos adversos , Falha de Tratamento
12.
Magn Reson Imaging ; 60: 93-100, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959178

RESUMO

PURPOSE: This study sought to determine the feasibility of using Simultaneous Non-contrast Angiography and intraPlaque Hemorrhage (SNAP) to detect the lipid-rich/necrotic core (LRNC), and develop a machine learning based algorithm to segment plaque components on SNAP images. METHODS: Sixty-eight patients (age: 58±9 years, 24 males) with carotid artery atherosclerotic plaque were imaged on a 3 T MR scanner with both traditional multi-contrast vessel wall MR sequences (TOF, T1W, and T2W) and 3D SNAP sequence. The manual segmentations of carotid plaque components including LRNC, intraplaque hemorrhage (IPH), calcification (CA) and fibrous tissue (FT) on traditional multi-contrast images were used as reference. By utilizing the intensity and morphological information from SNAP, a machine learning based two steps algorithm was developed to firstly identify LRNC (with or without IPH), CA and FT, and then segmented IPH from LRNC. Ten-fold cross-validation was used to evaluate the performance of proposed method. The overall pixel-wise accuracy, the slice-wise sensitivity & specificity & Youden's index, and the Pearson's correlation coefficient of the component area between the proposed method and the manual segmentation were reported. RESULTS: In the first step, all tested classifiers (Naive Bayes (NB), Support Vector Machine (SVM), Random Forest (RF), Gradient Boosting Decision Tree (GBDT) and Artificial Neural Network (ANN)) had overall pixel-wise accuracy higher than 0.88. For RF, GBDT and ANN classifiers, the correlation coefficients of areas were all higher than 0.82 (p < 0.001) for LRNC and 0.79 for CA (p < 0.001), and the Youden's indexes were all higher than 0.79 for LRNC and 0.76 for CA, which were better than that of NB and SVM. In the second step, the overall pixel-wise accuracy was higher than 0.78 for the five classifiers, and RF achieved the highest Youden's index (0.69) with the correlation coefficients as 0.63 (p < 0.001). CONCLUSIONS: The RF is the overall best classifier for our proposed method, and the feasibility of using SNAP to identify plaque components, including LRNC, IPH, CA, and FT has been validated. The proposed segmentation method using a single SNAP sequence might be a promising tool for atherosclerotic plaque components assessment.


Assuntos
Angiografia/métodos , Artérias Carótidas/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Aprendizado de Máquina , Placa Aterosclerótica/diagnóstico por imagem , Idoso , Algoritmos , Teorema de Bayes , Calcinose/diagnóstico por imagem , Artéria Carótida Primitiva/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Meios de Contraste , Feminino , Humanos , Lipídeos , Masculino , Pessoa de Meia-Idade , Necrose , Placa Amiloide/diagnóstico por imagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
N Engl J Med ; 380(18): 1716-1725, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30969506

RESUMO

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied. METHODS: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group. RESULTS: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease. CONCLUSIONS: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).


Assuntos
Encéfalo/patologia , Encefalopatia Traumática Crônica/patologia , Futebol Americano/lesões , Tomografia por Emissão de Pósitrons , Tauopatias/patologia , Proteínas tau/análise , Adulto , Idoso , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Química Encefálica , Concussão Encefálica/complicações , Estudos de Casos e Controles , Encefalopatia Traumática Crônica/diagnóstico por imagem , Encefalopatia Traumática Crônica/etiologia , Transtornos Cognitivos/etiologia , Etilenoglicóis , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Placa Amiloide/diagnóstico por imagem , Compostos Radiofarmacêuticos , Tauopatias/diagnóstico por imagem
14.
Nat Commun ; 10(1): 1144, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850633

RESUMO

Despite intense interests in developing blood measurements of Alzheimer's disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid ß (Aß) proteins - exosome-bound vs. unbound - directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aß aggregates preferentially bind with exosomes. We thus define a population of Aß as exosome-bound (Aß42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aß, the exosome-bound Aß measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Encéfalo/patologia , Exossomos/química , Neurônios/patologia , Fragmentos de Peptídeos/química , Placa Amiloide/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/sangue , Técnicas Biossensoriais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas Analíticas Microfluídicas , Neurônios/metabolismo , Neurônios/ultraestrutura , Fragmentos de Peptídeos/sangue , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Agregados Proteicos , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Ressonância de Plasmônio de Superfície , Células THP-1 , Tetraspanina 30/química , Tetraspanina 30/metabolismo
15.
Neuroimage Clin ; 22: 101762, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30884364

RESUMO

Although experimental studies have shown that global cerebral hypoperfusion leads to amyloid deposition in the hemisphere with carotid artery occlusion in rodents, the results of such occurrence are controversial in humans. Hence, we aim to determine whether global cerebral hypoperfusion leading to decreased blood flow relative to metabolic demand [increased oxygen extraction fraction (OEF), misery perfusion] is associated with increases in amyloid deposition in the hemisphere with atherosclerotic major cerebral artery disease in patients. We evaluated the distribution of ß-amyloid plaques using positron emission tomography and a [18F]-pyridylbenzofuran derivative (18F-FPYBF-2) in 13 patients with unilateral atherosclerotic disease of the internal carotid artery (ICA) or middle cerebral artery (MCA) disease and no cortical infarction. The distribution volume ratio (DVR) of 18F- FPYBF-2 was calculated using dynamic data and Logan graphical analysis with reference tissue and was correlated with the cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and OEF, obtained from 15O-gas PET. The mean cortical value was calculated as the mean value within the frontal, posterior cingulate, precuneus, parietal, and lateral temporal cortical regions. Significant reductions in CBF and CMRO2 and increases in OEF were found in the hemisphere ipsilateral to the arterial lesion compared with the contralateral hemisphere. There was no significant difference for 18F-FPYBF-2 DVR between hemispheres. The ipsilateral to contralateral ratio of the 18F- FPYBF-2 DVR was increased in 3 patients, while the ipsilateral to contralateral OEF ratio was increased in 4 patients. The incidence of an increased hemispheric DVR ratio was significantly higher in patients with an increased hemispheric OEF ratio (3/4) than in patients without (0/9) (p < 0.02). Although the 18F- FPYBF-2 DVR in the ipsilateral hemisphere was positively correlated with OEF after adjustment for the 18F- FPYBF-2 DVR in the contralateral hemisphere using multiple regression analysis (p < 0.05), the contribution rate of OEF was small (R2 = 5.5%). Only one of the 4 patients with an increased hemispheric OEF ratio showed amyloid positivity based on the DVR value. In atherosclerotic major cerebral artery disease, misery perfusion accompanied only small increases of amyloid deposition at best. Misery perfusion was not associated with amyloid positivity.


Assuntos
Doenças Arteriais Cerebrais , Circulação Cerebrovascular/fisiologia , Arteriosclerose Intracraniana , Placa Amiloide , Idoso , Peptídeos beta-Amiloides/metabolismo , Artéria Carótida Interna/diagnóstico por imagem , Doenças Arteriais Cerebrais/diagnóstico por imagem , Doenças Arteriais Cerebrais/metabolismo , Doenças Arteriais Cerebrais/fisiopatologia , Feminino , Radioisótopos de Flúor , Humanos , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/metabolismo , Arteriosclerose Intracraniana/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons
16.
Clin Nucl Med ; 44(5): 408-409, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30829855

RESUMO

Differentiating Alzheimer disease (AD) from other forms of cognitive impairment and from normal aging can be challenging. As a consequence, the diagnosis of AD can be delayed, often occurring too late for meaningful intervention. The role of ß-amyloid plaques in the pathogenesis of AD provides a target for highly sensitive and specific image quantification of amyloid plaque burden using ß-amyloid PET (F-florbetaben). Here we present the case of a 77-year-old woman with increasing memory impairment and striking white matter changes on MRI, with the "racoon eye" sign on F-florebetaben PET imaging.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Idoso , Compostos de Anilina , Diagnóstico Diferencial , Feminino , Humanos , Compostos Radiofarmacêuticos , Estilbenos
17.
Int. j. cardiovasc. sci. (Impr.) ; 32(2): 177-189, mar.-abr. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-988239

RESUMO

Amyloidosis is a disease caused by extracellular deposition of insoluble protein fibrils, that results in changes in tissue architecture and consequently modification of the organ structure. Cardiac involvement is common in amyloidosis. Two major types of systemic amyloidosis affect the myocardium ­ immunoglobulin light chain and transthyretin amyloidosis ­ each leading to different prognosis. Early detection and diagnosis of cardiac amyloidosis are the main objectives in the assessment of the disease. New techniques of magnetic resonance imaging have minimized the need for biopsies for the diagnosis. Late gadolinium enhancement technique, and more recently T1 mapping, have allowed a simplified evaluation of amyloid deposits and extracellular volume. The aim of this review was to describe basic concepts and updates of the use of magnetic resonance imaging for the diagnosis amyloidosis and evaluation of its severity


Assuntos
Humanos , Masculino , Feminino , Imagem por Ressonância Magnética/métodos , Amiloidose/diagnóstico , Amiloidose/terapia , Prognóstico , Diagnóstico por Imagem/métodos , Ecocardiografia/métodos , Biomarcadores , Cadeias Leves de Imunoglobulina , Meios de Contraste , Placa Amiloide/diagnóstico por imagem , Eletrocardiografia/métodos , Gadolínio , Ventrículos do Coração , Miocardite/patologia
18.
Int. j. cardiovasc. sci. (Impr.) ; 32(2): 177-189, mar.-abr. 2019. ilus
Artigo em Inglês | LILACS | ID: biblio-989990

RESUMO

Amyloidosis is a disease caused by extracellular deposition of insoluble protein fibrils, that results in changes in tissue architecture and consequently modification of the organ structure. Cardiac involvement is common in amyloidosis. Two major types of systemic amyloidosis affect the myocardium - immunoglobulin light chain and transthyretin amyloidosis - each leading to different prognosis. Early detection and diagnosis of cardiac amyloidosis are the main objectives in the assessment of the disease. New techniques of magnetic resonance imaging have minimized the need for biopsies for the diagnosis. Late gadolinium enhancement technique, and more recently T1 mapping, have allowed a simplified evaluation of amyloid deposits and extracellular volume. The aim of this review was to describe basic concepts and updates of the use of magnetic resonance imaging for the diagnosis amyloidosis and evaluation of its severity


Assuntos
Humanos , Masculino , Feminino , Imagem por Ressonância Magnética/métodos , Amiloidose/diagnóstico , Amiloidose/terapia , Prognóstico , Diagnóstico por Imagem/métodos , Ecocardiografia/métodos , Biomarcadores , Cadeias Leves de Imunoglobulina , Meios de Contraste , Placa Amiloide/diagnóstico por imagem , Eletrocardiografia/métodos , Gadolínio , Ventrículos do Coração , Miocardite/patologia
19.
Neuroimage ; 191: 176-185, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30739060

RESUMO

Beta amyloid is a protein fragment snipped from the amyloid precursor protein (APP). Aggregation of these peptides into amyloid plaques is one of the hallmarks of Alzheimer's disease. MR imaging of beta amyloid plaques has been attempted using various techniques, notably with T2* contrast. The non-invasive detectability of beta amyloid plaques in MR images has so far been largely attributed to focal iron deposition accompanying the plaques. It is believed that the T2* shortening effects of paramagnetic iron are the primary source of contrast between plaques and surrounding tissue. Amyloid plaque itself has been reported to induce no magnetic susceptibility effect. We hypothesized that aggregations of beta amyloid would increase electron density and induce notable changes in local susceptibility value, large enough to generate contrast relative to surrounding normal tissues that can be visualized by quantitative susceptibility mapping (QSM) MR imaging. To test this hypothesis, we first demonstrated in a phantom that beta amyloid is diamagnetic and can generate strong contrast on susceptibility maps. We then conducted experiments on a transgenic mouse model of Alzheimer's disease that is known to mimic the formation of human beta amyloid but without neurofibrillary tangles or neuronal death. Over a period of 18 months, we showed that QSM can be used to longitudinally monitor beta amyloid accumulation and accompanied iron deposition in vivo. Individual beta amyloid plaque can also be visualized ex vivo in high resolution susceptibility maps. Moreover, the measured negative susceptibility map and positive susceptibility map could provide histology-like image contrast for identifying deposition of beta amyloid plaques and iron. Finally, we demonstrated that the diamagnetic susceptibility of beta amyloid can also be observed in brain specimens of AD patients. The ability to assess beta amyloid aggregation non-invasively with QSM MR imaging may aid the diagnosis of Alzheimer's disease.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Mapeamento Encefálico/métodos , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Placa Amiloide/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Animais , Humanos , Processamento de Imagem Assistida por Computador/métodos , Ferro/análise , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia
20.
Curr Radiopharm ; 12(1): 58-71, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30605068

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia. Neuroimaging methods have widened the horizons for AD diagnosis and therapy. The goals of this work are the synthesis of 2-(3-fluoropropyl)-6-methoxynaphthalene (5) and its [18F]-radiolabeled counterpart ([18F]Amylovis), the in silico and in vitro comparative evaluations of [18F]Amylovis and [11C]Pittsburg compound B (PIB) and the in vivo preclinical evaluation of [18F]Amylovis in transgenic and wild mice. METHODS: Iron-catalysis cross coupling reaction, followed by fluorination and radiofluorination steps were carried out to obtain 5 and 18F-Amylovis. Protein/Aß plaques binding, biodistribution, PET/CT Imaging and immunohistochemical studies were conducted in healthy/transgenic mice. RESULTS: The synthesis of 5 was successful obtained. Comparative in silico studies predicting that 5 should have affinity to the Aß-peptide, mainly through π-π interactions. According to a dynamic simulation study the ligand-Aß peptide complexes are stable in simulation-time (ΔG = -5.31 kcal/mol). [18F]Amylovis was obtained with satisfactory yield, high radiochemical purity and specific activity. The [18F]Amylovis log Poct/PBS value suggests its potential ability for crossing the blood brain barrier (BBB). According to in vitro assays, [18F]Amylovis has an adequate stability in time. Higher affinity to Aß plaques were found for [18F]Amylovis (Kd 0.16 nmol/L) than PIB (Kd 8.86 nmol/L) in brain serial sections of 3xTg-AD mice. Biodistribution in healthy mice showed that [18F]Amylovis crosses the BBB with rapid uptake (7 %ID/g at 5 min) and good washout (0.11±0.03 %ID/g at 60 min). Comparative PET dynamic studies of [18F]Amylovis in healthy and transgenic APPSwe/PS1dE9 mice, revealed a significant high uptake in the mice model. CONCLUSION: The in silico, in vitro and in vivo results justify that [18F]Amylovis should be studied as a promissory PET imaging agent to detect the presence of Aß senile plaques.


Assuntos
Radioisótopos de Carbono/química , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacologia , Naftalenos/química , Neuroimagem/métodos , Placa Amiloide/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Radioquímica/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Animais , Simulação por Computador , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Distribuição Tecidual
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