Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 101
Filtrar
1.
Br J Ophthalmol ; 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243829

RESUMO

BACKGROUND/AIMS: To develop a convolutional neural network (CNN) to detect symptomatic Alzheimer's disease (AD) using a combination of multimodal retinal images and patient data. METHODS: Colour maps of ganglion cell-inner plexiform layer (GC-IPL) thickness, superficial capillary plexus (SCP) optical coherence tomography angiography (OCTA) images, and ultra-widefield (UWF) colour and fundus autofluorescence (FAF) scanning laser ophthalmoscopy images were captured in individuals with AD or healthy cognition. A CNN to predict AD diagnosis was developed using multimodal retinal images, OCT and OCTA quantitative data, and patient data. RESULTS: 284 eyes of 159 subjects (222 eyes from 123 cognitively healthy subjects and 62 eyes from 36 subjects with AD) were used to develop the model. Area under the receiving operating characteristic curve (AUC) values for predicted probability of AD for the independent test set varied by input used: UWF colour AUC 0.450 (95% CI 0.282, 0.592), OCTA SCP 0.582 (95% CI 0.440, 0.724), UWF FAF 0.618 (95% CI 0.462, 0.773), GC-IPL maps 0.809 (95% CI 0.700, 0.919). A model incorporating all images, quantitative data and patient data (AUC 0.836 (CI 0.729, 0.943)) performed similarly to models only incorporating all images (AUC 0.829 (95% CI 0.719, 0.939)). GC-IPL maps, quantitative data and patient data AUC 0.841 (95% CI 0.739, 0.943). CONCLUSION: Our CNN used multimodal retinal images to successfully predict diagnosis of symptomatic AD in an independent test set. GC-IPL maps were the most useful single inputs for prediction. Models including only images performed similarly to models also including quantitative data and patient data.

2.
J Alzheimers Dis ; 77(4): 1793-1803, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32925039

RESUMO

BACKGROUND: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. OBJECTIVE: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. METHODS: ENLIGHTEN participants were randomized using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). RESULTS: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d = 0.48, p = 0.015) and DASH improved metabolic function (d = 0.37, p = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = -2.3 [-4.3, -0.2], p = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7], p = 0.004), associated with increases in Executive Function. CONCLUSION: Changes in neurocognition after lifestyle modification are associated with improved metabolic function.

3.
Med Care ; 58(9): 842-849, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32826749

RESUMO

BACKGROUND: The CAregiver Perceptions About CommunIcaTion with Clinical Team members (CAPACITY) instrument measures how care partners perceive themselves to be supported by the patient's health care team and their experiences communicating with the team. OBJECTIVES: The objective of this study was to assess the measurement properties (ie, structural validity of the construct and internal consistency) of the CAPACITY instrument in care partners of patients with cognitive impairment, and to examine whether care partner health literacy and patient cognitive impairment are associated with a higher or lower CAPACITY score. RESEARCH DESIGN: This was a retrospective cohort study. SUBJECTS: A total of 1746 dyads of community-dwelling care partners and older adults in the United States with cognitive impairment who obtained an amyloid positron emission tomography scan. MEASURES: The CAPACITY instrument comprises 12 items that can be combined as a total score or examined as subdomain scores about communication with the team and care partner capacity-assessment by the team. The 2 covariates of primary interest in the regression model are health literacy and level of cognitive impairment of the patient (Modified Telephone Interview Cognitive Status). RESULTS: Confirmatory factor analysis showed the CAPACITY items fit the expected 2-factor structure (communication and capacity). Higher cognitive functioning of patients and higher health literacy among care partners was associated with lower communication domain scores, lower capacity domain scores, and lower overall CAPACITY scores. CONCLUSIONS: The strong psychometric validity of the CAPACITY measure indicates it could have utility in other family caregivers or care partner studies assessing the quality of interactions with clinical teams. Knowing that CAPACITY differs by care partner health literacy and patient impairment level may help health care teams employ tailored strategies to achieve high-quality care partner interactions.


Assuntos
Cuidadores/psicologia , Disfunção Cognitiva/epidemiologia , Comunicação , Pesquisas sobre Serviços de Saúde/normas , Letramento em Saúde/estatística & dados numéricos , Equipe de Assistência ao Paciente/organização & administração , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise Fatorial , Feminino , Nível de Saúde , Humanos , Masculino , Psicometria , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos
4.
Alzheimers Dement ; 16(8): 1107-1114, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32543781

RESUMO

INTRODUCTION: The Alzheimer's Disease Prevention Registry (ADPR) of the Joseph and Kathleen Bryan Alzheimer's Disease Research Center at Duke University has been successful in achieving a racially diverse and "research ready" cohort of cognitively healthy volunteers. METHODS: The ADPR is based on an infrastructure that includes: (1) an administrative leadership team; (2) a coordinating center; (3) an IT management team; (4) a community engagement team; and (5) collaborations with study partners across disciplines. RESULTS: The ADPR currently has more than 4677 members, 26% of whom are African American. The ADPR has supported 21 studies including 8 biomarker studies, 7 clinical trials, 4 cognitive neuroscience studies, and 2 studies assessing novel computerized measures. DISCUSSION: We describe our experiences establishing and maintaining a diverse ADPR as well as insights on recruitment strategies to increase the representation of African Americans in Alzheimer's disease studies.

5.
J Alzheimers Dis ; 74(2): 625-636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32065790

RESUMO

BACKGROUND: Amyloid-ß PET scans will likely become an integral part of the diagnostic evaluation for Alzheimer's disease if Medicare approves reimbursement for the scans. However, little is known about patients' and their care partners' interpretation of scan results. OBJECTIVE: This study seeks to understand how accurately patients with mild cognitive impairment (MCI) or dementia and their care partners report results of amyloid-ß PET scans and factors related to correct reporting. METHODS: A mixed-methods approach was used to analyze survey data from 1,845 patient-care partner dyads and responses to open-ended questions about interpretation of scan results from a sub-sample of 200 dyads. RESULTS: Eighty-three percent of patients and 85% of care partners correctly reported amyloid-ß PET scan results. Patients' higher cognitive function was associated with a small but significant decrease in the predicted probability of not only patients accurately reporting scan results (ME: -0.004, 95% CI: -0.007, -0.000), but also care partners accurately reporting scan results (ME: -0.006, 95% CI: -0.007, -0.001), as well as decreased concordance between patient and care partner reports (ME: -0.004, 95% CI: -0.007, -0.001). Content analysis of open-ended responses found that participants who reported the scan results incorrectly exhibited more confusion about diagnostic terminology than those who correctly reported the scan results. CONCLUSION: Overall, patients with MCI or dementia showed high rates of accurate reporting of amyloid-ß PET scan results. However, responses to questions about the meaning of the scan results highlight the need for improved provider communication, including providing written explanations and better prognostic information.

6.
J Am Geriatr Soc ; 68(3): 559-568, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31755550

RESUMO

OBJECTIVES: To evaluate the longer term changes in executive functioning among participants with cardiovascular disease (CVD) risk factors and cognitive impairments with no dementia (CIND) randomized to a diet and exercise intervention. DESIGN: A 2 (Exercise) × 2 (Dietary Approaches to Stop Hypertension [DASH] eating plan) factorial randomized clinical trial. SETTING: Academic tertiary care medical center. PARTICIPANTS: Volunteer sample of 160 older sedentary adults with CIND and at least one additional CVD risk factor enrolled in the ENLIGHTEN trial between December 2011 and March 2016. INTERVENTIONS: Six months of aerobic exercise (AE), DASH diet counseling, combined AE + DASH, or health education (HE) controls. MEASUREMENTS: Neurocognitive battery recommended by the Neuropsychological Working Group for Vascular Cognitive Disorders including measures of executive function, memory, and language/verbal fluency. Secondary outcomes included the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Six-Minute Walk Distance (6MWD), and CVD risk including blood pressure, body weight, and CVD medication burden. RESULTS: Despite discontinuation of lifestyle changes, participants in the exercise groups retained better executive function 1 year post-intervention (P = .041) compared with non-exercise groups, with a similar, albeit weaker, pattern in the DASH groups (P = .054), without variation over time (P's > .867). Participants in the exercise groups also achieved greater sustained improvements in 6MWD compared with non-Exercise participants (P < .001). Participants in the DASH groups exhibited lower CVD risk relative to non-DASH participants (P = .032); no differences in CVD risk were observed for participants in the Exercise groups compared with non-Exercise groups (P = .711). In post hoc analyses, the AE + DASH group had better performance on executive functioning (P < .001) and CDR-SB (P = .011) compared with HE controls. CONCLUSION: For participants with CIND and CVD risk factors, exercise for 6 months promoted better executive functioning compared with non-exercisers through 1-year post-intervention, although its clinical significance is uncertain. J Am Geriatr Soc 68:559-568, 2020.

7.
Ophthalmic Surg Lasers Imaging Retina ; 50(11): 709-718, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755970

RESUMO

BACKGROUD AND OBJECTIVE: To evaluate the relationship between retinal microvascular parameters on optical coherence tomography angiography (OCTA) and neurodegenerative changes assessed by measurement of brain volume on volumetric magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and mild cognitive impairment (MCI). PATIENTS AND METHODS: Sixteen subjects with AD and MCI underwent OCTA imaging (3 mm × 3 mm and 6 mm × 6 mm scans) and volumetric brain MRI imaging with automated volumetric segmentation and quantification. Spearman's correlation (ρ) was performed between forebrain parenchyma, cortical gray matter, inferolateral ventricle (ILV), lateral ventricle (LV), and hippocampus (HP) MRI volumes and vessel density (VD), along with perfusion density (PD) for the 6-mm circle, 6-mm ring, 3-mm circle, and 3-mm ring Early Treatment Diabetic Retinopathy Study regions of the superficial capillary plexus. RESULTS: Thirty eyes of 16 patients (seven MCI and nine AD) with good-quality OCTA images were analyzed. ILV volume inversely correlated with the VD in the 6-mm circle (ρ = -0 .565, P = .028) and 3-mm ring (ρ = -0.569, P = .027) and PD in the 3-mm ring (ρ = -0.605, P = .0169). Forebrain, cortical gray matter, LV, and HP volumes did not significantly correlate with either VD or PD (P > .05). CONCLUSIONS: In this pilot investigation, the authors found a significant correlation between reduction in the superficial capillary plexus VD and PD on OCTA and expansion of the ILV in MCI and AD. This relationship between the retinal microvasculature and cerebral volumetric changes deserves further investigation. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:709-718.].


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Vasos Retinianos/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Angiofluoresceinografia/métodos , Humanos , Imagem por Ressonância Magnética , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Projetos Piloto , Fluxo Sanguíneo Regional , Tomografia de Coerência Óptica/métodos
8.
Sci Transl Med ; 11(502)2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

9.
Alzheimers Dement (N Y) ; 5: 254-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31304231

RESUMO

Introduction: Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. Methods: Using a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face-name pairs. Results: Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face-name pairs at day 7 and day 14, relative to baseline. Discussion: Our exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.

10.
J Med Chem ; 62(20): 8973-8995, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

11.
J Med Chem ; 62(20): 8953-8972, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31314518

RESUMO

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.

12.
Anal Chem ; 91(13): 8443-8452, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31247719

RESUMO

We report a novel immunocapture (IC)-LC-MS/MS methodology to directly measure real time in vivo receptor occupancy (RO) for a covalent binding drug in blood lysate. A small molecule quencher was added immediately after sample collection to convert the free receptor to a quencher-bound receptor (QB-R) which was measured with the drug-bound receptor (DB-R) simultaneously by LC-MS/MS after immunocapture enrichment, followed by trypsin digestion. Addition of the quencher is necessary to prevent the free receptor from ex vivo binding with the drug. The real time RO was calculated based on the concentrations of DB-R and the free receptor (which is now QB-R) that were obtained from each sample. This strategy has been successfully applied to the measurement of the RO for Bruton's tyrosine kinase (BTK) in the blood lysate of monkeys after dosing with branebrutinib (BMS-986195), a covalent BTK inhibitor being evaluated to treat rheumatoid arthritis. A custom-made quencher, which is more reactive to BTK than branebrutinib, was added in excess amount to bind with all available free BTK to form quencher-bound BTK (QB-BTK) during blood sample collection. To measure a wide range of % BTK RO, including those of <5% or >95%, the required LLOQ at 0.125 nM for QB-BTK and 0.250 nM for drug-bound BTK (DB-BTK) in blood lysate were successfully achieved by using this IC-LC-MS/MS strategy. This proof-of-concept assay demonstrated its suitability with high throughput for real time in vivo BTK RO measurement as a pharmacodynamic (PD) biomarker for clinical drug development.

13.
Ophthalmol Retina ; 3(6): 489-499, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174670

RESUMO

PURPOSE: Evaluate and compare the retinal microvasculature in the superficial capillary plexus (SCP) in Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively intact controls using OCT angiography. OCT parameters were also compared. DESIGN: Cross-sectional study. PARTICIPANTS: Seventy eyes from 39 AD participants, 72 eyes from 37 MCI participants, and 254 eyes from 133 control participants were enrolled. METHODS: Participants were imaged using Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Dublin, CA) and underwent cognitive evaluation with Mini-Mental State Examination. MAIN OUTCOME MEASURES: Vessel density (VD) and perfusion density (PD) in the SCP within the Early Treatment Diabetic Retinopathy Study 6-mm circle, 3-mm circle, and 3-mm ring were compared between groups. Foveal avascular zone (FAZ) area, central subfield thickness (CST), macular ganglion cell-inner plexiform layer (GC-IPL) thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness were also compared. RESULTS: Alzheimer's participants showed significantly decreased SCP VD and PD in the 3-mm ring (P = 0.001 and P = 0.002, respectively) and 3-mm circle (P = 0.003 and P = 0.004, respectively) and decreased SCP VD in the 6-mm circle (P = 0.047) compared with MCI and significantly decreased SCP VD and PD in the 3-mm ring (P = 0.008 and P = 0.004, respectively) and 3-mm circle (P = 0.015 and P = 0.009, respectively) and SCP PD in the 6-mm circle (P = 0.033) when compared with cognitively intact controls. There was no difference in SCP VD or PD between MCI and controls (P > 0.05). FAZ area and CST did not differ significantly between groups (P > 0.05). Alzheimer's participants showed significantly decreased GC-IPL thickness over the inferior (P = 0.032) and inferonasal (P = 0.025) sectors compared with MCI and significantly decreased GC-IPL thickness over the entire (P = 0.012), superonasal (P = 0.041), inferior (P = 0.004), and inferonasal (P = 0.006) sectors compared to controls. MCI participants showed significantly decreased temporal RNFL thickness (P = 0.04) compared with controls. CONCLUSIONS: Alzheimer's participants showed significantly reduced macular VD, PD, and GC-IPL thickness compared with MCI and controls. Changes in the retinal microvasculature may mirror small vessel cerebrovascular changes in AD.


Assuntos
Doença de Alzheimer/complicações , Disfunção Cognitiva/complicações , Angiofluoresceinografia/métodos , Microvasos/patologia , Degeneração Retiniana/diagnóstico , Vasos Retinianos/patologia , Tomografia de Coerência Óptica/métodos , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Circulação Cerebrovascular , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Estudos Transversais , Feminino , Fundo de Olho , Humanos , Masculino , Fibras Nervosas/patologia , Neuroimagem/métodos , Degeneração Retiniana/etiologia , Células Ganglionares da Retina/patologia , Acuidade Visual
14.
J Med Chem ; 62(7): 3228-3250, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893553

RESUMO

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.

15.
ACS Med Chem Lett ; 10(3): 383-388, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30891145

RESUMO

In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.

16.
Neurology ; 92(3): e212-e223, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30568005

RESUMO

OBJECTIVE: To determine the independent and additive effects of aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet on executive functioning in adults with cognitive impairments with no dementia (CIND) and risk factors for cardiovascular disease (CVD). METHODS: A 2-by-2 factorial (exercise/no exercise and DASH diet/no DASH diet) randomized clinical trial was conducted in 160 sedentary men and women (age >55 years) with CIND and CVD risk factors. Participants were randomly assigned to 6 months of AE, DASH diet nutritional counseling, a combination of both AE and DASH, or health education (HE). The primary endpoint was a prespecified composite measure of executive function; secondary outcomes included measures of language/verbal fluency, memory, and ratings on the modified Clinical Dementia Rating Scale. RESULTS: Participants who engaged in AE (d = 0.32, p = 0.046) but not those who consumed the DASH diet (d = 0.30, p = 0.059) demonstrated significant improvements in the executive function domain. The largest improvements were observed for participants randomized to the combined AE and DASH diet group (d = 0.40, p = 0.012) compared to those receiving HE. Greater aerobic fitness (b = 2.3, p = 0.049), reduced CVD risk (b = 2.6, p = 0.042), and reduced sodium intake (b = 0.18, p = 0.024) were associated with improvements in executive function. There were no significant improvements in the memory or language/verbal fluency domains. CONCLUSIONS: These preliminary findings show that AE promotes improved executive functioning in adults at risk for cognitive decline. CLINICALTRIALSGOV IDENTIFIER: NCT01573546. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for adults with CIND, AE but not the DASH diet significantly improves executive functioning.


Assuntos
Envelhecimento , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/psicologia , Dieta , Exercício Físico , Estilo de Vida , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Transtornos Cognitivos/genética , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fatores de Risco
17.
Bioorg Med Chem Lett ; 28(18): 3080-3084, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30097367

RESUMO

Incorporation of a suitably-placed electrophilic group transformed a series of reversible BTK inhibitors based on carbazole-1-carboxamide and tetrahydrocarbazole-1-carboxamide into potent, irreversible inhibitors. Removal of one ring from the core of these compounds provided a potent irreversible series of 2,3-dimethylindole-7-carboxamides having excellent potency and improved selectivity, with the additional advantages of reduced lipophilicity and molecular weight.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Carbazóis/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Carbazóis/síntese química , Carbazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade
18.
PLoS One ; 13(2): e0192646, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29420642

RESUMO

Inner retina in Alzheimer's Disease (AD) may experience neuroinflammation resulting in atrophy. The objective of our study was to determine whether retinal GCIPL (ganglion cell-inner plexiform layer) or nerve fiber layer (NFL) thickness may serve as noninvasive biomarkers to diagnose AD. This cross-sectional case-control study enrolled 15 mild cognitive impairment (MCI) patients, 15 mild-moderate AD patients, and 18 cognitively normal adults. NFL and GCIPL thicknesses on optical coherence tomography (OCT) were measured using Duke Optical Coherence Tomography Retinal Analysis Program (DOCTRAP) and Spectralis software. We demonstrated that regional thicknesses of NFL or GCIPL on macular or nerve OCTs did not differ between groups. However, a multi-variate regression analysis identified macular areas with a significant thickening or thinning in NFL and GCIPL in MCI and AD patients. Our primary findings controvert previous reports of thinner NFL in moderate-to-severe AD. The areas of thickening of GCIPL and NFL in the macula adjacent to areas of thinning, as revealed by a more complex statistical model, suggest that NFL and GCIPL may undergo dynamic changes during AD progression.


Assuntos
Doença de Alzheimer/metabolismo , Biomarcadores/metabolismo , Transtornos Cognitivos/metabolismo , Retina/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica
19.
PLoS One ; 12(7): e0181782, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28742141

RESUMO

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/imunologia , Ligante RANK/imunologia
20.
J Med Chem ; 59(19): 9173-9200, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27583770

RESUMO

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.


Assuntos
Carbazóis/química , Carbazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Carbazóis/farmacocinética , Cristalografia por Raios X , Feminino , Humanos , Isomerismo , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA