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1.
J Am Geriatr Soc ; 2019 Nov 22.
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.

2.
Ophthalmic Surg Lasers Imaging Retina ; 50(11): 709-718, 2019 Nov 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.].

3.
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.

4.
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.

5.
Sci Transl Med ; 11(502)2019 Jul 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.

6.
Anal Chem ; 91(13): 8443-8452, 2019 Jul 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.

7.
Ophthalmol Retina ; 3(6): 489-499, 2019 Jun.
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.

8.
J Med Chem ; 62(7): 3228-3250, 2019 Apr 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.

9.
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 , 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 (Cuidados de Saúde) , Fatores de Risco
10.
Bioorg Med Chem Lett ; 28(18): 3080-3084, 2018 Oct 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.

11.
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
12.
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
13.
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
14.
J Med Chem ; 59(17): 7915-35, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27531604

RESUMO

Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.


Assuntos
Antirreumáticos/química , Carbazóis/química , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinonas/química , Administração Oral , Tirosina Quinase da Agamaglobulinemia , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Disponibilidade Biológica , Carbazóis/síntese química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Cães , Humanos , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Permeabilidade , Proteínas Tirosina Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Relação Estrutura-Atividade
15.
Genome Biol ; 17: 76, 2016 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-27122015

RESUMO

BACKGROUND: Epigenetic drift progressively increases variation in DNA modification profiles of aging cells, but the finale of such divergence remains elusive. In this study, we explored the dynamics of DNA modification and transcription in the later stages of human life. RESULTS: We find that brain tissues of older individuals (>75 years) become more similar to each other, both epigenetically and transcriptionally, compared with younger individuals. Inter-individual epigenetic assimilation is concurrent with increasing similarity between the cerebral cortex and the cerebellum, which points to potential brain cell dedifferentiation. DNA modification analysis of twins affected with Alzheimer's disease reveals a potential for accelerated epigenetic assimilation in neurodegenerative disease. We also observe loss of boundaries and merging of neighboring DNA modification and transcriptomic domains over time. CONCLUSIONS: Age-dependent epigenetic divergence, paradoxically, changes to convergence in the later stages of life. The newly described phenomena of epigenetic assimilation and tissue dedifferentiation may help us better understand the molecular mechanisms of aging and the origins of diseases for which age is a risk factor.


Assuntos
Doença de Alzheimer/genética , Epigênese Genética , Lobo Frontal/crescimento & desenvolvimento , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Gêmeos
16.
Alzheimers Dement (N Y) ; 2(1): 30-44, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27047990

RESUMO

BACKGROUND: A straightforward, reproducible blood-based test that predicts age dependent risk of Alzheimer's disease (AD) could be used as an enrichment tool for clinical development of therapies. This study evaluated the prognostic performance of a genetics-based biomarker risk algorithm (GBRA) established on a combination of Apolipoprotein E (APOE)/Translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes and age, then compare it to cerebrospinal fluid (CSF) biomarkers, neuroimaging and neurocognitive tests using data from two independent AD cohorts. METHODS: The GBRA was developed using data from the prospective Bryan-ADRC study (n=407; 86 conversion events (mild cognitive impairment (MCI) or late onset Alzheimer's disease (LOAD)). The performance of the algorithm was tested using data from the ADNI study (n=660; 457 individuals categorized as MCI or LOAD). RESULTS: The positive predictive values (PPV) and negative predictive values (NPV) of the GBRA are in the range of 70-80%. The relatively high odds ratio (approximately 3-5) and significant net reclassification index (NRI) scores comparing the GBRA to a version based on APOE and age alone support the value of the GBRA in risk prediction for MCI due to LOAD. Performance of the GBRA compares favorably with CSF and imaging (fMRI) biomarkers. In addition, the GBRA "high" and "low" AD-risk categorizations correlated well with pathological CSF biomarker levels, PET amyloid burden and neurocognitive scores. CONCLUSIONS: Unlike dynamic markers (i.e., imaging, protein or lipid markers) that may be influenced by factors unrelated to disease, genomic DNA is easily collected, stable, and the technical methods for measurement are robust, inexpensive, and widely available. The performance characteristics of the GBRA support its use as a pharmacogenetic enrichment tool for LOAD delay of onset clinical trials, and merits further evaluation for its clinical utility in evaluating therapeutic efficacy.

17.
Neuroimage Clin ; 11: 158-166, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26937384

RESUMO

Relational memory declines are well documented as an early marker for amnestic mild cognitive impairment (aMCI). Episodic memory formation relies on relational processing supported by two mnemonic mechanisms, generation and binding. Neuroimaging studies using functional magnetic resonance imaging (fMRI) have primarily focused on binding deficits which are thought to be mediated by medial temporal lobe dysfunction. In this study, prefrontal contributions to relational encoding were also investigated using fMRI by parametrically manipulating generation demands during the encoding of word triads. Participants diagnosed with aMCI and healthy control subjects encoded word triads consisting of a category word with either, zero, one, or two semantically related exemplars. As the need to generate increased (i.e., two- to one- to zero-link triads), both groups recruited a core set of regions associated with the encoding of word triads including the parahippocampal gyrus, superior temporal gyrus, and superior parietal lobule. Participants diagnosed with aMCI also parametrically recruited several frontal regions including the inferior frontal gyrus and middle frontal gyrus as the need to generate increased, whereas the control participants did not show this modulation. While there is some functional overlap in regions recruited by generation demands between the groups, the recruitment of frontal regions in the aMCI participants coincides with worse memory performance, likely representing a form of neural inefficiency associated with Alzheimer's disease.


Assuntos
Amnésia/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Amnésia/complicações , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Memória Episódica , Rede Nervosa/fisiopatologia , Testes Neuropsicológicos , Córtex Pré-Frontal/fisiopatologia
19.
J Am Geriatr Soc ; 63(6): 1105-11, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26032518

RESUMO

OBJECTIVES: To describe the stability of cognitive impairment, not dementia (CIND) in a longitudinal cohort of primary care veterans. To examine the association between baseline brief cognitive screening tests, demographic and clinical characteristics, and cognitive decline. DESIGN: Follow-up cognitive assessment after an average of 2.5 years of a cohort of veterans in primary care whose baseline status was CIND or normal cognition. SETTING: Three Department of Veterans Affairs primary care clinics. PARTICIPANTS: Subjects with CIND at baseline and a sampling of subjects with baseline normal cognition. MEASUREMENTS: Veterans underwent a standard assessment, including neuropsychological tests and informant interview. RESULTS: Of 293 potentially eligible individuals, 186 enrolled in the follow-up study. Of the 131 subjects with a baseline diagnosis of CIND, 16 (12%) progressed to dementia, 88 (67%) continued to have a diagnosis of CIND, and 27 (21%) improved to normal cognition. Of the 55 subjects with a baseline diagnosis of normal cognition, one (2%) progressed to dementia, 17 (31%) progressed to CIND, and 37 (67%) remained cognitively normal. In bivariate analyses, poorer performance on baseline cognitive screening tests was associated with cognitive decline, whereas Framingham Stroke Risk Profile (FSRP) and education were not. Similarly, higher scores on cognitive screening tests were associated with return to normal cognition. In multivariable logistic regression models, lower baseline Mini-Cog and Modified Mini-Mental State scores were associated with cognitive decline, whereas Memory Impairment Screen scores, FSRP, and years of education were not. CONCLUSION: A minority of subjects had worsening of cognitive function sufficient to change diagnostic category. Over an average of 2.5 years, subjects diagnosed with CIND at baseline reverted to normal cognition at a higher rate than progressed to dementia. Cognitive screening tests addressing multiple domains of cognitive impairment were predictive of cognitive decline.


Assuntos
Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/epidemiologia , Avaliação da Deficiência , Saúde Mental/estatística & dados numéricos , Veteranos/estatística & dados numéricos , Adulto , Demência/diagnóstico , Demência/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Estados Unidos/epidemiologia , United States Department of Veterans Affairs
20.
J Biol Chem ; 290(17): 11061-74, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25762719

RESUMO

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity.


Assuntos
Modelos Moleculares , Transdução de Sinais , Linfócitos T/enzimologia , TYK2 Quinase/química , Cristalografia por Raios X , Estabilidade Enzimática , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Estrutura Terciária de Proteína , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Receptores de Trombopoetina/genética , Receptores de Trombopoetina/metabolismo , TYK2 Quinase/genética
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