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BACKGROUND: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis. METHODS: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline. RESULTS: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group). CONCLUSIONS: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Profilaxis Posexposición , Ritonavir , SARS-CoV-2 , Humanos , Ritonavir/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/administración & dosificación , Método Doble Ciego , Masculino , Femenino , Adulto , Persona de Mediana Edad , COVID-19/prevención & control , Administración Oral , Indazoles/efectos adversos , Indazoles/uso terapéutico , Combinación de Medicamentos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , Indoles/efectos adversos , Indoles/uso terapéutico , Indoles/administración & dosificación , Adulto Joven , Quimioterapia Combinada , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. METHODS: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. RESULTS: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. DISCUSSION: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.
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Biomarcadores , Ensayos Clínicos como Asunto , Degeneración Lobar Frontotemporal/genética , Imagen por Resonancia Magnética , Atrofia , Congresos como Asunto , HumanosRESUMEN
Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD.
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Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Cuerpo Estriado/metabolismo , Enfermedad de Huntington/tratamiento farmacológico , Fármacos Neuroprotectores/administración & dosificación , Piperidinas/administración & dosificación , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Genoma , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/patología , Ratones , Fármacos Neuroprotectores/metabolismo , Ratas , Receptores de Dopamina D5/biosíntesis , Receptores de Dopamina D5/genética , Receptores de Glucocorticoides/biosíntesis , Receptores de Glucocorticoides/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aß42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , HumanosRESUMEN
The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aß39, Aß40, and Aß42 while increasing Aß37 and Aß38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aß40 and Aß42 were observed with no change in total Aß; in CSF, modest decreases in total Aß were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70% CSF Aß42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Aß lowering in Alzheimer's disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer's disease and other indications.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides , Compuestos de Anilina/farmacología , Compuestos de Anilina/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Adolescente , Adulto , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/química , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/química , Área Bajo la Curva , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Límite de Detección , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Pirimidinas/efectos adversos , Pirimidinas/química , Adulto JovenRESUMEN
The amyloid-ß peptide (Aß)-in particular, the 42-amino acid form, Aß1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aß synthesis or increase the clearance of Aß have entered clinical trials, including γ-secretase inhibitors, anti-Aß antibodies, and amyloid-ß precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aß1-42 production, and may also decrease Aß1-40 while simultaneously increasing one or more shorter Aß peptides, such as Aß1-38 and Aß1-37. GSMs are particularly attractive because they do not alter the total amount of Aß peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, ß-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aß1-42 and Aß1-40 levels while increasing Aß1-38 and Aß1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Compuestos de Anilina/farmacología , Compuestos de Anilina/farmacocinética , Encéfalo/efectos de los fármacos , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Compuestos de Anilina/química , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Hidrocarburos Aromáticos con Puentes/química , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Macaca fascicularis , Pirimidinas/química , Ratas Sprague-Dawley , Receptores Notch/metabolismo , Especificidad de la Especie , Distribución TisularRESUMEN
BACKGROUND: Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aß pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aß pathology. METHODS: 26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aß, total τ, and ptau181. Additional, novel ELISAs targeting different N-terminal and central τ epitopes were developed to examine CSF τ components and to investigate interactions between diagnostic group, demographics and genetic variables. RESULTS: PSP had lower CSF N-terminal and C-terminal τ concentrations than NC and AD measured with the novel τ ELISAs and the standard AlzBio3 τ and ptau assays. AD had higher total τ and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most τ species, with lower concentrations for male compared to female patients. CONCLUSIONS: CSF τ fragment concentrations are different in PSP compared with AD despite the presence of severe τ pathology and neuronal injury in both disorders. CSF τ concentration likely reflects multiple factors in addition to the degree of neuronal injury.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Parálisis Supranuclear Progresiva/líquido cefalorraquídeo , Parálisis Supranuclear Progresiva/diagnóstico , Tauopatías/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Enfermedad de Alzheimer/clasificación , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquídeo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/genética , Fosforilación , Pronóstico , Valores de Referencia , Parálisis Supranuclear Progresiva/clasificación , Parálisis Supranuclear Progresiva/genéticaRESUMEN
Apolipoprotein E (APOE) genotype is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD), but the utility of plasma ApoE levels for assessing the severity of underlying neurodegenerative changes remains uncertain. Here, we examined cross-sectional associations between plasma ApoE levels and volumetric magnetic resonance imaging indices of the hippocampus from 541 participants [57 with normal cognition (NC), 375 with mild cognitive impairment (MCI), and 109 with mild AD] who were enrolled in the Alzheimer's Disease Neuroimaging Initiative. Across the NC and MCI groups, lower plasma ApoE levels were significantly correlated with smaller hippocampal size, as measured by either hippocampal volume or hippocampal radial distance. These associations were driven primarily by findings from carriers of an APOE ε4 allele and are consistent with prior reports that lower plasma ApoE levels correlate with greater global cortical Pittsburgh Compound B retention. In this high-risk group, plasma ApoE levels may represent a peripheral marker of underlying AD neuropathology in nondemented elderly individuals.
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Enfermedad de Alzheimer/sangre , Apolipoproteína E4/sangre , Disfunción Cognitiva/genética , Hipocampo/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Apolipoproteína E4/genética , Biomarcadores/sangre , Estudios Transversales , Femenino , Genotipo , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Pruebas Neuropsicológicas , Tamaño de los ÓrganosRESUMEN
The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partner Scientific Board (PPSB) is comprised of representatives of private, for-profit entities (including pharmaceutical, biotechnology, diagnostics, imaging companies, and imaging contract research organizations), and nonprofit organizations that provide financial and scientific support to ADNI through the Foundation for the National Institutes of Health. The PPSB serves as an independent, open, and precompetitive forum in which all private sector and not-for-profit partners in ADNI can collaborate, share information, and offer scientific and private-sector perspectives and expertise on issues relating to the ADNI project. In this article, we review and highlight the role, activities, and contributions of the PPSB within the ADNI project, and provide a perspective on remaining unmet needs and future directions.
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Enfermedad de Alzheimer/diagnóstico , Consultores , Neuroimagen/métodos , Asociación entre el Sector Público-Privado , Enfermedad de Alzheimer/complicaciones , Biotecnología , Trastornos del Conocimiento/etiología , Industria Farmacéutica , Humanos , Estados UnidosRESUMEN
INTRODUCTION: We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aß1-42), t-tau, and p-tau181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. METHODS: Review publications authored or coauthored by ADNI Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aß1-42, t-tau, and p-tau181 data. RESULTS: CSF AD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. DISCUSSION: Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Bases de Datos Bibliográficas/estadística & datos numéricos , HumanosRESUMEN
INTRODUCTION: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. RESULTS: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. DISCUSSION: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Biomarcadores/metabolismo , Disfunción Cognitiva/genética , Apolipoproteínas E/genética , Bases de Datos Bibliográficas/estadística & datos numéricos , Progresión de la Enfermedad , Estudios de Asociación Genética , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , NeuroimagenRESUMEN
The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories.
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Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Guías como Asunto/normas , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , HumanosRESUMEN
Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
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Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/sangre , Progresión de la Enfermedad , HumanosRESUMEN
BACKGROUND: Apolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aß) and fibrillar brain Aß measured by Pittsburgh compound B positron emission tomography ([(11)C]PiB PET) has not been assessed. METHODS: Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [(11)C]PiB scans and plasma Aß1-40 and Aß1-42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [(11)C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aß1-40, Aß1-42, and Aß1-40/Aß1-42 with [(11)C]PiB uptake. RESULTS: In APOE ε4- but not ε4+ participants, positive relationships between plasma Aß1-40/Aß1-42 and [(11)C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aß1-40/Aß1-42 improved the explained variance in [(11)C]PiB binding compared with using APOE and plasma Aß1-40/Aß1-42 as separate terms. CONCLUSIONS: The results suggest that plasma Aß is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aß levels.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/metabolismo , Disfunción Cognitiva , Fragmentos de Péptidos/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Compuestos de Anilina , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Radiofármacos , TiazolesRESUMEN
Alzheimer's disease is the public health crisis of the 21st century. There is a clear need for a widely available, inexpensive and reliable method to diagnosis Alzheimer's disease in the earliest stages, track disease progression, and accelerate clinical development of new therapeutics. One avenue of research being explored is blood based biomarkers. In April 2012, the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened top scientists from around the world to discuss the state of blood based biomarker development. This manuscript summarizes the meeting and the resultant discussion, including potential next steps to move this area of research forward.
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Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Progresión de la Enfermedad , Diagnóstico Precoz , Ensayo de Inmunoadsorción Enzimática , HumanosRESUMEN
BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/terapia , Ensayos Clínicos como Asunto , Hipocampo/patología , Disfunción Cognitiva , Bases de Datos Factuales/estadística & datos numéricos , Progresión de la Enfermedad , Europa (Continente) , Humanos , Neuroimagen , Modelos de Riesgos Proporcionales , Curva ROCRESUMEN
BACKGROUND: Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays. MATERIAL AND METHODS: To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec. RESULTS: Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid-based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L. CONCLUSION: These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092).
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Background: Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs. Methods: We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)-treated and untreated individuals during the Omicron era (December 2021-November 2022) and prior to the Omicron era (October 2020-November 2021). Results: Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%-5.7%) in NMV-r-treated infections as compared with 1.5% (95% CI, 1.3%-1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%-2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (≥65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%-4.8%). Viral rebounds to high RNA levels in NMV-r-treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r-treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%-1.2%). Conclusions: Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.
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To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus Mpro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six Mpro mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and Mpro activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Farmacorresistencia Viral , Mutación , SARS-CoV-2 , SARS-CoV-2/genética , SARS-CoV-2/efectos de los fármacos , Farmacorresistencia Viral/genética , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/virología , COVID-19/genética , COVID-19/epidemiología , Proteasas 3C de Coronavirus/genética , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
Recognizing that international collaboration is critical for the acceleration of biomarker standardization efforts and the efficient development of improved diagnosis and therapy, the Alzheimer's Association created the Global Biomarkers Standardization Consortium (GBSC) in 2010. The consortium brings together representatives of academic centers, industry, and the regulatory community with the common goal of developing internationally accepted common reference standards and reference methods for the assessment of cerebrospinal fluid (CSF) amyloid ß42 (Aß42) and tau biomarkers. Such standards are essential to ensure that analytical measurements are reproducible and consistent across multiple laboratories and across multiple kit manufacturers. Analytical harmonization for CSF Aß42 and tau will help reduce confusion in the AD community regarding the absolute values associated with the clinical interpretation of CSF biomarker results and enable worldwide comparison of CSF biomarker results across AD clinical studies.