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The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non-profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. HIGHLIGHTS: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities. PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations.
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Enfermedad de Alzheimer , Investigación Biomédica , Factores de Coagulación Sanguínea , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Neuroimagen/métodos , BiomarcadoresRESUMEN
INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.
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INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022. METHODS: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (â¼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials. RESULTS AND DISCUSSION: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Participación de la Comunidad , Participación de los Interesados , Neuroimagen/métodos , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Péptidos beta-AmiloidesRESUMEN
PURPOSE: A Cognitive Task Force (CTF) was established for the MissionAD program with the aim of reducing the screen failure (SF) rate to â¼30% and thereby reduce unnecessary subject burden, site burden, and excess trial costs. METHODS/SUBJECTS: The MissionAD program consisted of 2 global phase 3 studies evaluating the BACE inhibitor elenbecestat in subjects with early Alzheimer disease. The CTF monitored and engaged with MissionAD clinical sites to provide support through collegial discussions to maximize the efficiency of the preconsent recruitment phase. RESULTS: The CTF significantly improved cognitive screening efficiency in the MissionAD program, with a 24% decline in cognitive SF rate for the sites that the CTF contacted. The study-wide 11.5% reduction in cognitive SF rates were likely further driven by wider country-level initiatives in which CTF members held CTF-specific Investigator meetings with the recruitment staff, speaking to all sites on a country level regardless of their recruitment performance. CONCLUSIONS: The establishment of a CTF to support efficient cognitive screening is highly recommended for future Alzheimer disease studies. Additional benefits included improved site relationships, increased engagement in MissionAD and access to a group of cognitive experts for consulting, with a focus on achieving more efficient trial recruitment.
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Enfermedad de Alzheimer , Cognición , Tamizaje Masivo , Enfermedad de Alzheimer/diagnóstico , Ensayos Clínicos Fase III como Asunto , HumanosRESUMEN
The Horizon 2020/IMI European Prevention of Alzheimer's Dementia (EPAD) project will undertake large-scale proof-of-concept trials in predementia Alzheimer's disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross-cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimer's disease.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Cognición , Pruebas Neuropsicológicas , Ensayos Clínicos como Asunto , Humanos , Síntomas ProdrómicosRESUMEN
Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimer's disease (AD). Cognitive dysfunction has been viewed, however, as a late-stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence-based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large-scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Cognición , Humanos , Pruebas Neuropsicológicas , Síntomas ProdrómicosRESUMEN
BACKGROUND: There is a need for feasible, scalable assessments to detect cognitive impairment and decline. The Cogstate Brief Battery (CBB) is validated for Alzheimer's disease (AD) and in unsupervised and bring your own device contexts. The CBB has shown usability for self-completion in the home but has not been employed in this way in a multisite clinical trial in AD. OBJECTIVE: The objective of the pilot was to evaluate feasibility of at-home, self-completion of the CBB in the Alzheimer's Disease Neuroimaging Initiative (ADNI) over 24 months. METHODS: The CBB was included as a pilot for cognitively normal (CN) and mild cognitive impairment (MCI) participants in ADNI-2, invited to take the assessment in-clinic, then at at-home over a period of 24 months follow-up. Data were analyzed to explore acceptability/usability, concordance of in-clinic and at-home assessment, and validity. RESULTS: Data were collected for 104 participants (46 CN, 51 MCI, and 7 AD) who consented to provide CBB data. Subsequent analyses were performed for the CN and MCI groups only. Test completion rates were 100%for both the first in-clinic supervised and first at-home unsupervised assessments, with few repeat performances required. However, available follow-up data declined sharply over time. Good concordance was seen between in-clinic and at-home assessments, with non-significant and small effect size differences (Cohen's d between -0.04 and 0.28) and generally moderate correlations (râ=â0.42 to 0.73). Known groups validity was also supported (11/16 comparisons with Cohen's d≥0.3). CONCLUSION: These data demonstrate the feasibility of use for the CBB for unsupervised at-home, testing, including MCI groups. Optimal approaches to the application of assessments to support compliance over time remain to be determined.
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Disfunción Cognitiva/diagnóstico , Pruebas Neuropsicológicas/estadística & datos numéricos , Telemedicina , Anciano , Femenino , Humanos , Masculino , Neuroimagen , Proyectos PilotoRESUMEN
Clinic-based estimates of SARS-CoV-2 may considerably underestimate the total number of infections. Access to testing in the US has been heterogeneous and symptoms vary widely in infected persons. Public health surveillance efforts and metrics are therefore hampered by underreporting. We set out to provide a minimally biased estimate of SARS-CoV-2 seroprevalence among adults for a large and diverse county (Orange County, CA, population 3.2 million). We implemented a surveillance study that minimizes response bias by recruiting adults to answer a survey without knowledge of later being offered SARS-CoV-2 test. Several methodologies were used to retrieve a population-representative sample. Participants (n = 2979) visited one of 11 drive-thru test sites from July 10th to August 16th, 2020 (or received an in-home visit) to provide a finger pin-prick sample. We applied a robust SARS-CoV-2 Antigen Microarray technology, which has superior measurement validity relative to FDA-approved tests. Participants include a broad age, gender, racial/ethnic, and income representation. Adjusted seroprevalence of SARS-CoV-2 infection was 11.5% (95% CI: 10.5-12.4%). Formal bias analyses produced similar results. Prevalence was elevated among Hispanics (vs. other non-Hispanic: prevalence ratio [PR] = 1.47, 95% CI 1.22-1.78) and household income < $50,000 (vs. > $100,000: PR = 1.42, 95% CI: 1.14 to 1.79). Results from a diverse population using a highly specific and sensitive microarray indicate a SARS-CoV-2 seroprevalence of ~ 12 percent. This population-based seroprevalence is seven-fold greater than that using official County statistics. In this region, SARS-CoV-2 also disproportionately affects Hispanic and low-income adults.
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Anticuerpos Antivirales/análisis , COVID-19 , Etnicidad/estadística & datos numéricos , Adolescente , Adulto , Sesgo , COVID-19/diagnóstico , COVID-19/epidemiología , California/epidemiología , Femenino , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Masculino , Persona de Mediana Edad , Prevalencia , Vigilancia en Salud Pública , Estudios Seroepidemiológicos , Adulto JovenRESUMEN
We analyzed data from two ongoing COVID-19 longitudinal serological surveys in Orange County, CA., between April 2020 and March 2021. A total of 8476 finger stick blood specimens were collected before and after a vaccination campaign. IgG levels were determined using a multiplex antigen microarray containing antigens from SARS-CoV-2, SARS, MERS, Common CoV, and Influenza. Twenty-six percent of specimens from unvaccinated Orange County residents in December 2020 were SARS-CoV-2 seropositive; out of 852 seropositive individuals 77 had symptoms and 9 sought medical care. The antibody response was predominantly against nucleocapsid (NP), full length, and S2 domain of spike. Anti-receptor binding domain (RBD) reactivity was low and not cross-reactive against SARS S1 or SARS RBD. A vaccination campaign at the University of California Irvine Medical Center (UCIMC) started on December, 2020 and 6724 healthcare workers were vaccinated within 3 weeks. Seroprevalence increased from 13% pre-vaccination to 79% post-vaccination in January, 93% in February, and 99% in March. mRNA vaccination induced higher antibody levels than natural exposure, especially against the RBD domain and cross-reactivity against SARS RBD and S1 was observed. Nucleocapsid protein antibodies can be used to distinguish vaccinees to classify pre-exposure to SARS-CoV-2 Previously infected individuals developed higher antibody titers to the vaccine than non pre-exposed individuals. Hospitalized patients in intensive care with severe disease reach significantly higher antibody levels than mild cases, but lower antibody levels compared to the vaccine. These results indicate that mRNA vaccination rapidly induces a much stronger and broader antibody response than SARS-CoV-2 infection.
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BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) was initially cloned and characterized in 1999. It is required for the generation of all monomeric forms of amyloid-ß (Aß), including Aß42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aß production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aß and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aß in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.
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Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide , Animales , Ácido Aspártico Endopeptidasas/genética , Humanos , Ratones , Ratones NoqueadosRESUMEN
AIMS: To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect. METHODS: Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 microg kg(-1) min(-1)), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 microg kg(-1) min(-1)), and (3) a delayed administration study (15.7 microg kg(-1) min(-1)) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first. RESULTS: Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml(-1)). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml(-1)) were well below pharmacologically active concentrations as determined in studies 1 and 2. CONCLUSIONS: S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.
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Ácidos Cafeicos , Antagonistas de los Receptores de la Endotelina A , Antebrazo/irrigación sanguínea , Ácido Oleanólico/análogos & derivados , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Adolescente , Adulto , Presión Sanguínea/efectos de los fármacos , Ácidos Cafeicos/farmacología , Método Doble Ciego , Endotelina-1 , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Ácido Oleanólico/farmacología , Pletismografía , Método Simple Ciego , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA. METHODS: Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke. RESULTS: The combination therapy of S-0139 and rtPA significantly (P<0.01) reduced infarct volume (24.8+/-0.9% versus 33.8+/-1.5% in control) and hemorrhagic area (7.1+/-6.1 microm(2) versus 36.5+/-19.2 microm(2) in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels. CONCLUSIONS: These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.