Dataset Information

European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow.

ABSTRACT: INTRODUCTION:In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (APOE) status predict response to Nilvadipine, and to investigate the effect of Nilvadipine on cerebral blood flow and blood biomarkers. METHODS AND ANALYSIS:All participants who fulfil criteria for the main NILVAD study are eligible for participation in the NILVAD substudies. Participation is subject to informed consent and whether the substudy is available at a particular NILVAD study site. Each substudy entails extra measurements during the course of the main NILVAD study. For example, in the blood and genetic biomarkers substudy, extra blood (30?mL) will be collected at week 0, week 13, week 52 and week 78, while in the cerebral blood flow substudy, participants will receive an MRI and transcranial Doppler measurements at week 0, week 26 and week 78. In the CSF substudy, 10?mL CSF is collected at week 0 and week 78. ETHICS AND DISSEMINATION:All NILVAD substudies and all subsequent amendments have received ethical approval within each participating country, according to national regulations. Each participant provides written consent to participate. All participants remain anonymised throughout and the results of each substudy will be published in an international peer reviewed journal. TRIAL REGISTRATION NUMBER:EUDRACT 2012-002764-27; Pre-results.

SUBMITTER: Meulenbroek O

PROVIDER: S-EPMC4964180 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow.

Meulenbroek Olga O O'Dwyer Sarah S de Jong Daan D van Spijker Gerrita G Kennelly Sean S Cregg Fiona F Olde Rikkert Marcel M Abdullah Laila L Wallin Anders A Walsh Cathal C Coen Robert R Kenny Rose Anne RA Daly Leslie L Segurado Ricardo R Borjesson-Hanson Anne A Crawford Fiona F Mullan Michael M Lucca Ugo U Banzi Rita R Pasquier Florence F Breuilh Laetitia L Riepe Matthias M Kalman Janos J Molloy William W Tsolaki Magda M Howard Robert R Adams Jessica J Gaynor Siobhan S Lawlor Brian B

BMJ open 20160719 7

<h4>Introduction</h4>In conjunction with the NILVAD trial, a European Multicentre Double-Blind Placebo Controlled trial of Nilvadipine in Mild-to-Moderate Alzheimer's disease (AD), there are four NILVAD substudies in which eligible NILVAD patients are also invited to participate. The main NILVAD protocol was previously published in BMJ Open (2014). The objectives of the NILVAD substudies are to determine whether frailty, cerebrospinal fluid (CSF), blood biomarker profile and Apolipoprotein E (AP ...[more]

PMID: 27436668

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Project description:BackgroundThis study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease.Methods and findingsNILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid.ConclusionsThe results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.Trial registrationClinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Project description:ObjectiveTo compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI).DesignRandomized controlled trial.SettingVeterans Affairs Medical Center clinical research unit.ParticipantsForty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years).InterventionParticipants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet.Main outcome measuresThe CSF concentrations of β-amyloid (Aβ42 and Aβ40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition.ResultsFor the aMCI group, the LOW diet increased CSF Aβ42 concentrations, contrary to the pathologic pattern of lowered CSF Aβ42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aβ42, whereas the HIGH diet increased CSF Aβ42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet.ConclusionOur results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Aβ42, lipoproteins, oxidative stress, and insulin.

Project description:Frailty is defined as a clinical syndrome. It reflects a decrease in physiological reserve capacities that alters the mechanisms of adaptation to stress. Its clinical expression is modulated by biological, physiological, social and environmental changes. Thus, the accumulation of declines in these multiple systems leads to vulnerability to adverse outcomes (Fried et al., 2001; Nourhashémi et al., 2001). Indeed, frailty increases the risk of disability, falls, hospitalization and death. Age is currently a major determinant of frailty but does not explain this syndrome alone. It has been estimated that the prevalence of frailty is 4% in people aged 65-69 years and increases to 26% in people aged over 85 years (Clegg et al., 2013). However, this parameter is not sufficient to understand why long-lived people can preserve their physical function even at extreme ages (Ayers et al., 2017). The characterization of frailty has therefore become a priority in order to put in place actions to reduce or delay its harmful consequences. Early diagnostic methods are needed to identify those at risk. The search for biomarkers is part of this approach. As a result, the search for biomarkers of frailty has led to the identification of several types of molecules linked to the inflammatory response (e.g. IL-6, CRP, TNF-α and homocysteine), to nutritional status (e.g. vitamin D, albumin) or even endocrine. metabolism (e.g. IGF-1 and testosterone) (Picca et al., 2022; Mailliez et al., 2020; Alvarez-Sanchez et al, 2020). The development of new analytical techniques now allows multiplexed analysis rather than an individual biomarker to characterize a biological profile of this complex and dynamic frailty syndrome (Picca et al., 2022). Proteomic analysis is the technique of choice for studying the complete protein content of a biological sample. This technique has already proven itself in the discovery of new biomarkers in age-related diseases such as Parkinson's disease (Raghunathan et al., 2022) and Alzheimer's disease (Bai et al., 2021). Several studies have already described the plasma proteomic profile of frailty (Shamsi et al., 2012; Lin et al., 2017; Landino et al., 2021; Sathyan et al., 2020; Verghese et al., 2021), highlighting the importance of biological pathways associated with frailty: immune response, coagulation pathway or lipid metabolism. On the other hand, the determination of the level of frailty of the patients thanks to a proteomic analysis could also make it possible to improve the prediction of this syndrome as well as its phenotyping. In a first work on plasma samples, Sathyan et al. constructed a frailty prediction model that was more strongly correlated with chronological age than observed clinical frailty (Sathyan et al., 2020). Cognitive impairment plays a key role in determining vulnerability to adverse outcomes (Cesari et al., 2013), leading to the proposal in 2013 of a concept and operational definition of “cognitive frailty”. (Sugimoto et al., 2022). Proteomic analysis of cerebrospinal fluid (CSF) is therefore an approach of choice for understanding brain responses to aging and frailty syndrome. Its analysis could allow the identification of new biomarkers linked to the frailty syndrome. Indeed, many of the CSF proteins are released by the various cells of the central nervous system (CNS). This biofluid thus reflects the molecular content of neuronal and glial cells. For this reason, any change in the composition of the CSF reflects the pathophysiological state of the brain (inflammation, infection, neurodegeneration...). CSF proteomics is therefore a technique of choice to comprehensively understand the cerebral pathogenic pathways linked to frailty. The PROLIPHYC cohort is composed of patients suspected of normal pressure hydrocephalus (NPH). We have previously shown that there is an association in these patients between an alteration of the biomechanical properties of the CNS and the frailty index, and that homocysteine is the only plasma macromolecule associated with these two clinical and biomechanical parameters (Vallet et al., 2020; Guillotin et al., 2022). In this new study, we sought to characterize the protein composition of CSF related to frailty by quantitative proteomic analysis. The second objective was to develop a model for predicting frailty from the abundance of CSF proteins. This model was then compared to the frailty estimated by the frailty index. Together, our results enabled us to highlight a possible link between inhibition of the expression of proteins involved in neurogenesis and the frailty index, then to propose a first proteomic profile of frailty in the CSF and a model for predicting frailty based on the biological signature of the CNS.

Dataset Information

European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow.

Publications

European multicentre double-blind placebo-controlled trial of Nilvadipine in mild-to-moderate Alzheimer's disease-the substudy protocols: NILVAD frailty; NILVAD blood and genetic biomarkers; NILVAD cerebrospinal fluid biomarkers; NILVAD cerebral blood flow.

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