56 research outputs found
Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting
Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided
Bayes analysis supports null hypothesis of anti‐amyloid beta therapy in Alzheimer's disease
Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment
Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed. \ua9 2010 Elsevier Inc
Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab
Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)
Characterization of the selective in vitro and in vivo binding properties of crenezumab to oligomeric Aβ
Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis
Background: Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer\u27s disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors. Methods: Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patient\u27s treatment,. APOE e{open}4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA. Findings: 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of. APOE e{open}4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001). Interpretation: ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among. APOE e{open}4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden. © 2012 Elsevier Ltd
First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized, Placebo-Controlled Study
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