Article

Enrichment through biomarkers in clinical trials of Alzheimer's drugs in patients with mild cognitive impairment.

LENITEM Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio-FBF, Brescia, Italy.
Neurobiology of aging (Impact Factor: 4.85). 08/2010; 31(8):1443-51, 1451.e1. DOI: 10.1016/j.neurobiolaging.2010.04.036
Source: PubMed

ABSTRACT 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 Initiative (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.

Download full-text

Full-text

Available from: Marco Lorenzi, Jan 22, 2015
3 Followers
 · 
102 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Current diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) require standardized tests that are capable of measuring a range of neurocognitive abilities in healthy elderly individuals and sensitive to detect change over time. There currently is no clearly-established "gold standard" for this purpose. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a widely used neuropsychological test battery for the clinical diagnosis/tracking of dementia also recently incorporated into clinical trials of new investigational medications for AD treatment. The RBANS has a number of design features that suggest possible utility in diagnosis/tracking of MCI. Eighty-one patients with MCI completed the RBANS and their scores were compared with 81 demographically matched healthy controls. RBANS Total Scale scores in both groups were normally distributed, demonstrating no floor/ceiling effects. The MCI group was most impaired on the Delayed Memory Index (DMI). Receiver operating characteristic analyses reflected good discrimination, with an area under the curve of 0.88 for the Total Scale score and 0.90 for the DMI score. The profile of performance for the MCI group was similar to that previously reported for mild AD patients. The RBANS may be a suitable neurocognitive battery for the detection and tracking of MCI presumed to be due to AD.
    Archives of Clinical Neuropsychology 07/2013; DOI:10.1093/arclin/act057 · 1.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tau proteins and amyloid-β (Aβ) peptides are the current recognized cerebrospinal fluid (CSF) biomarkers used as an aid in the diagnosis of Alzheimer's disease (AD). However, there is no consensus on their clinical use due to non-qualified cut-off values, probably related to the observed high pre-analytical and analytical variability. Standardized pre-analytical protocols have therefore been proposed. Importantly, these recommend the use of polypropylene collection/sampling tubes while, to date, no broad comparison of these types of tubes has been conducted. In this study, we first compared, as part of a real clinical workflow, the impact of four different collection tubes on the CSF concentration of Aβ peptides (Aβ42, Aβ40) and total (hTau) and phosphorylated (P-Tau181P) tau proteins measured using routine ELISA kits. We then extended this study to 11 polypropylene tubes used by different clinical laboratories, and investigated their plastic polymer composition using differential scanning calorimetry and Fourier Transformed Infrared spectroscopy. Significant concentration variations linked solely to the use of different types of tubes were observed. This was particularly marked for Aβ peptides, with >50% disparity occurring in less than five minutes. Polymer composition analysis revealed that most polypropylene tubes were in fact copolymers with at least polyethylene. There was no clear correlation between tube composition and pre-analytical behavior. Our results show that the use of polypropylene tubes does not guarantee satisfactory pre-analytical behavior. They also point to collection/sampling tubes being a major pre-analytical source of variability that could impact the significance of AD biological diagnosis.
    Journal of Alzheimer's disease: JAD 04/2012; 31(1):13-20. DOI:10.3233/JAD-2012-120361 · 3.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Designers of clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) are actively considering structural and functional neuroimaging, cerebrospinal fluid and genetic biomarkers to reduce the sample sizes needed to detect therapeutic effects. Genetic pre-selection, however, has been limited to Apolipoprotein E (ApoE). Recently discovered polymorphisms in the CLU, CR1 and PICALM genes are also moderate risk factors for AD; each affects lifetime AD risk by ~ 10-20%. Here, we tested the hypothesis that pre-selecting subjects based on these variants along with ApoE genotype would further boost clinical trial power, relative to considering ApoE alone, using an MRI-derived 2-year atrophy rate as our outcome measure. We ranked subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on their cumulative risk from these four genes. We obtained sample size estimates in cohorts enriched in subjects with greater aggregate genetic risk. Enriching for additional genetic biomarkers reduced the required sample sizes by up to 50%, for MCI trials. Thus, AD drug trial enrichment with multiple genotypes may have potential implications for the timeliness, cost, and power of trials.
    06/2013; 2. DOI:10.1016/j.nicl.2013.05.007