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Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.

ABSTRACT: Little is known about the utility of plasma amyloid beta (A?) in clinical trials of Alzheimer's disease (AD).We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).Baseline plasma A? was not related to cognitive or clinical progression. We observed a decrease in plasma A?40 and 42 among apolipoprotein E epsilon 4 (APOE ?4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in A? compared with placebo. We found significant storage time effects and considerable plate-to-plate variation.We found no support for the utility of plasma A? as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma A? may prove useful in pharmacodynamic studies of antiamyloid drugs.

SUBMITTER: Donohue MC

PROVIDER: S-EPMC4387108 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.

Donohue Michael C MC Moghadam Setareh H SH Roe Allyson D AD Sun Chung-Kai CK Edland Steven D SD Thomas Ronald G RG Petersen Ronald C RC Sano Mary M Galasko Douglas D Aisen Paul S PS Rissman Robert A RA

Alzheimer's & dementia : the journal of the Alzheimer's Association 20141007 9

<h4>Introduction</h4>Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).<h4>Methods</h4>We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months).<h4>Results</h4>Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 a ...[more]

PMID: 25301682

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Project description:Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer's disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II-III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.

Project description:BackgroundTo enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer's disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD.MethodsResting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration.ResultsWhole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures' rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power.ConclusionsResting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.

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Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.

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Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.

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