Neuroimaging Biomarkers for Clinical Trials of Disease- Modifying Therapies in Alzheimer’s Disease

Department of Neurology and the Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
NeuroRx 05/2005; 2(2):348-60. DOI: 10.1602/neurorx.2.2.348
Source: PubMed


The pathophysiologic process leading to neurodegeneration in Alzheimer's disease (AD) is thought to begin long before clinical symptoms develop. Existing therapeutics for AD improve symptoms, but increasing efforts are being directed toward the development of therapies to impede the pathologic progression of the disease. Although these medications must ultimately demonstrate efficacy in slowing clinical decline, there is a critical need for biomarkers that will indicate whether a candidate disease-modifying therapeutic agent is actually altering the underlying degenerative process. A number of in vivo neuroimaging techniques, which can reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise as biomarkers. These neuroimaging measures appear to relate closely to neuropathological and clinical data, such as rate of cognitive decline and risk of future decline. As this work has matured, it has become clear that neuroimaging measures may serve a variety of potential roles in clinical trials of candidate neurotherapeutic agents for AD, depending in part on the question of interest and phase of drug development. In this article, we review data related to the range of neuroimaging biomarkers of Alzheimer's disease and consider potential applications of these techniques to clinical trials, particularly with respect to the monitoring of disease progression in trials of disease-modifying therapies.

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Available from: Bradford Dickerson, Dec 13, 2013
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    • "Currently for clinical diagnosis of AD, neuroimaging examinations, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), are widely used. Among numerous imaging examination methods, morphological MRI scans are generally used to detect gray matter (GM) abnormalities for the early diagnosis of AD, including atrophy of the whole brain, hippocampal formation, and entorhinal cortex, as well as expansion of the temporal horn in the lateral ventricles [3]. However, there are increasing MRI investigations suggesting that AD patients also present with white matter (WM) abnormalities including WM volume (WMV) deficits and disruption of the integrity of WM pathways [4] [5] [6]. "
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    ABSTRACT: An increasing number of MRI investigations suggest that patients with Alzheimer's disease (AD) show not only gray matter decreases but also white matter (WM) abnormalities, including WM volume (WMV) deficits and integrity disruption of WM pathways. In this study, we applied multimodal voxel-wise meta-analytical methods to study WMV and fractional anisotropy in AD. Fourteen studies including 723 participants (340 with AD and 383 controls) were involved. The meta-analysis was performed using effect size signed differential mapping. Significant WMV reductions were observed in bilateral inferior temporal gyrus, splenium of corpus callosum, right parahippocampal gyrus, and hippocampus. Decreased fractional anisotropy was identified mainly in left posterior limb of internal capsule, left anterior corona radiata, left thalamus, and left caudate nucleus. Significant decreases of both WMV and fractional anisotropy were found in left caudate nucleus, left superior corona radiata, and right inferior temporal gyrus. Most findings showed to be highly replicable in the jackknife sensitivity analyses. In conclusion, AD patients show widespread WM abnormalities mainly in bilateral structures related to advanced mental and nervous activities.
    Journal of Alzheimer's disease: JAD 07/2015; 47(2):495-507. DOI:10.3233/JAD-150139 · 4.15 Impact Factor
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    • "In the following sections, specific strengths and weaknesses of the current technologies are reviewed. Because of their minimally invasive nature and sensitivity to the earliest changes within the brain substrate, many of the following neuroimaging methods have been promoted as being able to identify " leveraged cohorts " of individuals with an elevated risk of developing clinical AD in the short term [68]. This notion is yet to be realized, but many are hopeful that some of the novel techniques recently developed will provide breakthroughs in AD and other diseases. "
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    ABSTRACT: The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.
    Alzheimer's and Dementia 06/2014; 10(3):S196–S212. DOI:10.1016/j.jalz.2014.04.015 · 12.41 Impact Factor
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    • "Several recent reviews describe the use of single-photon emission computed tomography (SPECT) alone or in combination with PET and/or functional magnetic resonance imaging (fMRI) in studies of human cognition, imaging of neuroreceptor systems, aiding diagnosis or assessment of progression or treatment response in various psychiatric and neurologic disorders, neuropharmacologic challenge studies and in the new field of molecular imaging, including imaging of transgene expression (Devous 2002; Catafau 2001; Mazziotta and Toga 2002; Lee and Newberg 2005; Bonte and Devous 2003; Devous Sr 1998; Brooks 2005; Heinz et al. 2000; Dickerson and Sperling 2005; Bammer et al. 2005; Eckert and Eidelberg 2005; Kuzniecky 2005). Brain SPECT is now commonly used in the diagnosis, prognosis assessment, evaluation of response to therapy, risk stratification, detection of benign or malignant viable tissue, and choice of medical or surgical therapy, especially in head injury, malignant brain tumors, cerebrovascular disease, movement disorders, dementia, and epilepsy (Lee and Newberg 2005; Bonte and Devous 2003; Devous Sr 1998; Brooks 2005; Heinz et al. 2000; Dickerson and Sperling 2005; Bammer et al. 2005; and Kuzniecky 2005). The selection of the proper isotope to be used in labeling and in imaging is important because it should have a suitable short half-life to avoid unwarranted harmful exposure to radiation and suitable photon energy "
    01/2014; 5(1):23. DOI:10.1186/s40543-014-0023-4
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