MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD

Jack, Clifford R.; Słomkowski, M; Gracon, Stephen I.; Hoover, Toni M.; Felmlee, Joel P.; Stewart, Keith; Xu, Yun; Shiung, Maria M.; O’Brien, Peter C.; Cha, Ruitao; Knopman, David S.; Petersen, Ronald C.

doi:10.1212/01.wnl.0000042480.86872.03

Cited by 269 publications

(196 citation statements)

References 27 publications

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“…This is consistent with results obtained in single site observational studies of MCI subjects (Jack et al, 2000;Jack et al, 2004;Jack et al, 2005). It is also consistent with both single and multi site studies of AD patients, in which greater rates of brain atrophy are observed in individuals with more rapid concurrent clinical disease progression (Kaye et al, 1997;Fox et al, 1999;Jack et al, 2003;Mungas et al, 2005). Given the correlation between MRI rates and change in concurrent cognitive test performance noted in the preceding paragraph the observed correlation with conversion status is not surprising.…”

Section: Discussionsupporting

confidence: 89%

Section: Nih-pa Author Manuscriptsupporting

confidence: 89%

“…This tends to validate the use of MRI as a measure of disease progression in multisite therapeutic trials for MCI. This result is also concordant with results from single site natural history studies as well as multi-site studies (Kaye et al, 1997;Fox et al, 1999;Jack et al, 2003;Jack et al, 2004;Mungas et al, 2005).In the third objective of this study we found that concurrent rates of change of all four MRI measures were significantly greater in individuals who converted to AD than individuals who remained stable (Table 4). This is consistent with results obtained in single site observational studies of MCI subjects (Jack et al, 2000;Jack et al, 2004;Jack et al, 2005).…”

supporting

confidence: 89%

“…Nonetheless we believe that experience with MRI in this study has instructive lessons to offer for future clinical trials which employ imaging. Several earlier studies indicate greater power to detect change over time with structural MRI vs standard cognitive assessment instruments (Fox et al, 1999;Jack et al, 2003;Jack et al, 2004) thus improving the efficiency with which clinical trials may be conducted. This in turn would argue for performing imaging in a subset of subjects entered into clinical trials.…”

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confidence: 99%

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Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Jack

Petersen

Grundman³

et al. 2008

Neurobiology of Aging

133

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The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE ∈4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE ∈4 carriers than non-carriers. MRI APCs and changes Disclosure Statement for AuthorsThe authors have no conflicts of interest to disclose. The industry sponsors had no role in the analysis or interpretation of these data nor in the content of the paper. Appropriate approval procedures were used concerning human subjects. NIH Public Access IntroductionThe vitamin E and donepezil clinical trial for the treatment of mild cognitive impairment (MCI) was conducted in 769 subjects at 69 centers in North America . The study was designed to determine whether the antioxidant vitamin E or donepezil, the only cholinesterase inhibitor available at the time the study was designed, would be effective at delaying the clinical progression of subjects with the amnestic form of MCI to the clinical diagnosis of Alzheimer's disease (AD). While vitamin E had no beneficial effect, donepezil reduced the risk of progression from amnestic MCI to clinically possible or probable AD for up to 12 months. This treatment effect was extended to 24 months in carriers of the apolipoprotein E ∈4 (APOE e4) allele. Twenty-four of the recruiting sites voluntarily participated in a Magnetic Resonance Imaging (MRI) sub study which was grafted onto the existing clinical therapeutic study design. The purpose of the MRI sub study was to determine if a therapeutic effect of either vitamin E or donepezil could be detected on rates of brain atrophy from serial MRI studies. Four different brain atrophy brain measures were assessed; the hippocampus, entorhinal cortex (ERC), whole brain, and ventricular volume. Each of these MRI measurements has figured prominently in anatomic MRI based studies of MCI, AD, and normal aging (Jack et al., 1992;Fox et al., 1996;Jack et al., 1997;Fox et al., 1999;Killiany 2000;Dickerson et al., 2001;Killiany et al., 2002;Du et al., 2003). A primary objective of this analysis was to test the hypothesis that vitamin E or donepezil slowed the rate of brain atrophy relative to placebo in subjects with amnestic MCI (Petersen 1995;Pe...

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Section: Discussionsupporting

confidence: 89%

Section: Nih-pa Author Manuscriptsupporting

confidence: 89%

supporting

confidence: 89%

mentioning

confidence: 99%

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Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Jack

Petersen

Grundman³

et al. 2008

Neurobiology of Aging

133

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“…Another related type of brain map-a genetic brain map-can also reveal how heredity and environmental factors influence cortical development and disease Thompson et al, 2001a,b). These brain mapping techniques empower disease detection, exploration, and intervention, and offer new insights in clinical trials assessing drugs that slow degenerative brain changes (Ashburner et al, 2003;Jack et al, 2003;Zijdenbos et al, 1996). Many brain imaging studies focus on the cerebral cortex, which changes profoundly during development and disease.…”

Section: Introductionmentioning

confidence: 99%

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

et al. 2004

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This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhoodand adult-onset schizophrenia, bipolar disorder, attention-deficit/ hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages. D 2004 Published by Elsevier Inc.

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Application of Automated Medial Temporal Lobe Atrophy Scale to Alzheimer Disease

Ridha¹,

Barnes²,

Pol³

et al. 2007

Arch Neurol

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Objective: To compare an automated intensity-based measure of medial temporal atrophy in Alzheimer disease (AD) with existing volumetric and visually based methods. Design: Longitudinal study comparing a medial temporal atrophy measure with 2 criterion standards: (1) total hippocampal (HC) volume adjusted for total intracranial volume and (2) standard visual rating scale of medial temporal atrophy.

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MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD

Cited by 269 publications

References 27 publications

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Longitudinal MRI findings from the vitamin E and donepezil treatment study for MCI

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

Application of Automated Medial Temporal Lobe Atrophy Scale to Alzheimer Disease

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