New neuroimaging and biomarkers in MCI and AD initiativeAugust 1, 2003
A new National Institute on Aging (NIA) initiative will launch a multi-year neuroimaging study using serial magnetic resonance imaging (MRI) and positron emission tomography (PET) scans to examine how brains change as mild cognitive impairment (MCI) and Alzheimer's disease (AD) progress. Scientists will correlate the imaging information with clinical, neuropsychological, and biological markers from blood, cerebrospinal fluid (CSF), and urine samples.
Potential markers include levels of amyloid and tau, components of the plaques and tangles considered to be the hallmarks of AD; indicators of inflammation such as C-reactive protein and alpha-antichymotrypsin; and measures of oxidative stress such as oxysterols and isoprostanes. Markers for disease on brain scans and from these fluids can aid in early diagnosis and in the evaluation of response to treatment. "We hope that the AD Neuroimaging Initiative will help create rigorous imaging and biomarker standards that will provide the yardstick by which the success of future treatments can be measured," said Susan Molchan, M.D., Program Director for AD Clinical Trials, Dementias of Aging Branch, Neuroscience and Neuropsychology of Aging Program at NIA.
The initiative is being planned as a partnership among the NIA/NIH, university investigators, the pharmaceutical and the imaging equipment industries, the Food and Drug Administration, and the NIH Foundation, with participation from the Alzheimer's Association and the Institute for the Study of Aging. Like the Alzheimer's Disease Genetics Initiative, an important aspect of this initiative is that the clinical, imaging, and biological data collected will be made available to all qualified scientific investigators promptly.
Researchers will be conducting a longitudinal, multi-site study that will include approximately 150 cognitively normal individuals to be followed for 3 years, 350 people with MCI to be followed for 3 years, and 150 people with early AD to be followed for 2 years. Using MRI and PET scans at regularly scheduled intervals, investigators hope to learn when and where in the brain degeneration occurs as memory problems develop.
A Coordinating Center for the initiative will manage the tracking of subject recruitment and visits, including clinical/neuropsychological assessment, MRI and PET scans, blood/CSF collection, genotyping, data quality assurance/quality control, and transmission, storage, and assurance of confidentiality of data. A Neuroimaging Center will establish imaging protocols, assess and control the quality of scans, and process, store, and distribute the brain scans. Approximately 25 clinical sites throughout the country will evaluate potential participants for the initiative, collect the clinical and neuropsychological data, perform the MRI and PET scans, and collect blood, urine, and from some subjects, cerebrospinal fluid samples, for shipment to central storage facilities.
Brain Shrinkage and Metabolism
As MCI and AD progress, areas of the brain involved with memory, such as the hippocampus, shrink. Using the high resolution images produced by MRI, researchers will be evaluating the best ways of measuring this volume loss in the hippocampus and other structures. PET scans assess brain function by measuring the rate of metabolism of glucose, the brain's fuel. PET scans of people with AD show that glucose in certain parts of the brain is metabolized at lower levels than in healthy people. Previous studies have shown that low glucose metabolism can be seen in some people even before memory loss symptoms become prominent.
A number of studies in MCI and AD have demonstrated that imaging may provide more sensitive and consistent measures of disease progression than memory assessment. "The information collected during the Neuroimaging Initiative may allow for early identification of people with MCI and AD who may benefit from emerging preventive and treatment medications. The data also could determine whether neuroimaging measures, such as the size of the hippocampus, may serve as indicators of benefit from drug treatment in clinical trials," said Dr. Molchan. A slowed rate of shrinkage in a brain structure known to be affected by AD together with neuropsychological test data indicating that memory function was stabilizing or improving, would be strong evidence that a drug is slowing or stopping degeneration in the brain. The drugs currently available for AD temporarily relieve some symptoms for some people, but are not thought to actually slow degeneration.
Advances in the understanding of the pathophysiology and genetics of AD are providing opportunities for developing drugs that slow or stop the progression of disease. Early in drug development, imaging measures and other biological markers may help to rapidly identify appropriate doses, assess safety, and compare drugs. This may help to increase the safety and efficiency of clinical trials and may decrease the cost and time of developing drug treatments for this disease that robs people of their memories.
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