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Neuroimaging Refined to Reveal Early Signs of AD



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Investigators provided a round up of new research on neuroimaging advances that help early detection and tracking of Alzheimer disease progression.

CHICAGO—Refinements of existing neuroimaging technology are revealing early signs of Alzheimer disease (AD) and opening the way for drugs currently in the pharmaceutical pipeline that can keep the brain free of toxic beta-amyloid accumulation, at least in the early stages of the disease.

“I think there's a clear trend to early detection,” said John C. Morris, MD, the Friedman Distinguished Professor of Neurology and director of the Alzheimer's Disease Research Center at Washington University School of Medicine in St. Louis., who discussed biomarkers at the Alzheimer's Association International Conference on Alzheimer's Disease here in July. “This is built upon the yet unproven premise that the earlier we can detect the disease, the better chance we'll have for intervention.”


DR. JOHN C. MORRIS: “I think theres a clear trend to early detection.”


The NIH Alzheimer's Disease Neuroimaging Initiative (ADNI) involves nearly five dozen programs across the US that examine MRIs of healthy people and those with mild cognitive impairment (MCI) and AD to identify ways to tell who is going to progress in dementia, and at what rate.

“The role of ADNI has been to develop biomarkers for use in clinical trials,” said Michael W. Weiner, MD, professor of medicine, radiology, and psychiatry at the University of California-San Francisco, who is ADNI's principal investigator. “We'd like to be able to do clinical trials in which brain shrinkage is used as a marker rather than clinical data. If I test your memory, your functioning might be different next week or next month because you had a bad night's sleep, or because you have been worrying about some family matter. But if I do an MRI of your brain every six months, the results will be reliable and I'll be able to track the progression of the shrinkage with a great deal of accuracy.”


PET using the Pittsburgh Compound B (PiB), developed by William E. Klunk, MD, PhD, and Chester Mathis, PhD, at the University of Pittsburgh, clearly reveal amyloid-beta (Abeta) deposits in the brain. About 30 percent of healthy people over age 70 have PiB-positive scans, which suggests that Abeta may be an early marker of the disease.

But PiB is a carbon 11 isotope with a half-life of only 20 minutes, which means it has to be manufactured in a cyclotron located near the scanner where it will be used. Only about 40 sites in the world have this capability, according to Dr. Mathis.

However, several companies are competing to develop a variant of PiB with a much longer half-life, which means the compound could be shipped and increasing the number of scanners with access to PiB.


Some researchers are seeking biomarkers by combining existing techniques into a predictive formula. Prashanthi Vemuri, PhD, a research fellow at the Mayo Clinic in Rochester, MN, led a study to develop the STructural Abnormality iNDex, or STAND score, which measures brain deterioration by comparing atrophy patterns extracted from a large library of brain scans from patients with AD as well as cognitively normal subjects.

Dr. Vemuri verified the accuracy of STAND scores by comparing 101 patients with the traditional Braak staging of neurofibrillary tangles done after death. The STAND algorithm was 90 percent accurate at distinguishing AD MRI scans from normal scans.

“The results show that optimally extracted information from MRI such as STAND scores accurately capture the severity of neuronal pathology and can be used as an independent approximate surrogate marker for early identification of Alzheimer disease in individual subjects,” Dr. Vemuri concluded in a paper on her research. (The paper was published online May 20 in Neuroimage ahead of the Aug. 15 print edition).

Eric A. Mellon, MD, and colleagues at the University of Pennsylvania have coaxed greater predictive power out of the conventional MRI by administering the isotope 23Na, which is sensitive to cell death, one of the neuropathological changes associated with AD.


DR. REISA SPERLING reported that hyperactivation of the hippocampus and related structures in the medial temporal lobe may paradoxically serve as an early biomarker for dementia.

Reisa Sperling, MD, of Brigham and Women's Hospital, Boston, has conducted a two-year longitudinal fMRI study on 51 non-demented subjects. They found that the subjects with hyperactivation showed loss of hippocampal activation over time as they declined. They concluded that hyperactivation of the hippocampus and related structures in the medial temporal lobe may paradoxically serve as an early biomarker for dementia.

While patients with mild AD show decreased activation in these areas while encoding novel stimuli, people with early signs of mild cognitive impairment, or who carry the gene for apolipoprotein E4 (ApoE4) show hyperactivation, which “may be a harbinger of impending hippocampal failure and rapid clinical decline,” Dr. Sperling concluded.

John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research at the University of Pennsylvania, found that low amyloid beta was also a good predictor of the MCI patients who would go on to develop Alzheimer disease over the course of the study. Fifteen percent of the MCI patients converted to AD after one year, the same rate that was initially set by Ronald Petersen, MD, director of the Mayo Clinic Alzheimer's Disease Research Center.

Dr. Trojanowski also reported here that the CSF amyloid beta was low in AD patients and those with MCI, and tau and phosphorylated tau levels were high. He said that the ratio of tau to amyloid was a good indication of the severity of the disease process.


Norbert Schuff, PhD, assistant professor of radiology at the University of California-San Francisco, also reported that the rate of change in the Alzheimer brain is not linear over time but accelerated. He discovered that the rate of change was faster between the second and third scan than the first and second scan. “This is very important to know when scientists and pharmaceutical companies are designing clinical trials,” said Dr. Weiner.

The scientists also have mounted evidence that imaging has more power to detect changes in the progression of the disease than does standard neurocognitive tests. And Dr. Weiner said that using scanning technology can cut the number of patients necessary to power a study. For instance, a treatment study that would need 460 patients using standard cognitive measurements could be whittled down to 40 if scanning was incorporated into the study.

Mony de Leon, MD, director of the Center for Brain Health at NYU School of Medicine, has new evidence from brain scan studies that some forms of amyloid beta may affect blood perfusion and this reduction in blood flow may set the stage for cognitive problems.

Finally, Dean M. Connor, PhD, of Brookhaven National Lab and colleagues have used diffraction enhanced imaging (DEI), which heightens contrast from the refraction of X-rays, to reveal clearer images of amyloid deposits in mice. “As such, DEI provides novel physical information which is not currently available with other imaging techniques,” Dr. Connor concluded in a poster presentation at ICAD.


• Vemuri P, Whitwell JL, Jack CR Jr., et al. Antemortem MRI based STructural Abnormality iNDex (STAND)-scores correlate with postmortem Braak neurofibrillary tangle stage. Neuroimage 2008;42(2):559–567.