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Amyloid Imaging Predicts Conversion of MCI to Alzheimer Disease


doi: 10.1097/01.NT.0000361419.57550.21
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Eighty-two percent of patients with mild cognitive impairment who were PiB positive at baseline — meaning the PiB bound to the amyloid beta, which is held responsible for the development of AD — progressed to Alzheimer disease within three years.

An in vivo imaging tracer for amyloid-beta (Abeta) plaques in patients with mild cognitive impairment (MCI) may predict which subjects will progress to Alzheimer disease (AD) in three years.

Investigators compared rates of progression to AD in MCI patients both with and without plaques as detected by the PET with the radiotracer Pittsburgh Compound B (PiB). Eighty two percent of MCI patients who were PiB positive at baseline — meaning the PiB bound to the Abeta, which is held responsible for the development of AD — progressed to AD within three years.

This finding is consistent with results of a previous 11C-PiB PET study in MCI where those MCI subjects who converted to AD were all PiB-positive, said Aren Okello, MBBS, a clinical research fellow of the Division of Neurosciences and Mental Health at Imperial College Faculty of Medicine in London, in an e-mail to Neurology Today. Dr. Okello and fellow investigators conducted the study, which was published online in advance of the Sept. 12 print edition of Neurology.

The findings show that “in vivo detection of amyloid deposition in MCI with PiB PET provides useful prognostic information with respect to stratifying those amnestic MCI patients at increased risk of dementia,” she said.

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The investigators examined 31 amnestic MCI subjects who had been clinically followed-up for one to three years after baseline 11C-PiB PET. Seventeen of the 31 MCI subjects (55 percent) had significantly increased C-PiB retention compared with controls in all measured brain regions of interest. Eighty-two percent of these patients clinically converted to AD (as determined by neuropsychological testing and clinical observation) during follow-up, with 47 percent of the PiB-positive MCI patients converting to AD within one year. Seven of 17 (41 percent) MCI subjects who were known apolipoprotein E-e4 carriers — a genetic risk factor for AD — progressed significantly faster. Only one of the 14 PiB-negative MCI cases converted to AD.

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The findings are consistent with previous studies in which PiB-positive MCI subjects convert to AD with a high frequency and the PiB-negative subjects convert infrequently to AD over 1–3 years of follow-up, said Chester A. Mathis, PhD, professor of radiology and the director of the PET facility at the University of Pittsburgh. Dr. Mathis invented the PiB tracer with William E. Klunk, MD, PhD.



In a single PET scanning session, this noninvasive technique “differentiates MCI subjects who will progress to AD from those who will not progress,” said Dr. Mathis.

Yet the method is not quite ready for clinical use, he added. Larger, longitudinal studies with MCI subjects over five or more years of follow-up are needed, he said. It should also be combined with post-mortem confirmation of the absence of amyloid-beta plaque pathology in PiB-negative subjects and the presence of extensive amyloid-beta plaque pathology in PiB-positive subjects.

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There are current applications for the PiB PET technique, however, said Dr. Mathis. “It appears to be capable of identifying PiB-positive MCI subjects who would most benefit from anti-amyloid therapies and could provide a homogenous clinical trial population for future anti-amyloid drug therapy trials in MCI subjects. Also, it can be used to follow the course of amyloid deposition and its relationship to the progression of cognitive dysfunctions and assist in testing the amyloid cascade hypothesis in vivo in human subjects.”

The main challenges in applying this technology include availability and cost. About 20 PET centers in the US produce PiB for research PET studies, while there are several thousand PET scanners in the US, said Dr. Mathis. Because the 11C-labelled radiotracers have a 20 minute half-life, they cannot be shipped to off-site PET scanners. The development of longer-lived F-18-labeled amyloid agents (18F-flutemetamol and 18F-AV45) now in phase 3 clinical imaging trials, which would allow a much wider distribution to scanners across the US, “will be the method of choice for future use in centers with PET imaging capabilities,” Dr. Mathis said. “The cost of these studies will likely be similar to existing costs for [F-18]FDG PET oncology scans — on the order of $2,000 per scan.”



“The future combination of commercially available F-18-labeled amyloid plaque radiotracers and efficacious disease modifying therapies could someday make a real difference in the detection and treatment of early stage or presymptomatic AD,” he said.

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• Okello A, Koivunen J, Brooks DJ, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: An 11C-PIB PET study. Neurology 2009; E-pub 2009 July 22.
    ©2009 American Academy of Neurology