21 July 2002. On day one of the 8th International Conference on Alzheimer’s Disease and Related Disorders, held from July 20 to 25 in Sweden’s magnificent capital, the Alzheimer’s Imaging Consortium hosted a one-day symposium that highlighted recent advances in using MRI, SPECT and PET to aid in the diagnosis of AD as well as the assessment of experimental therapies.
Organized by Michael Weiner of the University of California, San Francisco, the symposium attracted well over 100 scientists. The talks ranged from imaging amyloid plaques in humans, early detection of AD by measuring the shrinkage of particular brain areas, to the role of functional MRI, longitudinal imaging studies, and other topics. Two things stood out. One was a presentation of new radioligands that can label amyloid plaques in humans and animals, the other was an attempt by the research community to reach a consensus on where AD imaging research should go next to validate the diverse research approaches and channel them towards clinical applications.
First, the news. Following a talk by Jorge Barrio of University of California, Los Angeles, (see ARF related news story). William Klunk of the University of Pittsburgh, Pennsylvania, presented new data of his attempt, together with Chester Mathis and collaborators in Boston and Uppsala, to develop a PET imaging agent that can quantify amyloid plaques in live humans. In addition to providing a pathological diagnosis, such an agent could track the success of clinical trials testing experimental therapies to lower amyloid deposition. Klunk introduced a thioflavin derivative called BTA-1, and reported that it fulfills all of the criteria needed to move such compounds into human trials: It binds amyloid with high affinity and high specificity, it readily crosses the blood-brain-barrier, but also clears rapidly. It is non-toxic and works well in transgenic mice.
Demonstrating BTA-1 action in PSAPP transgenic mice, Klunk’s collaborator Brian Bacskai in Brad Hyman’s group at Massachusetts General Hospital in Boston, Massachusetts, will present on Monday a movie made from multiphoton microscopy images, showing how the compound crosses the blood-brain barrier and, within 30 minutes, labels existing plaques from the outside in. Klunk previewed the movie in this talk.
The moment of truth, however, is the human study, he added. On Tuesday, Mathis will detail how BTA-1 compared in uptake and clearance with currently used PET tracers. And on Wednesday, Henry Engler of Uppsala University in Sweden will present results of a first, small human trial. In people with early AD, BTA-1 labeled frontal and temporoparietal association cortices, the anterior and posterior cingulated cortices and the caudate, all areas known to contain plaques. (PET cannot resolve individual plaques, that is part of why the scientists test this compound with multiphoton microscopy in mice). In the five controls, non-specific labeling washed out rapidly, leaving a clear separation between cases and controls, said Mathis. Next, the scientists want to test the compound in patients with even earlier stages of cognitive impairment, to see how amyloid load correlates with progression to AD. Klunk and Mathis are negotiating an agreement with a pharmaceutical company interested in marketing BTA-1 as a therapy-monitoring marker for SPECT.
In the ensuing discussion of amyloid imaging approaches, Steve Younkin of the Mayo Clinic in Jacksonville, Florida, said that radioligands will probably turn out to be safe and may be useful in conjunction with drug trials. However, he expects this method to remain too costly for use in routine diagnosis, and noted some knotty problems in validating it. How, for example, could one determine the variation in the signal obtained from two people with the same amyloid burden? Finally, Younkin cautioned that the increasing realization about soluble Aβ assemblies being as or even more toxic than fibrillar deposits might weaken the utility of this technique, should it turn out that soluble and fibrillar Aβ do not correlate.
Next, the consensus. This symposium also saw the beginning of emerging agreement among imaging researchers on how to move current research toward the clinic. The Imaging Working Group sponsored by the Alzheimer Association has over the past months solicited the views of scientists in this area, and some of those presented consensus statements aimed to direct programmatic and policy issues. Weiner, who chairs the working group, said that the group will soon formalize the consensus statements and submit them to the Alzheimer Association. But even as draft statements were introduced briefly at the end of today’s session, the consensus appeared fragile: Several members of the audience asked why SPECT imaging had been omitted from consideration, and urged the working group to consider this technology, which is widely available at many medical centers.
This news summary of the symposium does not include all 23 research presentations. Selected highlights included a talk by Marilyn Albert of Massachusetts General Hospital, in which she described MRI and SPECT studies to define which sorts of measurements best enable a prediction of who will convert from “questionable” to overt AD. The goal is to pick up selective changes in the brain that distinguish those who have normal age-related memory lapses from those with incipient AD. Studying a cohort of 123 people with a diagnosis of questionable AD and 42 controls who have been followed for several years, Albert has published previously that the entorhinal cortex shrunk in volume as people progressed from control status. The hippocampus also shrunk, but not until the subjects clearly had mild AD. To improve the accuracy of this prediction, Albert and colleagues included size measurements of the banks of the superior temporal sulcus and the anterior cingulate.
To address the most clinically important question, namely who of those with a “questionable” diagnosis will convert to AD, Albert et al. combined MRI and SPECT data. In unpublished work, they measured a total of nine regions of interest and used new SPECT quantification methods. This improved the prediction’s accuracy to 99 percent overall, and to 86 percent in that most difficult category. “This is much better than what a skilled neurologist could do,” she said.
In a similar study of 113 people with mild cognitive impairment (MCI) or clinical AD plus controls, Corina Pennanen of Kuopio University Hospital in Finland described MRI measurements revealing that entorhinal cortex volume is a better discriminator than hippocampal volume between controls and people with MRI. However, hippocampal volume better than entorhinal cortex volume distinguishes people with AD from controls and from those with MCI, suggesting that the hippocampus degenerates a bit later as the disease progresses. Over all, most talks echoed the finding that the entorhinal cortex heralds the earliest detectable changes, but that the hippocampus follows closely behind. This begins to settle the debate in the literature about whether morphometric measurements of the hippocampus were suitable in imaging early AD, says Albert.
Gene Alexander of Arizona State University in Tempe, used voxel-based MRI to measure how gray matter shrunk in cognitively normal people with one or two copies of the ApoE 4 allele. Previous work had shown that ApoE4 carriers show reduced glucose metabolism and greater declines in metabolism than those with the E2 or E3 alleles of this AD risk factor. Studying a group of 36 cognitively normal adults by imaging them once at baseline and then once again two years later, they found significant declines in certain brain regions of E4 carriers even though these people did not have any detectable cognitive decline. Homozygotes had a steeper decline than did heterozygotes for E4. E4 homozygotes also had greater degrees of whole brain atrophy than E2 or E3 carriers. Since all these findings are presymptomatic, this approach could eventually be used for diagnosis, said Alexander.
Mony de Leon of New York School of Medicine described a biomarker combination approach, in which hippocampal volume measurements together with CSF and plasma measurements of phosphorylated tau improved the specificity and sensitivity of either test alone. The combination did not, however, improve the clinical diagnosis. Gunhild Waldemar at Copenhagen University Hospital dampened the general enthusiasm, saying that the added value of these imaging approaches to a clinician’s daily practice will remain low as long as data analysis is non-standardized, control material is sometimes of poor quality, and the quality of the instruments varies greatly. She said that in her practice, volumetric measurements or other biomarkers offer real value only for a small minority of patients, such as middle-aged people with mild memory loss.
Scott Small of Columbia University described MRI studies in mouse models, asking whether MRI could pinpoint the lesion within the hippocampus inflicted by overexpressed AβPP. He showed that the CA3, CA1 areas change most between non-transgenic and transgenic mice. In normal aging, by contrast, the subiculum changes the most, confirming a previously found difference between normal aging and AD.-Gabrielle Strobel