6 May 2003. Successful radiotracers for positron emission tomography (PET) diagnosis of AD are a mere year or two away, according to leading researchers who met on May 1-2 in New York. The real challenge now will be in convincing the Food and Drug Administration that the technology is valuable.
The Institute for the Study of Aging (ISOA) organized the meeting, titled "Facilitating the Development of PET Diagnostics for Alzheimer’s Disease," to evaluate the status of the technology in early diagnosis, disease monitoring, and drug development. The meeting brought together PET experts, officials from the National Institutes of Health, economists, and insurance experts. The general consensus among attendees was that PET is effective in identifying people at risk before the appearance of clinical symptoms.
The number of performed PET procedures doubled between 2001 and 2002 to an estimated 500,000, according to Nadeem Ishaque, a researcher at General Electric. The technology is sensitive to nanomolar concentration of biomolecules, can specifically target a large number of moieties, and can be quantitative. It is limited in its image quality-it has poor spatial resolution and high image noise-but those are surmountable problems, Ishaque said.
The most commonly used PET tracer, F18-labeled 2-Deoxy-2-fluoro-D-glucose (FDG), is an excellent marker of metabolic activity in the brain, according to Daniel Silverman of the University of California in Los Angeles. Even in cases that cannot be detected by standard clinical tests, brains are already hypometabolic and can be labeled as such with FDG. In a multicenter trial that used both brain imaging and autopsy data, PET had 93 percent sensitivity, 76 percent specificity, and an overall diagnostic accuracy of 86 percent. (Silverman et al., 2001: See ARF news story).
The specificity rate was lower than the sensitivity because hypometabolism can also result from other disorders, such as depression and hypothyroidism, yielding false positives for AD. Amyloid labeling may, therefore, be a more specific approach to diagnose early AD. There are several amyloid-specific radiotracers in development, three of which are the furthest ahead.
William Klunk has previously reported results with a thioflavin derivative called BTA-1. This Aβ imaging agent crosses the blood-brain barrier and binds amyloid with high specificity (see ARF related news story). At the meeting, Klunk showed dramatic images of labeling with 6-OH-BTA-1, also called the Pittsburgh compound B (PIB). In transgenic mice, the agent even identifies individual plaques (see also Bacskai, Klunk, and Engler presentations in Ipsen meeting report).
UCLA’s Jorge Barrio presented the results of labeling with F18-labeled FDDNP, which specifically labels deposits of amyloid plaques and neurofibrillary tangles (NFT) in living AD patients (see ARF related news story).
A third group, with Hank Kung at the University of Pennsylvania, is developing radiolabeled stilbenes and iodine-labeled imidazole pyrimidine compounds such as IMSB and TZDM (Kung et al., 2001; Kung et al., 2003). Any of the three projects could reach the clinic within a year or two; however, to be validated they need testing in prospective trials of AD or mild cognitive impairment that include adequate follow-up.
Kung pointed out that Aβ aggregates have two distinctive binding sites for tracers, binding to which is not mutually exclusive. He added that it is important to consider which binding sites are most significant clinically; researchers may need to use multiple ligands to get the whole picture. Using multiple probes could benefit the diagnosis of related diseases, as well. Aβ, tau, and α-synuclein all interact with each other in vivo, but various probes bind to the three elements differently. For example, iodine-labeled IMSB, but not iodine-labeled TZDM, binds to neurofibrillary tangles. The different probes could, therefore, be used to quantify the three elements and help distinguish among different diseases, which sometimes overlap in their pathologies and symptoms (see ARF related news story).
The participants agreed that no single imaging technology will be useful for every purpose. What the best approach is may depend on what one wants to find. For example, FDG-PET is best suited to detect neuronal activity, fMRI to measure cognitive reserve, and FDDNP-PET to establish plaque-tangle load.
Eric Reiman, University of Arizona, advocated using both PET and MRI in clinical trials to increase confidence in a drug’s clinical and disease-modifying effects and to minimize the chance of missing the drug’s therapeutic value. The technology can also be used to test the relevance of the amyloid hypothesis, Reiman said. To evaluate PET, researchers will need to design phase I studies-particularly longitudinal studies-that can run in parallel with other drug development. Reiman estimated that in a clinical trial, following a relatively small number of people over a relatively short time would be enough to detect an effect.
Reiman struck an optimistic note in an otherwise somber outlook on the FDA’s expectations for PET clinical trials. "It’s pretty clear that the FDA is ratcheting up to get higher and higher efficacy," said Henry Royal of the Mallinckrodt Institute of Radiology at Washington School of Medicine in St. Louis, Missouri. But imaging studies are rarely done with the same level of robustness as is required of other medical studies, Royal said. He added that "imaging people don’t think randomizing works," even though drugs are evaluated in randomized clinical trials.
To make brain imaging routine in AD diagnosis, the imaging community will either have to find a way to meet the FDA’s expectations or convince the FDA to alter its requirements. For example, even though UCLA received its first PET grant in 1978, the technology is still underutilized 25 years later, mostly because it is considered unavailable and expensive.
In the long run, many speakers argued, the cost of preventing or delaying AD may more than offset the cost of PET scans. In the US, AD ranks third in cost after cancer and cardiovascular disease; hospitalization and skilled nursing facilities represent the bulk of the expense. Studies show that available treatments can lower costs significantly. For example, donepezil treatment reduces cost by about $4,000 per patient per year (Hill et al., 2002). Other cholinesterase inhibitors such as rivastigmine and galantamine have had similar effects on cost-effectiveness.
Using imaging to augment clinical diagnosis will also result in more true positives and fewer false positives receiving inappropriate therapy, participants argued (see ARF related news story). While costs may increase from better detection and the resulting increase in early treatment, patients are likely to spend less time in more expensive disease states. Moreover, PET has been shown to be more effective than clinical criteria in evaluating early cases of AD. Because many clinicians lack expertise in psychometric tests, they fail to recognize symptoms in up to 72 percent of cases, said ISOA’s executive director, Howard Fillit. Despite all this, the American Academy of Neurology does not recommend either PET or SPECT for routine screening and, according to some attendees, neurologists rarely consider PET an option in diagnosis.
Imaging experts should be careful in claiming that imaging outperforms clinical criteria, William Jagust from the University of California in Davis cautioned. This view is based on a direct, but invalid, comparison of studies of imaging accuracy with clinical studies, which draw subjects from different populations. At the same time, if imaging experts consider clinical criteria inferior to PET, how can they use them to validate the technology? "You can’t have it both ways," Jagust said. The ideal approach combines imaging with clinical and genetic markers in the same study, some said, and current clinical trials are indeed doing so. Prevention strategies may be more effective in ApoE4 carriers, for example, because of their more rapid metabolic decline. This strategy may also become more effective as more genetic markers are identified.
A combination of those approaches should be used to attack AD in the silent period, when available interventions may do some good, said UCLA’s Barrio. Just as we don’t wait for a heart attack to prevent heart disease, he said, people should use PET and other strategies to catch AD before symptoms appear.
In the absence of effective intervention strategies, using PET-amyloid imaging raises issues of genetic testing, such as with Huntington’s disease. Researchers will have to be careful to pace preclinical diagnoses and prevention interventions so that there is something to offer those who are diagnosed with the new technology, the participants concluded.-Apoorva Mandavilli.
Apoorva Mandavilli is a science writer and editor based in New York.
Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA. 2001 Nov 7;286(17):2120-7. Abstract
Kung HF, Lee CW, Zhuang ZP, Kung MP, Hou C, Plossl K. Novel stilbenes as probes for amyloid plaques. J Am Chem Soc. 2001 Dec 19;123(50):12740-1. Abstract
Kung et al. Detection of amyloid plaques by radioligands for Abeta40 and Abeta42: potential imaging agents in Alzheimer's patients. J Mol Neurosci. 2003 Feb ;20(1):15-24. Abstract
Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME. Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6037-42. Abstract
Hill JW, Futterman R, Mastey V, Fillit H. The effect of donepezil therapy on health costs in a Medicare managed care plan. Manag Care Interface. 2002 Mar;15(3):63-70. Abstract