24 March 2005. With the myriad of different techniques that are now available to visualize changes in the brain, neuroimaging seems poised to make a real difference for people with neurodegenerative diseases. But at this point, it is well-nigh impossible to predict which of the multifarious incarnations of PET, MRI, and SPECT will win out and become standard practice for diagnosing, and monitoring the treatment of, Alzheimer disease and its harbinger, mild cognitive impairment (MCI). Add to that a second layer of confusion that arises from differences between imaging centers in the way they acquire and analyze data for what should be comparable approaches. This state of affairs, where many labs have developed their own approaches, calls for a broad effort to coordinate, validate, and hopefully reach consensus on the best ones, which scientists can then present to regulatory agencies in unison. Otherwise there is a danger that a weaker technology might be adopted for the wrong reasons.
At the 7th International Conference on AD/PD held earlier this month in Sorrento, Italy, Michael Weiner of the University of California at San Francisco outlined a new strategy that hopes to provide a clearer picture of the pros and cons of neuroimaging. Weiner is the principal investigator of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This five-year multi-site study aims to set standards for image acquisition, build a data repository, and determine which methods provide the most power when it comes to interpreting the efficacy of treatments in clinical trials.
The project is funded to the tune of $60 million. A third of that comes from industry, the remainder from the National Institutes of Health via the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering. ADNI plans to spend the first six months establishing standard MRI and PET imaging techniques across the 40 to 50 sites throughout the U.S. and Canada that are expected to participate in the initiative.
This standard methodology will then be used to acquire images from the 800 study participants the project hopes to enroll by July 2006, reported Weiner. Four hundred will have MCI, 200 will have AD, and 200 will be control cases. ADNI will take images every six months, on average, for two to three years. At every time point, these images will be taken: 1.5 Tesla MRI images of all patients, FDG PET images of 50 percent, and 3-Tesla MRI images of 25 percent of participants. At every time point, participants will donate blood and urine samples. The project hopes that at least 20 percent of the volunteers will agree to give CSF samples at 0 and 12 months. Indeed, Weiner emphasized how precious these samples are and said he hoped that many more than 20 percent will agree to a spinal tap. Patients will also undergo a clinical assessment at each visit.
The project is ambitious and will be quite arduous for the patients, said Weiner. One of the major difficulties he foresees is getting volunteers to agree to participate in this lengthy study knowing that they will not receive any non-standard treatment. ADNI hopes that by emphasizing the importance of the study for future patients, they will be able to recruit enough participants to meet their enrollment goals.
Over the five years, ADNI will establish a brain imaging and biomarker database, and develop improved methods for monitoring trials. Tasks will be divided between a clinical and a neuroimaging core. Weiner stressed that all data will be freely and rapidly available to anyone who wants to view them online. Some of the specific aims of the project are:
- to develop imaging standards akin to the ADAS-COG scores that are currently used to measure cognition;
- to improve methodology;
- to determine optimum methods for acquiring and processing images and biomarkers;
- to validate the imaging and biomarker data by correlating it with neuropsychiatric behavioral data;
- to provide a database and biological samples for the pharmaceutical industry.
Other investigators are: Leon Thal at University of California, San Diego, who heads the Alzheimer’s Disease Cooperative Study (ADCS) core; Clifford Jack, head of the MRI core, and Ron Peterson at the Mayo Clinic, Rochester, New York; William Jagust at the University of California, Berkeley, head of the FDG-PET core; John Trojanowski at the University of Pennsylvania, Philadelphia, head of the biomarker core (see his recent magazine article on the promise of biomarkers and how ADNI will help in their discovery); Arthur Toga at the University of California, Los Angeles, head of the informatics core; Laurel Beckett at the University of California, Davis, head of the statistics core. Peter Sneider from Pfizer serves as chair of the industry advisory board.
The imaging data will be available at the Laboratory of Neuro Imaging (LONI) at UCLA and can be freely downloaded for analysis. A clinical database run by Leon Thal’s group at the Alzheimer’s Disease Cooperative Study will also be freely accessible. Anticipating that distribution of biomarker samples could become a contentious issue, ADNI has enlisted the help of an independent, outside advisory committee that will be set up by the NIA and chaired by Flint Beal at Cornell University, New York. This committee will take requests for biomarker samples and decide how to divvy up the specimens. For more information on ADNI, go to the project’s website.—Tom Fagan.