14 March 2013. Among global initiatives aimed at understanding how biomarkers elucidate the progression of Alzheimer’s disease, DESCRIPA appears to do much with little. Costing a mere €400,000 (about $520,000) in toto, this large, prospective study was launched in 2003 with the goal of developing guidelines for screening and diagnosing predementia AD in a clinical setting. How does this multisite project stack up against more expensive efforts, including the $140 million Alzheimer’s Disease Neuroimaging Initiative (ADNI)? DESCRIPA uses multiple protocols to collect data, while ADNI is standardized. Though the studies use different types of volunteers and procedures, they are complementary, scientists say, and several recent DESCRIPA papers, including one published last month in Neurology, seem to bear this out.
Headed by Pieter Jelle Visser of Maastricht University and VU University Medical Centre Amsterdam in the Netherlands, DESCRIPA recruited 881 seniors with mild cognitive impairment from 20 academic memory centers in 11 countries. Between 2003 and 2005, the study enrolled people and followed them for two to five years. In this initial phase, supported by €350,000 from the European Commission, investigators collected medical history, lifestyle information, blood and cerebrospinal fluid (CSF) measurements, cognitive data, as well as magnetic resonance (MR) and other neuroimaging scans. They analyzed which of these baseline markers could best identify those who progressed to AD at follow-up several years later (Visser et al., 2008). The European Commission later gave DESCRIPA an additional €50,000 for a second phase that investigates potential AD markers and risk factors in ongoing, population-based studies in Europe.
All data were collected for DESCRIPA as part of routine clinical practice at each center, which means there is no rigid standardization, Visser said. To deal with the variability of these assessments, researchers analyze pooled data. For example, researchers at Imperial College London, U.K., and VU Medical Center, Amsterdam, the Netherlands, independently analyzed imaging data, while CSF analysis was conducted in Gothenburg, Sweden. For cognitive batteries, the team pools scores from four domains—memory, language, visual/drawing, and attention/executive function—and converts them into “z scores” that measure deviation from the norm. For example, a z score of -2 indicates that the participant fell two standard deviations below the average score for people in the same age group. “The strength of this approach is that it reflects clinical practice,” Visser said. By contrast, ADNI participants undergo all biomarker measurements with standardized protocols in order to simulate a clinical trial.
Lack of standardization may not be a fatal weakness, as Visser and colleagues show in a paper recently accepted for publication in Neurobiology of Aging. The researchers examined four medial temporal lobe measurements in MCI patients and found that each identified who would progress to AD in the multicenter DESCRIPA study just as well as in a single-center cohort. This suggests that the MRI measures should work even in a clinical trial involving multiple sites that use different MRI scanners, Visser said.
How have DESCRIPA scientists put this shoestring budget to effect? Last year, Visser and colleagues reported that CSF amyloid and tau, and MRI measures of hippocampal volume, helped identify MCI patients who progressed to AD (Vos et al., 2012). DESCRIPA scientists found that hippocampal atrophy and CSF measures of tau and phospho-tau predicted further cognitive loss in MCI patients with abnormal CSF Aβ1-42 (van Rossum et al., 2012). And in a Neurology paper published online February 27, first author Stephanie Vos of Maastricht University and colleagues report that CSF Aβ42 and tau, MRI hippocampal volume, and the risk allele apolipoprotein E4 predicted progression to AD even in people with MCI of the non-amnestic variety (naMCI).
Compared to amnestic MCI patients who have memory loss as a dominant symptom, people with non-amnestic MCI have deficits in other thinking skills, and a smaller proportion of them develop AD. Yet according to revised AD diagnostic criteria (see ARF related news story and ARF Webinar), the National Institute on Aging and the Alzheimer’s Association criteria consider both forms of MCI as potential prodromal stages of AD. Vos and colleagues were able to identify who in aMCI and naMCI groups progressed to AD with comparable accuracy. “We were surprised to find that the biomarkers were equally predictive in both groups,” Vos told Alzforum.
Beyond the recent finding that AD biomarkers are useful in aMCI and naMCI, DESCRIPA studies have shown that MCI patients progress to AD dementia at an approximate rate of 15 percent per year. These figures are comparable to ADNI’s, noted Ron Petersen of the Mayo Clinic, Rochester, Minnesota.
Yet DESCRIPA and ADNI differ in several key ways. In one sense, DESCRIPA is more focused because it studies a single predementia population, while ADNI aims to validate AD biomarkers across the disease spectrum, enrolling cognitively normal elderly and mild AD patients in addition to people with MCI. In another sense, DESCRIPA is broader than ADNI because it includes people with non-amnestic MCI, whereas ADNI only enrolls amnestic MCI patients. By comparison, the population-based Mayo Clinic Study of Aging aligns with the typical clinical setting even more so than DESCRIPA, said Petersen. He heads the Mayo study, which tracks cognitively healthy elderly people randomly selected from local communities to see if they develop MRI or dementia (see Roberts et al., 2008). ADNI, with its use of state-of-the-art technology and standardized protocols, is least generalizable to a typical clinic setting. Across the globe, the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing, AIBL for short, lies between DESCRIPA and the Mayo study. Like DESCRIPA, AIBL brings in people from the community who are worried about their memory. However, the AIBL sample is not random; it consists of those responding to a general advertising campaign.
On cost, AIBL’s $4 million per year, to a total of $28 million since its start in 2004, lies between the thrifty DESCRIPA and the costly ADNI, noted Christopher Rowe of Austin Hospital, Melbourne, a lead scientist on the AIBL research team. Because DESCRIPA relies on data from tests in routine clinical use, it does not include cutting-edge research technology such as positron emission tomography (PET) imaging measures of brain amyloid or glucose metabolism.
DESCRIPA and the other initiatives share a common goal, which is “to elucidate AD biomarker trajectories in the context of cognitive and clinical measures,” Aisen said. “It’s terrific that all these groups talk with one another and collaborate to contribute to progress.” As an example of this, DESCRIPA and ADNI researchers published a joint paper last year, linking anxiety with CSF biomarkers in people with MCI (Ramakers et al., 2012). And like ADNI, which has advanced public data sharing and collaboration, a major effort is underway in Europe to improve access to research data in order to speed research. The philosophy of this new initiative, called the European Medical Information Framework (EMIF), is similar to that of DESCRIPA. “You can address some major research questions by using existing datasets,” Visser said. EMIF is funded by €56.4 million from the Innovative Medicines Initiative (IMI), which is a joint undertaking between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA).—Esther Landhuis.
Vos SJ, van Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund LO, Hampel H, Tsolaki M, Minthon L, Frisoni GB, Froelich L, Nobili F, van der Flier W, Blennow K, Wolz R, Scheltens P, Visser PJ. Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI. Neurology. 2013 Feb 27. Abstract