New DIAN Data
At this meeting, Bateman for the first time presented a glimpse of what kind of longitudinal data scientists can expect soon. By March 2012, some 40 DIAN participants have had two of each type of assessment (clinical, neuropsychological, MRI, FDG, PIB, CSF), and seven participants had three. By the end of this year, the number of baseline visits is projected to stand at 308; 100 people will have come for two visits, 60 people for three visits, and 10 will have completed their fourth. As the longitudinal data are coming in, they are being analyzed to estimate power for the planned trials.
Tammy Benzinger of WashU offered the latest cut of cross-sectional and some longitudinal PIB-PET imaging. Asymptomatic carriers show the first signs of amyloid deposition around 18 years prior to expected age at onset. From there, deposition spreads and becomes AD-like, even before the clinical dementia rating budges from 0 to 0.5. That spread appears to happen at roughly the same rate in each affected brain region, Benzinger said. Longitudinal data are beginning to show that, for each brain region, baseline and follow-up PIB measures correlate, such that uptake increases on the second compared to the first scan, Bateman added. How many participants a trial would need for PIB to detect a treatment effect depends on whether the treatment reduces the rate of amyloid growth, halts its growth, or even reduces the absolute amount of brain amyloid, as has been reported for two different immunotherapies (Rinne et al., 2010; Ostrowitzki et al., 2011). Thirty people per arm would be highly powered to see at least the last effect, Bateman said.
Furthermore, Bateman noted that the amyloid loads measured in DIAN, as well as other parameters such as standard deviation and annual increase in deposition, are comparable to those published for other MCI or AD observational cohorts such as ADNI and the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL).
These data raise the question of which amyloid PET tracers to choose for AD prevention trials. To help the clinical and pharma scientists address it, Victor Villemagne of Melbourne University, Australia, compared published data on the three most developed of the available candidates, florbetapir/Amyvid, flutemetamol, and florbetaben. All three stick to white matter longer than PIB, their signal is weaker, and their dynamic range smaller. Among these three 18F compounds, there are small differences as well. Therefore, these three 18F tracers are unlikely to pick up the very beginnings of amyloid deposition as sensitively as does PIB, said Villemagne. However, each of them is well capable of detecting whether there is significant amyloid in a prospective study participant’s brain, Villemagne added. Each can predict progression and support subject selection for trials. The tracer’s response to drug remains unproven, though florbetapir is being used in some ongoing AD therapeutic trials.
Florbetapir gained FDA approval for clinical use and is supported by Eli Lilly and Company; hence, it is likely to be available in the long run for trials that will last multiple years. Florbetaben was sold to the Indian company Piramal Imaging; Phase 3 autopsy data were presented at the American Academy of Neurology Conference in April of 2012 in New Orleans, Louisiana. GE Healthcare’s flutemetamol just completed an autopsy study and a biopsy study (see ARF related news story). A fourth compound, 18F-AZD4694, appears promising in early studies, with a signal much like PIB’s, but has not reached Phase 3 yet.
Villemagne works with Chris Rowe in a nuclear medicine center that tests all experimental amyloid tracers it can obtain. Asked essentially which tracer was the fairest of them all, Villemagne’s dodge injected a moment of levity into otherwise serious proceedings, “That I leave up to you. We practice promiscuity.”
Bateman presented Anne Fagan’s latest fluid biomarker data, which, like PET imaging, are beginning to include longitudinal results as DIAN participants undergo their second lumbar punctures. As expected, plasma Aβ40 is the same in non-carriers as in both asymptomatic and symptomatic carriers. Plasma Aβ42 is higher in carriers, but the data overlap and no clear age effect jumps out. Plasma Aβ42 does not differ strongly whether carriers are 30 years or five years away from their expected age at onset, Bateman said. Fagan and Bateman also showed data comparing DIAN’s CSF data to published data in sporadic cohorts using ADNI cutoffs. This comparison is limited because ADNI cutoffs were established with the help of an autopsy series and cognitive assessments, whereas the DIAN data come from living and, in large part, cognitively normal subjects, and were measured in different labs. With these provisos, the general trend in both sporadic and familial AD is that the amount of CSF Aβ42 in symptomatic individuals is reduced to about half that in controls, whereas tau and phospho-tau rise two- to threefold. “The take-home message is that DIAN CSF data are similar to sporadic AD CSF data,” Bateman said.—Gabrielle Strobel.
This is Part 1 of a two-part series. See also Part 2. Read a PDF of the series.