Biomarkers that can effectively be used for early diagnosis or to track response to investigational therapies in clinical trials are critically needed for drug development. Marek Brzezinski (University of California, San Francisco) is seeking to identify those at high risk of postoperative cognitive decline, and is currently undertaking a clinical trial that will test whether preoperative brain Aβ levels predict cognitive decline after surgery. The information from this work may accelerate clinical trials and identify high-risk patients in need of preventative treatment.
While AV-45 (Avid Radiopharmaceuticals), an amyloid imaging agent for Aβ, has recently been approved by the Food and Drug Administration, no imaging agent for tau is currently available. Jeff Kuret (Ohio State University) is developing tau imaging biomarkers for early diagnosis, differential diagnosis, and monitoring response to treatment. The major barriers for development are selectivity and the binding potential, and Kuret is working to overcome these barriers using pharmacokinetic modeling.
A second tau imaging program was presented by Victor Villemagne (Austin Health and The Mental Health Research Institute) with data for 18F-THK523 in 20 patients. Interestingly, preliminary results showed higher white-matter retention in AD patients compared with control subjects, frontotemporal dementia patients, and progressive supranucleur palsy patients. Villemange reported that there appears to be a specific component to this largely nonspecific binding seen with other positron emission tomography ligands. However, at this time - with small patient numbers - it is difficult to parse out specificity.
In the frontotemporal dementia field, Marcel Verbeek (Radboud University Medical Center, Nijmegen) presented data on optimizing and increasing the sensitivity of a TDP-43 ELISA for CSF measurement. The hypothesis is that TDP-43 and phospho-TDP-43 measures could improve the diagnosis of frontotemporal dementia-tau versus frontotemporal dementia-TDP-43. While TDP-43 can be measured in the CSF with this assay, the phosphorylated tau/tau ratio was still the most effective at differentiating patients. Combining the total tau measurement with total TDP-43 may further enhance the diagnostic utility, but requires further validation.
On a systems-wide approach, William Seeley (University of California, San Francisco) discussed large-scale brain network mapping techniques to understand selective neuronal variability. Such an approach could be more sensitive to early changes and thus be useful in monitoring disease progression. Further short-term reliability studies and longitudinal natural history studies are in development.
Ying Wu (Northshore University Health System Research Institute) presented data on the development of an automated toolbox that extracts regions of interest and improves the spatial resolution of magnetic resonance imaging scans. In addition to magnetic resonance imaging, fibers in the hippocampus and entorhinal cortex can be tracked. The techniques have been validated on normal patients and recruitment is underway to compare results for AD patients.