PI: Howard Rosen, MD, Neurology, UCSF
This proposal describes a plan to study frontotemporal lobar degeneration (FTLD) using the infrastructure established by the Alzheimer's Disease Neuroimaging Initiative (ADNI). FTLD is a common cause of dementia, especially in patients under the age of 65, with large economic and social costs. Over the next few years, potential therapeutic agents for FTLD will likely emerge and require clinical testing. In preparation for these clinical trials, it is important to establish precise, reliable and cost-effective markers for disease progression, to maximize the power of treatment trials to detect disease modifying effects. In the proposed study, 120 patients with FTLD and 120 age-matched controls will be studied with MRI, FDG-PET, and blood, urine and CSF biomarkers over the course of one year to determine the best regions and best methods for following the progression of FTLD. All patients will also undergo PIB-PET scanning, which identifies beta-amyloid plaques associated with Alzheimer's disease. The specific aims of the study are: 1) To identify the regions where FTLD shows greatest longitudinal changes in glucose metabolism, cerebral perfusion, and gray matter volume with the lowest variance, 2) To identify regions where FTLD shows greatest longitudinal changes with lowest variance in white matter tract integrity, 3) To contrast the performance of FDG-PET, ASL perfusion, gray matter volume and white matter tract integrity to detect longitudinal changes in FTLD, 4) To establish the clinical correlates of longitudinal changes in glucose metabolism, perfusion, gray matter volume and white matter integrity in FTLD, 5) To quantify the changes in CSF tau and A-beta1-42 levels and tau/abeta ratios over time in FTLD, and 6) To define the metabolic, structural imaging and CSF biomarker features predicting increased PIB retention with a clinical diagnosis of FTLD. Should these aims be achieved, the proposed study would provide firm data about which regions are the most sensitive indicators for following the course of disease in FTLD, and whether PET is significantly better than MRI for this purpose or visa-versa. The data would also provide estimates from which power could be calculated for clinical studies. All the data will eventually be available in a publicly accessible database for use by other researchers. PUBLIC HEALTH RELEVANCE: The frontotemporal lobar degeneration (FTLD) neuroimaging initiative will provide information on how to use brain images to follow the course of FTLD over time, and what techniques are best for this purpose. This information will be valuable to researchers planning trials of new medications for FTLD, so they can use brain imaging to help decide which drugs show the most promise for treating the disease.
Dr. Norbert Schuff is PI of a subcontract to this project. The overall goal of this subcontract is to determine the patterns of structural and functional brain changes over time in patients with FTLD. Specifically, this subcontract adds setup of MRI protocols at the participating imaging centers, quality assurance of MRI during the study, processing of structural, diffusion and perfusion MRI data and providing the data for analysis. This proposed subcontract will first establish and calibrate the imaging protocol for structural MRI and diffusion MRI at all three participating centers as well as arterial spin labeling MRI at the two sites which share a common platform (UCSF and MGH). Image calibration will be evaluated quantitatively using test-retest scans on a small number of subjects. For the main study, this subcontract will generate the following primary MRI quantitative variables: 1) probabilistic maps of gray matter, white matter, CSF, and white matter lesions (WML); 2) maps of mean diffusivity and fractional anisotropy based on diffusion tensor imaging; and 3) maps of cerebral blood flow based on arterial spin labeling MRI. Processing will be performed for 130 patients with FTDL and 130 control subjects, who each will have longitudinal MRI scans at 4 timepoints (0, 6, 12 and 18 months). Thus, a total of 1040 MRI sets will be processed. The results will be made available in a databank to allow voxelwise analyses of the imaging data. The work in this subcontract aims 1) to identify the regions where changes in metabolism and structure occur over time in FTLD, and to compare these changes with those that occur in normal controls, AD and MCI over the same time period; and 2) to establish the clinical correlates of longitudinal changes in local structural, diffusion, and perfusion alterations in FTLD: These changes will be analyzed across clinical subtypes. It is expected hat the proposed study will provide firm data on which brain regions are the most sensitive indicators for following progression in FTLD. In addition, the study will provide estimates of rates of progression of the disease, which could have huge diagnostic value, and for power calculations in clinical trials.
PI: Howard Rosen, MD, Neurology, UCSF