Funded Programs Early Detection

Metabolomic Signatures of Preclinical and Early Alzheimer's Disease: Discovery of Novel Biomarkers for Drug and Disease Monitoring Investigator(s): Rima Kaddurah-Daouk, PhD Institution(s): Duke University Medical Center, Durham, NC

Summary:
Alzheimer's disease (AD) is the most common cause of dementia among the elderly and affects over 5 million Americans. Causes are not known and therapies are not optimal. Increasing evidence now suggests that the early pathogenesis of Alzheimer's disease is frequently characterized by progressive isolated memory deficits - referred to in research settings as amnestic mild cognitive impairment (MCI). It is important to study the different biochemical pathways that may be affected in AD and MCI. Metabolomics is a new but rapidly growing field that offers analytical instruments that can simultaneously quantitate thousands of substances present in a biological sample of interest, such as cerebrospinal fluid (CSF). In this collaborative project between Duke, University of Pennsylvania and centers of excellence in metabolomics and informatics the investigators plan to identify differences in banked CSF of a well characterized cohort of 90 subjects (30 AD patients, 30 MCI and 30 controls). This cohort is unique since thorough baseline testing is already completed and the cohort will have been followed for about two years before this funding period starts. The long-term goal is to then confirm these findings using the national multicenter ADNI biobank and clinical data. Future studies will connect these central changes with peripheral metabolic changes to enable identification of biomarkers that can be measured easily in plasma and that are also disease specific.

Expedient and Versatile Methods for the Production of Investigational Drugs for SPECT and PET Imaging of AD Investigator(s): Graham Jones, PhD Institution(s): Northeastern University

Summary:
Early detection of Alzheimer's disease (AD) can widen the range of intervention options available. While clinical diagnosis of late-stage AD had become quite accurate based on clinical and laboratory observations, diagnosing pre-symptomatic AD has remained a challenge. For this reason, there is a direct need for accurate and meaningful clinical imaging technologies for early diagnosis of AD and for monitoring efficacy of potential therapies. Photon emission computed tomography (SPECT) and positron emission tomography (PET) are two of the most promising technologies for clinical neuroimaging. In addition to providing insight to metabolic events and structural mapping, radionuclide imaging can be applied to investigational drug development by assessing the potency of agents used in combination with a SPECT or PET ligand. Though powerful, a limiting factor of these technologies is that the molecules used are chemically unstable and must be prepared and administered to the patient immediately prior to imaging, placing substantial limitations on the chemistry involved. There exists an acute need for new technologies for the production of imaging agents in order for the full potential of SPECT and PET to be realized in prognostic and diagnostic medicine and drug development for CNS disorders. A general challenge thus exists for medicinal chemists to be able to modify drugs with defined biological targets by rapidly and selectively introducing radionuclides to create "piggybacked" agents for SPECT and PET brain imaging. A new technology, outlined in this proposal, uses microwave energy to allow routine synthesis of designed imaging agents for PET and SPECT, and if developed fully, is likely to have a substantial impact in the field. This proposal outlines proof-of-principle studies on initial applications for this new technology for the study of CNS disorders. Extremely detailed brain imaging maps can be developed using PET and SPECT scanning, and in the case of AD and related CNS disorders (e.g. Frontotemporal Dementia), pathology can be assessed together with metabolic activity. Beyond assessments of CNS activity, the general methods will also be of use during the development of investigational new treatments for AD and related neurodegenerative diseases, by rapidly assessing the distribution of drugs in the brain. The chemistry community is now rising to this challenge and Northeastern University (NU) is playing a leading role. A major advance was recently made by chemists working in collaboration with NU's Center for Translational Imaging (CTI). The technology, which uses microwave energy, promises to allow routine synthesis of designed imaging agents for PET and SPECT, and if developed fully is likely to have a substantial impact in the field.

Spinal Fluid Proteomics for IVIg Immunotherapy Investigator(s): Kelvin Lee, PhD Institution(s): University of Delaware

Summary:
The proposal will use a sophisticated and novel technology for generating protein fingerprints of spinal fluid from patients who have participated in a Phase II AD immunotherapy clinical trial. These fingerprints will provide critical information that links disease modifying effects at the molecular level with the positive clinical outcomes that were observed. Ultimately, this research may lead to a new, sensitive and specific diagnostic test for AD that would also be used in monitoring the effects of drugs in clinical trials and in clinical practice.

Validation and Optimization of an Immunoprecipitation Assay for Amyloid Beta from Human Cerebrospinal Fluid Using Novel Antibodies Investigator(s): Tim West, Ph.D. Institution(s): C2N Diagnostics

Summary:
There is currently no validated biomarker for AD, making early detection and diagnosis, monitoring of disease progression, and the objective biological assessment of potential therapeutics in clinical trials difficult. C2N Diagnostics is a start-up company that is commercializing new technology developed at the Washington University, St. Louis, MO. This "break-through" technology provides a new method for the detection of ß-amyloid as it is synthesized and cleared in the brain. The test requires the administration of a radio-labelled amount of beta-amyloid to humans, followed by a spinal tap to obtain spinal fluid and determine how much beta-amyloid has been produced during a given period of time. It is considered that in Alzheimer's disease, more beta-amyloid is being produced, while with novel anti-amyloid drugs, one could measure and demonstrate the reduction in beta-amyloid. Thus, the test could be useful for early diagnosis and in monitoring effectiveness of new drugs in development for AD. The availability and further development of this test has very important implications for research and clinical care of patients with AD.

A Peripheral Molecular Biomarker for Alzheimer\'s Disease: Transgenic and Clinical Studies to Define CNS Pathophysiologic Significance Investigator(s): Daniel Alkon, MD Institution(s): Blanchette Rockefeller Neurosciences Institute

Summary:
There is an urgent need for early diagnosis in Alzheimer\'s disease for which therapeutic interventions might alleviate, and even slow, the progression of the disease. The considerable expense in clinical and brain-imaging-based diagnosis of AD, however, may limit drug discovery, development and clinical testing of drugs for disease treatment. To address this diagnostic need, Dr. Alkon\'s group has recently developed a novel peripheral molecular biomarker for AD based on a procedure that isolates cells from within the skin. In this proposal, Dr. Alkon will extend his initial findings to provide validation of the skin biomarker as an early diagnostic of AD.