Funded Programs Early Detection

Frontotemporal Lobar Degeneration (FTLD) Biomarker Assays Investigator(s): Virginia M. Y. Lee, PhD Institution(s): Hospital of the University of Pennsylvania

Summary:
The laboratory of Drs. Lee and Trojanowski has recently discovered TDP-43 as the disease protein that accumulates in inclusions in Frontotemporal Lobar Degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Further, mutations in the TDP-43 gene (TARDBP) are associated with FTLD with ALS. This proposal aims to translate these exciting new discoveries into TDP-43 blood and spinal fluid biomarker tests for the early diagnosis of FTLD in order to expedite clinical trials of disease modifying therapies and to make these diagnostic assays available to the FTLD and neurodegenerative disease research community. Biomarker tests based on monitoring the levels of proteins from disease-specific central nervous system (CNS) lesions in biofluids have have been previously developed for Alzheimer\'s disease. In this proposal, Dr. Lee plans develop sensitive and specific diagnostic TDP-43 sandwich ELISAs utilizing the lab\'s knowledge about normal and pathologic TDP-43 modifications observed in FTLD-TDP brains. Successful development of these ELISAs will allow investigators to determine if various forms of TDP-43 in plasma and cerebrospinal fluids can be used as early and reliable biomarker tests to identify FTLD-TDP patients. Finally, these TDP-43 ELISAs will be made available to the scientific community of FTLD and neurodegenerative disease researchers world-wide to enhance the pace of finding better ways to establish an early diagnosis of FTLD-TDP and more effective disease modifying therapies to treat this disorder.

A highly accurate and predictive imaging tool for the diagnosis of dementias Investigator(s): Dawn Matthews, MS, MBA Institution(s): Abiant, Inc.

Summary:
Published data indicates that up to 50% of the people who have Alzheimer's disease have not been diagnosed, and misdiagnosis rates reach 20% even in leading clinical centers. Clinicians, caregivers, and families seek a definitive diagnosis in order to provide proper care. Early detection is vital, as even today's drugs can defer symptom progression when in early stages. Predictive diagnosis and response detection will become even more critical as promising pipeline drugs become available for specific dementias. Similarly, objective measures of disease and treatment response are important in order to evaluate and progress promising drug candidates. Building upon three important advances in the processing and analysis of PET image data, Abiant is developing an accurate, predictive, and commercially practical imaging diagnostic tool to assist in the diagnosis and development of effective therapeutics for patients with major neurodegenerative dementing disorders. These include Alzheimer's disease (AD), Lewy Body Dementia (DLB), and frontotemporal dementia (FTD), beginning with their earliest presymptomatic stages. The product would provide three significant benefits over other approaches: (1) superior accuracy and specificity, (2) early prediction of decline or response, and (3) practicality and clinical relevance allowing broad adoption. Abiant's work builds upon advances in the analysis of Positron Emission Tomography (PET) imaging and Magnetic Resonance Imaging (MRI) developed at New York University (NYU), and their integration with advanced pattern recognition algorithms and user focused design. The advances are significant because they allow measurement of regions that are early predictors of decline, and which distinguish the different forms of dementia. The pattern recognition we will employ is able to identify and quantify the complex changes associated with these dementias and make them interpretable for clinical use. The NYU approach has already been applied successfully to over 650 patients from multiple imaging sites, and using data collected through the Alzheimer's Disease Neuroimaging Initiatve (ADNI) program. The pattern recognition has been applied successfully in our drug development studies and to a pilot set of Alzheimer's data. This research and the positive results achieved have created a path to successful development. The commercial application of this work is twofold: (1) a diagnostic service and potentially licensable software package, where the customer audience includes radiologists, neurologists, general practitioners, and ultimately the general population as screening may be adopted over time; and (2) use in drug development trials.

Immunosignatures: a simple method to potentially diagnose Alzheimer\'s disease Investigator(s): Stephen Albert Johnston, PhD Institution(s): Arizona State University Foundation

Summary:
Progress in treating Alzheimer's disease will rest almost as much on the development of an effective and inexpensive diagnostic as it will on the therapeutics themselves. Ideally, a diagnostic would allow distinguishing AD from other dementias and allow detection of the disease before the onset of symptoms. If well people are going to use the diagnostic regularly it must also be inexpensive. Dr. Johnston and team have invented a simple technology -- immunosignaturing -- that may be useful toward these goals. It allows the display of the complexity of antibodies in an individual. If AD produces changes in the immune system and the investigators can read it on these arrays they have developed, it offering a new and simple way to diagnose AD.

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.