Funded Programs Early Detection

TDP-43 and tau as cerebrospinal fluid biomarkers to discriminate frontotemporal dementia subtypes

Summary:
Frontotemporal dementia (FTD) is one of the most prevalent forms of dementia, being second after the better-known Alzheimer\'s disease. FTD comprises a heterogeneous subgroup of dementia that can be distinguished by neuropathological inspection of the brain or at the genetic level. Analysis of the brains of FTD patients, obtained after death, revealed that the accumulation of two types of proteins form the major cause of FTD: almost half of the cases are characterized by inclusions formed by the so-called protein tau, and the remaining patients are mostly characterized by accumulation of the TDP-43 protein. In addition, these latter cases can be even subdivided into four subtypes based on extensive neuropathological analysis. Currently, it is not possible to differentiate between these various FTD subtypes during life. Our goal is to investigate whether a correlation exists between the neuropathological/genetic phenotype of FTD and the composition of cerebrospinal fluid (CSF). We hypothesize that CSF tau and TDP-43 levels reflect the underlying FTD pathogenesis and, as a consequence, provide a tool to diagnose FTD during life which may aid in directing future treatment strategies and clinical trial design. In this project, we aim to identify and quantify the presence of (abnormal) tau and TDP-43 proteins in the CSF. To reach this goal, we will develop new techniques to quantify these proteins. Our second aim is to investigate whether the combined analysis of CSF tau and TDP-43 levels may yield FTD subtype-specific CSF profiles that correlate with the neuropathological or genetic abnormalities. This approach has not been performed previously and we expect that this will yield valuable new tools for improved diagnostics of FTD and may also result in better tools for directing future treatment strategies and clinical trial design of this devastating disease.

Combined CSF biomarkers and GBA genotype for diagnosis of LBD

Summary:
Lewy Body Dementia (LBD) is the second most common dementia of the elderly. There is a strong need for tools to better distinguish Lewy Body Dementia from Alzheimer\'s disease (AD). This proposal is to combine two sorts of biomarkers, namely genotype and cerebrospinal fluid (CSF) protein analysis to develop a better tool to distinguish these two common dementias. We propose to recruit participants for CSF analysis and DNA genotyping for glucocerebrosidase (GBA) and apolipoprotein E (APOE). We have shown that GBA is a risk factor for LBD, and propose that combining CSF biomarker analysis with genotyping may allow distinction of LBD from AD.

Summary:
Lewy Body Dementia (LBD) is the second most common dementia of the elderly. There is a strong need for tools to better distinguish Lewy Body Dementia from Alzheimer\'s disease (AD). This proposal is to combine two sorts of biomarkers, namely genotype and cerebrospinal fluid (CSF) protein analysis to develop a better tool to distinguish these two common dementias. We propose to recruit participants for CSF analysis and DNA genotyping for glucocerebrosidase (GBA) and apolipoprotein E (APOE). We have shown that GBA is a risk factor for LBD, and propose that combining CSF biomarker analysis with genotyping may allow distinction of LBD from AD.

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.