Project Grant R43NS139747

A NOVEL BLOOD TEST FOR EARLY DIAGNOSIS OF FRONTOTEMPORAL LOBAR DEGENERATION - PROJECT SUMMARY OUR OBJECTIVE IS TO DEVELOP A BLOOD-BASED DIAGNOSTIC FOR EARLY DIAGNOSIS AND CLASSIFICATION OF FRONTOTEMPORAL LOBAR DEGENERATION (FTD). FTD IS A COMMON PRESENILE DEMENTIA THAT AFFLICTS AN ESTIMATED 60,000 PATIENTS IN THE US WITH MOST CASES OCCURRING BETWEEN THE AGES OF 45 AND 641. FOR PATIENTS UNDER 65, FTD IS THE SECOND MOST PREVALENT SUBTYPE OF DEMENTIA AFTER ALZHEIMER'S DISEASE (AD). FTD IS A HETEROGENEOUS NEURODEGENERATIVE DISEASE CHARACTERIZED BY PROGRESSIVE LOSS OF BEHAVIOR AND LANGUAGE SKILLS ASSOCIATED WITH DEGENERATION OF THE FRONTAL AND ANTERIOR LOBES1. CURRENTLY, AN ACCURATE DIAGNOSIS OF FTD TAKES APPROXIMATELY 3.6 YEARS1. THIS IS MAINLY BECAUSE DIAGNOSIS OF FTD IS COSTLY AND COMPLEX, INVOLVING NEUROLOGICAL TESTS, BRAIN IMAGING, A FULL SET OF BLOOD WORK (TO RULE OUT OTHER CAUSES FOR THE SYMPTOMS), AND SOMETIMES A LUMBAR PUNCTURE PLUS ELECTROPHYSIOLOGIC TESTING. AS A RESULT, UP TO TWO THIRDS OF PATIENTS FAIL TO COMPLETE TESTING, CONTRIBUTING TO THE ~58% OF ALL FTD PATIENTS REMAINING UNDIAGNOSED2. IN AD, STUDIES REVEAL THAT VARIOUS AGGREGATED PROTEIN VARIANTS, COMMONLY FOUND IN THE BRAINS OF PATIENTS, CAN ALSO BE DETECTED IN THE BLOOD, SHOWING PROMISE FOR THE DEVELOPMENT OF A BLOOD-BASED DIAGNOSTIC. SO FAR, STUDIES HAVE FOCUSED ON SINGLE MARKERS OVER A MULTIPARAMETER APPROACH, WITH NO CONSENSUS AS TO WHICH MARKER IS SUPERIOR3-9. CURRENTLY, THERE ARE NO KNOWN BIOMARKER ASSAYS AVAILABLE TO DIAGNOSE FTD. IT IS OUR HYPOTHESIS THAT A SIMPLE BLOOD TEST IDENTIFYING DISTINCT VARIANT OLIGOMERIC BIOMARKERS WILL ENABLE MORE ACCURATE DIAGNOSIS OF FTD. RECENTLY, OUR PROJECT TEAM APPLIED NOVEL BIOPANNING TECHNIQUES TO IDENTIFY SINGLE CHAIN ANTIBODY VARIABLE DOMAIN ANTIBODIES (SCFVS) THAT BIND TO DISEASE-SPECIFIC VARIANTS OF FOUR KEY NEURONAL PROTEINS IMPLICATED IN FTD AND RELATED DEMENTIAS: TAU, TDP-43, AB, AND A-SYN. OUR NOVEL SCFVS REACT ONLY TO THE VARIANTS FOUND IN BRAIN AND PLASMA SAMPLES FROM FTD PATIENTS, BUT NOT COGNITIVELY NORMAL CONTROLS10-12. MORE INTERESTINGLY, A SUBGROUP OF ANTIBODIES IS ABLE TO DISTINGUISH THE TWO MAJOR FTD SUBTYPES, FTD-TAU AND FTD-TDP. OUR PRELIMINARY RESULTS SUGGEST THAT A BLOOD BIOMARKER APPROACH MAY PROVE TO BE AN EXTREMELY VALUABLE TOOL TO DIAGNOSE FTD EARLIER IN DISEASE PROGRESSION, AND POTENTIALLY IDENTIFY FTD SUBTYPES. BUILDING FROM THIS INNOVATIVE WORK, THIS PROPOSAL IS DESIGNED TO DEVELOP A BLOOD-BASED DIAGNOSTIC FOR EARLY DIAGNOSIS AND CLASSIFICATION FTD. THE SPECIFIC AIMS ARE TO: 1) DEVELOP A LOW-VOLUME, ANTIBODY-BASED ASSAY FOR QUANTITATION OF PLASMA PROTEIN VARIANTS; 2) IDENTIFY THE OPTIMAL BIOMARKER SET FOR EARLY DIAGNOSIS AND STRATIFICATION OF FTD SUBTYPES; 3) MEASURE THE ASSAY PERFORMANCE IN A BLINDED STUDY OF ANTE-MORTEM FTD PATIENT SAMPLES. A NOVEL BLOOD TEST FOR EARLY DIAGNOSIS AND CLASSIFICATION OF FTD WOULD PROVIDE A SIGNIFICANT ADVANCEMENT FOR A CLEAR UNMET MEDICAL NEED.