Circulating Blood-Based Diagnostic for Mild Cognitive Impaired Victims

DESCRIPTION provided by applicant This project aims to generate blood tests for mild cognitive impairment MCI and conversion risk from MCI to full blown Alzheimerandapos s disease AD We have reported that systemic footprints increases in key micro RNA miR levels are identifiable in AD blood samples here we suggest that this is also true for MCI the pre AD phase Our recent results suggest two stages of cognitive decline continuum Stage for key microRNAs increased from circulating blood of normal elderly controls NEC to that of MCI patients but not further to AD and Stage for specific circulating blood microRNA increases from MCI to AD This led us to suggest our mo del Stage circulating microRNAs as MCI specific biomarkers and Stage circulating microRNAs as biomark ers for conversion of MCI to AD Prototypes of these biomarkers are Stage miR b increases from NEC to MCI levels but not further in AD plasma samples Stage increased miR a andamp miR c levels observed only from MCI to AD but not from NEC to MCI plasma These results suggest that the MCI cognitive decline may start with increased Stage microRNAsandapos expression then Stage increases add insult to injury the for mer being MCI specific biomarkers and the latter specific for AD and or converter patients Our goal is then to establish two sets of stage specific biomarkers based on a highly reproducible data for identified blood micro RNAs b training datasets for next stage development for FDA approval and c validated specificity for de mentia due to AD in contrast to other types of dementia Toward this end Phase I will study archived sam ples each of MCI NEC and AD blood to attain Aim establishing the reproducibility of our protocol for opti mal blood microRNA assays and identifying lead microRNAsandapos origins by determining concordance and or dis cordance among the above three microRNAsandapos increases in three circulating blood compartments peripheral blood mononuclear cells PBMC plasma serum and its derivative exosomes and Aim identifying other members of four lead array profiled and PCR validated microRNA families miR andamp Let to expand our pool of candidate Stage and Stage biomarkers In Phase II Aim expands to a larger cohort of MCI patientsandapos samples to establish a Stage biomarker training dataset tracing microRNAs of these families Aim establishes a repertoire of Stage biomarkers in archived specimens from MCI subjects in our study of whom have converted to AD within the past decade by comparing freshly collected with archived blood samples from converters versus non converters by qPCR assays of the listed miRNAs and array profiling to identify additional novel ones and Aim establishes the identified biomarkers as specific for AD in contrast with non AD dementias i e Frontotemporal FTD Lewy body LBD and Parkinsonandapos s disease PD with dementia PDD Success of this project will provide blood miRNA based diagnostics for MCI and predict conversion from MCI to AD unprecedented tests to monitor disease onset progression and drug efficacy for novel therapies to retard the decline of MCI to bona fide AD PUBLIC HEALTH RELEVANCE Like Alzheimerandapos s disease AD health care mild cognitive impairment MCI due to AD suffers from the lack of a noninvasive blood test which is a major roadblock to MCI diagnosis in its absence the disease is largely de fined by neuropsychological assessment and costly MRI imaging and secondarily by identified cerebrospinal fluid biomarkers a less ideal approach due to its invasive nature This project aims to generate cost effective noninvasive blood tests for serial diagnosis and staging of MCI and its conversion to full blown AD based on unique biomarkers microRNA expressions whose levels in circulating blood are andapos footprintsandapos of disease patho genesis reflecting cognitive declin in brain Quantitative metrics of circulating key microRNAs may serve as numerical indices for diagnosis of MCI and prognosis of conversion to AD as well as objective drug efficacy measurements for novel therapies to retard the further decline of these victims from developing full blown Alzheimerandapos s disease and thus halting the tidal wave of a fast increasing aging population suffering this devastating mind robbing peril