SBIR-STTR Award

This project responds to the important need for improved diagnostics for Alzheimer's disease (AD). Existingmethods based on biomarkers such as Ab and tau protein ratios from cerebrospinal fluid (CSF) are useful butincomplete. Furthermore, CSF sampling requires lumbar puncture and is too expensive for broad screening. Aclass of extracellular vesicles (EVs), exosomes, provide an attractive target for AD diagnostics. Exosomesfreely cross the blood-brain barrier and can be readily sampled in peripheral blood, enabling a blood-basedliquid biopsy. Exosomes also provide rich signatures for disease detection, including both proteins and nucleicacids (mRNA, miRNA, and other non-coding RNAs). The majority of studies on EVs and AD have beenperformed with bulk or batch analyses. Bulk analysis has a fundamental limitation because the relatively rareexosomes specific to the central nervous system (CNS) are easily confounded (swamped) by the exosomecontributions of peripheral cells. To overcome this limitation, we are developing methods for combinedprotein/nucleic acid analysis in single exosomes. Our innovative, high-content, high-throughput method isdesigned to simultaneously analyze, in one pass, up to 10 potential AD biomarker cargoes in as many as 107individual, CNS-tagged blood exosomes. These unique capabilities provide multiple advantages over previousapproaches. Our method can rapidly: 1) distinguish and separately analyze both exosomes and other EVs; 2)discriminate and simultaneously evaluate multiple CNS-specific exosome surface markers, whereasconventional approaches can only evaluate one CNS-specific surface marker at a time, significantly limiting theability to identify exosomes of CNS origin; 3) individually interrogate each and every exosome in a sample forits cargoes, dramatically raising information content compared to conventional methods where exosomecargoes must be pooled; and 4) search for unique combinations of biomarkers within unique, CNS-specificexosomal populations, an impossibility with conventional approaches. We therefore propose the followingstepwise objectives for this Phase I project. First, to optimize the combined protein/nucleic acid analysis ofexosomes produced by human SH-SY5Y cells. Second, to assay exosomes in brain homogenate samplesfrom rapid autopsies of 40 AD, 40 mild cognitive impairment (MCI), 40 non-AD neurological conditions(nADneuro) (e.g., Parkinson's disease, amyotrophic lateral sclerosis), and 40 normal elderly control (NC)subjects. Third, to assay exosomes in rapid autopsy blood samples from AD, MCI, nADneuro, and NC subjectsthat provided brain samples used in Objective 2. We anticipate that our novel imaging platform has the potential to become a new research/diagnostic/prognostic tool for the clinical management of AD or other pathologies in which EV/exosomal analysis couldprovide clinically useful information, such as other neurodegenerative diseases, cancer, and cardiovasculardisease. This capability may even assist in developing exosome-based therapies for these pathologies. PROJECT NARRATIVE Natural biological nanoparticles called exosomes are involved in neurodegenerative diseases, cancer and cardiovascular diseases, as well as in normal physiology. We will develop and test a new technology for detailed exosome analysis that, in the long term, is designed to improve methods for diagnosis and prognosis of Alzheimer's disease and other pathologies, and may ultimately lead to better outcomes and new treatment methods. Age ; ages ; Elderly ; advanced age ; elders ; geriatric ; late life ; later life ; older adult ; older person ; senior citizen ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Amyotrophic Lateral Sclerosis ; Amyotrophic Lateral Sclerosis Motor Neuron Disease ; Gehrig's Disease ; Lou Gehrig Disease ; Autopsy ; necropsy ; postmortem ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood ; Blood Reticuloendothelial System ; Blood - brain barrier anatomy ; Blood-Brain Barrier ; Hemato-Encephalic Barrier ; bloodbrain barrier ; Brain ; Brain Nervous System ; Encephalon ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cardiovascular Diseases ; cardiovascular disorder ; Cell Culture Techniques ; cell culture ; Cells ; Cell Body ; Centrifugation ; Centrifugation Fractionation ; Cerebrospinal Fluid ; cerebral spinal fluid ; spinal fluid ; Cost Analysis ; Cost Analyses ; assess cost ; cost assessment ; Diagnosis ; Disease ; Disorder ; Health ; Hematological Disease ; Blood Diseases ; Hematologic Diseases ; Hematological Disorder ; blood disorder ; Human ; Modern Man ; Immunoprecipitation ; Immune Precipitation ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Membrane Proteins ; Membrane Protein Gene ; Membrane-Associated Proteins ; Surface Proteins ; Methods ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Nucleic Acids ; Parkinson Disease ; Paralysis Agitans ; Parkinson ; Parkinson's disease ; Parkinsons disease ; Primary Parkinsonism ; Pathology ; Patients ; Physiology ; Proteins ; Research ; Research Institute ; Messenger RNA ; mRNA ; Sensitivity and Specificity ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Spinal Puncture ; Lumbar Puncture ; Technology ; Testing ; Time ; Amyloid beta-Protein ; Alzheimer beta-Protein ; Alzheimer's Amyloid beta-Protein ; Alzheimer's amyloid ; Amyloid Alzheimer's Dementia Amyloid Protein ; Amyloid Beta-Peptide ; Amyloid Protein A4 ; Amyloid β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Gender ; Measures ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; τ Proteins ; Structure of superior frontal gyrus ; Superior Frontal Convolution ; Superior Frontal Gyrus ; base ; Blood specimen ; Blood Sample ; improved ; Procedures ; Venous blood sampling ; Phlebotomy ; Peripheral ; Area ; Surface ; Clinical ; Phase ; Biological ; Neurologic ; Neurological ; anandamide ; N arachidonoyl 2 hydroxyethylamide ; N-arachidonoylethanolamine ; arachidonoyl ethanolamide ; arachidonoylethanolamide ; arachidonylethanolamide ; Evaluation ; peripheral blood ; Individual ; Disease Progression ; Inflammation Mediators ; inflammatory mediator ; Funding ; tau-1 ; p-tau ; p-τ ; phospho-tau ; phospho-τ ; phosphorylated tau ; Diagnostic ; sun ; The Sun ; Consensus ; Hour ; Source ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; particle ; Speed ; expectation ; novel ; novel technologies ; new technology ; Reporting ; Sampling ; Functional RNA ; Non-Coding ; Non-Coding RNA ; Non-translated RNA ; Noncoding RNA ; Nontranslated RNA ; noncoding ; Untranslated RNA ; CNS Nervous System ; Central Nervous System ; Neuraxis ; CALL protein ; CamL1 Gene Product ; Cell Surface Glycoprotein L1 ; F11 Glycoprotein ; L1 Cell Adhesion Molecule ; L1CAM ; NGF-Inducible Glycoprotein ; NILE Glycoprotein ; NILE Protein ; Nerve Growth Factor-Inducible Large External Glycoprotein ; Neural Adhesion Molecule L1 ; Neural Cell Adhesion Molecule L1 ; Micro RNA ; miRNA ; miRNAs ; MicroRNAs ; CD56 ; NCAM ; NCAM1 ; NCAM1 gene ; Mediator ; Mediator of Activation ; Mediator of activation protein ; Address ; Data ; Detection ; Diagnostics Research ; Clinical Management ; Cognitive ; Preparation ; Process ; Image ; imaging ; systems research ; virtual ; neuroinflammation ; neuroinflammatory ; design ; designing ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Outcome ; Population ; innovation ; innovate ; innovative ; fluorescence imaging ; fluorescent imaging ; minimally invasive ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; screening ; mild cognitive impairment ; mild cognitive disorder ; amplification detection ; imaging platform ; Alzheimer's disease pathology ; AD pathology ; Alzheimer's pathology ; imaging system ; prognostic tool ; exosome ; extracellular vesicles ; liquid biopsy ; Alzheimer's disease biomarker ; Alzheimer's biomarker ; Alzheimer's disease biological marker ; Alzheimer's biological marker ; Alzheimer's disease diagnosis ; Alzheimer's diagnosis ; Alzheimer's disease brain ; Alzheimer's brain ; detection method ; detection procedure ; detection technique ; Alzheimer's disease diagnostic ; AD diagnostic ; Alzheimer's diagnostic ; Prognosis ;