Project Grant R21AG085366

IMPAIRED CEREBRAL METABOLISM AND BLOOD FLOW BY NEURONAL AND ASTROCYTIC DYSFUNCTIONS IN ALZHEIMER'S DISEASE - ABSTRACT ALZHEIMER'S DISEASE (AD) IS A MAJOR GLOBAL HEALTH CRISIS, IN USA ALONE 6 MILLION PEOPLE ARE DIAGNOSED WITH AD, AND WITHOUT ANY BREAKTHROUGH THIS NUMBER WILL BE DOUBLED IN THE NEXT 3 DECADES. WHILE NEW TREATMENTS (E.G. LECANEMAB) CAN EXTEND THE SELF-SUSTAINING LIFE TO 5-6 MONTHS, EFFECTIVE AD TREATMENT STILL DOES NOT EXIST, PARTIALLY BECAUSE OF THE LACK OF COMPREHENSIVE UNDERSTANDING OF THE ORIGIN AND AD DEVELOPMENT. COGNITIVE DYSFUNCTION HAS BEEN LINKED TO ALTERED BRAIN FUNCTION AND STRUCTURE. RECENT BRAIN IMAGING STUDIES OF AD PATIENTS SUGGEST ABNORMAL BRAIN ACTIVITY AND CONNECTIVITY, HYPOMETABOLISM, AND LOSS OF CEREBRAL AUTOREGULATION, IMPLYING SEQUELAE OF DYSFUNCTIONAL EVENTS OCCURRING WITHIN THE NEUROGLIOVASCULAR UNIT. THE HYPOMETABOLISM HYPOTHESIS OF AD IS THAT DECREASE IN GLUCOSE METABOLISM CAUSES INSULIN RESISTANCE WHICH CONSEQUENTLY ALTERS AMYLOID PRECURSOR PROTEIN PROCESSING, CAUSES OXIDATIVE STRESS WHICH LEAD TO MITOCHONDRIAL DYSFUNCTION, AND CHANGES THE NEURONAL AND GLIAL SIGNAL TRANSDUCTION. TECHNOLOGICAL BARRIERS HAVE LIMITED THE POSSIBILITY OF DISENTANGLING WHEN EXACTLY NEURONAL AND/OR ASTROCYTIC DYSFUNCTIONAL EVENTS OCCUR IN RELATION TO HYPOMETABOLISM, EXHAUSTED CEREBRAL AUTOREGULATION, AND VASCULAR DAMAGE. TO UNRAVEL THE SEQUELAE OF NEURONAL AND ASTROCYTIC DYSFUNCTIONS IN RELATION TO CEREBRAL METABOLISM AND CEREBROVASCULAR HEALTH, WE PROPOSE A NOVEL FUSION OF OPTICAL-MRI TO STUDY AD LONGITUDINALLY. WE WILL CONDUCT MULTI-MODAL OPTICAL-MRI EXPERIMENTS IN MICE DURING AD PATHOGENESIS, SPECIFICALLY WITH INNOVATIVE ADVANCES THAT ALLOW SIGNIFICANTLY HIGHER SENSITIVITY OF CA2+ IMAGING AND WITH A NEWLY DEVELOPED MULTI-WAVELENGTH OPTICAL SYSTEM TO MEASURE REFLECTOMETRIC HEMOGLOBIN SIGNALS. CONVENTIONAL FMRI WILL TRACK ALTERED FUNCTIONAL CONNECTIVITY AND CEREBROVASCULAR REACTIVITY, CALIBRATED FMRI WILL MEASURE FLOW-METABOLISM UNCOUPLING, AND 3D TIME-OF-FLIGHT (TOF) ANGIOGRAPHY WILL MAP DAMAGED MACROVESSELS. USING THE REFLECTOMETRIC SIGNALS TO MEASURE BLOOD VOLUME, AND 2D FLUORESCENCE IMAGING TO MAP NEURONAL (RED) AND ASTROCYTIC (GREEN) ACTIVITY, AND ANGIOGRAPHY OF MICROVESSELS (I.E., 40MM) MAPPING BY MRI. OUR SPECIFIC AIMS ARE TO BEHAVIORALLY MONITOR THE DEVELOPMENT OF AD TO DETERMINE THE ONSET OF AD, BUT IN CONJUNCTION WITH MAPPING DEFICITS OF NEURONAL/ASTROCYTIC DYSFUNCTION IN RELATION TO HYPOMETABOLISM AND REDUCED CBF REGULATION IN AD BRAIN, AND MICROLEVEL TO MACROLEVEL IMPAIRMENTS OF CEREBRAL VASCULATURE IN AD BRAIN IN A SERIES OF LONGITUDINAL EXPERIMENTS. MEASURES OF FUNCTIONAL ACTIVITY AND CONNECTIVITY, CEREBROVASCULAR REACTIVITY, METABOLISM, AND VASCULAR HEALTH IN AD BRAIN WILL REVEAL INSIGHTS OF WHEN AND WHERE THESE DYSFUNCTIONS OCCUR AND HOW DISTRIBUTED THEY ARE, INFORMATION WHICH COULD GUIDE AND TRACK TARGETED TREATMENTS OF AD PATIENTS. IN SUMMARY, THIS IS AN EXTREMELY SIGNIFICANT SCIENTIFIC GOAL BECAUSE IT CAN REVEAL NEURONAL, ASTROCYTIC, AND VASCULAR INTERACTIONS UNDERLYING AD METABOLISM.