R01NS128843

Novel Volumetric Optical Microscopy to Unravel Cerebral Microvascular Architecture and the Role in Functional Neuroimaging in Human Alzheimer's Disease - Project Summary

Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests as progressive loss of memory and the ability in thinking and action. Despite thirty years accumulation of our knowledge on the pathological mechanisms, over 400 clinical trials of drugs targeting the pathological pathways have largely failed to reduce cognitive decline.

Recent evidences from epidemiological, neuroimaging, and clinical reports have suggested that vascular contributions are critical in the pathogenesis of AD. A reduction of cerebral blood flow (CBF) has been recognized in preclinical AD population, many years before the onset of symptoms and the observed structural atrophy in the brain. In parallel, vascular pathophysiology is associated with a lower threshold of AD pathology in cognitive decline and dementia.

The characteristic of preceding vascular alterations may offer a new opportunity in early-stage AD diagnosis and therapeutical assessment. However, current in vivo neuroimaging tools such as magnetic resonance imaging (MRI) and functional MRI (fMRI) exclusively focus on large vessels, due to their limited resolution and sensitivity, while leaving the microvascular territories largely unexplored.

Our biophysical simulation work and other studies have indicated that capillaries, small arterioles and venules could contribute more than 50% of fMRI signals and alterations of microvascular architecture lead to profound functional changes in the human brain. Despite its intriguing insight on neurodegenerative diseases, those models were either based on oversimplified vascular geometry or anatomical networks derived from ~1mm3 of mouse cerebral cortex, which often failed to predict the complex architecture and hemodynamics in the human brain.

The goal of the study is to establish a multiscale optical imaging technique to unravel the microvascular architecture network in the human brain from single capillary level to tens of cubic centimeters of tissue blocks. Pivoting on a serial sectioning optical coherence tomography combined with a two-photon microscopy, the multiscale imaging technique leverages a high-throughput and thorough study of vasculature pathophysiology in AD progression.

The study will reconstruct volumetric architectural networks in human brain tissues at different stages of AD, seek for important features to characterize vascular pathological alterations, and correlate with quantitative neuropathological assessment to understand the converging path of AD pathology during disease progression.

With the foundation of imaging-based microvascular networks in the human brain, the study will further build a computational model to investigate the cerebral blood flow, oxygenation, and fMRI signals during AD progression. This computational framework has been validated using the microvascular anatomy and dynamics from small animal models, and here we extend it for the first time to the human cortex.

Completion of this project will significantly advance our understanding of the role microvascular architecture plays in AD progression that may open new avenues for early intervention and targeted therapy of AD.

The General Hospital Corporation

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Institute on Aging (NIA) [HHS - NIH]

Charlestown, Massachusetts 02129 United States

Single Zip Code

Selectively Target Technology Development to Understand How Changes or Dysfunction at the Capillary, Arterioles, and Small Lymphatic Vessels Level Can Have Long-term Impact on AD/ADRD (R01 Clinical Trial Not Allowed) (PAR-22-026)

Amendment Since initial award the total obligations have increased 284% from $798,774 to $3,069,316.