U24NS141774

Aria pathophysiology characterized by in vivo neuroimaging, plasma biomarkers and post-mortem proteomics - project summary

There is an urgent and crucial unmet need for tools and resources developed to understand the vascular pathophysiology of in vivo neuroimaging findings in amyloid-related imaging abnormalities (ARIA).

We propose to develop and validate a comprehensive set of in vivo and ex vivo post-mortem MR imaging protocols, along with analytical tools focusing on vascular pathogenesis and pathophysiology.

These resources will help link MR imaging findings with clinical symptoms, cognitive functions, plasma biomarkers, and histopathological findings in a cohort that will be longitudinally followed with both ante-mortem and post-mortem data.

We have assembled a multi-disciplinary research team with leading experts in several key aspects of the proposed study to achieve the following specific aims.

Specific Aim 1. Characterize the vascular pathology contributing to ARIA using advanced MRI techniques in a prospective cohort of patients developing ARIA following anti-amyloid antibody treatment, compared to controls.

Utilizing multi-modal vascular imaging protocols including the widely applied MARKVCID 3T imaging protocol with high reproducibility, we will assess water permeability across a vessel wall, cerebrovascular reactivity (CVR), and cerebral blood flow (CBF) before and after anti-amyloid treatment.

Additionally, free water (FW) imaging, peak width of skeletonized mean diffusivity (PSMD), and cerebral oxygen metabolism will be used to assess neuronal/axonal injury associated with ARIA.

Specific Aim 2. Characterize longitudinal changes of plasma biomarkers before and after ARIA is identified and correlate these changes with the imaging findings described in Aim 1 and clinical performance in patients with and without ARIA.

The plasma biomarkers include markers of neurodegeneration, neuroinflammation, and vascular pathology used in studies of Alzheimer's disease (AD) and AD-related dementias (ADRD) to better understand disease mechanisms and identify ARIA risk factors.

Specific Aim 3. Conduct histopathology and proteomics studies on patients with ARIA who have participated in Aims 1 and 2 as well as utilizing available post-mortem brains from other patients with ARIA, to provide mechanistic insights and potentially identify novel ARIA-associated biomarkers.

Specific Aim 4. Develop in vivo and postmortem tools and resources, along with relevant biomaterials of ARIA, to be shared with the research community from the above studies.

We will leverage the synergy between the current project and two other large ongoing studies, which focus on in vivo clinical biomarkers and vascular pathophysiology, alongside postmortem tools and resource development for AD/ADRD.

This unique synergetic effort will greatly enhance the success of our initiatives.

Together, we aim to build a comprehensive schema for capturing metadata in prospectively designed in vivo and ex vivo studies.

This schema will aid in determining the cause, impact, and prognosis of ARIA, ultimately informing future clinical guidance.

New York University

(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.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

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

New York, New York 100166066 United States

Single Zip Code

Tools and resources to understand the vascular pathophysiology of in vivo neuroimaging findings in ARIA (U24 - Clinical Trials Not Allowed) (RFA-NS-24-034)