R01NS115771

Gas-Free Cerebrovascular Reactivity (CVR) MRI in Vascular Cognitive Impairment - Project Summary/Abstract

Vascular cognitive impairment (VCI) is the second leading cause of dementia after Alzheimer's disease (AD). However, while AD biomarkers are relatively well developed, biomarkers for VCI pathology in the brain are more limited. Cerebrovascular reactivity (CVR), an index of the cerebral vessel's capacity to dilate in response to stimulation, is a promising marker of the brain's vascular function. Our overarching hypothesis is that CVR is a plausible biomarker for the diagnosis of VCI, for which no other biomarkers are currently available.

Despite some promises, CVR is not commonly measured in clinical practice, primarily due to logistical difficulties in applying a vascular "challenge" during imaging. Current CVR measurement requires a vascular challenge during imaging, involving either the injection of a pharmacological agent (e.g., acetazolamide) or inhalation of CO2 gas. However, these strategies are not ideal in terms of both patient burden and costs, due to the complexity of the procedure, requirement of special equipment, and possible side effects of physiological maneuver to induce vascular challenge. Therefore, development of a CVR technique that does not need an explicit vascular challenge will broaden the clinical utility of CVR in the diagnosis of VCI and vascular dementia.

The central goal of this project is to develop a gas-free CVR MRI technique that can provide comparable sensitivity to CO2-inhalation CVR yet maintains a high comfort level to the subjects. This new technique is largely based on resting-state scan and exploits spontaneous fluctuations in the subject's breathing pattern, but also introduces intermittent modulations of their breathing rhythm to enhance fluctuations in their end-tidal CO2 (ETCO2). This project is divided into three logical steps.

First, we will develop the gas-free CVR technique in healthy subjects, for BOLD and CBF readouts as well as their integration (in Aim 1). Second, since previous work on gas-based CVR has suggested that a large portion (~2/3) of variations in CVR data can be attributed to physiological noise, we will identify physiological mechanism(s) of normal variations in gas-free CVR and then account/control for them in order to reduce variations (in Aim 2). We will focus on two of the most important factors that affect vascular tone in daily life, CO2 and caffeine levels, but will also consider other physiological factors.

Finally, we will apply the gas-free CVR technique in patients with mild cognitive impairment with and without vascular risk factors, and compare its diagnostic sensitivity to an established dementia biomarker of CSF ASS42 as a benchmark, in order to examine the utility of gas-free CVR as a potential biomarker in vascular cognitive impairment and dementia (in Aim 3).

Impact: Once these specific aims are accomplished, clinically practical methods of CVR will have been developed that will have important applications for the development of biomarkers (in conjunction with other biomarkers) for the diagnosis and treatment monitoring of vascular cognitive impairment and dementia.

University Of Maryland, Baltimore

(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]

Baltimore, Maryland 21201 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been extended from 07/31/25 to 07/31/26 and the total obligations have increased 562% from $483,923 to $3,201,560.