R01AG068062

The Wandering Nerve: Gateway to Boost Alzheimer's Disease Related Cognitive Performance - Abstract

Series of disappointing clinical trial outcomes have ushered the Alzheimer's field (AD) into an era of preventive interventions. Researchers now recognize that AD is a continuum and that interventions should start in the pre-symptomatic phase. To that end, transcutaneous vagus nerve stimulation (TVNS) is a promising non-invasive approach, as its mechanisms have been attributed to the brain system that is initially affected by AD pathology, the norepinephrine locus coeruleus (LC) system.

Animal and preliminary studies in patients and healthy individuals from our group and others demonstrated that TVNS alters locus coeruleus (LC) and nucleus tractus solitarius (NTS) functioning and enhances memory. This indicates that TVNS targets the site of initial AD pathology and might have the potential to delay AD-related cognitive impairment. Thus, TVNS could address an important challenge in the field: non-invasively delaying disease progression prior to onset of cognitive decline or significant accumulation of pathology.

The overarching goal of this proposal is to apply single and repeated TVNS in pre-symptomatic older individuals with varying degrees of AD pathology, with the aim to determine the extent of the cognitive effects of TVNS in domains and time, and to relate TVNS outcome to demographics, neurophysiological properties of the LC and NTS as well as burden of AD biomarkers.

Our accomplishments in optimizing TVNS and sensitive cognitive measures, ultra-high field brainstem imaging and blood-based biomarkers allow us to examine our central hypothesis: that serial TVNS enhances memory functioning more than single, and in particular in at-risk individuals, in whom AD pathology burden is low to moderate and the NTS-LC system is still responsive to stimulation.

To that end, 140 pre-symptomatic older individuals (APOE-E4 enriched) will be enrolled to a double-blind randomized cross-over design of stimulation versus sham TVNS during 7T imaging and blood sampling. This will be followed by randomized allocation to repeated TVNS or sham for 2 weeks and a follow-up cognitive assessment after 2 months.

The results of this study will yield important information for future trials assessing TVNS in three important ways: 1) through investigating which cognitive domains are modulated by TVNS on the short and long-term, important for monitoring and determining outcome measures, 2) through identifying demographic characteristics, functional brain and AD-related markers that predict beneficial responses to TVNS, which will be important to identify trial eligibility (Aim 1 and 2) and 3) understanding biological pathways contributing to TVNS success to confirm target engagement, aid in biomarker stratification or enrichment of the population, and which could serve to monitor progression (Aim 2 and 3).

The research proposed is innovative because it aims to define the target population in whom TVNS can be efficacious, based on the known underlying biological pathways of both TVNS and AD. Refining the target population is critical as it is expected to inform eligibility criteria of large-scale randomized clinical trials, which in turn will contribute to their success in delaying disease progression.

The General Hospital Corporation

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE 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. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH 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 on Aging (NIA) [HHS - NIH]

Charlestown, Massachusetts 02129 United States

Single Zip Code

Non-Invasive Neurostimulation in AD/ADRD (R01 Clinical Trial Optional) (PAR-19-298)

Amendment Since initial award the total obligations have increased 444% from $838,407 to $4,558,716.