R01AG070077

Neurobiological Mechanisms of Altered Cortical Plasticity in Type-2 Diabetes Mellitus - Project Summary

Nearly 25% of Americans aged 65 and older have Type-2 Diabetes Mellitus (T2DM), and more than half have elevated hemoglobin A1C indicating impaired glucose tolerance, or prediabetes. T2DM can affect the brain through neuronal toxicity of hyper- and hypoglycemia episodes, microvascular insults, impaired glucose transfer, and insulin resistance. The neurologic impact of T2DM is widespread and can lead to structural, functional, and metabolic brain changes. Clinically, T2DM is associated with faster cognitive decline and a higher risk of dementia, including Alzheimer's disease (AD).

The link between T2DM-associated brain changes and cognitive decline is not completely understood, resulting in a paucity of targets for therapeutic intervention. One potential target is cortical plasticity itself, the mechanisms of which can be assessed in vivo in humans using transcranial magnetic stimulation (TMS). This approach uses single-pulse TMS to index cortical excitability and a form of repetitive TMS called intermittent theta-burst stimulation (ITBS) to induce NMDA-receptor dependent changes in cortical excitability that resemble the synaptic mechanisms of long-term potentiation (LTP) plasticity.

In a previous NIH-funded study (R21 NS082870), which serves as the foundation for the current proposal, we used this TMS-ITBS approach to show that older adults with T2DM had reduced LTP-like plasticity compared to healthy controls. Moreover, plasticity in T2DM patients was associated with both cognition and cortical glutamate metabolism as assessed by magnetic resonance spectroscopy (MRS). We performed these TMS and MRS assessments in the motor cortex (M1) using electromyography to record the output of TMS as a motor evoked potential (MEP).

The current study seeks to extend these findings to brain regions more directly involved in cognition, including the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobule (IPL). We will combine TMS with electroencephalography (EEG) and use the TMS-evoked EEG potential (TEP) to index cortical excitability and its modulation by ITBS. Our pilot data supports this approach by showing that ITBS to M1 induces correlated changes in MEPs and TEPs and that the ITBS-induced modulation of TEPs in DLPFC and IPL are associated with tests of executive function and memory, respectively.

Our hypothesis is that cognitive dysfunction in T2DM is associated with abnormal glutamatergic neurotransmission, which can be assessed using TMS and MRS. We will perform these assessments in non-demented older patients with T2DM and demographically similar non-diabetic participants, divided into healthy and prediabetic subgroups on the basis of A1C levels. We will collect structural magnetic resonance imaging (MRI) measures of cortical atrophy and comprehensive neuropsychological testing, plus data on known AD risk factors, such as apolipoprotein-E4 status and plasma amyloid-beta levels.

If successful, this study will identify neurophysiological markers of cognitive impairment that are potentially modifiable and could thus be translated into therapeutic targets for interventions to slow cognitive aging in T2DM and reduce the risk of developing AD.

Beth Israel Deaconess Medical Center

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]

Boston, Massachusetts 022155400 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 385% from $883,634 to $4,283,713.