Tuesday, December 23, 2025 12/23/2025

Neurobiological mechanisms of altered cortical plasticity in Type-2 diabetes mellitus

Award Number: R01AG070077
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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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-associate 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 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	5	12/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $839,964 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	5	3/7/2025	NON-COMPETING CONTINUATION	$771,395
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	001	5	6/9/2025	NON-COMPETING CONTINUATION	$68,569
														Subtotal = $839,964

Issue Date FY: 2024 ( Subtotal = $851,427 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	4	2/16/2024	NON-COMPETING CONTINUATION	$766,286
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	001	4	6/28/2024	NON-COMPETING CONTINUATION	$85,141
														Subtotal = $851,427

Issue Date FY: 2023 ( Subtotal = $851,245 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	$851,245
														Subtotal = $851,245

Issue Date FY: 2022 ( Subtotal = $857,443 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$85,747
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	2	2/7/2022	NON-COMPETING CONTINUATION	$771,696
														Subtotal = $857,443

Issue Date FY: 2021 ( Subtotal = $883,634 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	1	2/22/2021	NEW	$883,634
														Subtotal = $883,634

Grand Total All Awards = $4,283,713

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Neurobiological mechanisms of altered cortical plasticity in Type-2 diabetes mellitus

Award Number: R01AG070077

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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