SMART-HS: Supplemental Funding Request to Complete NIA R01AG061111

Abstract The proposed project is a pilot clinical trial to treat hippocampal sclerosis of aging (HS-Aging), a prevalent, high-morbidity disease with symptoms that mimic Alzheimer’s disease (AD). The primary aims are to test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism for this prevalent cause of cognitive decline and dementia in the aging population as described below. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population, which has not been tested in humans for the purpose of preventing or treating dementia. “AD mimics” (diseases with pathologies other than AD-type plaques and tangles but with similar symptoms) are increasingly appreciated to be important causes of dementia. HS-Aging is a major subtype of “AD and related dementia” (ADRD), affecting ~10-25% of all persons beyond age 85 years, strongly associated with dementia, and with a very large public health impact. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-aging pathology both cross-sectionally and longitudinally in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, single- center, parallel arms design clinical trial of nicorandil in 62 participants (both sexes, >80 years of age, CDR<=1) who exhibit an HS-Aging profile in CSF biomarkers over a 100-week period (96 weeks of treatment, with a four-week post end of study safety visit); b. Evaluating the safety of nicorandil administration including careful cardiovascular assessments; c. Measuring structural MRI (3D-T1; hippocampal atrophy is primary outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and Abeta(1-42) at baseline and week 96; and, d. Conducting exploratory analyses to elucidate cardiovascular and metabolic effects of nicorandil to inform future trial design. Specific Aim #2: To optimize and further explore HS-Aging biomarkers, we propose the following: a. Refining MR imaging analysis (including arterial spin labeling, ASL) techniques that distinguish participants with probable HS-Aging from those with positive A/T/N (amyloid/tau/neurodegeneration) AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with Abeta (1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework (27) for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that predicts HS-Aging pathology, we will optimize the neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.