Development and Validation of a Quantitative Diagnostic Biomarker for Silent Brain Injury

PROJECT SUMMARY Alzheimer's disease (AD) is among the leading causes of death and disability worldwide with the number of patients in the US estimated to reach 16 million by 2050, associated with an annual cost of care projected to reach $1.1 trillion. Vascular contributions to dementia contribute to the pathogenesis of AD and directly cause

vascular dementia, the primary AD-related dementia (ADRD). Presently, vascular dementia cannot be reliably diagnosed without costly MRI studies and detailed imaging analysis. There is a pressing need to develop better diagnostic tools, particularly those that target the vascular contributions to dementia in order to value the

contribution of vascular injury in establishing a dementia diagnosis. In addition, improving the ability to discriminate between AD and vascular dementia can directly inform prognosis and treatment plans. The goal of the proposed studies is to develop and validate a novel, minimally invasive diagnostic assay to discriminate AD

from vascular dementia. Sage Cerebrovascular Diagnostics has developed a panel-based diagnostic assay incorporating six interconnected inflammatory molecules that preliminary data indicate can reliably detect the presence of cerebrovascular injury. This panel-based assay to detect silent cerebrovascular injury using a

capture-detection immunoassay on the Luminex platform is technically reliable and reproducible across populations using a log-normalized, population mean-adjusted composite scoring approach. These diagnostic biomarkers for silent brain injury (SageSignalTM at-home test assay) are increased in individuals with

cerebrovascular risk factors for dementia including hypertension, diabetes, and stroke. Further, SageSignalTM at-home test assay results are sensitive for Magnetic Resonance Imaging (MRI) metrics of both early and late cerebrovascular damage as demonstrated on MRI. With extensive data indicating a link between inflammation

and cerebrovascular injury, the SageSignalTM at-home test assay is ready for diagnostic validation as a novel biomarker with utility in the diagnosis of AD and ADRDs. Here, we propose studies to validate the robustness of the SageSignalTM at-home test assay in the CLIA lab environment with establishment of pre-analytic, analytic,

and post-analytic performance characteristics (Aim 1), identify the optimal at-home collection methodology (Aim 2), and determine the sensitivity and specificity of the assay for vascular brain injury using clear pre-specific milestones to judge diagnostic accuracy (Aim 3). The proposed project will demonstrate that SageSignalTM at-

home test can function as a sensitive and specific innovative diagnostic tool to improve the detection and stratification of individuals with cognitive impairment due to vascular damage to the brain. At the successful conclusion of this Phase I SBIR, we will have a novel and minimally invasive biomarker test ready for subsequent

clinical prospective validation to identify individuals at risk for vascular cognitive impairment and discriminate between individuals with different subtypes of dementia. This will not only advance the care of AD/ADRD and expand the tools available to providers to reduce the overall burden of dementia while biologic insights.