Modular Design-Accelerated Development of Minimally Invasive Dried Plasma and Saliva Tests for Detecting TBI Sequelae for AD Dementia
Abstract
Background: U.S. military Service Members and civilians are at risk of acquiring single or repeated traumatic brain injury (TBI), including non-blast and blast pressure wave induced TBI, and are also at increased risk for Alzheimer’s disease (AD) and AD-related dementias (ADRD) over time. How can we predict whether a TBI patient might develop AD/ADRD? How can we determine if this patient is responding to treatment? Since 2008, considerable progress has been made on the development of blood and cerebrospinal fluid (CSF) biomarker tests for TBI and AD/ADRD patients. However, current tests are not able to identify those at highest risk for post-TBI cognitive decline who might develop AD/ADRD and benefit from prompt treatment. Moreover, current tests are not practical for chronic TBI patients who were injured months to years ago and are no longer hospitalized. This is particularly true now during the COVID-19 pandemic when older patients are justifiably reluctant to come to the hospital or testing site several times a year. Lastly, different tests are needed for distinct types of post-TBI cognitive decline. Hypothesis: We hypothesize that a new, game-changing “modular-design” approach will allow us to quickly develop practical dried plasma or dried saliva biomarker tests that civilian or military TBI patients can give themselves at home or during prolonged field care, respectively, to establish whether they are post-TBI cognitive decliners that might develop AD/ADRD. Unlike traditionally slow, linear approaches to developing biomarker tests, we will develop five interacting and interrelated modules with various submodules in parallel. Like pieces in a puzzle, we will select the best submodule combinations for distinct types of post-TBI cognitive decliners to see the big picture. In Module 1, to develop our tests even more quickly, we propose to collect and test samples from distinct types of TBI patients, including: (i) older civilian patients with acute TBI; (ii) older civilian and military patients with subacute and chronic TBI; (iii) adults of all ages with chronic military TBI; and (iv) older adults with consensus diagnosis of normal cognition, mild cognitive impairment, and AD confirmed by CSF protein biomarkers. These samples will be used for discovery and verification of protein and microRNA biomarkers of post-TBI cognitive decliners. In Module 2, to provide a meaningful metric to correlate biomarkers to, we will begin to define distinct types of post-TBI cognitive decliners with cognitive tests given at multiple time points. At least 10 cognitive tests will be evaluated. In Module 3, to make time-course sampling of biomarkers in chronic TBI patients more practical, we will develop new biomarker tests for wet/dried plasma and wet/dried saliva. In Module 4, we will begin to define distinct types of post-TBI cognitive decliners by testing for top-ranked biomarkers in dried plasma and dried saliva. At least 10 protein biomarkers and at least 10 miRNA biomarker pairs will be evaluated in each sample at multiple time points. Here, we will begin to link cognitive test results from Module 2 to reveal which types of biomarkers and samples are the best for spotting distinct types of post-TBI cognitive decline. For example, the “remembering to remember” or Memory for Intentions Test might be strongly correlated to levels of the protein Tau over time in dried plasma from older civilian and military patients with subacute and chronic TBI. Tau has been shown to be an important biomarker for both TBI and AD in blood and CSF tests. In Module 5, we will optimize the detection of multiple biomarkers at the same time with three distinct types of testing machines. For example, we might discover that one type of testing machine is easier to use or is more sensitive or specific than another machine for detecting multiple protein or microRNA biomarkers. This is a critical step for making sure the tests can be widespread
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110469
Entities
People
- William Haskins
Organizations
- United States Army