microRNA in Cerebral Spinal Fluid as Biomarkers of Alzheimer s Disease Risk After Brain Injury
Abstract
Alzheimer s disease (AD) is a neurodegenerative disorder, with symptoms progressing from mild cognitive impairment to debilitating dementia developing over ~10 years. Unfortunately, years of accumulated damage have already occurred by the time that symptoms are apparent. Once diagnosed, AD progression can be slowed, but not stopped, with currently available therapies. The greatest known risk factor for AD is aging; more than 10% of Americans over the age of 65 have AD, placing significant care and financial burdens on families, caregivers, and the medical system. Beyond aging, the precise cause(s) of AD are unknown, although genetic risk factors have been identified. Relevant to this proposal, a history of a traumatic brain injury (TBI) increases odds for developing AD by 2.5 times in the general population, and by 4-6 times in the military population. Between the years 2000 and 2014, more than 313,000 TBIs have been reported by the Department of Defense; as these Veterans age, the care burden on families, social services, and the Veterans Administration will continue to escalate. Treatment for AD currently begins at the onset of cognitive and memory impairment. While early treatment of cognitive impairment has the greatest efficacy, significant irreversible brain damage has already occurred by the onset of clinical symptoms, and current treatments can only slow the continuing degeneration. Thus, establishing a distinction between AD and stress, normal aging, or other central nervous system disorders that result in cognitive impairment is essential, as each disorder responds best to different treatments. Levels of the protein biomarkers amyloid beta (A-beta) and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) are very sensitive indicators of AD-specific brain pathology and are used along with cognitive and behavioral tests to confirm an AD diagnosis. One surprising limitation of these biomarkers is that individuals with no signs of cognitive impairment may have protein levels indicating AD; it is not yet clear whether this might reflect a very early disease stage or whether additional, as yet unknown, processes are involved in AD. We know that brain protein expression is altered in individuals with AD and that some of these changes can be detected in CSF. Protein expression is regulated in part by microRNAs (miRNAs), which regulate the conversion of messenger RNA into protein. MiRNAs can be reliably measured in human CSF, and our preliminary data show that certain miRNAs are significantly different in CSF from individuals diagnosed with AD, making them candidates for a new class of non-protein biomarkers. Given that TBI increases the risk for developing AD, we hypothesize that TBI induces changes in CSF miRNA expression that reflect the initial molecular responses to brain injury that precede, and likely drive, changes in protein expression that lead to the development of AD. To investigate this hypothesis, we propose to examine miRNAs in CSF individuals with a history of TBI. We will compare CSF collected and banked in a prior study from three groups: (i) previously deployed Veterans with a history of blast-related mild TBI; (ii) previously deployed Veterans with no lifetime history of TBI; and (iii) community controls with no lifetime history of TBI. These data will allow us to distinguish between biomarkers that are specific for TBI and those related to deployment stress that may explain the elevated risk of AD in Veterans. In addition, we will compare TBI-specific miRNAs to those identified in our independent AD study to determine whether TBI might directly or indirectly cause AD-associated microRNA changes. These studies will potentially provide novel mechanisms that link TBI and AD, which are critical for the development of new therapies for AD. The proposed 2-year study is the first step in a series of studies designed to improve our understanding of the specific role of TBI as a root
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510318
Entities
People
- Joseph Quinn
Organizations
- Oregon Health & Science University
- United States Army