Longitudinal Neuroimaging and Molecular Biomarkers of Cerebrovascular Health in ALS
Abstract
Vascular alterations have recently emerged as a common feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). These alterations are thought to occur prior to neuronal degeneration, at least in ALS mouse models. Yet, the role of the cerebrovasculature in human ALS pathobiology as it correlates to disease progression is largely unknown. Since the neurovasculature is both a gate for drug delivery into the brain and a gateway for peripheral immune infiltration into the central nervous system, there is a critical need for accurate minimally invasive biomarkers of its health. The ongoing Target ALS longitudinal biofluids clinical research study is a longitudinal study occurring at the Barrow Neurological Institute in Phoenix, AZ, along with other sites across the nation. It collects clinical information, blood, CSF, urine, RNA, DNA for whole genome sequencing, and at-home measures of speech and respiratory function. All samples, genetic and clinical information are de-identified and made available to the research community. We propose to use Department of Defense funding to add longitudinal neuroimaging measures of cerebrovascular function and blood flow, along with biofluid biomarkers of vascular injury. In addition, we will use samples from this study to investigate molecular biofluid markers of vascular injury in the CSF and blood and explore the immune cell composition of these biofluids by single cell RNA-sequencing (scRNA-seq). Finally, we will correlate neuroimaging data of vascular health with markers of vascular injury and peripheral neuroimmune infiltration to identify quantitative biomarkers of vascular health and dysfunction in ALS. This approach leverages existing infrastructure and patient samples thus reducing redundant efforts and costs to patients and researchers, while maximizing the data collected. Linking this information to the Target ALS datasets will provide an excellent means to maximize sample and data utilization and enable future studies that combine all these data types with clinical information. This comprehensive multidisciplinary study will provide a novel understanding of cerebrovascular structure and function in ALS patients, as well as the timing of vascular alterations with respect to various clinical measures of disease. Since disruption of vascular physiology is thought to occur early in the neurodegenerative disease process, this knowledge can provide a potential target to prevent or delay disease progression, but also prove essential for discovery and development of prognostic biomarkers of disease progression and pharmacodynamic biomarkers for therapies that target the BBB or BCSFB.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310352
Entities
People
- Nadine Bakkar
Organizations
- United States Army