Development and validation of age-relative measures of biochemical intervertebral disc health

PROJECT SUMMARY The link between intervertebral disc degeneration and chronic low back pain (cLBP) is widely acknowledged but poorly understood. Emerging evidence suggests that early deficits in disc health increase cLBP risk, but this potentially important association is difficult to study because conventional imaging methods for quantifying disc health are qualitative, subjective, and insensitive to early deficits in disc health. Spin-lock T1ρ MRI, which is sensitive to disc biochemical composition, overcomes this limitation. Indeed, we recently found that T1ρ biomarkers of disc health in cLBP patients were distinct from the normal age-course of disc degeneration in asymptomatic controls. This led to the discovery of a new cLBP phenotype that’s not apparent with conventional MRI: young adult patients (20–40-year-olds) who have abnormal disc biochemical composition for their age. What’s more, this T1ρ biomarker of poor age-relative biochemical disc health — what we term a low T1ρ “Z-score” — predicts the development of new disc pathologies and associates with earlier onset of symptoms. A critical unknown is the etiology of low T1ρ Z-scores and whether poor age-relative disc health reflects lower peak disc health before skeletal maturity or a faster decline in disc health after. It’s also unknown if this T1ρ biomarker predicts clinical outcomes and stratifies future cLBP risk better than conventional MRI. Three complementary aims are proposed. In Aim 1 we’ll perform T1ρ MRI in 10–25-year-old subjects to discover the age-course of biochemical disc composition. Specifically, we’ll determine population variability in peak disc health and clarify whether early deficits in disc health reflect a lower peak before skeletal maturity or a faster decline after. In Aim 2 we’ll discover risk factors for early deficits in biochemical disc health using an innovative two-stage approach. In the first stage, we’ll conduct a meta-GWAS of adults with standardized measures of structural disc degeneration. The result will be a multi-ethnic, genome-wide polygenic risk score (PRS) for genetic propensity to disc degeneration. In the second stage, we’ll genotype the young subjects in Aim 1 and test if the genetic propensity to structural disc degeneration in adulthood associates with early deficits in biochemical disc health. Specifically, we’ll test if PRS associates with age-adjusted T1ρ values and how the association depends on sex and anatomic risk factors, e.g., lumbar lordosis. In Aim 3, we’ll leverage access to previously acquired spine MRIs (T1ρ and conventional), brain fMRIs, functional measurements, psychosocial profiles, and 24-month clinical outcomes in an ongoing surveillance study of 300 adult cLBP patients and 75 controls. This will enable us to test for associations between T1ρ Z-scores and cLBP status and to discover how changes in pain and disability from baseline depend on a variety of patient characteristics, including metrics from T1ρ and conventional MRI. Through these studies, we will establish a quantitative diagnostic framework for contextualizing disc degeneration in relation to cLBP risk that could eventually improve clinical management of cLBP and help shift clinical paradigms from reactive to preventative.