These results provide the first in vivo evidence that lumbar disc degeneration severity in patients with cLBP relates to compositional deficits in the CEP. We found that CEPs with lower T2* values—reflecting lower CEP hydration, lower GAG content, a higher ratio of collagen-to-GAG, and lower permeability [4, 6]—were associated with more severe disc degeneration both before and after accounting for patient age, sex, BMI, and multiple measurements per subject. Conversely, higher BMFF values in the adjacent vertebral body—reflecting less hematopoietic marrow and decreased perfusion [7,8,9,10, 18]—were not associated with disc degeneration after accounting for covariates (namely, subject age). Taken together, these collective findings suggest that poor CEP composition may play a significant role in disc degeneration severity in patients with cLBP, and that CEP composition can affect disc health both with and without deficits in vertebral perfusion.
CEP composition and vertebral vascularity are important factors in disc health, though their relative importance has remained unclear because prior studies have focused on each factor alone. For example, in vitro experiments have demonstrated that variations in the amounts of aggrecan, mineral, and collagen in the CEP can impede nutrient diffusion to a degree sufficient to hinder NP cell viability and function [4, 19]. Experiments using diffusion chambers have also shown that limiting the reservoir of available nutrients can reduce NP cell viability . Those prior findings demonstrate the potential mechanisms by which CEP composition and vertebral vascularity may affect NP cells; our present findings demonstrate the clinical importance of CEP composition in the context of variations in vertebral vascularity. Specifically, unlike vertebral BMFF, CEP composition was significantly associated with disc health after accounting for co-variates, which demonstrates the relative importance of poor CEP composition in disc degeneration in patients with cLBP.
These findings help clarify mechanistic factors influencing disc degeneration in a cohort of patients with non-specific cLBP, but they do not imply that CEP composition is uniquely important to patients with cLBP relative to asymptomatic subjects with disc degeneration, or that disc degeneration was the pain generator in this cohort. Since we did not study asymptomatic subjects, it remains unclear whether the relationships discovered here in cLBP patients are the same in asymptomatic subjects. Likewise, factors differentiating painful disc degeneration from asymptomatic disc degeneration as seen on MRI also remain unclear. These are important areas for future research.
Our finding that disc health strongly associates with CEP composition has implications for the clinical translation of emerging biologic therapies designed to regenerate the disc. The therapeutic potential of cell-based regenerative therapies likely depends on disc nutrient supply: mesenchymal stem cell chondrocytic differentiation, proliferation, and function depend on glucose and oxygen concentrations (the same nutrients vital to NP cell survival) and on matrix acidity (related to lactate production, an NP cellular metabolic waste product) . Given the established effects of CEP composition on nutrient transport in combination with the data shown here, it follows that the efficacy of cell-based therapies may likewise depend on CEP composition. If so, CEP composition could be a possible diagnostic target to help identify patients with adequate CEP permeability to support increased cell density or metabolic activity in the NP. Similarly, poor CEP composition could also be a possible therapeutic target to enhance the disc’s regenerative potential, e.g., through enzymatic augmentation . Non-invasive assessment of CEP composition with UTE MRI may thus provide a powerful tool to improve selection of patients and spinal levels likely to respond to anabolic treatment, helping to maximize the efficacy of novel biologic therapies.
The variations in biomarker values with age reported here are consistent with established age-associated biochemical changes in these tissues [18, 22, 23]. Lumbar CEP GAG and water contents in 51–67 year old subjects ranged from 43–185 µg/mg dry weight and 22–62%, respectively, in a previous study . For patients with similar ages in the current study (49–65 year old), the estimated GAG and water content ranges (65–84 µg/mg dry weight and 52–63% water) are within the range previously published. A prior study using CSE-MRI  found that higher levels of BMFF were associated with more severe disc degeneration, consistent with the univariate regression results shown here. These findings collectively support the validity of our approach.
One strength of our study is the utilization of two recently developed neural networks [15, 16] to perform automated tissue segmentation. This enabled rapid and unbiased evaluation of the MRI biomarkers, demonstrating the relevance of neural networks to a diverse class of problems and addressing the inefficiency and subjectivity associated with manual tissue segmentation. Notably, we also demonstrated the feasibility of non-invasively assessing CEP composition with a new MRI biomarker (mean CEP T2*) in a clinical population.
This study has several limitations. First, the cross-sectional study design precludes establishment of causality. However, prior research has demonstrated the causal effects of these same CEP compositional traits on NP cell survival and function , which provides a mechanistic explanation for our results. A second limitation relates to the spatial resolution of the vertebral BMFF maps (voxel dimensions 1.0 × 1.0 × 4.0 mm), which does not capture subtle morphologic variations in endplate-specific vascularity which may affect nutrient supply . However, the conversion from hematopoietic to fatty marrow has been shown to associate with vascular changes in both the femur and vertebral body and with age-associated changes in perfusion [9, 10, 18], suggesting that vertebral BMFF values likely provide an accurate measure of overall changes in vertebral vascularity.
In summary, we found that after adjusting for age, sex, and BMI, deficits in CEP composition—as indicated by lower T2* values—were associated with more severe disc degeneration. Conversely, lower vertebral vascularity—as indicated by higher vertebral BMFF values—was not associated with disc degeneration after adjusting for age. We conclude that poor CEP composition plays a significant role in disc degeneration severity in patients with cLBP both with and without deficits in vertebral vascularity.