Normalizing automatic spinal cord cross-sectional area measures

Spinal cord cross-sectional area (CSA) is a relevant biomarker to assess spinal cord atrophy in various neurodegenerative diseases. However, the considerable inter-subject variability among healthy participants currently limits its usage. Previous studies explored factors contributing to the variability, yet the normalization models were based on a relatively limited number of participants (typically < 300 participants), required manual intervention, and were not implemented in an open-access comprehensive analysis pipeline. Another limitation is related to the imprecise prediction of the spinal levels when using vertebral levels as a reference; a question never addressed before in the search for a normalization method. In this study we implemented a method to measure CSA automatically from a spatial reference based on the central nervous system (the pontomedullary junction, PMJ), we investigated various factors to explain variability, and we developed normalization strategies on a large cohort (N=804). Cervical spinal cord CSA was computed on T1w MRI scans for 804 participants from the UK Biobank database. In addition to computing cross-sectional at the C2-C3 vertebral disc, it was also measured at 64 mm caudal from the PMJ. The effect of various biological, demographic and anatomical factors was explored by computing Pearsons correlation coefficients. A stepwise linear regression found significant predictors; the coefficients of the best fit model were used to normalize CSA. The correlation between CSA measured at C2-C3 and using the PMJ was y = 0.98x + 1.78 (R2 = 0.97). The best normalization model included thalamus volume, brain volume, sex and interaction between brain volume and sex. With this model, the coefficient of variation went down from 10.09% (without normalization) to 8.59%, a reduction of 14.85%. In this study we identified factors explaining inter-subject variability of spinal cord CSA over a large cohort of participants, and developed a normalization model to reduce the variability. We implemented an approach, based on the PMJ, to measure CSA to overcome limitations associated with the vertebral reference. This approach warrants further validation, especially in longitudinal cohorts. The PMJ-based method and normalization models are readily available in the Spinal Cord Toolbox.