Progressive neurodegeneration following spinal cord injury: Implications for clinical trials

Abstract

Objective: To quantify atrophy, demyelination, and iron accumulation over 2 years following acute spinal cord injury and to identify MRI predictors of clinical outcomes and determine their suitability as surrogate markers of therapeutic intervention.

Methods: We assessed 156 quantitative MRI datasets from 15 patients with spinal cord injury and 18 controls at baseline and 2, 6, 12, and 24 months after injury. Clinical recovery (including neuropathic pain) was assessed at each time point. Between-group differences in linear and nonlinear trajectories of volume, myelin, and iron change were estimated. Structural changes by 6 months were used to predict clinical outcomes at 2 years.

Results: The majority of patients showed clinical improvement with recovery stabilizing at 2 years. Cord atrophy decelerated, while cortical white and gray matter atrophy progressed over 2 years. Myelin content in the spinal cord and cortex decreased progressively over time, while cerebellar loss decreases decelerated. As atrophy progressed in the thalamus, sustained iron accumulation was evident. Smaller cord and cranial corticospinal tract atrophy, and myelin changes within the sensorimotor cortices, by 6 months predicted recovery in lower extremity motor score at 2 years. Whereas greater cord atrophy and microstructural changes in the cerebellum, anterior cingulate cortex, and secondary sensory cortex by 6 months predicted worse sensory impairment and greater neuropathic pain intensity at 2 years.

Conclusion: These results draw attention to trauma-induced neuroplastic processes and highlight the intimate relationships among neurodegenerative processes in the cord and brain. These measurable changes are sufficiently large, systematic, and predictive to render them viable outcome measures for clinical trials.

Figure 1. Longitudinal changes in spinal cord MRI indices

(A) Illustration of measures of cross-sectional spinal cord area, left-right width, and anterior-posterior width at cervical level C2-C3. (B) Change in cross-sectional spinal cord area at the C2-C3 level and (C) left-right width and (D) anterior-posterior width after injury in patients with spinal cord injury and in controls over 2 years. (E) Change in mean MT (in % loss of magnetization) at the C2-C3 level after injury in patients with spinal cord injury and in controls over 2 years. Note that black, solid lines depict the fitted model; blue and red points and lines show observed individual longitudinal data for controls and patients, respectively. MT = magnetization transfer saturation; SCI = spinal cord injury.

Figure 2. Longitudinal changes in brain volume, myelin, and iron shown by longitudinal voxel-based morphometry (A) and voxel-based quantification (B)

(A, B) Overlay of statistical parametric maps (t values uncorrected p < 0.001, shown for descriptive purposes, masked by the union of regions of interest) showing regions of volume changes in GM volume (in blue), and WM CST volume (yellow), WM excluding the CST (red), MT (cyan), and effective transverse relaxation rate (in green). Corresponding structural trajectories are shown for local effects in voxel-based morphometry and voxel-based quantification ([C.a] CST, [C.b] anterior cingulate cortex, [C.c] thalamus, [C.d] sensorimotor cortex). Note that black, solid lines depict the fitted model; blue and red points and lines show observed individual longitudinal data for controls and patients, respectively. CST = corticospinal tract; GM = gray matter; MT = magnetization transfer saturation; R2* = effective transverse relaxation rate; SCI = spinal cord injury; WM = white matter.

Figure 3. Correlation between brain MRI changes at 6 months and 2-year clinical outcome (t values uncorrected p < 0.001, shown for descriptive purposes, masked by the union of the regions of interest)

Better lower extremity motor score (Lems) (yellow) at 2 years was associated with greater volume (brainstem) and a smaller decrease in MT (sensorimotor cortex) over 6 months. Better functional independence score (Scim) (red) was associated with a smaller decrease in MT in the somatosensory cortex, bilaterally. A worse pinprick (PP) (blue) score at 2 years was associated with increases in R2* in the right cerebellum and right ACC over 6 months. Greater increases in neuropathic pain intensity score (green) was associated with greater R2* increases in the right secondary sensory cortex, in left ACC, and the cerebellum, bilaterally over 6 months. Note that not all clusters are shown, but are presented in Table e-1. ACC = anterior cingulate cortex; MT = magnetization transfer saturation; R2* = effective transverse relaxation rate; SCIM = Spinal Cord Independence Measure.