Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis

Abstract

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

Keywords: MS: biomarkers; MS: clinical trials; MS: imaging; neuroinflammation; white matter lesion.

Figure 1

Chronic brain tissue damage as measured by increasing non-enhancing T₁ hypointense lesion volume is reduced by ocrelizumab and may occur independently from new T₂ lesion formation. (A) Change in total non-enhancing T₁ lesion volume^a. (B) Change in total T₂ lesion volume. (C) New focal T₂ lesion formation. (D) Chronic brain tissue damage mostly occurs within pre-existing T₂ lesions. An animated version of D is more appropriate for data visualization and is available in the Supplementary material. OCR = ocrelizumab; T₁w = T₁-weighted. ^aThe analysis of total non-enhancing T₁ lesion volume was based on a T₁ hypointense lesion threshold definition (as per pre-specified ORATORIO study protocol) that was subsequently optimized for all T₁ lesion volume analyses performed. Estimates and P-values are from a mixed-effect model of repeated measures using an unstructured covariance matrix. ^bRates and P-values are from a negative binomial model adjusted for baseline T₂ lesion count, geographic region (rest of world, US) and age (≤45 years, >45 years).

Figure 2

T₁ hypointense volume accumulation may occur in SELs showing longitudinal expansion and in non-SEL areas of pre-existing baseline T₂ lesions. In this example, effectively all T₁ hypointense lesion volume accumulation in this slice occurs within baseline T₂ lesions. An animated version of this figure is more appropriate for data visualization and is available in the Supplementary material. T₁w = T₁-weighted; T₂w = T₂-weighted.

Figure 3

T₁ hypointense lesion volume change from baseline to Week 120 by lesion type and treatment group. Box-and-whisker plots: box displays the quartiles; asterisks represent the mean values; bars represent the median values; whiskers extend from the lowest datum ≥ 1.5 × lower quartile − IQR to the highest datum ≤ 1.5 IQR upper quartile + IQR; range of values in placebo/ocrelizumab, respectively: pre-existing T₂ burden: −0.46–12.90/−6.23–24.54; non-SELs: −0.68–8.71/−6.61–17.65; all SELs: −0.02–5.29/−0.07–6.89; new T₂ lesions: 0–3.36/0–1.18. IQR = interquartile range; OCR = ocrelizumab. ^aVan Elteren test stratified by treatment group (ocrelizumab, control) and baseline T₂ lesion volume category based on tertiles. n = the number of patients evaluable at Week 120. ^bFor each patient the sum change from baseline in T₁ volume of evaluable lesions was calculated. Missing changes from baseline in volume are imputed to zero.

Figure 4

T₁-weighted intensity measures of chronic white matter lesion activity from baseline to Week 120. (A) Total baseline T₂ lesion burden. (B) All SEL candidates. (C) SELs (with a score ≥0). (D) Non-SELs. Asterisks represent the median values. OCR = ocrelizumab. ^aVan Elteren test stratified by treatment group (ocrelizumab, control) and baseline T₂ lesion volume category based on tertiles. n = the number of patients with at least one SEL at each visit. Volume normalization is calculated as: sum(SEL_volume × SEL_intensity) / sum(SEL_volume): SEL volume is based on baseline T₂ volume of SELs. For each patient, the sum relative change from baseline in T₁ lesion volume of SELs was calculated and this value was then summarized for the ITT population. ^bn-values at Week 120 for all panels. Reproduced from Elliott et al. (2018a).