Longitudinal diffusion MRI as surrogate outcome measure for myelopathy in adrenoleukodystrophy

Abstract

ObjectiveTo prospectively determine the potential of diffusion MRI (dMRI) of the cervical spinal cord and the corticospinal tracts in brain as surrogate outcome measure for progression of myelopathy in men with adrenoleukodystrophy, as better outcome measures to quantify progression of myelopathy would enable clinical trials with fewer patients and shorter follow-up.MethodsClinical assessment of myelopathy included Expanded Disability Status Scale (EDSS), Severity Scoring System for Progressive Myelopathy (SSPROM), Timed Up-and-Go, and 6-Minute Walk Test. Applied dMRI metrics included fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity.ResultsData were available for 33 controls and 52 patients. First, cross-sectionally, differences between groups (controls vs patients; controls vs asymptomatic patients vs symptomatic patients) were statistically significant for fractional anisotropy, mean diffusivity, and radial diffusivity in spinal cord and brain corticospinal tracts (effect size 0.31–0.68). Correlations between dMRI metrics and clinical measures were moderate to strong (correlation coefficient 0.35–0.60). Second, longitudinally (n = 36), change on clinical measures was significant after 2-year follow-up for EDSS, SSPROM, and Timed Up-and-Go (p ≤ 0.021, effect size ≤0.14). Change on brain fractional anisotropy and radial diffusivity was slightly larger (p ≤ 0.002, effect sizes 0.16–0.28). In addition, a statistically significant change was detectable in asymptomatic patients using brain dMRI and not using the clinical measures. Change on clinical measures did not correlate to change on dMRI metrics.ConclusionAlthough effect sizes were small, our prospective data illustrate the potential of dMRI as surrogate outcome measure for progression of myelopathy in men with adrenoleukodystrophy.

Plasma NfL and GFAP as biomarkers of spinal cord degeneration in adrenoleukodystrophy

“…Most outcomesfor example clinical parameters (EDSS, SSPROM, timed walking activities) or imaging biomarkers (spinal cord atrophy, diffusion tensor imaging)represent disability or accumulated spinal cord damage resulting from years of spinal cord degeneration. 1,[30][31][32] NfL and GFAPwith an estimated half-life of a number of days and months respectivelyreflect current or recent neurodegeneration and are therefore the markers of ongoing or recent disease activity. 33,34 This makes the relationship between NfL and severity of myelopathy not straightforward.…”

“…There is an important difference between molecular biomarkers such as NfL and GFAP and other (surrogate) outcomes used for myelopathy in ALD. Most outcomes – for example clinical parameters (EDSS, SSPROM, timed walking activities) or imaging biomarkers (spinal cord atrophy, diffusion tensor imaging) – represent disability or accumulated spinal cord damage resulting from years of spinal cord degeneration 1,30‐32 . NfL and GFAP – with an estimated half‐life of a number of days and months respectively – reflect current or recent neurodegeneration and are therefore the markers of ongoing or recent disease activity 33,34 .…”

Postural Body Sway as Surrogate Outcome for Myelopathy in Adrenoleukodystrophy

“…Finally, application of body sway as surrogate outcome is also limited by disability, as it cannot be used for more severely affected and wheelchair-bound patients. This so-called ceiling effect is, however, also a problem for other outcome measures such as the 6MWT and DTI ( Huffnagel et al, 2019c ).…”

“…Traditional clinical outcomes – such as the Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), timed up-and-go test, and 6-minute walk test (6MWT) – are limited by their low sensitivity and high interrater and intrarater variability ( Huffnagel et al, 2019b ). Studies on more sophisticated surrogate outcomes such as magnetization transfer (MT) imaging ( Fatemi et al, 2005 ), diffusion tensor imaging (DTI) ( Huffnagel et al, 2019c ), and optical coherence tomography (OCT) ( van Ballegoij et al, 2020 ) provide evidence that they could be more sensitive and rater-independent. However, they lack direct clinical relevance, meaning that they are not of direct importance to the patient in terms of functional impairment or quality of life, while that is usually required for approval by regulatory agencies.…”

HARDI-ZOOMit protocol improves specificity to microstructural changes in presymptomatic myelopathy

“…After the Stejskal and Tanner 1965 experiment 1 , it took almost 3 decades until the diffusion magnetic resonance imaging (dMRI) was first applied to human brain imaging, utilizing estimation of the diffusion tensor imaging (DTI) model 2 , 3 . Since 2000 DTI has been used in the spinal cord (SC) imaging 4 and become considered for clinical applications 5 , 6 , such as SC injury 7 , 8 , multiple sclerosis 4 , amyotrophic lateral sclerosis (ALS) 9 , Walerian degeneration 10 , adrenoleukodystrophy 11 and degenerative cervical myelopathy (DCM) 12 – 18 . Recently, DTI detected microstructural SC injury 19 , and microstructural abnormality in patients with non-myelopathic degenerative cervical cord compression (NMDCCC) prior to development of subsequently expected neurological myelopathic symptoms and signs, i.e.…”