Clinical StudyDiffusion tensor imaging of acute inflammatory lesion evolution in multiple sclerosis
Introduction
Identification of initiating events in the evolution of MS lesions is critical for understanding the pathophysiology of MS and exploring novel therapeutic interventions. While pathological investigations of MS lesions have elucidated much of the understanding of lesion pathophysiology, such techniques are limited to post mortem tissue and biopsy samples. Tissue samples obtained post mortem are commonly representative of late stage disease, and biopsy tissue is typically acquired when a differential diagnosis of tumour is being explored in the context of a gadolinium (Gd)-enhancing, symptomatic brain lesion, often before MS is suspected or known in that individual. Neither scenario is likely to shed light on early lesion evolution. In contrast, MRI can reveal pathological characteristics of MS lesions in vivo including techniques relatively specific for demyelination, axonal injury, inflammation and gliosis,1, 2, 3 myelin repair,4 and potentially, tissue alteration prior to Gd-enhancement.5, 6, 7, 8, 9
Conventional T2-weighted and T1-weighted MRI are critical for the diagnosis of MS and are increasingly important for monitoring the extent of ongoing lesion development in MS, but are insensitive to subtle injury to normal-appearing white matter (NAWM) and grey matter. More recently, quantitative MRI modalities, such as diffusion weighted imaging (DWI) and magnetisation transfer imaging, have been developed. DWI measures the microscopic motion of water molecules to provide information about the orientation and geometry of white matter axonal bundles.10 Diffusion can be characterised by a tensor ellipsoid (DTI) from which the mean diffusivity (MD) and fractional anisotropy (FA) can be calculated. MD is a measure of the magnitude of molecular diffusion whereas FA reflects the directional heterogeneity of molecular diffusion.11, 12 Both MD and FA can reveal subtle but definite pathological changes that cannot be visualised with conventional T2-weighted or T1-weighted MRI in NAWM.13, 14
Traditionally, blood–brain barrier (BBB) leakage, visible as regions of T1-weighted contrast enhancement following intravenous Gd administration, has been regarded as an initial or early event in MS lesion evolution. However, several studies have challenged this by demonstrating quantitative MRI alterations in NAWM before the appearance of Gd enhancement or visible T2-weighted contrast change.5, 6, 7, 8, 9 In particular, Werring et al.7 investigated five patients (four with relapsing-remitting MS [RRMS] and one with secondary progressive MS) monthly for 12 months using DWI and found a significant increase in the average apparent diffusion coefficient (ADC) in white matter regions of interest (ROI) that subsequently enhanced. The authors reported that pre-lesional ADC alterations preceded enhancement by up to 5 months. Our aim was to investigate the evolution of DTI measures, specifically FA and MD, prior to the appearance of Gd-enhancing lesions that may indicate acute inflammatory demyelination. We assessed FA and MD in white matter 4 months to 6 months, and 1 month prior to the appearance of Gd enhancement in that location, and compared those DTI measures with DTI measures in carefully selected matching contralateral white matter. We hypothesised that pre-lesional MD and FA alterations would predict the severity of DTI alterations during and subsequent to acute inflammation.
Section snippets
Participants
Scans were obtained from 22 adults with RRMS participating in a randomised control trial of high-dose vitamin D for MS (trial registry: The Australian Clinical Trials Registry; registry number: ACTRN12606000359538; registry database URL <www.anzctr.org.au/trial_view.aspx?ID=41541>). In brief, patients were randomised to the double-blind placebo-controlled addition of high-dose vitamin D2 to low-dose vitamin D2 supplementation.15 Treatment was 6000 IU vitamin D2 capsules (Cardinal Health,
Results
From the 22 patients, only 13 contrast enhancing lesions from five patients matched the strict inclusion criteria (Table 1). Of the lesions studied, 10 were solid, two were ring enhancing and one was a half ring. In all instances, enhancing lesions were evident on one scan only, so BBB restoration occurred within 1 month. The volume of lesions was highly variable and ranged between 11.5 mm3 and 128 mm3. One-way ANOVA revealed no change in MD or FA over time in NAWM ROI (Table 2).
Analyses of
Discussion
The cellular processes of early lesion evolution in MS remain controversial, due to the difficulty in obtaining pre-lesional pathological tissue samples. However, MRI provides an opportunity to characterise lesion evolution through the analysis of serial MRI scans obtained in longitudinal studies of active disease. These studies provide the opportunity for detailed evaluation of white matter regions prior to the development of overt Gd-enhancement and/or T2-weighted abnormality, demonstrated on
Conflicts of Interest/Disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Acknowledgements
This work was generously supported by philanthropic funding from the Myer Foundation as well as the McDonald Fellowship from the Multiple Sclerosis International Federation (MSIF) and the National Science Foundation of China (Nos 81101038, 30930029) (Y. Liu), the Australian National Health and Medical Research Council (NHMRC) Principal Research Fellowship (Grant 400317, G. F. Egan), Australia, the joint MS Research Australia / Trish MS Foundation / NHMRC Betty Cuthbert Fellowship (Grant 400476,
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Both authors contributed equally to this work.