Elsevier

NeuroImage

Volume 32, Issue 2, 15 August 2006, Pages 531-537
NeuroImage

MRI time series modeling of MS lesion development

https://doi.org/10.1016/j.neuroimage.2006.04.181Get rights and content

Abstract

A mathematical model was applied to new lesion formation in multiple sclerosis, as apparent on frequent T2-weighted MRI. The pathophysiologically motivated two-process model comprises two opposing nonlinear self-limiting processes, intended to represent degenerative and reparatory processes, respectively, investigating T2 activity from a dynamic/temporal rather than a spatial/static perspective. Parametric maps were obtained from the model to characterize the MRI dynamics of lesion development, answering the questions of how long new T2 lesion activity persists, how much residual damage/hyperintensity remains and how the T2 dynamics compare to those of contrast-enhancing MRI indicating active inflammation.

997 MRI examinations were analyzed, acquired weekly to monthly from 45 patients over a 1-year period. The model was applied to all pixels within 332 new lesions, capturing the time profiles with excellent fidelity (r = 0.89 ± 0.03 average correlation between model and image data). From this modeling perspective, the observed dynamics in new T2 lesions are in agreement with two opposing processes of longitudinal intensity change, such as inflammation and degeneration versus resorbtion and repair. On average, about one third of a new lesion consisted of transient signal change with little or no residual hyperintensity and activity of 10 weeks or less. Global lesion burden as MRI surrogate of disease activity may therefore be confounded by large amounts of transient hyperintensity. T2 activity also persisted significantly beyond the period of contrast enhancement, thereby defining MRI sensitivity toward a subacute phase of lesion development beyond blood–brain barrier patency. Concentric patterns of dynamic properties within a lesion were observed, consistent with concentric histological appearance of resulting MS plaques.

Introduction

We present a model-based approach to the pixel-wise assessment of the short-term dynamics of new lesion formation in multiple sclerosis (MS), as apparent from serial T2-weighted magnetic resonance imaging (MRI). Serial MRI provides effective and valuable data for understanding both natural history and treatment effects of neurodegenerative diseases. In MS, the current state of knowledge supposes a dynamic sequence of inflammatory/autoimmune, degenerative, and restorative processes that result in the pathological findings of focal demyelination and remyelination, inflammatory infiltrates, axonal loss and fibrillary astrocytosis. Little is known about the timing, sequence and interplay of these processes leading to both white and gray matter damage. From the MRI perspective, lesion pathogenesis comprises an acute phase with blood–brain barrier leakage lasting a few weeks followed by a chronic phase of T2 hyperintensity (T2 lesions) and occasional T1 hypointensity (black holes). Morphometric assessment of MRI lesion burden is a commonly used surrogate in large-scale clinical trials (Filippi et al., 1995, Jacobs et al., 1996, Li and Paty, 1999, Miller et al., 1999), and long-term trends thereof serve as indicators of disease activity and therapeutic effect (Molyneux et al., 1998). T2 hyperintensity is considered pathologically non-specific, but it remains unclear to what extent different pathological processes could be distinguished based on the sequence and dynamics of the T2 signal. That such dissociative potential exists in serial MRI is illustrated, for example, by a recent study on the evolution of enhancing inflammatory lesions into permanent T1-hypointense lesions (black holes), which showed that less than a quarter of all enhancing lesions became “black holes” and that those were preceded by longer duration of enhancement (Bagnato et al., 2003).

We have previously presented a time series analysis strategy to study longitudinal changes in tissue quality (composition) (Meier and Guttmann, 2003). Based on this work, we here examine the dynamics of new T2 lesions in the context of a pathologically motivated mathematical model. Specifically, we aim to answer the following:

  • How well is the short-term variation of new T2 lesions explained by a model of two opposing processes (e.g. representative of inflammation/degeneration and resorbtion/repair)?

  • How long is new T2 lesion activity sustained on average? Does this differ from the duration of contrast enhancement ?

  • Does the spatio-temporal distribution of new T2 hyperintense lesions exhibit a characteristic pattern?

Section snippets

Image acquisition and preprocessing

Weekly to monthly MRI was obtained from 45 MS patients (64% female) over 1 year. Mean subject age was 39 ± 8 years (25–55 years), with 26 patients classified as relapsing–remitting MS (RRMS), 14 as secondary progressive (SPMS) and 5 as “stable MS” (Weiner et al., 2000). The MRI was obtained at 1.5 T with a conventional spin echo sequence with 3 mm contiguous axial slices (axial spin echo, variable echo multi-planar, PDw/T2w, TE = 30/80 ms, TR = 3000 ms, with 0.93 × 0.93 × 3 mm3 nominal voxel

Results

Results are reported in three sections: (1) how well the model fitted each time profile, (2) the spatial patterns of lesion dynamics represented as feature maps and (3) the statistical distribution of duration and residuals over the examined cohort.

Discussion

The presented model-based analysis of lesion formation presents an attempt to approach structural MRI change as a process rather than in terms of the end result. T2 hyperintensity alone is considered non-specific with respect to the outcome of processes such as inflammation, neurodegeneration and repair. The return to T2 isointensity also is not necessarily equivalent with complete lesion repair (Barkhof et al., 2003) nor is T2 “activity” necessary for diffuse WM changes to occur (Goodkin et

Acknowledgments

This work was supported in part by funding provided by the Harvard Center for Neurodegeneration and Repair (Clinical Trials Pilot Study Grant) and the National Multiple Sclerosis Society (RG 3574-A-1), as well as the National Institutes of Health (R01 NS35142; P41 RR13218-01). We would like to thank Drs. Howard Weiner and Ferenc Jolesz for providing the longitudinal MRI data.

References (17)

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