Clinical Study
Validation of linear cerebral atrophy markers in multiple sclerosis

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Abstract

Linear measures of cerebral ventricular enlargement may act as surrogate measures of cerebral atrophy in multiple sclerosis (MS). Linear atrophy markers were measured from routine MRI scans during a population survey of 171 Tasmanian MS patients and 91 healthy controls. Thirty-five Victorian MS clinic patients were recruited as a validation cohort with 14 of these re-assessed 4 years later. In the population survey, we measured three linear brain atrophy markers: inter-caudate distance (ICD), third ventricle width (TVW) and frontal horn width (FHW). TVW (OR 2.0, p = 0.001) and ICD (OR 16.1, p < 0.001) differentiated between MS cases and controls. In the validation study, we correlated the intercaudate ratio (ICR = ICD/brain width) and third ventricular ratio (TVR = TVW/brain width) with brain parenchymal volume. Cross-sectionally, ICR (R = −0.453, p < 0.01) and TVR (R = −0.653, p < 0.01) were correlated with brain parenchymal volume. Longitudinally, brain parenchymal volume loss was inversely correlated with increased ICD (R = −0.77, p < 0.01) and TVW (R = −0.71, p < 0.01). This study shows that ICD measurements obtained from clinical MRI scans are valid brain atrophy measures for use in monitoring MS progression.

Introduction

Multiple sclerosis (MS) is a disease of long duration with a highly variable rate of progression.1 Establishing medium to long-term prognosis in the early phase of MS is a topic of intense research efforts, because it would allow the development of differential evidence-based management plans. Magnetic resonance imaging (MRI) analysis has been at the forefront of these efforts, initially focusing on the most obvious MRI abnormality in MS, namely T2 hyperintense lesions. The development of new T2 lesions is an indicator of the inflammatory component of the disease2 and total T2 lesion load is a good predictor of the development of clinically definite MS in the context of clinically isolated syndromes3 and is therefore a useful tool for case definition. However, T2 lesion load alone is a poor predictor of clinical disability in patients with established disease.[4], [5]

A second, less obvious but highly prevalent and progressive abnormality is cerebral atrophy. Loss of cerebral volume is seen at all clinical stages of MS, and is even present at diagnosis.6 It likely reflects both inflammation-induced axonal loss and post-inflammatory Wallerian degeneration.[6], [7] Although the correlation between the degree of cerebral atrophy and clinical disability remains controversial, cortical grey matter volume has been shown to correlate negatively with Expanded Disability Status Score (EDSS) in both relapsing-remitting (RR) and primary-progressive (PP) cohorts[8], [9] and to correlate positively with measures of cognitive impairment.10

More recently, Bielekova et al. have confirmed that MRI measures reflecting either inflammation (gadolinium [Gd]-enhancing lesion load) or tissue loss (brain parenchymal fraction) are, to some extent, independent.11 In their study, the best cross-sectional correlation with clinical disability was found in a subgroup of MS patients who had both severe inflammation and cerebral atrophy.

At least one prominent proposal for a clinical management algorithm specifically includes progression of cerebral atrophy as well as accumulation of new T2 lesions as part of a composite set of clinical and imaging variables to define “level of concern” about a patient’s likelihood of early disease progression.12 Implicitly, if concern is high, the proponents of this algorithm suggest escalating treatment.

Unfortunately, unlike T2 lesion load or Gd-enhancing lesion number, brain volume measures are almost never available to clinicians during routine practice, as they require prospectively planned, sophisticated MRI acquisition techniques combined with detailed image post-processing analyses. Typically, scans available to the practising clinician only exist in hard-copy format, and multiple imaging facilities may produce scans at different time-points, utilising a variety of acquisition protocols in an individual patient.

One practical method may be the application of linear markers of ventricular size, which can be obtained from hard-copy scans. Several linear measures of atrophy have been assessed cross-sectionally in early MS, including third ventricular width (TVW)[13], [14] and lateral ventricular/frontal horn width (FHW).[13], [14] Our group and others have additionally presented data on distance measurements between the medial borders of the caudate nuclei, variously termed inter-caudate distance (ICD),15 bi-caudate ratio[16], [17] or intercaudate nucleus ratio18 as a new putative linear atrophy marker in MS. This marker has previously been utilised to measure atrophy in normal ageing,19 Huntington’s disease20 and HIV dementia.21

The current study examines the utility of TVW, FHW and ICD to differentiate MS patients from healthy controls in a large population study of MS. We then correlate these linear measures with brain and ventricular volume measures using research-quality MRI and examine the extent to which they increase over time in individual patients, in order to confirm their potential utility for cross-sectional and prospective assessments of cerebral atrophy.

Section snippets

Subjects for population-based study of linear atrophy markers

The MS patients used in this study were recruited for a population genetic study in the island state of Tasmania, Australia. The recruitment strategy attempted to identify every person with MS with at least one grandparent born in Tasmania in order to exploit a putative founder effect. Therefore, the recruited cohort is best considered as an ancestrally and regionally defined population cohort. The extensive recruitment campaign is described in detail elsewhere.22

Patients had to fulfil the

Inter-caudate distance (ICD) and third ventricle width (TVW) obtained from routine clinical scans differentiate between MS patients and healthy controls

In order to investigate the utility of the three potential linear atrophy markers to differentiate between an MS population (n = 171) and healthy controls (n = 93), we performed a multivariate conditional logistic regression analysis including each of the linear markers separately, as well as age, gender and TSD as additional variables. The MS patients had larger ICD (p < 0.001, OR 16.1) and TVW (p = 0.001, OR 2.0) values than healthy controls (Table 3). These results indicate that for every 1-mm

Discussion

Our study has revealed a relationship between linear measures ICD and TVW and more sophisticated measures of brain atrophy in two independent cohorts of MS patients, giving clinicians a useful MRI marker to quantify brain volume loss. In addition to measures of cerebral atrophy, other MRI markers potentially useful as indicators of long-term clinical end-points include: magnetisation transfer,[29], [30], [31], [32] a putative marker of macromolecular loss in normal-appearing white matter;

Acknowledgement

We thank the MS patients of Tasmania and Victoria and the staff of the Menzies Centre, Hobart, for their support. The primary investigators (HB and SK) had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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