Connecting white matter injury and thalamic atrophy in clinically isolated syndromes

https://doi.org/10.1016/j.jns.2009.02.379Get rights and content

Abstract

Previous studies suggest that thalamic degeneration is prominent in multiple sclerosis (MS) and even in pre-MS patients presenting with a clinically isolated syndrome (CIS). However, the relationships between white matter lesions and deep grey matter loss are not well understood.

We analyzed the association between white matter lesions and the thalami in CIS patients to determine if connectivity is an important determinant. We studied 24 CIS patients and 18 normal controls with anatomical and diffusion tensor (DTI) MRI images. DTI fiber tracking was used to create probabilistic templates of the thalamocortical white matter and to define white matter connecting lesions and thalami. DTI metrics in the lesions and normal-appearing white matter (NAWM) regions were compared between CIS and controls, and correlated with thalamic volume changes estimated by voxel-based morphometry.

There was 10 times higher density of lesions in thalamocortical compared to other brain white matter. Increased diffusivities and decreased fractional anisotropies were measured in the thalamocortical NAWM of CIS patients compared to controls. A step-wise regression analysis demonstrated that thalamocortical lesion volume and the mean diffusivity in track regions connecting lesion and thalami were significantly correlated with thalamic volumes in patients (Rsq = 0.66, p < 0.001), a finding not observed in regions outside the thalamocortical white matter. These results provide compelling evidence for a direct relationship between white matter lesions and thalamic atrophy in CIS patients.

Introduction

While white matter lesions are the most important MRI metric currently used for the diagnosis of multiple sclerosis (MS), the detection of decreased grey matter volumes suggests the presence of irreversible neuronal degeneration [1], [2]. The cause of grey matter volume loss is poorly understood however and is receiving well-deserved attention recently [3], [4], [5].

Reduced regional volume in CIS patients at presentation using voxel-based morphometry (VBM) was previously demonstrated [6]. In this group of CIS patients, a wide variation in global grey matter atrophy was observed; however, this total grey matter volume was not significantly different between CIS and controls. On the other hand, the thalamus exhibited consistent reduced volume across CIS patients. Functionally, the human thalamus is a complex brain relay center responsible for both sensory and motor functions, along with awareness, attention, memory and language [7]. Up to 50–60 thalamic nuclei project individual afferent neurons to several well-defined cortical areas, which in return send information through efferent neurons back to the thalamus [8].

The reason for thalamic atrophy at this earliest stage of CIS patients suggestive of MS is unclear but is supported by previous observations of thalamic degeneration in early relapsing–remitting MS, including lesions in this grey matter region [9], [10]. The relationship between lesion volume and thalamic atrophy is also unclear and may represent concurrent injury due to a mutual correlation of white and grey matter injury to a common disease process. On the other hand, there may be a direct relationship between the white and grey matter pathology due to injury in lesions in the white or grey matter, and subsequent degeneration of axonal projections connected to thalamic nuclei.

In order to further establish the relationship between thalamic atrophy and white matter lesions, we have utilized diffusion tensor MRI (DTI) to define the structural connectivity between white matter lesions and the thalami in untreated CIS patients at first clinical presentation. Furthermore, we propose to determine the distribution of white matter lesions relative to thalamocortical (TC) white matter projections, and investigate a structural rationale for connecting the white matter lesions and thalamic volume loss. Finally, we correlate the DTI metrics in lesional and normal-appearing white matter (NAWM) TC tracts with thalamic volumes from a VBM study.

Section snippets

Methods

The study cohort consisted of twenty-four untreated CIS patients (M/F = 7/17, age range 21–56) and eighteen control subjects (M/F = 8/10, age range 23–46) who were evaluated at the University of California, San Francisco Multiple Sclerosis Center. The subjects presenting with their first well-defined, neurological event persisting for more than 48 h involving the optic nerve, brainstem, cerebellum or spinal cord were included in the classification as patients with CIS and invited for participation.

Results

Examples of the thalamocortical white matter template in a CIS patient, and the individual tracking between lesions and thalami are shown in Fig. 4. The thalamocortical white matter is connected to the parietal lobe (Fig. 4a). The tracks are colored from red to yellow representing increasing mean diffusivity (Fig. 4b).

Discussion

Multiple sclerosis injury is present in both grey and white matters in the central nervous system. Tissue loss and foci of demyelination, with varying degrees of inflammation, have been described in all neocortical layers, deep grey matter nuclei and throughout the white matter. Understanding the relation between focal lesions and tissue degeneration is crucial to demystify the underlying mechanisms leading to disease progression and to prevent clinical deterioration using the correct treatment

Acknowledgements

We would like to acknowledge the funding of this work by the National Multiple Sclerosis Society research grant RG3240A1. Dr. Pelletier is a Harry Weaver Neuroscientist Scholar of the U.S. National Multiple Sclerosis Society.

First page preview

First page preview
Click to open first page preview

References (34)

  • Q. Wu et al.

    MR diffusion changes correlate with ultra-structurally defined axonal degeneration in murine optic nerve

    Neuroimage

    (2007)
  • S.D. Roosendaal et al.

    Regional DTI differences in multiple sclerosis patients

    Neuroimage

    (2009)
  • M.E. Bastin et al.

    Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age

    Neurobiol Aging

    (2009)
  • M.W. Vernooij et al.

    White matter atrophy and lesion formation explain the loss of structural integrity of white matter in aging

    Neuroimage

    (2008)
  • A.M. Fjell et al.

    The relationship between diffusion tensor imaging and volumetry as measures of white matter properties

    Neuroimage

    (2008)
  • E. Fisher et al.

    Gray matter atrophy in multiple sclerosis: a longitudinal study

    Ann Neurol

    (2008)
  • B.P. Brink et al.

    The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions

    J Neuropathol Exp Neurol

    (2005)
  • Cited by (0)

    View full text