Elsevier

NeuroImage

Volume 40, Issue 1, 1 March 2008, Pages 19-25
NeuroImage

Brain white matter tracts degeneration in Friedreich ataxia. An in vivo MRI study using tract-based spatial statistics and voxel-based morphometry

https://doi.org/10.1016/j.neuroimage.2007.11.050Get rights and content

Abstract

Background and purpose:

Neuropathological examination in Friedreich ataxia (FRDA) reveals neuronal loss in the gray matter (GM) nuclei and degeneration of the white matter (WM) tracts in the spinal cord, brainstem and cerebellum, while the cerebral hemispheres are substantially spared. Tract-based spatial statistics (TBSS) enables an unbiased whole-brain quantitative analysis of the fractional anisotropy (FA) and mean diffusivity (MD) of the brain WM tracts in vivo.

Patients and methods:

We assessed with TBSS 14 patients with genetically confirmed FRDA and 14 age- and sex-matched healthy controls who were also examined with voxel-based morphometry (VBM) to assess regional atrophy of the GM and WM.

Results:

TBSS revealed decreased FA in the inferior and superior cerebellar peduncles and the corticospinal tracts in the medullary pyramis, in WM tracts of the right cerebellar hemisphere and in the right occipito-frontal and inferior longitudinal fasciculi. Increased MD was observed in the superior cerebellar peduncles, deep cerebellar WM, posterior limbs of the internal capsule and retrolenticular area, bilaterally, and in the WM underlying the left central sulcus. Decreased FA in the left superior cerebellar peduncle correlated with clinical severity. VBM showed small symmetric areas of loss of bulk of the peridentate WM which also correlated with clinical severity.

Conclusions:

TBSS enables in vivo demonstration of degeneration of the brainstem and cerebellar WM tracts which neuropathological examination indicates to be specifically affected in FRDA. TBSS complements VBM and might be a more sensitive tool to detect WM structural changes in degenerative diseases of the CNS.

Introduction

Friedreich ataxia (FRDA) is the most common inherited ataxia and in most cases is due to a GAA repeat expansion in a gene on chromosome 9q13 coding for a mitochondrial protein named frataxin (Klockgether, 2000). Neuropathological studies show that FRDA is characterized by neuronal loss and WM tracts degeneration in the spinal cord, brainstem and cerebellum (Lowe et al., 1997). MRI studies in FRDA patients pointed out atrophy of the cervical spinal cord and dorsal medulla, of the GM in the rostral vermis and infero-medial portions of the cerebellar hemispheres and of the WM in the peridentate regions (Della Nave et al., 2007, Schöls et al., 1997, Wullner et al., 1993, Huang et al., 1993). No signal change, notably with a tract distribution, was reported in the brain of patients with FRDA, but using a T2*-weighted sequence Waldvogel et al. (1999) reported abnormally increased T2* relaxation rate assumed to reflect increased iron content in the dentate nuclei of the cerebellum. Conversely, the atrophy of the spinal cord is combined with symmetric hyperintensity in proton density and T2-weighted images of the WM tracts in the lateral and posterior columns of cervical spinal cord reflecting wallerian degeneration in the cuneatus, gracilis and spinocerebellar tracts (Mascalchi et al., 1995).

In last years the capability of diffusion tensor MR images (DTI) to demonstrate the WM tracts has found increasing application for the structural evaluation of the normal and abnormal brain (Mori and Zhang, 2006). Recently, a voxel-wise analysis of multi-subject diffusion tensor data named tract-based spatial statistics (TBSS) was developed (Smith et al., 2006, Smith et al., 2007).

We hypothesized that TBSS could demonstrate in vivo the degenerating WM tracts in the brain of patients with genetically proven FRDA. Moreover we compared the sensitivity of TBSS in revealing structural damage of the brain WM tracts with that of voxel based morphometry (VBM) in detecting brain GM and WM atrophy in the same patients.

Section snippets

Patients and methods

Between March 2006 and April 2007 fourteen consecutive outpatients (9 women, 5 men, mean age 31 ± 9 years) with genetically proven FRDA regularly followed at the ambulatories for ataxic diseases of the Neurological Department of the University of Florence, Siena and Bologna gave their informed consent to participate in this prospective study which was approved by the Ethical Committee of the University of Florence.

Molecular diagnostic methods were previously reported (Bidichandani et al., 1998)

Results

No signal changes in PD- and T2-weighted images were seen in the brain of 13 FRDA patients and all controls. In one FRDA patient a small cavernous angioma was present in the right peritrigonal white matter. No motion artifacts in DTI and T1-weighted images were observed in patients and controls.

TBSS group comparison revealed in FRDA patients a nearly symmetric decrease of FA (Fig. 1) in many WM tracts of the brainstem and cerebellum including the inferior and superior cerebellar peduncles, the

Discussion

VBM and TBSS are automated methods which explore the whole-brain with an intrinsically strong statistical power and without any a priori hypothesis. In particular, TBSS enables investigation of WM tracts without the limitations caused by alignment inaccuracies and by uncertainty about smoothing extent typical of other voxel-wise methods of analysis of FA and MD data (Smith et al., 2006, Smith et al., 2007).

The combination of molecular genetic diagnosis with VBM or TBSS offers the possibility to

Acknowledgments

This study was supported in part by research grants of the Italian Ministry of Research to Professor Giuseppe De Michele (PRIN 2005) and to Professor Mario Mascalchi (PRIN 2007).

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