Multimodal assessment of white matter tracts in amyotrophic lateral sclerosis

RESEARCH ARTICLE Multimodal assessment of white matter tracts in amyotrophic lateral sclerosis Florian Borsodi1, Valeriu Culea1, Christian Langkammer1, Michael Khalil1, Lukas Pirpamer1, Stefan Quasthoff1, Christian Enzinger1,2, Reinhold Schmidt1, Franz Fazekas1, Stefan Ropele1* 1 Department of Neurology, Medical University of Graz, Graz, Austria, 2 Department of Radiology, Division of Neuroradiology, Medical University of Graz, Graz, Austria * a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Borsodi F, Culea V, Langkammer C, Khalil M, Pirpamer L, Quasthoff S, et al. (2017) Multimodal assessment of white matter tracts in amyotrophic lateral sclerosis. PLoS ONE 12(6): e0178371. https://doi.org/10.1371/journal. pone.0178371 Editor: Yi Wang, Cornell University, UNITED STATES Received: October 14, 2016 Accepted: May 11, 2017 Published: June 2, 2017 Copyright: © 2017 Borsodi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the Austrian Science Fund (FWF project P23576-B18, SR). www.fwf.ac.at. Competing interests: The authors have declared that no competing interests exist. Abstract Several quantitative magnetic resonance imaging (MRI) techniques have been proposed to investigate microstructural tissue changes in amyotrophic lateral sclerosis (ALS) including diffusion tensor imaging (DTI), magnetization transfer imaging, and R2* mapping. Here, in this study, we compared these techniques with regard to their capability for detecting ALS related white matter (WM) changes in the brain and their association with clinical findings. We examined 27 ALS patients and 35 age-matched healthy controls. MRI was performed at 3T, after which we analyzed the diffusion properties, the magnetization transfer ratio (MTR), and the effective transversal relaxation rate R2* in 18 WM tracts that were obtained by a fully automated segmentation technique. ALS patients, especially with a bulbar onset, showed a bilateral increase in radial and mean diffusivity, as well as a reduction in fractional anisotropy of the corticospinal tract (CST), and diffusion changes in the parietal and temporal superior longitudinal fasciculus. A reduction of the MTR was found in both CSTs and an R2* reduction was seen only in the left CST. Tract-specific diffusion properties were not related to clinical status in a cross-sectional manner but demonstrated some association with disease progression over three subsequent months. DTI reveals more widespread WM tissue changes than MTR and R2*. These changes are not restricted to the CST, but affect also other WM tracts (especially in patients with bulbar onset), and are associated with the short term course of the disease. Introduction Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and invariably fatal disorder of the motor neuron system, which characteristically affects both upper and lower motor neurons [1]. According to the revised El Escorial criteria, ALS diagnosis is based on specific clinical and electrophysiological findings [2]. In the early stage of the disease, however, these may still be subtle and thus provide only limited diagnostic certainty and prognostic information. Additional insights may come from quantitative assessment of the severity of damage to the corticospinal tract (CST), which is a pathologic hallmark feature of ALS besides the loss of motor PLOS ONE | https://doi.org/10.1371/journal.pone.0178371 June 2, 2017 1 / 13 Multimodal assessment of WM tracts in ALS neurons in the anterior horn. Several magnetic resonance imaging (MRI) techniques have already been applied to identify distinct morphological and structural changes in ALS [3,4]. So far, most quantitative MRI studies have been performed with various tract-based diffusion tensor imaging (DTI) techniques [5–8]. These attempts have been paralleled by a limited number of magnetization transfer imaging (MTI) studies [7,9]. More recently, there have also been reports on elevated iron levels in the motor cortex [10], as well as changes in R2 in the CST [11]. Post mortem analyses of ALS brains indicate that large areas of the white matter (WM), beyond the CST, may be affected by the disease, as well [12,13]. However, the extent to which pathological changes in WM tracts outside the CST may contribute to the clinical presentation and course of ALS is still largely unresolved. Apart from other techniques to assess ALS pathology DTI, MTI, and R2 mapping are now readily available on clinical MR scanners and require comparable acquisition time. It has not yet been investigated, however, how these imaging modalities compare in probing ALS related abnormalities in the same patient. Therefore, this study aimed for a comprehensive assessment of microstructural tissue changes in ALS, both in a technical and a tract-related manner. The different contributions of tract-specific DTI, MTI analyses and iron mapping were compared with regards to their ability of defining ALS pathologies and we assessed the relation of observed abnormalities with disease progression. Furthermore, the presence of tract-specific abnormalities, beyond the CST, was also investigated by using a new probabilistic tractography approach. Materials and methods Subjects In this prospective study we recruited 46 patients with suspected ALS over a 6-year period who were willing to undergo a comprehensive diagnostic work-up, including MRI of the brain and spinal cord, CSF examination and neurophysiologic assessment by an expert in neuromuscular diseases. During follow-up 15 patients were found to have other neuromuscular disorders. Furthermore, four patients had to be excluded due to inadequate image quality or lack of at least one 3-month clinical follow-up after the baseline MRI examination. From the remaining 27 patients, 13 were initially classified as possible and 14 as probable ALS according to the El Escorial criteria [2]. Furthermore, patients with already definite ALS classification were not included in this study. The overall severity of functional disturbances was described using the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R), which consists of 13 items with a score ranging from 48 (best) to 0 points (worst) [14]. From this assessment at baseline and the duration of the disease, we calculated a disease progression rate RDP [5] as follows: RDP ¼ 48 ALSFRS R : TdiseaseðmoÞ ð1Þ The severity of upper motor neuron (UMN) impairment was described with the Penn UMN score, which contains of a bulbar segment and one segment for each limb, and ranges between 0 (best) and 32 (worst) [15]. For inclusion all patients also had t (...truncated)