Abstract
Previous diffusion tensor imaging (DTI) studies have shown white matter pathology in amyotrophic lateral sclerosis (ALS), predominantly in the motor pathways. Further these studies have shown that DTI can be used longitudinally to track pathology over time, making white matter pathology a candidate as an outcome measure in future trials. DTI has demonstrated application in group studies, however its derived indices, for example fractional anisotropy, are susceptible to partial volume effects, making its role questionable in examining individual progression. We hypothesize that changes in the white matter are present in ALS beyond the motor tracts, and that the affected pathways and associated pattern of disease progression can be tracked longitudinally using automated diffusion connectometry analysis. Connectometry analysis is based on diffusion spectrum imaging and overcomes the limitations of a conventional tractography approach and DTI. The identified affected white matter tracts can then be assessed in a targeted fashion using High definition fiber tractography (a novel white matter MR imaging technique). Changes in quantitative and qualitative markers over time could then be correlated with clinical progression. We illustrate these principles toward developing an imaging biomarker for demonstrating individual progression, by presenting results for five ALS patients, including with longitudinal data in two. Preliminary analysis demonstrated a number of changes bilaterally and asymmetrically in motoric and extramotoric white matter pathways. Further the limbic system was also affected possibly explaining the cognitive symptoms in ALS. In the two longitudinal subjects, the white matter changes were less extensive at baseline, although there was evidence of disease progression in a frontal pattern with a relatively spared postcentral gyrus, consistent with the known pathology in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, marked by progressive failure of both upper (UMN) and lower motor neurons (LMN)
Corresponding to each scan session, the patients will undergo extensive clinical evaluation and scoring including that of ALSFRS-R (Brooks et al, 2000), frontotemporal dementia assessment, forced vital capacity (FVC) and Ashworth spasticity scale as part of an ALS multidisciplinary clinic
TWO-STEP APPROACH TOWARD EVALUATING WHITE MATTER DISEASE IN ALS We propose and have currently adopted a two-step approach to evaluating white matter disease in a longitudinal fashion in ALS patients with the first primary step involving diffusion connectometry (Yeh et al, 2013a) analysis to identify the affected white matter tracts followed by a detailed tractography approach toward the evaluation of these identified abnormal fiber pathways
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, marked by progressive failure of both upper (UMN) and lower motor neurons (LMN). DTI (Jacob et al, 2003; Graham et al, 2004; Sach et al, 2004; Nickerson et al, 2009; Iwata et al, 2011; van der Graaff et al, 2011; Menke et al, 2012) studies in ALS have been carried out to investigate the involvement of the white matter tracts and their potential correlation with clinical markers of progression like the revised ALS functional rating scale (ALSFRS-R; Cedarbaum et al, 1999; Brooks et al, 2000). FA is a commonly used DTI-derived quantitative measure of anisotropy (Basser and Pierpaoli, 1996; Oouchi et al, 2007) and has been applied in the evaluation of white matter integrity in Frontiers in Human Neuroscience www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
