Abstract
A sequential transaxonal disease spread of amyotrophic lateral sclerosis (ALS)-associated TDP-43 pathology in four stages has been defined by post-mortem data, which have been transferred to in vivo imaging by diffusion tensor imaging (DTI) studies. Here, we aimed to investigate whether DTI meta-data are consistent with this proposed pattern of progression in ALS. A systematic literature search using the search engines PubMed and Scopus yielded a total of 370 publications. Of these, 57 studies with cross-sectional data and 10 longitudinal studies of human whole-brain analyses of fractional anisotropy (FA) were included in the final data analysis. Statistical meta-analyses on coordinates of significant FA alterations were performed on a grand average alteration data set using a fixed-effect model. A widespread pattern of white matter impairment was identified from cross-sectional meta data (n = 2064 ALS patients vs. n = 1688 controls) and supported from longitudinal meta data (n = 266 ALS patients over 8 months). The results from cross-sectional meta-analyses corresponded to the brain regions and tract systems according to the sequential disease spread of ALS. Structural alterations in ALS patients vs. controls followed a power gradient, i.e., the most frequent alterations were observed along the corticospinal tract (CST, related to ALS stage 1), followed by frequent alterations along the corticorubral/-pontine tract (related to ALS stage 2), together with corticostriatal pathways (related to ALS stage 3), and, finally, alterations in the hippocampal regions adjacent to the proximal portion of the perforant path (related to ALS stage 4). The results from the DTI-based neuroimaging meta-analysis strongly support the model of the corticoefferent axonal disease progression in ALS and provides further in vivo evidence for the proposed staging scheme of ALS-associated pathology.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease and is characterized clinically by a rapidly progressive paresis leading to death within approximately three years[1]
Following the concept of meta-analysis, we hypothesized that the analysis of clustered diffusion tensor imaging (DTI)-based studies within the framework of a systematic meta-study in both cross-sectional and longitudinal studies would result in the identical pattern of tract structures that become sequentially involved during the disease course according to the amyotrophic lateral sclerosis (ALS) propagation concept
By using a meta-analysis approach, DTI data from 57 cross-sectional studies with n = 7 up to n = 387 ALS patients were pooled to investigate microstructural differences in ALS patients compared to controls
Summary
Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease and is characterized clinically by a rapidly progressive paresis leading to death within approximately three years[1]. Post-mortem studies of brains from patients with sporadic ALS permitted the definition of a four-stage corticoefferent sequential axonal spread of phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43)[3,4] This corticoefferent spreading model includes different clinical subtypes, such as bulbar or spinal site-of-onset[5]. ALS patients with a family history, including cases with the C9orf[72] hexanucleotide expansion, showed the same distribution pattern of pTDP-43 pathology as apparently sporadic cases[5]. This post-mortem staging model has been transferred in vivo to MRI-based concepts by in silico models[6], microstructural data[7,8], and additional functional connectivity evidence[9]. We further hypothesized that the resulting alterations from the meta-analysis with respect to their frequency resembled the pattern of sequential involvement of ALS-associated tracts and in pathways associated with the in-vivo staging scheme[8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
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 call
