Cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A two-centre tract of interest-based DTI analysis

Abstract

BackgroundAfter the demonstration of a corticoefferent propagation pattern in amyotrophic lateral sclerosis (ALS) by neuropathological studies, this concept has been used for in vivo staging of individual patients by diffusion tensor imaging (DTI) techniques, both in `classical` ALS and in restricted phenotypes such as primary lateral sclerosis (PLS).ObjectiveThe study was designed to investigate that microstructural changes according to the neuropathologically defined ALS alteration pattern in PLS patients could be confirmed to be identical to ´classical´ ALS patients. The novelty in this approach is that the results were independent of the subject samples and the data acquisition parameters (as was validated in two samples from two different centres). That way, reproducibility across (international) centres in addition to harmonisation/standardisation of data analysis has been addressed, for the possible use of MRI-based staging to stratify patients in clinical trials.MethodsTractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern was applied to DTI data (pooled from two ALS centres) of 88 PLS patients and 88 ALS patients with a ‘classical’ phenotype in comparison to 88 matched controls in order to identify white matter integrity alterations.ResultsIn the tract-specific analysis, alterations were identical for PLS and ALS in the tract systems corresponding to the ALS staging pattern, independent of the subject samples and the data acquisition parameters. The individual categorisation into ALS stages did not differ between PLS and ALS patients.ConclusionsThis DTI study in a two-centre setting demonstrated that the neuropathological stages can be mapped in vivo in PLS with high reproducibility and that PLS-associated cerebral propagation, although showing the same corticofugal patterns as ALS, might have a different time course of neuropathology, in analogy to its much slower clinical progression rates.

The same cortico-efferent tract involvement in progressive bulbar palsy and in ‘classical’ ALS: A tract of interest-based MRI study

“…On the basis of this neuroimaging study, we believe that the proposed staging scheme for ALS (Braak et al, 2013) is valid also for PBP patients, who should, as a result, receive an appropriate therapy, including the same access to health care systems and the opportunity to be enrolled in clinical trials as ALS patients. Our present findings are an analogy of the demonstration of corticofugal tract involvement in other restricted ALS phenotypes, namely, both fast progressive lower motor neuron disease (Rosenbohm et al, 2016; Müller et al, 2018a) and PLS (Müller et al, 2018b; Müller et al, 2018c).…”

“…An unbiased whole brain-based approach demonstrated alterations (i.e., FA reductions) in multiple cerebral areas with a focus on the corticospinal tracts in these patients – similar to patients with ALS, but remarkably with an additional cluster in the pons, most probably as a correlate of the clinically prominent brainstem involvement. In vivo neuropathological staging by TOI-based DTI analysis (Kassubek et al, 2014; Kassubek et al, 2018; Müller et al, 2018a, Müller et al, 2018b, Müller et al, 2018c) demonstrated that patients with PBP showed a pattern of microstructural alterations in corticofugal tracts identical with those seen in ALS. In summary, patients with MND of the PBP phenotype showed the same tract involvement as ALS according to the proposed neuropathological staging in support of the hypothesis that PBP shares the cerebral involvement pattern with ALS and is, as such, an ALS sub-phenotype.…”

“…Defined tract systems according to the ALS-staging system (Braak et al, 2013; Ludolph and Brettschneider, 2015) were identified with the tract-of interest (TOI) approach (Kassubek et al, 2014; Kassubek et al, 2018; Müller et al, 2018a, Müller et al, 2018b, Müller et al, 2018c). TOIs for the four ALS stages were the corticospinal tract (CST, representative or stage 1), the corticorubral and corticopontine tracts (stage 2), the corticostriatal pathway (stage 3), the proximal perforant path (stage 4).…”

Structural and functional brain connectome in motor neuron diseases

“…Particularly, PLS patients showed widespread structural and functional alterations encompassing both motor and extra-motor areas with a pattern resembling classic ALS patients (Figure 4), in line with previous studies. 5,47 By contrast, PMA patients did not show any structural or functional damage relative to healthy controls. These findings are in line with previous studies that could not demonstrate central nervous system damage in PMA patients, 6,7 even using a technique that is highly sensitive to local disruptions in the brain networks.…”

Detecting Abnormal Brain Regions in Schizophrenia Using Structural MRI via Machine Learning

“…To test the performance of different P values, two-sample t-tests were performed with three different P values (<0.05 [57][58][59], <0.01 [60], and <0.001 [61]). e cluster-size value was set to 50 [62][63][64][65], and three differentiated tissue maps of GM and WM were obtained and are shown in Figures 3 and 4.…”