Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis

Abstract

BackgroundThe criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant.ObjectiveThe study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy).MethodsDTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a ‘classical’ phenotype to identify white matter structural alterations.ResultsThe analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls.ConclusionsThis study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

Brain MRI shows white matter sparing in Kennedy's disease and slow‐progressing lower motor neuron disease

“…The distributed involvement of motor and extra-motor WM regions in our ALS cohort is largely consistent with previous literature Chio et al, 2014;Spinelli et al, 2016). The absence of significant WM alterations in KD patients is also in line with previous observations in slow-progressing MND phenotypes with predominant LMN involvement (Muller et al, 2018;Spinelli et al, 2016) and confirms the role of DT MRI metrics as promising markers of upper motor neuron (UMN) damage. Of note, the presence of CST alterations in both the ALS and LMND-fast groups suggests that DT MRI is highly sensitive to UMN degeneration below the clinical threshold of detection, possibly even indicating those LMND cases which might represent early ALS presentations (Muller et al, 2018).…”

“…The absence of significant WM alterations in KD patients is also in line with previous observations in slow‐progressing MND phenotypes with predominant LMN involvement (Muller et al, ; Spinelli et al, ) and confirms the role of DT MRI metrics as promising markers of upper motor neuron (UMN) damage. Of note, the presence of CST alterations in both the ALS and LMND‐fast groups suggests that DT MRI is highly sensitive to UMN degeneration below the clinical threshold of detection, possibly even indicating those LMND cases which might represent early ALS presentations (Muller et al, ). It is noteworthy that some prior MRI studies have reported WM changes in KD, mainly encompassing frontal regions, as well as the limbic system and CST (Kassubek et al, ; Unrath et al, ).…”

Survival prediction models in motor neuron disease

“…This finding was expected, as PUMN and PLMN phenotypes are known to show a more benign course , and a significant proportion of patients in our cohort met the criteria of primary lateral sclerosis or progressive muscular atrophy , based on their already long disease duration at baseline. In fact, as demonstrated by VBM and WM tractography, these phenotypes had distinctive anatomical damage compared with ALS, with PUMN showing a relatively selective involvement of the motor system and PLMN having no significant brain alterations, consistent with previous neuroimaging studies assessing these opposite ends of the MND spectrum. Diagnostic delay is another known favorable prognostic factor , as a more indolent disease course is probably reflected by a longer time to seek medical attention.…”

“…Moreover, a larger proportion of ALS patients were selected into the long-surviving group, suggesting that milder neuroanatomical damage may indicate long survivors amongst unfavorable clinical phenotypes. On the other hand, a significant proportion of PLMN patients were classified into the short-and intermediate-surviving groups by the combined model, suggesting that MRI might distinguish and stratify those PLMN patients with subtle central nervous system alterations, probably representing early ALS presentations [20]. All PUMN patients were classified into the long-surviving group by both the clinical and combined models, supporting the notion that these patients constitute a rather homogeneous clinical phenotype.…”

Finding Markers in Amyotrophic Lateral Sclerosis Diagnosis

“…Others authors have reported hyperintensity of corticospinal tract, however, the sensitivity of such changes has been estimated at <40% and the specificity <70 [22][23][24][25][26][27][28][29].…”