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. 2023 Sep 26:14:1249429.
doi: 10.3389/fneur.2023.1249429. eCollection 2023.

The impact of upper motor neuron involvement on clinical features, disease progression and prognosis in amyotrophic lateral sclerosis

Eleonora Colombo  1 , Francesco Gentile  2 , Alessio Maranzano  1 , Alberto Doretti  1 , Federico Verde  1   3 , Marco Olivero  2 , Delia Gagliardi  3   4 , Matteo Faré  5   6 , Megi Meneri  3   4 , Barbara Poletti  1 , Luca Maderna  1 , Stefania Corti  3   4 , Massimo Corbo  7 , Claudia Morelli  1 , Vincenzo Silani  1   3 , Nicola Ticozzi  1   3
Affiliations

The impact of upper motor neuron involvement on clinical features, disease progression and prognosis in amyotrophic lateral sclerosis

Eleonora Colombo et al. Front Neurol. .

Abstract

Objectives: In amyotrophic lateral sclerosis (ALS) both upper (UMNs) and lower motor neurons (LMNs) are involved in the process of neurodegeneration, accounting for the great disease heterogeneity. We evaluated the associations of the burden of UMN impairment, assessed through the Penn Upper Motor Neuron Score (PUMNS), with demographic and clinical features of ALS patients to define the independent role of UMN involvement in generating disease heterogeneity, predicting disease progression and prognosis.

Methods: We collected the following clinical parameters on a cohort of 875 ALS patients: age and site of onset, survival, MRC scale, lower motor neuron score (LMNS), PUMNS, ALSFRS-R, change in ALSFRS-R over time (DFS), MITOS and King’s staging systems (KSS). Transcranial magnetic stimulation was performed on a subgroup of patients and central motor conduction time (CMCT) and cortical silent period (CSP) were calculated.

Results: We observed that patients with an earlier age at onset and bulbar onset had higher PUMNS values. Higher values were also associated to lower ALSFRS-R and to higher DFS scores, as well as to higher MITOS and KSS, indicating that a greater UMN burden correlates with disease severity. Conversely, we did not appreciate any association between UMN involvement and survival or markers of LMN impairment. Moreover, PUMNS values showed a positive association with CMCT and a negative one with CSP values.

Interpretation: Our results suggest that the burden of UMN pathology, assessed through PUMNS, has an important independent role in defining clinical characteristics, functional disability, disease progression and prognosis in ALS patients. We also support the role of TMS in defining severity of UMN involvement.

Keywords: Penn upper motor neuron score; amyotrophic lateral sclerosis; motor neuron disease; transcranial magnetic stimulation; upper motor neuron involvement.

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Conflict of interest statement

VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG and Zambon. Receives or has received research supports form the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. NT received compensation for consulting services and/or speaking activities from Amylyx Pharmaceuticals, Italfarmaco and Zambon Biotech SA. He received research funding from the Italian Ministry of Health and AriSLA. He is Associate Editor for Frontiers in Aging Neuroscience. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Correlation between total PUMNS values, age at onset (A), site of onset (B) and motor phenotype (C). (A) Scatter plot showing the correlation between total PUMNS values and age at onset (R2 = 0.011; p = 0.002). Each gray circle represents an ALS patient. Trend line is shown in black. (B) Box plot showing the correlation between total PUMNS values and site of onset (p = 2.3×10−4). For each group the bold line shows the median, the gray boxes include the middle 50% of the data and whiskers show the minimum and maximum values. B, bulbar; S, spinal. (C) Box plot showing the correlation between total PUMNS values and motor phenotype. For each group the bold line shows the median, the gray boxes include the middle 50% of the data and whiskers show the minimum and maximum values. Empty circles represent outliers (below Q1−1.5IQR and above Q3+1.5IQR), asterisks represent extreme outliers (below Q1−31QR and above Q3+3IQR).
Figure 2
Figure 2
Box plots showing the correlation between total PUMNS values with KSS (A) and MITOS stages (B). For each group the bold line shows the median, the gray boxes include the middle 50% of the data and whiskers show the minimum and maximum values. Empty circles represent outliers (below Q1−1.5IQR and above Q3+1.5IQR).
Figure 3
Figure 3
Kaplan–Meier curves of survival probabilities for ALS patients with total PUMNS values above (blue) or below (red) the median value of 9.0. We did not appreciate any association with survival (p-not significant: A). Kaplan–Meier curves of survival probabilities for ALS patients with bulbar PUMNS values of 0 (blue), 1 (green), 2 (yellow), 3 (red) and 4 (black). We found that patients without bulbar UMN impairment had a significantly prolonged survival (68.4 months) compared to patients with a score of 1 (55.4 months; p-0.047), 2 (43.5 months; p = 1.5 × 10−4), 3 (43.3 months; p=8.3 × 10−5) or 4 (36.7 months, p = 0.006: B).
Figure 4
Figure 4
Scatter plot showing the correlation of total PUMNS values with CMCT values derived for the right arm [R2 = 0.167, p = 3.5×10−16; (A)], left arm [R2 = 0.121, p = 2.8×10−18; (B)], right leg [R2 = 0.066, p = 2.0×10−8; (C)] and left leg [R2 = 0.059; p = 2.0×10−6; (D)], as well as with CSP values derived from the right [R2 = 0.012, p = 0.011; (E)] and left arm [R2 = 0.010, p = 0.024; (F)]. Each gray circle represents an ALS patient. Trend line is shown in black. CMCT, central motor conduction time; CSP, cortical silent period.
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