Early Detection of Automatic Breathing Impairments in ALS: A Novel Diagnostic Approach

Purpose/Hypothesis: Early detection of respiratory impairments in amyotrophic lateral sclerosis (ALS) has profound implications for survival and quality of life. Identifying these impairments can enhance disease monitoring and support targeted disease ameliorating therapies. However, early detection of respiratory impairments is hindered by clinical tests that inadequately challenge the respiratory neural drive. Unlike limb muscles, respiratory muscles are innervated by two independent but overlapping neural pathways: the ponto-medullary-spinal pathway for involuntary/automatic breathing and the cortico-spinal pathway for volitional breathing. ALS respiratory care guidelines focus on volitional breathing tests like functional vital capacity (FVC) and maximum inspiratory pressure (MIP), which may miss early impairments in automatic breathing. The purpose of this study is to detect if subclinical impairments in automatic breathing are present, despite normal volitional respiratory measures such as FVC and MIP, in the asymptomatic phase of ALS. To confirm the histopathological correlates of early breathing impairments in ALS, we also performed MRI diffusion tensor imaging (DTI) of the cervical spinal cord and neurofilament level estimation in the blood. Materials and Methods: This observational study included asymptomatic ALS ( C9orf72 gene carriers, C9; n=6; aged 46.5±9.3 years, female=4), healthy controls (n=6; aged 39.5±7.9 years, female=3), and symptomatic ALS of heterogeneous etiology (n=3; aged 57.33±14.05 years, female=2). Tests measured 1) maximum volitional respiratory force (MIP and sniff nasal inspiratory pressure, SNIP) and volume production (FVC); 2) automatic respiratory drive (mouth occlusion pressure, P0.1, and waking average oxygen saturation [~30 min epoch of waking SpO 2 %]). Histopathology in asymptomatic C9 carriers was confirmed using diffusion MR (iFOV-HYDI) imaging to assess changes in the cervical spinal cord (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) compared to healthy controls with an unpaired T-test. Blood samples are currently being processed for neurofilament analysis. Results: Symptomatic ALS participants showed significant reductions in volitional respiratory measures: MIP=-52±32 cm H 2 O, SNIP=-35±21 cm H 2 O, and FVC=1.95±0.95 L/s ( p<0.05 ). No deficits in volitional respiratory measures were observed in C9 carriers: MIP=-125±17 cm H 2 O, SNIP=-104±16 cm H 2 O, and FVC=3.5±0.91 L/s. However, C9 carriers aged >48 years showed significant deficits in automatic respiratory measures: P0.1=1.14±0.43 cm H 2 O and SpO 2 =92.4±2.14%. DTI FA analysis showed lower values in asymptomatic C9 carriers, with significant differences compared to healthy controls at the C6 cord ( p<0.05 ), indicating loss of white matter integrity; higher radial diffusivity (RD) indicating greater myelin sheath disruption; and lower axial diffusivity (AD) indicating white matter axonal damage at the C4 spinal cord ( p<0.05 ), the core region for the phrenic motor pool. Conclusions: This study highlights the utility of automatic breathing measures in detecting early ALS progression in asymptomatic individuals. Preliminary results suggest reduced automatic brainstem respiratory neural drive in C9 carriers without concomittant deficits in conventional volitional breathing measures. Histopathological evidence of early impairments in C9 carriers was also evident with MRI DTI analysis. This multimodal biomarker approach could fill a critical gap in ALS care by providing markers for earlier intervention and endpoints in future clinical trials. Thomas Jefferson University Provost Award 2022-23 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.