Theme 08 - Clinical Imaging and Electrophysiology

Background: The functional reorganization of brain networks sustaining gait is poorly characterized in amyotrophic lateral sclerosis (ALS) despite ample evidence of progressive discon- nection between brain regions. Objectives: The main objective of this fMRI study is to assess gait imagery-specific networks in ALS patients using dynamic causal modelling (DCM) complemented by parametric empir-ical Bayes (PEB) framework. Methods: Seventeen lower motor neuron predominant (LMNp) ALS patients, fourteen upper motor neuron predominant (UMNp) ALS patients and fourteen healthy controls par- ticipated in this study. Each subject performed a dual motor imagery task: normal and precision gait. The Movement Imagery Questionnaire (MIQ-rs) and imagery time (IT) were used to evaluate gait imagery in each participant. In a neuro-biological computational model, the circuits involved in imagined gait and postural control were investigated by modelling the relationship between normal/precision gait and connection strengths. Results: Behavioral results showed significant increase in IT in UMNp patients compared to healthy controls ( p corrected < 0.05) and LMNp ( p corrected < 0.05). During precision gait, healthy controls activate the model ’ s circuits involved in the imagined gait and postural control. In UMNp, decreased con- nectivity (inhibition) from basal ganglia (BG) to supplemen-tary motor area (SMA) and from SMA to posterior parietal cortex (PPC) is observed. Contrary to healthy controls, DCM detects no cerebellar-PPC connectivity in neither UMNp nor LMNp ALS. During precision gait, bilateral connectivity (excit- ability) between SMA and BG is observed in the LMNp group contrary to UMNp and healthy controls. Discussion: Our findings demonstrate the utility of imple-menting both DCM and PEB to characterize connectivity patterns in specific patient phenotypes. Our approach enables the identification of specific circuits involved in postural deficits, and our findings suggest a putative excitatory – inhibitory imbalance. More broadly, our data demonstrate how clinical manifestations are underpinned by network-specific discon- nection phenomena in ALS. Background: The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. Objectives: We used MRI to analyze white matter (WM) vol-umes in presymptomatic and symptomatic C9orf72 expan- sion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods: We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regres- sions to assess group-by-age interactions. Results: A reduced WM ratio was found in all brainstem sub-regions in symptomatic carriers compared to both noncar- riers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differen- ces were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion: We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking. Objective: Age is the most important single risk factor of sporadic amyotrophic lateral sclerosis (ALS). Neuroimaging together with machine learning allows estimating individuals ’ brain age. Deviations from normal brain ageing trajectories (so called predicted brain age difference or PAD) were reported for many of neuropsychiatric disorders. While all of them showed increased PAD, there is surprisingly few data on PAD in motor neurodegenerative diseases. Methods: In this observational study we used previously trained algorithms of 3377 healthy individuals and derived PAD from volumetric MRI of 112 ALS patients and 70 healthy controls. We correlated PAD scores with voxel-based morph- ometry data and multiple different motoric disease characteristics as well as cognitive/behavioral impairment. Results: Against our primary hypothesis, there was no higher PAD in the ALS patients per se. None of the motoric characteristics influenced PAD. However, cognitive/behavioral impairment led to significantly increased PAD, while slowly progressive as well as cognitive/behavioral normal ALS patients had even younger brain ages than healthy controls. Of note, the cognitive/behavioral normal ALS patients showed increased cerebellar brain volume as potential resilience factor. Interpretation: Younger brain age in ALS is able to predict slower disease progression / longer survival, possibly providing a cerebral reserve against cognitive / behavioral impairment and faster disease progression. Brain age analysis pipeline ’ s ease of use might suggest it as novel biomarker for monitoring disease modifying effects. Background and purpose: Synaptic loss is well established as the major correlate of characteristic and consistent path- ology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of 18F- SynVesT-1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes. Background and objectives: Hirayama ’ s disease (HD) is a rare juvenile distal upper limb ’ s amyotrophy. It has been strongly debated whether HD should be considered a MND or a cervical myelopathy. The aim of this study is to explore HD demographic, clinical, neurophysiological and magnetic resonance imaging (MRI) characteristics to better define this clinical entity compared to ALS. Methods: We retrospectively analysed clinical, neurophysiological and MRI data of HD patients referring to our Center. We, then, compared HD and ALS patients with distal upper limb onset and available compound muscle action potential (CMAP) values of abductor pollicis brevis (APB) and abductor digiti minimi (ADM), calculating APB/ADM and ADM/ APB ratios. Results: We included 7HD and 20 ALS patients. 5HD patients were males (71.4%); mean age at onset was 16.86 years. Brachioradialis sparing (oblique amyotrophy) was evi- dent in all HD patients. Cold paralysis and tremor were fre-quent findings (5 out of 5 and 5 out of 6, respectively). No patients showed lower limbs weakness, while sensitive Background: Multimodal neuroimaging of the spinal cord and brain provides promising sensitive diagnostic and prog- nostic capabilities in ALS (1,2). However, very few neuroimaging studies have focused on examining changes in brainstem regions in ALS. Because the brainstem contains the special- ized medullary respiratory rhythm generators and the lower bulbar motor nuclei, and its degeneration is a characteristic feature of ALS (3), the present study aims primarily to investigate longitudinal structural and diffusion changes in the brainstem regions of ALS patients and their relationship to bulbar and respiratory functions assessed with standar-dized tools. Methods: This study is an ancillary analysis using data from the Paris center, part of the PULSE study, an ongoing large French multicenter observational study and prospective mul- ticenter cohort (protocol 2013-A00969-36) in ALS patients. A total of 45 ALS patients, 12 healthy controls, and 4 diseased controls were included in the analysis. T1-weighted and diffusion tensor imaging scans were performed using a Siemens 3 Tesla MRI scanner. Volumetric analysis of brainstem regions, midbrain, pons, and medulla oblongata was performed using Bayesian segmentation of brainstem structures using T1- weighted images in freesurfer 7.1.1. Diffusion tensor imaging analysis was performed in collaboration with the BrainTale platform, which includes the BrainQuant module that allows processing of MRI diffusion images of the brain. Clinical varia-bles including demographic data, ALSFRS-R, muscle strength test, respiratory parameters (ALSFRS-R respiratory subscale, Borg scale, spirometry, NIV initiation data, nocturnal oxim-etry). Data were collected at five time points: baseline, 3, 6, 9, and 12 months. Neuroimaging, clinical, and demographic analyses are evaluated for group comparison, correlation analysis, and linear regression prediction model analysis. Results: Volumetric analysis of brainstem regions showed no significant differences between ALS and the healthy and dis- eased control subjects. Correlation analysis of volumetric measures of brainstem regions, particularly the pontine, midbrain, and total brainstem volumes, showed strong correlations with ALSFRS-R scores for speech, salivation, and swallowing. Discussion: This study will allow and diffusion measures of the brainstem Background: Sporadic and familial forms of Amyotrophic Lateral Sclerosis (ALS) are characterized by perturbed excita-tion/inhibition (E/I) input balance to motoneurons. Indeed, previous studies using paired-pulse TMS (ppTMS) had shown that ALS is distinguished by a depressed Short-Intracortical Inhibition (sICI) and an enhanced Intracortical Facilitation (ICF) leading to an early cortical hyperexcitability that results in motoneurons death. It is commonly assumed that impaired sICI results in degeneration of upper motoneurons Object