Spinal Cord Imaging in Amyotrophic Lateral Sclerosis: Historical Concepts—Novel Techniques

Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neuron disease with no effective disease modifying therapies at present. Spinal cord degeneration is a hallmark feature of ALS, highlighted in the earliest descriptions of the disease by Lockhart Clarke and Jean-Martin Charcot. The anterior horns and corticospinal tracts are invariably affected in ALS, but up to recently it has been notoriously challenging to detect and characterize spinal pathology in vivo. With recent technological advances, spinal imaging now offers unique opportunities to appraise lower motor neuron degeneration, sensory involvement, metabolic alterations, and interneuron pathology in ALS. Quantitative spinal imaging in ALS has now been used in cross-sectional and longitudinal study designs, applied to presymptomatic mutation carriers, and utilized in machine learning applications. Despite its enormous clinical and academic potential, a number of physiological, technological, and methodological challenges limit the routine use of computational spinal imaging in ALS. In this review, we provide a comprehensive overview of emerging spinal cord imaging methods and discuss their advantages, drawbacks, and biomarker potential in clinical applications, clinical trial settings, monitoring, and prognostic roles

L’utilisation de l’approche IRM multiparamétrique pour l’analyse de l’intégrité structurale de la moelle épinière dans les maladies du motoneurone

Degenerative motor neuron diseases (MND) are characterized by a progressive dysfunction and loss of ventral horn motor neurons of the spinal grey matter. Beyond this common anatomical susceptibility, which is responsible for a progressive and diffuse weakness, other neurological systems are also impaired. The corticospinal tract (CST) degeneration is a classical feature of amyotrophic lateral sclerosis (ALS), which is the most common adult onset motor neuron disease, but a more widespread multisystem involvement is now well recognized. In particular, early sensory system involvement has been demonstrated in animal models of ALS and also of survival motor neuron 1 gene linked spinal muscular atrophy (SMN1-linked SMA). In human patients, magnetic resonance imaging (MRI) has emerged as the most powerful approach at the brain level to extract quantitative data on neuronal loss, axonal degeneration and demyelination in degenerative conditions. Studies at the spinal cord levels are scarce mainly because of technical and methodological difficulties. The objective of the present thesis project was to use a multi-parametric MRI approach at the spinal cord level to analyze grey and white matter structures that are impaired in two most common MND, i.e. ALS and SMN1-linked SMA, their temporal alterations during the disease course and the functional correlates, as assessed by clinical and electrophysiological examinations.Les pathologies du motoneurone sont caractérisées par une atteinte progressive des motoneurones au niveau de la corne antérieur de la moelle épinière. Au delà de cette susceptibilité anatomique commune, qui est responsable d’une atteinte motrice progressive et diffuse dans ces pathologies, d’autres systèmes neurologiques sont touchés. La dégénérescence du faisceau corticospinal est une caractéristique classique dans la sclérose latérale amyotrophique, qui est la maladie du motoneurone la plus commune chez l’adulte. Cependant, il est de plus en plus reconnu que la SLA est une maladie multisystémique. En particulier, une atteinte précoce du système sensoriel a été démontrée dans la modèle animal de la SLA ainsi que dans l’amyotrophie spinal liée à la mutation du gène SMN1 (survival motor neuron 1 en anglais). Chez les patients, l’imagerie par résonance magnétique (IRM) a émergé comme l’approche la plus performant à l’étage cérébral, permettant d’extraire des indices quantitatifs sur la perte neuronale, la dégénérescence axonale et la démyélinisation dans les pathologies neurodégénératives. Cependant, l’investigation de l’étage médullaire dans ces pathologies est difficile à mener à cause des nombreux défis techniques et méthodologiques que représente l’IRM de la moelle épinière.L’objectif de ce projet de thèse a été d’utiliser l’approche IRM multiparamétrique au niveau de la moelle épinière pour analyser les structures de la matière grise et blanche qui sont atteintes dans deux des pathologies du motoneurone les plus répondues, c’est-à-dire la SLA et la SMA, leurs altérations au cours du temps et leurs corrélations fonctionnelles avec les données cliniques et électrophysiologiques

Neuroimaging to Investigate Multisystem Involvement and Provide Biomarkers in Amyotrophic Lateral Sclerosis

International audienceNeuroimaging allows investigating the extent of neurological systems degeneration in amyotrophic lateral sclerosis (ALS). Advanced MRI methods can detect changes related to the degeneration of upper motor neurons but have also demonstrated the participation of other systems such as the sensory system or basal ganglia, demonstrating in vivo that ALS is a multisystem disorder. Structural and functional imaging also allows studying dysfunction of brain areas associated with cognitive signs. From a biomarker perspective, numerous studies using diffusion tensor imaging showed a decrease of fractional anisotropy in the intracranial portion of the corticospinal tract but its diagnostic value at the individual level remains limited. A multiparametric approach will be required to use MRI in the diagnostic workup of ALS. A promising avenue is the new methodological developments of spinal cord imaging that has the advantage to investigate the two motor system components that are involved in ALS, that is, the lower and upper motor neuron. For all neuroimaging modalities, due to the intrinsic heterogeneity of ALS, larger pooled banks of images with standardized image acquisition and analysis procedures are needed. In this paper, we will review the main findings obtained with MRI, PET, SPECT, and nuclear magnetic resonance spectroscopy in ALS

An optimized MP2RAGE sequence for studying both brain and cervical spinal cord in a single acquisition at 3T

International audienceMagnetization Prepared 2 Rapid Acquisition Gradient Echo (MP2RAGE) is a T1 mapping technique that has been used broadly on brain and recently on cervical spinal cord (cSC).The growing interest for combined investigation of brain and SC in numerous pathologies of the central nervous system such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and traumatic injuries, now brings about the need for optimization with regards to this specific investigation. This implies large spatial coverage with high spatial resolution and short acquisition time, high CNR and low B1+ sensitivity, as well as high reproducibility and robust post-processing tools for T1 quantification in different regions of brain and SC.In this work, a dedicated protocol (referred to as Pr-BSC) has been optimized for simultaneous brain and cSC T1 MP2RAGE acquisition at 3T. After computer simulation optimization, the protocol was applied for in vivo validation experiments and compared to previously published state of the art protocols focusing on either the brain (Pr-B) or the cSC (Pr-SC). Reproducibility and in-ROI standard deviations were assessed on healthy volunteers in the perspective of future clinical use.The mean T1 values, obtained by the Pr-BSC, in brain white, gray and deep gray matters were: (mean ± in-ROI SD) 792 ± 27 ms, 1339 ± 139 ms and 1136 ± 88 ms, respectively. In cSC, T1 values for white matter corticospinal, posterior sensory, lateral sensory and rubro/reticulospinal tracts were 902 ± 41 ms, 920 ± 35 ms, 903 ± 46 ms, 891 ± 41 ms, respectively, and 954 ± 32 ms for anterior and intermediate gray matter. The Pr-BSC protocol showed excellent agreement with previously proposed Pr-B on brain and Pr-SC on cSC, with very high inter-scan reproducibility (coefficients of variation of 0.52 ± 0.36% and 1.12 ± 0.62% on brain and cSC, respectively).This optimized protocol covering both brain and cSC with a sub-millimetric isotropic spatial resolution in one acquisition of less than 8 min, opens up great perspectives for clinical applications focusing on degenerative tissue such as encountered in MS and ALS

MUTANT : a new image filtering paradigm for improved parameters determination. Application to myelin water fraction mapping and sodium concentrations imaging

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Symmetry-based reorientation algorithm for spinal cord 3T MR images

Congrès sous l’égide de la Société Française de Génie Biologique et Médical (SFGBM).National audienceImaging the spinal cord of spinal cord injury (SCI) patients is challenging due to pain and sores problems that could be caused by a prolonged lying position in the scanner. Once positioned within the MRI the subject cannot be displaced and therefore subject centering within the scanner (A-P and L-R directions) is not ensured. Thus, centering spinal cord images in the A-P and L-R directions is necessary to make group analysis and accurately quantifying cord atrophy in SCI patients. A Symmetry-based reorientation algorithm for the spinal cord 3T R images was proposed and evaluated on 32 data using both an imposed rotation angle and visual strategies. The proposed reorientation algorithm was proven to be efficient at C2 vertebral level

Electrophysiological and spinal imaging evidences for sensory dysfunction in amyotrophic lateral sclerosis

International audienceObjectives: The prevalence of sensory impairment at an early stage of amyotrophic lateral sclerosis (ALS) is still debated. The study aim was to investigate the anatomofunctional properties of sensory pathways in patients with ALS, combining spinal diffusion tensor imaging (DTI) and somatosensory evoked potentials (SEPs). Design: Case–control study. Settings: ALS referral centre and laboratory of biomedical imaging (Paris, France). Participants: Well-characterised group of 21 patients with ALS with moderate disability (mean amyotrophic lateral sclerosis Functional Rating Scale (ALSFRS) score 39.3±1.0) and no clinical sensory signs and control group of 21 gender and age-matched healthy subjects. Outcome measures: Fractional anisotropy and diffusivity of the dorsal columns at C5-T1 levels (DTI metrics) and SEPs after median and ulnar nerve stimulations (latency and amplitude of N9 and N20 components). Results: Abnormal DTI metrics indicated anatomical damages of ascending sensory fibres in ∼60% of patients (p0.16). Their normalisation to prestimulus activity strengthened the difference between groups (p0.32) but based on N20 latency, the central conduction time (between spinal cord and parietal cortex) was found to be slower (p<0.05). Significant correlation was found between DTI metrics and N9 amplitude (p<0.05). Altered SEPs were also correlated with the disease duration (p<0.05). Taken together, spinal imaging and electrophysiology helped to identify ∼85% of patients with subclinical sensory defect while separated methods revealed abnormal values in ∼60%. Conclusions: Sensory impairments have been underestimated at early stages of ALS. These results show for the first time the interest to combine electrophysiology and imaging to assess non-motor system involvement in ALS

Association between brain and upper cervical spinal cord atrophy assessed by MRI and disease aggressiveness in amyotrophic lateral sclerosis

PurposeTo study the relative contributions of brain and upper cervical spinal cord compartmental atrophy to disease aggressiveness in amyotrophic lateral sclerosis (ALS).MethodsTwenty-nine ALS patients and 24 age- and gender-matched healthy controls (HC) were recruited. Disease duration and the Revised-ALS Functional Rating Scale (ALSFRS-R) at baseline, 3- and 6-months follow-up were assessed. Patients were clinically differentiated into fast (n=13) and slow (n=16) progressors according to their ALSFRS-R progression rate. Brain grey (GM) and white matter, brainstem sub-structures volumes and spinal cord cross-sectional area (SC-CSA) at C1-C2 vertebral levels were measured from a 3D-T1-weighted MRI.ResultsFast progressors showed significant GM, medulla oblongata and SC atrophy compared to HC (p<0.001, p=0.013 and p=0.008) and significant GM atrophy compared to slow progressors (p=0.008). GM volume correlated with the ALSFRS-R progression rate (Rho/p=-0.487/0.007), the ALSFRS-R at 3-months (Rho/p=0.622/0.002), and ALSFRS-R at 6-months (Rho/p=0.407/0.039). Medulla oblongata volume and SC-CSA correlated with the ALSFRS-R at 3-months (Rho/p=0.510/0.015 and Rho/p=0.479/0.024). MRI measures showed high performance to discriminate between fast and slow progressors.ConclusionOur study suggests an association between compartmental atrophy and disease aggressiveness. This result is consistent with the combination of upper and lower motor neuron degeneration as the main driver of disease worsening and severity in ALS. Our study highlights the potential of brain and spinal cord atrophy measured by MRI as biomarker of disease aggressiveness signature

Increased Sodium Concentration in Substantia Nigra in Early Parkinson's Disease: A Preliminary Study With Ultra-High Field (7T) MRI

International audiencePathophysiology of idiopathic Parkinson's disease (iPD) is complex and still misunderstood. At a time when treatments with disease-modifying potential are being developed, identification of early markers of neurodegeneration is essential. Intracerebral sodium accumulation could be one of them. Indeed, it may be in relation to the mitochondrial dysfunction that early exists in iPD. For the first time, we used brain sodium ( 23 Na) MRI to explore sodium concentration changes that have already been reported to be related to neurodegeneration in other diseases. We prospectively included 10 iPD patients (mean age 52.2 ± 5.9 years-old) with motor symptoms that started &lt;36 months before inclusion and 12 healthy subjects (mean age 53 ± 6.4 years-old). Patients were scanned in OFF medication state by using proton ( 1 H) and 23 Na MRI at 7T. We then extracted quantitative Total Sodium Concentration (TSC) from five regions of interest known to be early impaired in iPD [substantia nigra (SN), putamen, caudate nucleus, pallidum, thalamus] and in one region supposed to be relatively spared in the first stages of the disease [cortical gray matter (neocortex)]. Potential atrophy in these structures was also investigated with 1 H MRI. Relative to healthy subjects, iPD patients showed higher TSC in the SN (43.73 ± 4.64 vs. 37.72 ± 5.62, p = 0.006 after Bonferroni correction). A trend of increase in sodium concentrations was found within the pallidum (45.80 ± 4.19 vs. 41.07 ± 4.94, p = 0.017), putamen (48.65 ± 4.58 vs. 43.66 ± 5.04, p = 0.041) and the cortical gray matter (56.34 ± 3.92 vs. 50.81 ± 5.50, p = 0.021). No significant brain atrophy was found in patients compared to controls. Thus, alteration of sodium homeostasis in the SN in the absence of atrophy could be considered as a potential early marker of cellular dysfunction in iPD