Spinal Cord Gray Matter Research Articles

Inter-Strain Differences in the Lumbar Spinal Cord Anatomy and Neuromorphology: Wistar Versus Dark Agouti Rats.

Rat strains differ in physiology, behavior, and recovery after central nervous system injury. To assess these differences, we compared the gross and local anatomy and neuromorphology of the lumbar spinal cord of the Wistar and Dark Agouti (DA) strains. The key findings include (i) distinct spatial relationships between vertebrae and spinal segments in the two strains; (ii) Wistar rats have larger volumes of spinal cord gray and white matter; (iii) DA rats have smaller total neuronal populations, thus indicating an expectation of smaller local neuronal populations; (iv) this expectation was confirmed for interneurons expressing calbindin 28kDa. But contrary to expectations, (v) DA rats had more numerous populations of the interneurons expressing parvalbumin and a population of α-motoneurons. Consequently, these strains displayed divergent ratios in specific spinal neuronal populations. Researchers should consider these inter-strain differences when comparing data across different strains.

Assessing disease progression and treatment response in progressive multiple sclerosis.

Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies.

Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice.

Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMCs) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein-Barr virus reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord gray matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization, and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.

Spontaneous human CD8 T cell and autoimmune encephalomyelitis-induced CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis humanized immune system mice

Autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are only partially represented in current experimental models and the development of humanized immune mice is crucial for better understanding of immunopathogenesis and testing of therapeutics. We describe a humanized mouse model with several key features of MS. Severely immunodeficient B2m-NOG mice were transplanted with peripheral blood mononuclear cells (PBMCs) from HLA-DRB1-typed MS and healthy (HI) donors and showed rapid engraftment by human T and B lymphocytes. Mice receiving cells from MS patients with recent/ongoing Epstein–Barr virus reactivation showed high B cell engraftment capacity. Both HLA-DRB1*15 (DR15) MS and DR15 HI mice, not HLA-DRB1*13 MS mice, developed human T cell infiltration of CNS borders and parenchyma. DR15 MS mice uniquely developed inflammatory lesions in brain and spinal cord gray matter, with spontaneous, hCD8 T cell lesions, and mixed hCD8/hCD4 T cell lesions in EAE immunized mice, with variation in localization and severity between different patient donors. Main limitations of this model for further development are poor monocyte engraftment and lack of demyelination, lymph node organization, and IgG responses. These results show that PBMC humanized mice represent promising research tools for investigating MS immunopathology in a patient-specific approach.

Developmental Anatomy of Gray Matter of Spinal Cord in Animals with Special Reference to Prenatal Goat: A Review

Spinal cord is the major nerve tract of vertebrates, extending from the brain through the vertebral canal. Primordium, the neural tube was initially with thick lateral walls having three layers: inner germinal/ependymal layer, middle mantle layer forming the gray matter and outer marginal layer forming white matter. It presented a diamond-shaped lumen with a sulcus limitans, alar, basal, roof and floor plates and limiting membranes. Gray matter of the cord occupies the central region of spinal cord and in amniotes has in cross section, the well-known ‘H’ or butterfly-like shape. The white matter forms a thick peripheral zone of the cord and is divided by the gray columns into dorsal, lateral and ventral funiculi. There are three coumns for the gray matter, viz. the dorsal, ventral and lateral horns, with ventral ones being wider at the enlargements of the cord. Lateral horn appears only at thoracic, anterior lumbar and middle sacral levels. The layers of gray matter were laminae I to X. Lamina I or marginal zone capped the dorsal horn. Lamina II represented substantia gelatinosa and covered the dorsal horn, beneath marginal zone. Lamina III was an area with loosely arranged larger cells, entering the substantia gelatinosa. Lamina IV was a poorly defined cell column with nucleus proprius. Lamina V was a broad zone extending across the cervix of the dorsal horn; had spinal reticular nucleus and reticular processes. The region showed small to medium-sized cells which were most numerous in the zone between the ventral part of the dorsal horn and the lateral funiculus of white matter. Lamina VI was broad with unclear boundaries, related medially to central canal. It had compact medial and less compact lateral zones. Lamina VII shows the intermediate gray matter, with intermediolateral and intermediomedial nuclei, cervical nucleus of Stilling and Clark’s column. Lamina VIII had cells of small and medium size and was not sharply distinguished from lamina VII. Lamina IX had alpha and gamma type of neurons, which were larger at enlargements. Ventral horn had lateral and medial nuclear groups of multipolar neurons. Medial nuclear groups were seen in all regions and lateral groups only at enlargements. Medial nuclear group had dorsomedial and ventromedial nuclei; whereas the smaller lateral nuclear group had dorsolateral and ventrolateral nuclei. In addition, the enlargements also had central and retrodorsolateral nuclei. Lamina X was seen around the central canal. Laminae varied in cell size and thickness between regions of the cord. Development of laminae and nuclei of spinal gray in fetuses corresponded to the progressive growth of muscles and skeleton. All the ten laminae were together present in the spinal gray matter by the end of gestation.

Cervical and thoracic spinal cord gray matter atrophy is associated with disability in patients with amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator-independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA-derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS. A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age- and sex-matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two-dimensional axial rAMIRA imaging at the inter-vertebral disc levels C2/3-C5/C6 and the lumbar enlargement level Tmax. ALS Functional Rating Scale-revised (ALSFRS-R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed. Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax. Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax. SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS-R (p < 0.001) and SNIP (p = 0.0016). Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted.

Neurodegeneration within the rostral spinal cord is associated with brain gray matter volume atrophy in the early stage of cervical spondylotic myelopathy.

Case-control study. Investigating the association between neurodegeneration within rostral spinal cord and brain gray matter volume (GMV) and assessing the relationship between remote neurodegenerative changes and clinical outcomes at the early phase of Cervical Spondylotic Myelopathy (CSM). University/hospital. Using Spinal Cord Toolbox, spinal cord morphometrics (cross-sectional area [CSA], gray matter area [GMA], white matter area [WMA]) of 40 patients with CSM and 28 healthy controls (HCs) were computed and compared using two-sample t test. Brain GMV of the two groups was analyzed using voxel-based morphometry approach. Pearson's correlation between spinal cord morphometrics and altered brain GMV and Spearman's relationship between remote neurodegenerations and clinical outcomes were conducted in CSM group. Compared to HCs, CSA and WMA at C2/3 and GMV in right postcentral gyrus (PoCG.R) and left supplementary motor area (SMA.L) were significantly decreased in patients with CSM. CSA and WMA at C2/3 were associated with GMV in SMA.L and MCG.R in patients with CSM. CSA at C2/3 and GMV in PoCG.R were related to modified Japanese Orthopedic Association score in patients with CSM. The associations between CSA and WMA at C2/3 and GMV in SMA.L and MCG.R suggest a concordant change pattern and adaptive mechanisms for neuronal plasticity underlying remote neurodegeneration in early CSM. The atrophy of CSA at C2/3 and GMV loss in PoCG.R can serve as potential neuroimaging biomarkers of early structural changes within spinal cord and brain preceding marked clinical disabilities in patients with CSM.

Regional spinal cord volumes and pain profiles in AQP4-IgG + NMOSD and MOGAD.

Aquaporin-4-antibody-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder (MOGAD) are relapsing neuroinflammatory diseases, frequently leading to chronic pain. In both diseases, the spinal cord (SC) is often affected by myelitis attacks. We hypothesized that regional SC volumes differ between AQP4-IgG + NMOSD and MOGAD and that pain intensity is associated with lower SC volumes. To evaluate changes in the SC white matter (WM), gray matter (GM), and pain intensity in patients with recent relapses (myelitis or optic neuritis), we further profiled phenotypes in a case series with longitudinal imaging and clinical data. Cross-sectional data from 36 participants were analyzed in this retrospective study, including 20 AQP4-IgG + NMOSD and 16 MOGAD patients. Pain assessment was performed in all patients by the Brief Pain Inventory and painDETECT questionnaires. Segmentation of SC WM, GM, cervical cord volumes (combined volume of WM + GM) was performed at the C2/C3 cervical level. WM% and GM% were calculated using the cervical cord volume as a whole per patient. The presence of pain, pain severity, and clinical disability was evaluated and tested for associations with SC segmentations. Additionally, longitudinal data were deeply profiled in a case series of four patients with attacks between two MRI visits within one year. In AQP4-IgG + NMOSD, cervical cord volume was associated with mean pain severity within 24 h (β = -0.62, p = 0.009) and with daily life pain interference (β = -0.56, p = 0.010). Cross-sectional analysis showed no statistically significant SC volume differences between AQP4-IgG + NMOSD and MOGAD. However, in AQP4-IgG + NMOSD, SC WM% tended to be lower with increasing time from the last attack (β = -0.41, p = 0.096). This tendency was not observed in MOGAD. Our case series including two AQP4-IgG + NMOSD patients revealed SC GM% increased by roughly 2% with either a myelitis or optic neuritis attack between visits. Meanwhile, GM% decreased by 1-2% in two MOGAD patients with a myelitis attack between MRI visits. In AQP4-IgG + NMOSD, lower cervical cord volume was associated with increased pain. Furthermore, cord GM changes were detected between MRI visits in patients with disease-related attacks in both groups. Regional SC MRI measures are pertinent for monitoring disease-related cord pathology in AQP4-IgG + NMOSD and MOGAD.

Synergistic effect of chemogenetic activation of corticospinal motoneurons and physical exercise in promoting functional recovery after spinal cord injury

Single therapeutic interventions have not yet been successful in restoring function after spinal cord injury. Accordingly, combinatorial interventions targeting multiple factors may hold greater promise for achieving maximal functional recovery. In this study, we applied a combinatorial approach of chronic chemogenetic neuronal activation and physical exercise including treadmill running and forelimb training tasks to promote functional recovery. In a mouse model of cervical (C5) dorsal hemisection of the spinal cord, which transects almost all descending corticospinal tract axons, combining selective activation of corticospinal motoneurons (CMNs) by intersectional chemogenetics with physical exercise significantly promoted functional recovery evaluated by the grid walking test, grid hanging test, rotarod test, and single pellet-reaching tasks. Electromyography and histological analysis showed increased activation of forelimb muscles via chemogenetic stimuli, and a greater density of vGlut1+ innervation in spinal cord grey matter rostral to the injury, suggesting enhanced neuroplasticity and connectivity. Combined therapy also enhanced activation of mTOR signaling and reduced apoptosis in spinal motoneurons, Counts revealed increased numbers of detectable choline acetyltransferase-positive motoneurons in the ventral horn. Taken together, the findings from this study validate a novel combinatorial approach to enhance motor function after spinal cord injury.

Ifit2 restricts murine coronavirus spread to the spinal cord white matter and its associated myelin pathology.

Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is critical in restricting neurotropic murine-β-coronavirus, RSA59 infection. RSA59 intracranial injection of Ifit2-deficient (-/-) compared to wild-type (WT) mice results in impaired acute microglial activation, reduced CX3CR1 expression, limited migration of peripheral lymphocytes into the brain, and impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence during the chronic demyelinating phase of RSA59 infection. To understand this, RSA59 infected Ifit2-/- and Ifit2+/+ (WT) were observed for neuropathological outcomes at day 5 (acute phase) and 30 post-infection (chronic phase). Our study demonstrates that Ifit2 deficiency causes extensive RSA59 spread throughout the spinal cord gray and white matter, associated with impaired CD4+ T and CD8+ T cell infiltration. Further, the cervical lymph nodes of RSA59 infected Ifit2-/- mice showed reduced activation of CD4+ T cells and impaired IFNγ expression during acute encephalomyelitis. Interestingly, BBB integrity was better preserved in Ifit2-/- mice, as evidenced by tight junction protein Claudin-5 and adapter protein ZO-1 expression surrounding the meninges and blood vessels and decreased Texas red dye uptake, which may be responsible for reduced leukocyte infiltration. In contrast to sparse myelin loss in WT mice, the chronic disease phase in Ifit2-/- mice was associated with severe demyelination and persistent viral load, even at low inoculation doses. Overall, our study highlights that Ifit2 provides antiviral functions by promoting acute neuroinflammation and thereby aiding virus control and limiting severe chronic demyelination. IMPORTANCE Interferons execute their function by inducing specific genes collectively termed as interferon-stimulated genes (ISGs), among which interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is known for restricting neurotropic viral replication and spread. However, little is known about its role in viral spread to the spinal cord and its associated myelin pathology. Toward this, our study using a neurotropic murine β-coronavirus and Ifit2-deficient mice demonstrates that Ifit2 deficiency causes extensive viral spread throughout the gray and white matter of the spinal cord accompanied by impaired microglial activation and T cell infiltration. Furthermore, infected Ifit2-deficient mice showed impaired activation of T cells in the cervical lymph node and relatively intact blood-brain barrier integrity. Overall, Ifit2 plays a crucial role in mounting host immunity against neurotropic murine coronavirus in the acute phase while preventing mice from developing viral-induced severe chronic neuroinflammatory demyelination, the characteristic feature of human neurological disease multiple sclerosis (MS).

The complete acute and post-acute care course of children affected by acute flaccid myelitis in Western Pennsylvania: A case series.

Acute flaccid myelitis (AFM) is a "polio-like" neurologic disorder of the spinal cord gray matter characterized by asymmetric, flaccid limb weakness of rapid onset following prodromal viral illness. It has affected the pediatric population of the United States since 2014, but there is a paucity of literature describing the post-acute comprehensive rehabilitation management that maximizes functional outcomes for patients. This case series attempts to mitigate this by describing the complete acute and post-acute care course of six children diagnosed with AFM in Western Pennsylvania. It is critical that pediatric rehabilitation medicine providers be knowledgeable about the complex medical and rehabilitation management for patients with AFM.

Multiparametric magnetic resonance imagingfor detection of pathological changes in the central nervous system of a mouse model of multiple sclerosis in vivo.

Multiple sclerosis (MS) is an autoimmune disease involving demyelination and axonal damage in the central nervous system (CNS). In this study, we investigated pathological changes in the lumbar spinal cord of C57BL/6 mice induced with progressive experimental autoimmune encephalomyelitis (EAE) disease using 9.4-T magnetic resonance imaging (MRI). Multiparametric MRI measurements including MR spectroscopy, diffusion tensor imaging (DTI) and volumetric analyses were applied to detect metabolic changes in the CNS of EAE mice. Compared with healthy mice, EAE mice showed a significant reduction in N-acetyl aspartate and increases in choline, glycine, taurine and lactate. DTI revealed a significant reduction in fractional anisotropy and axial diffusivity and an increase in radial diffusivity in the lumbar spinal cord white matter (WM), while in the grey matter (GM), fractional anisotropy increased. High-resolution structural imaging also revealed lumbar spinal cord WM hypertrophy and GM atrophy. Importantly, these MRI changes were strongly correlated with EAE disease scoring and pathological changes in the lumbar (L2-L6), particularly WM demyelination lesions and aggregation of immune cells (microglia/macrophages and astrocytes) in this region. This study identified changes in MRI biomarker signatures that can be useful for evaluating the efficacy of novel drugs using EAE models in vivo.

Association of Daily Physical Activity with Cervical Spinal Cord Areas in Multiple Sclerosis

Background and purpose Remote activity monitoring has the potential to evaluate real-world motor function and disability outside of the clinic. The relationships of daily physical activity with spinal cord white matter and grey matter areas, MS disability, and leg function are unknown. Our purpose was to evaluate the association of remotely captured ambulatory activity with structural central nervous system pathology via quantitative magnetic imaging, in people with multiple sclerosis (MS). Methods Fifty adults with progressive or relapsing MS with motor disability who could walk at least 2 minutes, were assessed using clinical, patient-reported, and quantitative brain and spinal cord MRI measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 consecutive days. Univariate and multivariate analyses were performed to assess correlations between remote physical activity and other disability metrics. Results The mean age of the cohort was 53.3 years and the median EDSS was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures (i.e., Timed 25-foot Walk, Timed up and Go tests, and subjective 12- item MS Walking Scale). Greater STEPS correlated with greater C2-C3 spinal cord grey matter areas (rho=0.39, p=0.04), total cord area (rho=0.35, p=0.04), and brain volume (rho=0.32, p=0.04). Discussion These results provide preliminary evidence that spinal cord grey matter area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology. Longitudinal observations are needed to determine directionality and value of STEPS as a proxy for generalized brain and cord volume loss. These results have potential implications for structural and functional modification of disease progression via therapeutic interventions aimed at altering STEPS. Remote activity monitoring has the potential to evaluate real-world motor function and disability outside of the clinic. The relationships of daily physical activity with spinal cord white matter and grey matter areas, MS disability, and leg function are unknown. Our purpose was to evaluate the association of remotely captured ambulatory activity with structural central nervous system pathology via quantitative magnetic imaging, in people with multiple sclerosis (MS). Fifty adults with progressive or relapsing MS with motor disability who could walk at least 2 minutes, were assessed using clinical, patient-reported, and quantitative brain and spinal cord MRI measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 consecutive days. Univariate and multivariate analyses were performed to assess correlations between remote physical activity and other disability metrics. The mean age of the cohort was 53.3 years and the median EDSS was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures (i.e., Timed 25-foot Walk, Timed up and Go tests, and subjective 12- item MS Walking Scale). Greater STEPS correlated with greater C2-C3 spinal cord grey matter areas (rho=0.39, p=0.04), total cord area (rho=0.35, p=0.04), and brain volume (rho=0.32, p=0.04). These results provide preliminary evidence that spinal cord grey matter area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology. Longitudinal observations are needed to determine directionality and value of STEPS as a proxy for generalized brain and cord volume loss. These results have potential implications for structural and functional modification of disease progression via therapeutic interventions aimed at altering STEPS.

Cervical Spinal Cord Gray Matter Atrophy as an Emerging Imaging Marker in Spinal Muscular Atrophy (P2-8.014)

<h3>Objective:</h3> To prospectively evaluate cervical spinal cord (SC) gray matter (GM) area and its association with upper limb function in patients with 5q-Spinal Muscular Atrophy (SMA) using rAMIRA (radially sampled Magnetization Inversion Recovery Acquisitions) MR-imaging. <h3>Background:</h3> With the approval of the first disease modifying treatments for SMA, there is an increasing need for biomarkers that allow easy to perform, reliable, and valid disease course- and therapeutic response monitoring. The novel rAMIRA method enables high in-plane resolution MR-imaging with improved contrast of SC GM in clinically feasible acquisition times at 3 Tesla. <h3>Design/Methods:</h3> Using axial 2D rAMIRA imaging, we prospectively investigated 21 patients with 5q-SMA, types 2 and 3 (mean age/SD 41.3/11.6y, 9 women) and 21 age- and sex-matched healthy controls (HC) (mean age/SD 41.7/11.4y, 9 women) at the intervertebral disc levels C2/C3-C5/C6 perpendicular to the cord. SC GM areas were determined using a semi-automated approach. The associations between SC GM area and Revised Upper Limb Module (RULM), an established measure of upper limb disability in SMA, were assessed using multivariable regression analysis covarying for age. <h3>Results:</h3> Compared to HC cervical SC GM areas were significantly reduced in patients with SMA at C3/C4 with a relative reduction (RR) of 13.6% (p&lt;0.0001), at C4/5 RR = 16.7%, (p&lt;0.0001), at C5/6 RR = 17.1% (p&lt;0.0001), but not significantly at C2/C3 RR = 5.3% (p=0.071). In multivariable regression analysis covarying for age, GM area at C3/C4 explained 28% of RULM variance in patients with SMA. <h3>Conclusions:</h3> Cervical SC GM atrophy is detectable in patients with 5q SMA compared to HC and correlates with clinical measures of upper limb function, namely RULM. Further longitudinal investigations are necessary next steps to evaluate the potential of this novel and easy to assess imaging marker for monitoring the disease course and therapeutic response. <b>Disclosure:</b> Dr. Kesenheimer has nothing to disclose. Dr. Wendebourg has nothing to disclose. An immediate family member of Dr. Weidensteiner has received personal compensation for serving as an employee of Siemens Healthineers. Dr. Sander has nothing to disclose. The institution of Matthias Weigel, PhD has received research support from Biogen. Matthias Weigel, PhD has received intellectual property interests from a discovery or technology relating to health care. Tanja Haas has nothing to disclose. The institution of Dirk Fischer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hoffmann La Roche AG. The institution of Dirk Fischer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann La Roche AG. Christoph Neuwirth has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen USA. Christoph Neuwirth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen Switzerland. Nathalie Braun has nothing to disclose. Dr. Weber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Idec. Dr. Weber has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Granziera has nothing to disclose. Prof. Sinnreich has nothing to disclose. The institution of Oliver Bieri has received research support from Swiss National Science Foundation. The institution of Oliver Bieri has received research support from MIAC Foundation. The institution of Oliver Bieri has received research support from Biogen. Oliver Bieri has received intellectual property interests from a discovery or technology relating to health care. Regina Schlaeger has nothing to disclose.

Cervical Spinal Cord Gray Matter Area is Associated with Motor Unit Number Index in Spinal Muscular Atrophy (S33.008)

<h3>Objective:</h3> To evaluate the association between spinal cord (SC) gray matter (GM) atrophy and Motor Unit Number Index (MUNIX) in patients with 5q-Spinal Muscular Atrophy (SMA). <h3>Background:</h3> There is an unmet need for valid imaging markers to monitor the disease course and therapeutic outcome in SMA. The novel rAMIRA (radially sampled Averaged Magnetization Inversion Recovery Acquisitions) method enables high in-plane resolution MR-imaging with improved contrast of SC GM in clinically feasible acquisition times. MUNIX is an established quantitative neurophysiological measure that provides an index of the number of functioning lower motor neurons that supply a muscle. The association between SC GM area and MUNIX has not been investigated in SMA yet. <h3>Design/Methods:</h3> Using axial 2D rAMIRA imaging, we prospectively investigated 21 patients with 5q-SMA, types 2 and 3 (mean age/SD 41.3/11.6y, 9 women) and 21 age- and sex-matched healthy controls (HC) (mean age/SD 41.7/11.4y, 9 women) at the intervertebral disc level C5/C6 perpendicular to the spinal cord. SC GM areas were determined using a semi-automated approach. MUNIX of the biceps brachii (BB) was measured following the ENCALS protocol. The association between SC GM area and MUNIX was assessed using multivariable regression analysis covarying for age and sex. <h3>Results:</h3> SC GM area at C5/6 was significantly reduced in patients compared to HC (mean GM area in mm² (SD): SMA 17.5 (2.2); HC 21.1 (2.3); relative reduction: 17.1% (p&lt;0.0001)). In multivariable regression analysis SC GM area at C5/6 explained 53% of MUNIX variance of the BB in SMA patients. <h3>Conclusions:</h3> In patients with SMA, SC GM area is strongly associated with motor neuron function quantitated by MUNIX in the corresponding myotome, indicating the functional relevance of this structural marker. Further longitudinal studies are necessary to evaluate the potential of this novel imaging marker for monitoring the disease course and therapeutic outcome. <b>Disclosure:</b> Dr. Wendebourg has nothing to disclose. Dr. Kesenheimer has nothing to disclose. An immediate family member of Dr. Weidensteiner has received personal compensation for serving as an employee of Siemens Healthineers. Dr. Sander has nothing to disclose. The institution of Matthias Weigel, PhD has received research support from Biogen. Matthias Weigel, PhD has received intellectual property interests from a discovery or technology relating to health care. Tanja Haas has nothing to disclose. The institution of Dirk Fischer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hoffmann La Roche AG. The institution of Dirk Fischer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffmann La Roche AG. Christoph Neuwirth has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen USA. Christoph Neuwirth has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen Switzerland. Nathalie Braun has nothing to disclose. Dr. Weber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen Idec. Dr. Weber has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Granziera has nothing to disclose. Prof. Sinnreich has nothing to disclose. The institution of Oliver Bieri has received research support from Swiss National Science Foundation. The institution of Oliver Bieri has received research support from MIAC Foundation. The institution of Oliver Bieri has received research support from Biogen. Oliver Bieri has received intellectual property interests from a discovery or technology relating to health care. Regina Schlaeger has nothing to disclose.

Association of Daily Physical Activity with Cervical Spinal Cord Areas in Multiple Sclerosis (S27.009)

Association of Daily Physical Activity with Cervical Spinal Cord Areas in Multiple Sclerosis (S27.009)

Association of volumetric MRI measures and disability in MS patients of the same age: Descriptions from a birth year cohort.

Although MRI-based markers of neuroinflammation have proven crucial for the diagnosis of multiple sclerosis (MS), predicting clinical progression with inflammation remains difficult. Neurodegenerative markers such as brain volume loss show stronger clinical (predictive) correlations, but also harbor age-related variation that must be disentangled from disease duration. In this study we investigated how clinical disability is related to volumetric MRI measures in a cohort of MS patients and healthy controls (HC) of the same age: Project Y. This study included 234 MS patients born in 1966 and 112 HC born between 1965 and 1967 in the Netherlands. Disability was quantified using the expanded disability status scale (EDSS), nine hole peg test (9HPT), and timed 25 foot walking test (T25FWT). Volumes were quantified on 3T MRI as normalized whole brain (NBV) and regional gray matter (GM) volumes using the same scanner and MRI protocol: cortical (normalized cortical gray matter volume; NCGMV), deep (NDGMV), thalamic (NThalV), and cerebellar (NCbV) GM volumes. In addition, mean upper cervical cord area (MUCCA), white matter lesion volume (LV), and spinal cord lesions were assessed. These measures were compared between patients and HC, and related to disability measures using linear regression. Mean age of people with MS (PwMS) was 52.8 years (SD 0.9) and median disease duration 15.8 years (IQR 8.7-24.8). All global and regional brain measures were lower in MS patients compared to HC. Univariate regression models showed that NDGMV (β=-0.20) and MUCCA (β=-0.38) were most strongly related to the EDSS in all PwMS. After subtype stratification, MUCCA was most strongly related to the EDSS (β=-0.60) and 9HPT (β=-0.55) in secondary progressive PwMS. Multivariate regression models demonstrated that in all PwMS, the EDSS was best explained by lower MUCCA, longer disease durations and a progressive disease course (adjusted-R (Sastre-Garrigaetal., 2017)=0.26, p < 0.001). MUCCA was a consistent correlate in separate models of the EDSS for all PwMS, relapsing and progressive onset PwMS. The 9HPT (adjusted-R (Sastre-Garrigaetal., 2017)=0.20, p < 0.001) was best explained by lower MUCCA, higher LV and pack years, while lower limb disability (adjusted-R (Sastre-Garrigaetal., 2017)=0.11, p < 0.001) was best explained by lower MUCCA, progressive onset MS and female sex. Our results indicate that in a cohort unbiased by age differences, spinal cord and deep gray matter volumes best related to physical disability. Our results support the use of these measures in clinical practice and trials.

An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a recessive, neurodegenerative disorder. It is one of the most common genetic causes of infant mortality and is characterized by muscle weakness, loss of ambulation, and respiratory failure. SMA is primarily caused by a homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene. Humans possess a second, nearly identical copy of SMN, known as the SMN2 gene. Although the disease severity correlates inversely with the number of SMN2 copies present, it can never completely compensate for the loss of SMN1 in patients with SMA; SMN2 expresses only a fraction of the functional SMN transcript. The SMN protein is ubiquitous in human cells and plays several roles, ranging from assembling the spliceosome machinery to autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Although the underlying mechanism remains unclear, anterior horn cells of the spinal cord gray matter are highly vulnerable to decreased SMN protein levels. To harness SMN2's ability to provide SMN function, two treatment strategies have been approved by the Food and Drug Administration (FDA), including an antisense oligonucleotide, nusinersen (Spinraza), and a small molecule, risdiplam (Evrysdi). Onasemnogene abeparvovec (Zolgensma) is an FDA-approved adeno-associated virus 9-mediated gene replacement therapy that creates a copy of the human SMN1 gene. In this review, we summarize the SMA etiology and FDA-approved therapies, and discuss the development of SMA therapeutic strategies and the challenges we faced.

Label fusion and training methods for reliable representation of inter-rater uncertainty

Medical tasks are prone to inter-rater variability due to multiple factors such as image quality, professional experience and training, or guideline clarity. Training deep learning networks with annotations from multiple raters is a common practice that mitigates the model’s bias towards a single expert. Reliable models generating calibrated outputs and reflecting the inter-rater disagreement are key to the integration of artificial intelligence in clinical practice. Various methods exist to take into account different expert labels. We focus on comparing three label fusion methods: STAPLE, average of the rater’s segmentation, and random sampling of each rater’s segmentation during training. Each label fusion method is studied using both the conventional training framework and the recently published SoftSeg framework that limits information loss by treating the segmentation task as a regression. Our results, across 10 data splittings on two public datasets (spinal cord gray matter challenge, and multiple sclerosis brain lesion segmentation), indicate that SoftSeg models, regardless of the ground truth fusion method, had better calibration and preservation of the inter-rater rater variability compared with their conventional counterparts without impacting the segmentation performance. Conventional models, i.e., trained with a Dice loss, with binary inputs, and sigmoid/softmax final activate, were overconfident and underestimated the uncertainty associated with inter-rater variability. Conversely, fusing labels by averaging with the SoftSeg framework led to underconfident outputs and overestimation of the rater disagreement. In terms of segmentation performance, the best label fusion method was different for the two datasets studied, indicating this parameter might be task-dependent. However, SoftSeg had segmentation performance systematically superior or equal to the conventionally trained models and had the best calibration and preservation of the inter-rater variability. SoftSeg has a low computational cost and performed similarly in terms of uncertainty to ensembles which require multiple models and forward passes. Our code is available at &lt;href='https://ivadomed.org'&gt;https://ivadomed.org&lt;/a&gt;.

Protozoal meningoencephalitis and myelitis in 4 dogs associated with Trypanosoma cruzi infection.

American trypanosomiasis is caused by the zoonotic protozoa Trypanosoma cruzi and primarily results in heart disease. Organisms also infect the central nervous system (CNS). The Texas A&M University veterinary teaching hospital archive was searched for dogs with CNS disease with intralesional protozoal amastigotes. This study summarizes 4 cases of dogs with disseminated trypanosomiasis and CNS involvement confirmed by quantitative polymerase chain reaction (qPCR) with T. cruzi primers. Clinical signs included lethargy, respiratory distress, tetraparesis, and seizures. Central nervous system lesions included meningeal congestion (1/4), necrosis with hemorrhage in the spinal cord gray and white matter (2/4), and histiocytic meningoencephalitis (4/4), and meningomyelitis (2/4) with intralesional and intracellular protozoal. Genotyping identified 1 case of T. cruzi discrete typing unit (DTU) TcI and 2 cases as TcIV, both are common variants in the United States. Trypanosomiasis should be considered a differential diagnosis for dogs with CNS signs in T. cruzi-endemic areas.