Background and purpose
Considerable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional ...adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction.
Methods
Seventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study‐group‐specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures.
Results
Increased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self‐initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato‐cerebellar connectivity.
Conclusions
Our findings indicate that, despite the dysfunction of SMA–striatal and SMA–cerebellar networks, cerebello‐striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS.
The field of spinal cord MRI is lacking a common template, as existing for the brain, which would allow extraction of multi-parametric data (diffusion-weighted, magnetization transfer, etc.) without ...user bias, thereby facilitating group analysis and multi-center studies. This paper describes a framework to produce an unbiased average anatomical template of the human spinal cord. The template was created by co-registering T2-weighted images (N=16 healthy volunteers) using a series of pre-processing steps followed by non-linear registration. A white and gray matter probabilistic template was then merged to the average anatomical template, yielding the MNI–Poly–AMU template, which currently covers vertebral levels C1 to T6. New subjects can be registered to the template using a dedicated image processing pipeline. Validation was conducted on 16 additional subjects by comparing an automatic template-based segmentation and manual segmentation, yielding a median Dice coefficient of 0.89. The registration pipeline is rapid (~15min), automatic after one C2/C3 landmark manual identification, and robust, thereby reducing subjective variability and bias associated with manual segmentation. The template can notably be used for measurements of spinal cord cross-sectional area, voxel-based morphometry, identification of anatomical features (e.g., vertebral levels, white and gray matter location) and unbiased extraction of multi-parametric data.
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•First unbiased template of the human spinal cord: MNI–Poly–AMU•Probabilistic atlas of white and gray matter•Framework for registering data to the template (T1, T2, DTI, fMRI, MTR, etc.)•Open source software, actively maintained
There is an emerging need for biomarkers to better categorize clinical phenotypes and predict progression in amyotrophic lateral sclerosis. This study aimed to quantify cervical spinal gray matter ...atrophy in amyotrophic lateral sclerosis and investigate its association with clinical disability at baseline and after 1 year.
Twenty-nine patients with amyotrophic lateral sclerosis and 22 healthy controls were scanned with 3T MR imaging. Standard functional scale was recorded at the time of MR imaging and after 1 year. MR imaging data were processed automatically to measure the spinal cord, gray matter, and white matter cross-sectional areas. A statistical analysis assessed the difference in cross-sectional areas between patients with amyotrophic lateral sclerosis and controls, correlations between spinal cord and gray matter atrophy to clinical disability at baseline and at 1 year, and prediction of clinical disability at 1 year.
Gray matter atrophy was more sensitive to discriminate patients with amyotrophic lateral sclerosis from controls (
= .004) compared with spinal cord atrophy (
= .02). Gray matter and spinal cord cross-sectional areas showed good correlations with clinical scores at baseline (
= 0.56 for gray matter and
= 0.55 for spinal cord;
< .01). Prediction at 1 year with clinical scores (
= 0.54) was improved when including a combination of gray matter and white matter cross-sectional areas (
= 0.74).
Although improvements over spinal cord cross-sectional areas were modest, this study suggests the potential use of gray matter cross-sectional areas as an MR imaging structural biomarker to monitor the evolution of amyotrophic lateral sclerosis.
Background and purpose
Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and ...several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival.
Methods
Forty‐nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross‐sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model.
Results
On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2–C3, C4–C5, C5–C6 and C6–C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3–C4 and C5–C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1.
Conclusions
It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted.
Background and purpose
The ‘snake eyes’ sign refers to bilateral hyperintensities of the anterior horns on axial spinal cord imaging. Based on sporadic reports, it has been associated with a range of ...lower motor neuron (LMN) syndromes, such as spondylotic amyotrophy and Hirayama disease, as well as spinal cord infarction. The objective of our study was to comprehensively characterize the full diagnostic spectrum of LMN syndromes with this radiological clue and discuss potential aetiological factors.
Methods
A large patient cohort with snake eyes sign and upper limb LMN degeneration was recruited from three French neuromuscular units. Patients underwent detailed electrophysiological, radiological, clinical and anamnestic profiling.
Results
Twenty‐nine patients were ascertained and followed up for 9.5 ± 8.6 years. The majority of the patients were male (86.2%) with a mean age of 37.3 ± 14.4 years. Symptoms were bilateral in most cases (86.2%). Patients with predominantly proximal and distal deficits were equally represented (44.8% and 55.2%, respectively). A history of preceding trauma or intense physical activity was confirmed in 58.6% of the cases; 27.6% of the patients were given an initial clinical diagnosis of amyotrophic lateral sclerosis (ALS), and 51.7% were originally suspected to have multifocal motor neuropathy. None of the patients developed ALS on longitudinal follow‐up.
Conclusion
The snake eyes sign on magnetic resonance imaging is associated with a wide spectrum of neurological conditions and is more common in young men with a history of strenuous activity or antecedent trauma. The recognition of this syndrome is crucial as many of these patients are initially misdiagnosed with ALS.
Background
Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation ...(NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis.
Methods
Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period.
Results
Both the clinical model (
R
2
= 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures’ volumes model (
R
2
= 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (
R
2
= 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (
R
2
= 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes.
Conclusions
Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.
Background and purpose
The objectives of this study were to define the metabolomic profile of cerebrospinal fluid in amyotrophic lateral sclerosis (ALS) patients, to model outcome through combined ...clinical and metabolomic parameters and independently to validate predictive models.
Methods
In all, 74 consecutive newly diagnosed patients were enrolled into training (Tr, n = 49) and test (Te, n = 25) cohorts. Investigators recorded clinical data and the metabalomic profile of cerebrospinal fluid at baseline was analyzed with 1H nuclear magnetic resonance spectroscopy. Markers of disease progression, collected in 1‐year prospective follow‐up, included change in ALS Functional Rating Scale (var_ALSFRS), change in weight (var_weight) and survival time. Stepwise multiple regression selected from metabolomic and clinical parameters to model rate of progression in the Tr cohort. Best fit models were validated independently in the Te cohort.
Results
The best‐fit statistical models, using both metabolomic and clinical covariates, predicted outcome with 70.8% (var_weight), 72% (var_ALSFRS) and 76% (survival) accuracy in the Te cohort. Models that used metabolomics or clinical data alone predicted outcome less well. Highlighted metabolites are involved in pathophysiological pathways previously described in ALS.
Conclusion
Cerebrospinal fluid metabolomics can aid in predicting the clinical course of ALS and tap into pathophysiological processes. The precision of predictive models, independently reproduced in this study, is enhanced through inclusion of both metabolomic and clinical parameters. The findings bring the field closer to a clinically meaningful disease marker.
Characterizing demyelination/degeneration of spinal pathways in traumatic spinal cord injured (SCI) patients is crucial for assessing the prognosis of functional rehabilitation. Novel techniques ...based on diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetization transfer (MT) imaging provide sensitive and specific markers of white matter pathology. In this paper we combined for the first time high angular resolution diffusion-weighted imaging (HARDI), MT imaging and atrophy measurements to evaluate the cervical spinal cord of fourteen SCI patients and age-matched controls. We used high in-plane resolution to delineate dorsal and ventrolateral pathways. Significant differences were detected between patients and controls in the normal-appearing white matter for fractional anisotropy (FA, p<0.0001), axial diffusivity (p<0.05), radial diffusivity (p<0.05), generalized fractional anisotropy (GFA, p<0.0001), magnetization transfer ratio (MTR, p<0.0001) and cord area (p<0.05). No significant difference was detected in mean diffusivity (p=0.41), T1-weighted (p=0.76) and T2-weighted (p=0.09) signals. MRI metrics were remarkably well correlated with clinical disability (Pearson's correlations, FA: p<0.01, GFA: p<0.01, radial diffusivity: p=0.01, MTR: p=0.04 and atrophy: p<0.01). Stepwise linear regressions showed that measures of MTR in the dorsal spinal cord predicted the sensory disability whereas measures of MTR in the ventro-lateral spinal cord predicted the motor disability (ASIA score). However, diffusion metrics were not specific to the sensorimotor scores. Due to the specificity of axial and radial diffusivity and MT measurements, results suggest the detection of demyelination and degeneration in SCI patients. Combining HARDI with MT imaging is a promising approach to gain specificity in characterizing spinal cord pathways in traumatic injury.
► We combined DTI, magnetization transfer and atrophy measure in spinal cord injury. ► Differences in normal-appearing white matter for DTI and MTR. ► Results suggest degeneration and demyelination in SCI patients. ► DTI, MTR and atrophy can predict impairment in spinal cord injury (SCI).
The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new ...insight about the mechanisms involved in this severe neurodegenerative disease.
To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported.
In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS.
Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.
Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic ...options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category ‘probable’ PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.
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