Magnetic resonance metrics to evaluate the effect of therapy in amyotrophic lateral sclerosis: the experience with edaravone

Abstract Background Edaravone was approved as a new treatment for amyotrophic lateral sclerosis (ALS), although there are different opinions on its effectiveness. Magnetic resonance (MRI) measures appear promising as diagnostic and prognostic indicators of disease. However, published studies on MRI using to monitor treatment efficacy in ALS are lacking. Purpose The objective of this study was to investigate changes in brain MRI measures in patients treated with edaravone. Methods Thirteen ALS patients assuming edaravone (ALS-EDA) underwent MRI at baseline (T0) and after 6 months (T6) to measure cortical thickness (CT) and fractional anisotropy (FA) of white matter (WM) tracts. MRI data of ALS-EDA were compared at T0 with those of 12 control subjects (CS), and at T6 with those of 11 ALS patients assuming only riluzole (ALS-RIL), extracted from our ALS cohort using a propensity-score-matching. A longitudinal MRI analysis was performed in ALS-EDA between T6 and T0. Results At T0, ALS-EDA showed a cortical widespread thinning in both hemispheres, particularly in the bilateral precentral gyrus, and a reduction of FA in bilateral corticospinal tracts, in comparison to CS. Thinning in bilateral precentral cortex and significant widespread reduction of FA in several WM tracts were observed in ALS-EDA at T6 compared to T0. At T6, no significant differences in MRI measures of ALS-EDA versus ALS-RIL were found. Conclusions Patients treated with edaravone showed progression of damage in the motor cortex and several WM tracts, at a six-month follow-up. Moreover, this study showed no evidence of a difference between edaravone and riluzole.

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Quantitative susceptibility-weighted imaging in amyotrophic lateral sclerosis with 3.0 T magnetic resonance imaging

Journal of International Medical Research ◽

10.1177/0300060521992222 ◽

2021 ◽

Vol 49 (2) ◽

pp. 030006052199222

Author(s):

Meng-Yu Liu ◽

Zhi-Ye Chen ◽

Jin-Feng Li ◽

Hua-Feng Xiao ◽

Lin Ma

Keyword(s):

Magnetic Resonance Imaging ◽

Amyotrophic Lateral Sclerosis ◽

Phase Shift ◽

Susceptibility Weighted Imaging ◽

Precentral Gyrus ◽

Healthy Controls ◽

Resonance Imaging ◽

3.0 T ◽

Als Patients ◽

Lateral Sclerosis

Objective To evaluate alterations in phase-shift values in the gray matter of patients with amyotrophic lateral sclerosis (ALS) using susceptibility-weighted imaging (SWI). Methods Twenty patients with definite or probable ALS and 19 age- and sex-matched healthy controls were enrolled. SWI was performed using a 3.0 T magnetic resonance imaging scanner. Phase-shift values were measured in corrected phase images using regions of interest, which were placed on the bilateral precentral gyrus, frontal cortex, caudate nucleus, globus pallidus, and putamen. Results Phase-shift values of the precentral gyrus were significantly lower in ALS patients (−0.176 ± 0.050) than in the control group (−0.119 ± 0.016) on SWI. The average phase-shift values of the frontal cortex, caudate nucleus, globus pallidus, and putamen in ALS patients (−0.089 ± 0.023, −0.065 ± 0.016, −0.336 ± 0.191, and −0.227 ± 0.101, respectively) were not significantly different from those in the healthy controls (−0.885 ± 0.015, −0.079 ± 0.018, −0.329 ± 0.136, and −0.229 ± 0.083, respectively). Conclusions Compared with healthy controls, ALS patients had a lower phase-shift value in the precentral gyrus, which may be related to abnormal iron overload. Thus, SWI is a potential method for identifying ALS patients.

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Advanced magnetic resonance neuroimaging in bulbar and limb onset early amyotrophic lateral sclerosis

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.165423 ◽

2016 ◽

Vol 7 (01) ◽

pp. 102-108 ◽

Cited By ~ 5

Author(s):

Maulik Vora ◽

Suresh Kumar ◽

Sanjiv Sharma ◽

Sudhir Sharma ◽

Sushma Makhaik ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Magnetic Resonance ◽

Early Diagnosis ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Consistent Finding ◽

Bulbar Onset ◽

Als Patients ◽

Lateral Sclerosis ◽

Limb Onset

ABSTRACT Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal and most common motor neuron disease, caused by progressive loss of motor neurons. Diffusion tensor imaging (DTI) and magnetic resonance spectroscopic (MRS) studies detect pathological changes in neuronal fibers in vivo. We evaluated the role of DTI and MRS in early course of the disease, which may prove beneficial in the early diagnosis and better management. Materials and Methods: Twenty-one patients with ALS and 13 age-matched controls received 1.5T DTI and three-dimensional multi-voxel MRS. Fractional anisotropy (FA), apparent diffusion coefficient, N-acetyl aspartate (NAA)/Creatine (Cr), and NAA/Choline (Ch) ratios were analyzed in various regions of the brain and compared with healthy controls. ALS patients were classified as definite, possible, and probable category, and patients were also studied in limb versus bulbar onset. Results: Decreased FA and increase mean diffusivity values in regions of corticospinal tract (CST) and corpus callosum (CC) was consistent finding in definite and probable disease category (P < 0.05). In possible disease, CC involvement was not significant. NAA/Cr and NAA/Ch ratios were lower in CC and regions of CST. However, in possible disease, CC involvement was not significant, while regions of CST were showing significant reduction in NAA/Cr and NAA/Ch ratios (P < 0.05). Conclusion: DTI and MRS detect changes associated with ALS even in the early phase of the disease. Bulbar onset and limb onset ALS patients show different pattern of involvement. Extramotor involvement suggested by CC involvement is a feature seen in bulbar onset patient and can suggest poor outcome in such patients. The present findings may be helpful for designing further studies in the direction of more early diagnosis of disease and its management.

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Cortical Thinning of Motor and Non-Motor Brain Regions Enables Diagnosis of Amyotrophic Lateral Sclerosis and Supports Distinction between Upper- and Lower-Motoneuron Phenotypes

Biomedicines ◽

10.3390/biomedicines9091195 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1195

Author(s):

Stefano Ferrea ◽

Frederick Junker ◽

Mira Korth ◽

Kai Gruhn ◽

Torsten Grehl ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Temporal Lobe ◽

Cortical Thickness ◽

Neurodegenerative Disorder ◽

Brain Regions ◽

Precentral Gyrus ◽

Healthy Controls ◽

Cortical Thinning ◽

Als Patients ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder clinically characterized by muscle atrophy and progressive paralysis. In addition to the classical ALS affecting both the upper and lower motoneurons (UMN and LMN), other subtypes with the predominant (or even exclusive) affection of the UMN or LMN have been identified. This work sought to detect specific patterns of cortical brain atrophy in the UMN and LMN phenotypes to distinguish these two forms from the healthy state. Methods: Using high-resolution structural MRI and cortical thickness analysis, 38 patients with a diagnosis of ALS and predominance of either the UMN (n = 20) or the LMN (n = 18) phenotype were investigated. Results: Significant cortical thinning in the temporal lobe was found in both the ALS groups. Additionally, UMN patients displayed a significant thinning of the cortical thickness in the pre- and postcentral gyrus, as well as the paracentral lobule. By applying multivariate analyses based on the cortical thicknesses of 34 brain regions, ALS patients with either a predominant UMN or LMN phenotype were distinguished from healthy controls with an accuracy of 94% and UMN from LMN patients with an accuracy of 75%. Conclusions: These findings support previous hypothesis that neural degeneration in ALS is not confined to the sole motor regions. In addition, the amount of cortical thinning in the temporal lobe helps to distinguish ALS patients from healthy controls, that is, to support or discourage the diagnosis of ALS, while the cortical thickness of the precentral gyrus specifically helps to distinguish the UMN from the LMN phenotype.

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Texture Analysis to Detect Cerebral Degeneration in Amyotrophic Lateral Sclerosis

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.267 ◽

2018 ◽

Vol 45 (5) ◽

pp. 533-539 ◽

Cited By ~ 3

Author(s):

Abdullah Ishaque ◽

Rouzbeh Maani ◽

Jerome Satkunam ◽

Peter Seres ◽

Dennell Mah ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Texture Analysis ◽

Brain Mri ◽

Texture Features ◽

Visual Assessment ◽

Image Resolution ◽

Healthy Controls ◽

Als Patients ◽

Lateral Sclerosis ◽

Cerebral Degeneration

AbstractBackgroundEvidence of cerebral degeneration is not apparent on routine brain MRI in amyotrophic lateral sclerosis (ALS). Texture analysis can detect change in images based on the statistical properties of voxel intensities. Our objective was to test the utility of texture analysis in detecting cerebral degeneration in ALS. A secondary objective was to determine whether the performance of texture analysis is dependent on image resolution.MethodsHigh-resolution (0.5×0.5 mm2 in-plane) coronal T2-weighted MRI of the brain were acquired from 12 patients with ALS and 19 healthy controls on a 4.7 Tesla MRI system. Image data sets at lower resolutions were created by down-sampling to 1×1, 2×2, 3×3, and 4×4 mm2. Texture features were extracted from a slice encompassing the corticospinal tract at the different resolutions and tested for their discriminatory power and correlations with clinical measures. Subjects were also classified by visual assessment by expert reviewers.ResultsTexture features were different between ALS patients and healthy controls at 1×1, 2×2, and 3×3 mm2 resolutions. Texture features correlated with measures of upper motor neuron function and disability. Optimal classification performance was achieved when best-performing texture features were combined with visual assessment at 2×2 mm2 resolution (0.851 area under the curve, 83% sensitivity, 79% specificity).ConclusionsTexture analysis can detect subtle abnormalities in MRI of ALS patients. The clinical yield of the method is dependent on image resolution. Texture analysis holds promise as a potential source of neuroimaging biomarkers in ALS.

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Role of the nigrosome 1 absence as a biomarker in amyotrophic lateral sclerosis

Journal of Neurology ◽

10.1007/s00415-021-10729-w ◽

2021 ◽

Author(s):

María Isabel Moreno-Gambín ◽

José I. Tembl ◽

Miguel Mazón ◽

Antonio José Cañada-Martínez ◽

Luis Martí-Bonmatí ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Substantia Nigra ◽

Muscular Atrophy ◽

Brain Mri ◽

Transcranial Sonography ◽

Male Sex ◽

Als Patients ◽

Independent Marker ◽

Lateral Sclerosis

Abstract Introduction The absence of nigrosome 1 on brain MRI and the hyperechogenicity of substantia nigra (SNh) by transcranial sonography are two useful biomarkers in the diagnosis of parkinsonisms. We aimed to evaluate the absence of nigrosome 1 in amyotrophic lateral sclerosis (ALS) and to address its meaning. Methods 136 ALS patients were recruited, including 16 progressive muscular atrophy (PMA) and 22 primary lateral sclerosis (PLS) patients. The SNh area was measured planimetrically by standard protocols. The nigrosome 1 status was qualitatively assessed by two blind evaluators in susceptibility weight images of 3T MRI. Demographic and clinical data were collected and the C9ORF72 expansion was tested in all patients. Results Nigrosome 1 was absent in 30% of ALS patients (36% of PLS, 29% of classical ALS and 19% of PMA patients). There was no relationship between radiological and clinical laterality, nor between nigrosome 1 and SNh area. Male sex (OR = 3.63 [1.51, 9.38], p = 0.005) and a higher upper motor neuron (UMN) score (OR = 1.10 [1.02, 1.2], p = 0.022) were independently associated to nigrosome 1 absence, which also was an independent marker of poor survival (HR = 1.79 [1.3, 2.8], p = 0.013). Conclusion In ALS patients, the absence of nigrosome 1 is associated with male sex, UMN impairment and shorter survival. This suggests that constitutional factors and the degree of pyramidal involvement are related to the substantia nigra involvement in ALS. Thus, nigrosome 1 could be a marker of a multisystem degeneration, which in turn associates to poor prognosis.

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Diagnostic and Prognostic Value of Conventional Brain MRI in the Clinical Work-Up of Patients with Amyotrophic Lateral Sclerosis

Journal of Clinical Medicine ◽

10.3390/jcm9082538 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2538 ◽

Cited By ~ 1

Author(s):

Giovanni Rizzo ◽

Anna Marliani ◽

Stella Battaglia ◽

Luca Albini Riccioli ◽

Silvia De Pasqua ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Predictive Value ◽

Brain Mri ◽

Clinical Signs ◽

Clinical Work ◽

3T Mri ◽

Mri Features ◽

Als Patients ◽

Work Up ◽

Lateral Sclerosis

Clinical signs of upper motor neuron (UMN) involvement are important in the diagnosis of amyotrophic lateral sclerosis (ALS) though are often difficult to analyze. Many studies using both qualitative and quantitative evaluations have reported abnormal Magnetic Resonance Imaging (MRI) findings at the level of the pyramidal pathway in patients with ALS. Although the most interesting results were obtained by quantitative studies using advanced MR techniques, the qualitative evaluation of MRI images remains the most-used in clinical practice. We evaluated the diagnostic and prognostic contribution of conventional 3T-MRI in the clinical work-up of ALS patients. Two neuroradiologists retrospectively assessed 3T-MRI data of 93 ALS patients and 89 controls. The features of interest were corticospinal tract (CST) T2/FLAIR hyperintensity, motor cortex (MC) T2*/SWI hypointensity, and selective MC atrophy. All MRI features were significantly more prevalent in ALS patients than in controls. The simultaneous presence of CST FLAIR hyperintensity and MC SWI hypointensity was associated with the highest diagnostic accuracy (sensitivity: 70%; specificity: 81%; positive predictive value, PPV: 90%; negative predictive value, NPV: 51%; accuracy: 73%) and a shorter survival (HR: 6.56, p = 0.002). Conventional 3T-MRI can be a feasible tool to detect specific qualitative changes based on UMN involvement and to support clinical diagnosis of ALS. Importantly, CST FLAIR hyperintensity and MC SWI hypointensity are predictors of shorter survival in ALS patients.

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Is the Hypointensity in Motor Cortex the Hallmark of Amyotrophic Lateral Sclerosis?

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.382 ◽

2019 ◽

Vol 46 (2) ◽

pp. 166-173 ◽

Cited By ~ 1

Author(s):

Marie Catherine Boll ◽

Oscar René Marrufo Meléndez ◽

Camilo Rios ◽

Jesus Maciel Zenil ◽

Yara de Alba

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Brain Mri ◽

Rapid Evolution ◽

Mean Value ◽

Precentral Gyrus ◽

Signal Attenuation ◽

Potential Marker ◽

Significant Difference ◽

Lateral Sclerosis

ABSTRACT:Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease that targets motor neurons. Upper motor neurons degeneration is pathologically characterized by brain iron accumulation. Signal attenuation in the shape of a ribbon at the posterior border of the precentral gyrus can be observed on conventional magnetic resonance imaging (MRI) sequences including T2-weighted sequence. Methods: With the aim to know the qualities of this potential marker of ALS, we conducted a prospective study. Patients with definite ALS in the age range of 40–70 years and healthy controls underwent 3T brain MRI using a standardized sequence. A second MRI was performed 18 months later under the same conditions in the patients with ALS. Results: Most of the patients with ALS (91.66%) exhibited a “black ribbon” (BR) with an average area of 79.98 mm3. Signal attenuation discriminated ALS with a mean value of 63.97 arbitrary units (AU) on the left BR (95% CI: 60.67–67.27), a mean value of 59.15 AU (95% CI: 54.78–63.53) on the right BR, and a significant difference with control subjects presenting a mean value of 107.85 AU (p < 0.001). The optimal cut-off point for differentiating patients with ALS from controls (sensitivity, 0.92; specificity, 0.93) was 83 AU. Forced vital capacity and muscle strength in the contralateral upper extremity were significantly correlated with the ribbon intensity in ALS. Patients who underwent a second study exhibited significant changes in the BR related to the rapid evolution of the disease. Conclusions: This marker represents a valuable tool for the selection of candidates and their follow-up in clinical trials.

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Spinal cord infusion of stem cells in amyotrophic lateral sclerosis: Magnetic resonance spectroscopy shows metabolite improvement in the precentral gyrus

Cytotherapy ◽

10.1016/j.jcyt.2016.03.296 ◽

2016 ◽

Vol 18 (6) ◽

pp. 785-796 ◽

Cited By ~ 9

Author(s):

José M. García Santos ◽

Alberto Inuggi ◽

Joaquín Gómez Espuch ◽

Carlos Vázquez ◽

Francisca Iniesta ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Amyotrophic Lateral Sclerosis ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Resonance Spectroscopy ◽

Precentral Gyrus ◽

Lateral Sclerosis

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Cerebral Atrophy in Amyotrophic Lateral Sclerosis Parallels the Pathological Distribution of TDP43

10.1101/2020.02.18.954883 ◽

2020 ◽

Author(s):

Mahsa Dadar ◽

Ana Laura Manera ◽

Lorne Zinman ◽

Lawrence Korngut ◽

Angela Genge ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

White Matter ◽

Motor Cortex ◽

Corticospinal Tract ◽

Cerebral Atrophy ◽

Precentral Gyrus ◽

Cerebral Disease ◽

Als Patients ◽

Deformation Based Morphometry ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a preferential involvement of both upper and lower motor neurons. Evidence from neuroimaging and post-mortem studies confirms additional involvement of brain regions extending beyond the motor cortex. The aim of this study was to assess the extent of cerebral disease in ALS cross-sectionally and longitudinally, and to compare the findings with a recently proposed disease-staging model of ALS pathology. Deformation-based morphometry (DBM) was used to identify the patterns of brain atrophy associated with ALS and to assess their relationship with clinical symptoms. Longitudinal T1-weighted MRI data and clinical measures were acquired at baseline, 4 months, and 8 months, from 66 ALS patients and 43 age-matched controls who participated in the Canadian ALS Neuroimaging Consortium (CALSNIC) study. Whole brain voxel-wise mixed-effects modelling analysis showed extensive atrophy patterns differentiating ALS patients from the normal controls. Cerebral atrophy was present in the motor cortex and corticospinal tract, involving both GM and WM, and to a lesser extent in non-motor regions. More specifically, the results showed significant bilateral atrophy in the motor cortex, the corticospinal tract including the internal capsule and brainstem, with an overall pattern of ventricular enlargement; along with significant progressive longitudinal atrophy in the precentral gyrus, frontal and parietal white matter, accompanied by ventricular and sulcal enlargement. Atrophy in the precentral gyrus was significantly associated with greater disability as quantified with the ALS Functional Rating Scale-Revised (ALSFRS-R) (p<0.0001). The pattern of atrophy observed using DBM was consistent with the Brettschneider’s four stage pathological model of the disease. Deformation based morphometry provides a sensitive indicator of atrophy in ALS, and has potential as a biomarker of disease burden, in both gray and white matter.

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Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

Current Neurovascular Research ◽

10.2174/1567202617666200409125227 ◽

2020 ◽

Vol 17 (3) ◽

pp. 275-285 ◽

Cited By ~ 5

Author(s):

Si Chen ◽

Qiao Liao ◽

Ke Lu ◽

Jinxia Zhou ◽

Cao Huang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rat Model ◽

Microglial Activation ◽

Transgenic Rat ◽

Intragastric Administration ◽

Behavioral Deficits ◽

Als Patients ◽

Lateral Sclerosis ◽

Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

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