Dataset Information

Longitudinal evaluation of cerebral and spinal cord damage in Amyotrophic Lateral Sclerosis.

ABSTRACT:

Objective

To evaluate MRI-based parameters as biomarkers of Amyotrophic Lateral Sclerosis (ALS) progression.

Methods

Twenty-seven patients and 27 controls performed two clinical and MRI acquisitions 8 months apart. ALSFRS-R scale was used to quantify disease severity at both time points. Multimodal analyses of MRI included cortical thickness measurements (FreeSurfer software), analysis of white matter integrity using diffusion-tensor imaging (tract-based spatial statistics-TBSS) and measurement of cervical spinal cord cross-sectional area (SpineSeg software). All analyses were corrected for multiple comparisons. The standardized response mean (SRM = mean score change / standard deviation of score change) was calculated for all methods herein employed and used for comparison purposes.

Results

There were 18 men and mean age at first examination was 51.9 years. Mean ALSFRS-R scores at baseline and follow-up were 34.0 and 29.0, respectively. There was no region with progressive cortical thinning, but there was significant brainstem volumetric reduction (p = 0.001). TBSS analyses revealed progressive increase of AD (axial diffusivity) and MD (mean diffusivity) at the corpus callosum (p < 0.05), whereas SpineSeg showed progressive cord area reduction (p = 0.002). Cervical spinal cord cross-sectional area reduction was the only MRI parameter that correlated with ALSFRS-R change (r = 0.309, p = 0.038). SRM for ALSFRS-R was 0.95, for cord area 0.95, for corpus callosum AD 0.62 and MD 0.65, and for brainstem volume 0.002.

Conclusions

Structural MRI is able to detect short term longitudinal changes in ALS. Cervical spinal cord morphometry is a promising neuroimaging marker to assess ALS course.

SUBMITTER: de Albuquerque M

PROVIDER: S-EPMC5294732 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Longitudinal evaluation of cerebral and spinal cord damage in Amyotrophic Lateral Sclerosis.

de Albuquerque Milena M Branco Lucas Melo T LM Rezende Thiago Junqueira R TJ de Andrade Helen Maia Tavares HM Nucci Anamarli A França Marcondes Cavalcante MC

NeuroImage. Clinical 20170124

<h4>Objective</h4>To evaluate MRI-based parameters as biomarkers of Amyotrophic Lateral Sclerosis (ALS) progression.<h4>Methods</h4>Twenty-seven patients and 27 controls performed two clinical and MRI acquisitions 8 months apart. ALSFRS-R scale was used to quantify disease severity at both time points. Multimodal analyses of MRI included cortical thickness measurements (FreeSurfer software), analysis of white matter integrity using diffusion-tensor imaging (tract-based spatial statistics-TBSS) a ...[more]

PMID: 28203530

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Project description:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.

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Dataset Information

Longitudinal evaluation of cerebral and spinal cord damage in Amyotrophic Lateral Sclerosis.

Objective

Methods

Results

Conclusions

Publications

Longitudinal evaluation of cerebral and spinal cord damage in Amyotrophic Lateral Sclerosis.

Similar Datasets

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