Side of Limb-Onset Predicts Laterality of Gray Matter Loss in Amyotrophic Lateral Sclerosis

Zhang, Qiuli; Mao, Cuiping; Jin, Jiaoting; Niu, Chen; Bai, Lijun; Dang, Jingxia; Zhang, Ming

doi:10.1155/2014/473250

Cited by 19 publications

(32 citation statements)

References 66 publications

(108 reference statements)

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“…DPR is correlated with the thickness of the right inferior temporal cortex, the postcentral cortex and the right paracentral cortex.Westenberg et al, 2014112/60GM volume reduction in the hippocampus and left subiculum.Larger ventricles are correlated to a lower ALSFRS-R score. Smaller basal ganglia, smaller limbic structures and larger ventricles are associated with shorter survival.Zhang et al, [28]43/43GM reduction in the left precentral cortex, left supplemental area and left postcentral gyrus. Reduction in neocortex volume, GM and WM volume and brain parenchymal fraction.GM volume reduction is most important in the motor cortex of the contralateral hemisphere of the limb of onset.…”

Section: Resultsmentioning

confidence: 99%

“…However, some DTI studies used VBM to show that ALS vs. control differences in the fractional anisotropy (FA) of the precentral gyri were not due to atrophy [33, 34]. In other studies, cortical atrophy was not limited to the precentral gyri but extended to other regions of the frontal lobe [18–24, 26–28, 32, 35] - especially in apathetic patients with involvement of the cingulate cortex [27, 36]. Other regions involved include several parts of the temporal cortex [19–24, 32, 35], the hippocampus [24, 37–39], the parietal cortex (mostly in the post-central cortex [18, 21, 23, 28]) and the insula [24].…”

Section: Resultsmentioning

confidence: 99%

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The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review

et al. 2016

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BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug’s clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers.MethodsThe PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking.ResultsA total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected.ConclusionDespite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review

et al. 2016

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“…both mono-and pluri-synaptic in primates, and essentially pluri-synaptic in adult mice [36], it is worth highlighting that many mouse models of the disease recapitulate CSN or SubCerPN degeneration [22,28,38,42,50,70,71]. In this regard, we recently showed that Sod1 G86R mice not only display pre-symptomatic CSN degeneration, but also that CSN and spinal motoneuron degeneration are somatotopically related [42], similarly to what had been described in ALS patients [46,53,72].…”

Section: Introductionmentioning

confidence: 75%

Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS

Burg

Bichara

Scekic‐Zahirovic

et al. 2019

Preprint

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Sclérose Latérale Amyotrophique" (ARSLA) to CB. JCZ was supported by a post-doctoral fellowship from the AFM-Telethon. The authors are extremely thankful to Véronique Marchand-Pauvert, Pascal Branchereau, Pierre Veinante and Luc Dupuis for critical reading of the manuscript, and insightful comments.2 AbstractAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of adulthood that affects voluntary motricity and rapidly leads to full paralysis and death. ALS arises from the combined degeneration of motoneurons in the spinal cord and brain stem, responsible for muscle denervation, and corticospinal projection neurons (CSN), responsible for emergence of the upper motor neuron syndrome. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets. However, this "corticofugal hypothesis" of ALS has not yet been specifically challenged. Here, we provide a direct test of this hypothesis by genetically removing subcerebral projection neurons (SubCerPN), including CSN, in Sod1 G86R mice, a mouse model of ALS. Ablation of the transcription factor Fezf2, leading to the complete absence of all SubCerPN, delays disease onset, reduces weight loss and motor impairment, and increases survival without modifying disease duration. Importantly absence of SubCerPN and CSN also limits pre-symptomatic hyperreflexia. Together, our results demonstrate that major corticofugal tracts are critical to ALS onset, and that SubCerPN and CSN in particular may carry detrimental signals to their downstream targets. In its whole, this study provides first experimental arguments in favour of the corticofugal hypothesis of ALS.

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“…In clinics, ALS diagnosis relies on evidences for combined degeneration of CSN and MN. While the origin and propagation of the disease between the two neuronal populations has always been debated 34 , number of studies reported on the somatotopic relationship between cortical and spinal impairments [35][36][37] , ruling out the possibility that CSN and MN degenerations are independent, and rather supporting a propagation from one neuronal population to the other, whether descendent, from the cerebral cortex to the spinal cord, or ascendant, from the spinal cord to the cerebral cortex (not to be confused with the Wallerian or retrograde degeneration of the MN, from their axonal terminals to their cell bodies). In spite of its classical text book definition, ALS is highly heterogeneous and, amongst other parameters, relative upper (CSN) and lower (MN) motor neuron involvement and site of disease onset greatly vary across ALS patients 38 .…”

Section: Discussionmentioning

confidence: 99%

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Marques

Fischer

Keime

et al. 2019

Preprint

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease clinically defined as the combined degeneration of corticospinal and corticobulbar neurons (CSN), and bulbar and spinal motor neurons (MN). A growing body of evidence points to the motor cortex, where CSN are located, as the potential initiation site of ALS. However, little is known about the spatiotemporal dynamics of CSN degeneration and the molecular pathways involved. Here, we show in the Sod1 G86R mouse model of ALS that CSN loss precedes MN degeneration and that CSN and MN degenerations are somatotopically related, highlighting the relevance of CSN to ALS onset and progression. To gain insights into the molecular mechanisms that selectively trigger CSN degeneration, we purified CSN from the motor and somatosensory cortex of adult mice and analysed their transcriptome from presymptomatic ages to disease end-stage. Significant RNA metabolism and splicing alterations, novel in the context of Sod1 mutation, were identified, including mis-splicing events that largely trigger genes involved in neuronal functions. Together, the data indicate that CSN dysfunction and degeneration upon mutant Sod1 expression involve alterations of RNA metabolism and splicing, emphasizing shared mechanisms across various ALS-related genes.3 ALS is an incurable and fatal neurodegenerative disease that mostly starts in adulthood with a rapidly progressing paralysis and death within only 2 to 5 years of diagnosis 1,2 . In clinics, ALS is defined as the combined degeneration of both corticospinal and corticobulbar neurons (CSN, or upper motor neurons) whose cell bodies are located in the cerebral cortex and that extend axons to the medulla and spinal cord, and of spinal and bulbar motor neurons (MN, or lower motor neurons) whose cell bodies are located in the medulla and spinal cord, and that connect to the skeletal muscles. If the cellular and molecular mechanisms behind MN degeneration are relatively well known, the numerous related clinical trials have unfortunately failed to translate into improved treatment of ALS 1-4 , a discrepancy that contributed to the emergence of the CSN and the overall cerebral cortex as alternative therapeutic targets.A growing body of evidence points to the motor cortex as the likely initiation site of ALS 5,6 . A first series of arguments arose from the recent genetic, pathological and clinical evolution links established between ALS and FrontoTemporal Dementia (FTD), a neurodegenerative disease that affects solely the cerebral cortex and results in behavioural and cognitive deficits 7 . A second series of arguments emerged following extensive examination of the TDP-43 aggregates, a pathological hallmark of the disease in post-mortem brains from ALS patients, identifying the motor cortex as the most affected region of the brain, and leading to the corticofugal hypothesis 8-10 which proposes a sequential pattern of pathology spreading from the motor cortex to its projection sites. Finally, transcranial magnetic stimulation studi...

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Side of Limb-Onset Predicts Laterality of Gray Matter Loss in Amyotrophic Lateral Sclerosis

Cited by 19 publications

References 66 publications

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review

Absence of subcerebral projection neurons delays disease onset and extends survival in a mouse model of ALS

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

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