The neuropathological signature of bulbar-onset ALS: A systematic review

Shellikeri, Sanjana; Karthikeyan, Vishwathsen; Martino, Rosemary; Black, Sandra E.; Zinman, Lorne; Keith, Julia; Yunusova, Yana

doi:10.1016/j.neubiorev.2017.01.045

Cited by 56 publications

(38 citation statements)

References 92 publications

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“…We observed that both bulbar- and spinal-onset subgroups develop atrophy of similar anatomical regions, which is congruent to neuropathologic studies. 45 However, we found a differential pattern of cerebral involvement in patients with bulbar or spinal onset at baseline and at follow-up: bulbar-onset patients showed prominent gray matter atrophy and some white matter changes at baseline, whereas spinal-onset patients mainly displayed widespread loss of connectivity. At follow-up, gray matter became affected in spinal-onset patients, whereas bulbar-onset patients showed no additional brain changes.…”

Section: Discussionmentioning

confidence: 60%

Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis

et al. 2020

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ObjectiveTo understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal, and multimodal MRI.MethodsWe assessed cortical thickness, subcortical volumes, and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 patients with ALS (follow-up: n = 150) and 156 controls (follow-up: n = 72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls.ResultsPatients with a C9orf72 mutation (n = 24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72-negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Patients with spinal onset displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas patients with bulbar onset started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate.ConclusionsHeterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration.

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Section: Discussionmentioning

confidence: 60%

Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis

et al. 2020

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“…In fact, differences in pathology between bulbar-onset and spinal-onset ALS patients have been reported. For example, some bulbar-onset ALS cases presented with atypical pathology such as neuro brillary tangles and basophilic inclusion, which were not found in the spinal-onset ALS cases [50].…”

Section: Discussionmentioning

confidence: 96%

Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

Liu

Yuan

et al. 2020

Preprint

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Background: Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases.Methods: Serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson’s disease (PD), and 82 healthy controls (HCs). A meta-analysis including data from this study was performed to evaluate the differences in the levels of immunoglobulin and complement between ALS patients and HCs. The serum levels of immunoglobulin and complement were compared between patient groups and HCs or between ALS patient groups established by age at onset, site at onset, disease duration, or disease severity. The correlations between the levels of immunoglobulin and complement and the clinical characteristics of ALS were analysed using Spearman correlation analysis.Results: The pooled results showed that patients with ALS had higher C4 levels than did HCs, and no significant differences between these two groups in IgG, IgA, IgM, or C3 levels were found. Multiple comparisons revealed that there were no significant differences between patients with ALS and other neurodegenerative diseases in IgG, IgA, IgM, C3, or C4 levels. In addition, the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs. The correlations between age at onset of ALS and IgG and IgA levels were significantly positive. Moreover, spinal-onset ALS patients had lower serum IgG levels than did HCs, but no difference was found between bulbar-onset ALS patients and HCs.Conclusions: Peripheral immunity abnormalities existed in patients with ALS, and lower IgG levels were associated with early-onset ALS.

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“…Furthermore, it is noteworthy that brainstem motoneurons may not share precisely the same pathophysiological characteristics as those of spinal motoneurons (Shellikeri et al . ): indeed, in the same SOD1 G93A mouse model, there is hyperexcitability of trigeminal fast motoneurons, as well as signs of hypoexcitability in slow ones (Venugopal et al . ).…”

Section: Discussionmentioning

confidence: 96%

Functional up‐regulation of the M‐current by retigabine contrasts hyperexcitability and excitotoxicity on rat hypoglossal motoneurons

Ghezzi

Monni

Nistri

2018

The Journal of Physiology

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Neuronal hyperexcitability is a symptom characterizing several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In the ALS bulbar form, hypoglossal motoneurons (HMs) are an early target for neurodegeneration because of their high vulnerability to metabolic insults. In recent years, our laboratory has developed an in vitro model of a brainstem slice comprising the hypoglossal nucleus in which HM neurodegeneration is achieved by blocking glutamate clearance with dl-threo-β-benzyloxyaspartate (TBOA), thus leading to delayed excitotoxicity. During this process, HMs display a set of hallmarks such as hyperexcitability (and network bursting), reactive oxygen species (ROS) generation and, finally, cell death. The present study aimed to investigate whether blocking early hyperexcitability and bursting with the anti-convulsant drug retigabine was sufficient to achieve neuroprotection against excitotoxicity. Retigabine is a selective positive allosteric modulator of the M-current (I ), an endogenous mechanism that neurons (comprising HMs) express to dampen excitability. Retigabine (10 μm; co-applied with TBOA) contrasted ROS generation, release of endogenous toxic factors into the HM cytoplasm and excitotoxicity-induced HM death. Electrophysiological experiments showed that retigabine readily contrasted and arrested bursting evoked by TBOA administration. Because neuronal I subunits (Kv7.2, Kv7.3 and Kv7.5) were expressed in the hypoglossal nucleus and in functionally connected medullary nuclei, we suggest that they were responsible for the strong reduction in network excitability, a potent phenomenon for achieving neuroprotection against TBOA-induced excitotoxicity. The results of the present study may have translational value for testing novel positive pharmacological modulators of the I under pathological conditions (including neurodegenerative disorders) characterized by excessive neuronal excitability.

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The neuropathological signature of bulbar-onset ALS: A systematic review

Cited by 56 publications

References 92 publications

Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis

Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis

Evaluation of Peripheral Immune Activation in Amyotrophic Lateral Sclerosis

Functional up‐regulation of the M‐current by retigabine contrasts hyperexcitability and excitotoxicity on rat hypoglossal motoneurons

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