Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation

Aggarwal, Arun Kumar; Nicholson, Garth A.

doi:10.1136/jnnp.73.2.199

Cited by 117 publications

(80 citation statements)

References 10 publications

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“…24 Studies in presymptomatic patients with mutations of the superoxide dismutase-1 gene suggest that cortical excitability, 25 as well as LMN loss, 26 is an early event associated with the development of symptoms.…”

Section: Figure 2 Regional Fractional Anisotropy (Fa) Reductions and mentioning

confidence: 99%

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Filippini

Douaud²,

Mackay³

et al. 2010

Neurology

265

241

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Objective: While the hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract in combination with lower motor neuron degeneration, the clinical involvement of both compartments is characteristically variable and the site of onset debated. We sought to establish whether there is a consistent signature of cerebral white matter abnormalities in heterogeneous ALS cases. Methods:In this observational study, diffusion tensor imaging was applied in a whole-brain analysis of 24 heterogeneous patients with ALS and well-matched healthy controls. Tract-based spatial statistics were used, with optimized voxel-based morphometry of T1 images to determine any associated gray matter involvement. Results:A consistent reduction in fractional anisotropy was demonstrated in the corpus callosum of the ALS group, extending rostrally and bilaterally to the region of the primary motor cortices, independent of the degree of clinical upper motor neuron involvement. Matched regional radial diffusivity increase supported the concept of anterograde degeneration of callosal fibers observed pathologically. Gray matter reductions were observed bilaterally in primary motor and supplementary motor regions, and also in the anterior cingulate and temporal lobe regions. A post hoc group comparison model incorporating significant values for fractional anisotropy, radial diffusivity, and gray matter was 92% sensitive, 88% specific, with an accuracy of 90%. Conclusion:Callosal involvement is a consistent feature of ALS, independent of clinical upper motor neuron involvement, and may reflect independent bilateral cortical involvement or interhemispheric spread of pathology. The predominantly rostral corticospinal tract involvement further supports the concept of independent cortical degeneration even in those patients with ALS with predominantly lower motor neuron involvement clinically. Neurology ® 2010;75:1645-1652 GLOSSARY ALS ϭ amyotrophic lateral sclerosis; ALSFRS-R ϭ revised Amyotrophic Lateral Sclerosis Functional Rating Scale; CC ϭ corpus callosum; CST ϭ corticospinal tract; DD ϭ disease duration; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; FTD ϭ frontotemporal dementia; GM ϭ gray matter; LMN ϭ lower motor neuron; MD ϭ mean diffusivity; PLS ϭ primary lateral sclerosis; PMA ϭ progressive muscular atrophy; RD ϭ radial diffusivity; UMN ϭ upper motor neuron; WM ϭ white matter.A major issue in amyotrophic lateral sclerosis (ALS) is phenotypic heterogeneity. While ALS is characterized by simultaneous upper motor neuron (UMN) and lower motor neuron (LMN) degeneration, phenotypes are recognized in which degeneration in one or more compartments appears dominant, termed progressive muscular atrophy (PMA) where there is LMN-only involvement clinically and primary lateral sclerosis (PLS) where involvement is UMN only. The nature of this observed spectrum of compartmentalization of motor neuron pathology is not understood, and extremes can present a diagnostic challenge early in the disease course.

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Section: Figure 2 Regional Fractional Anisotropy (Fa) Reductions and mentioning

confidence: 99%

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Filippini

Douaud²,

Mackay³

et al. 2010

Neurology

265

241

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“…At presymptomatic time points (i.e., weeks 9-12), focal activation occurs for PNS macrophages and spinal cord microglia. Following clinical onset (i.e., weeks [12][13][14][15][16][17][18][19], activation of innate immunity becomes widespread in both tissues as indicated by FACS and histological analysis.…”

Section: Macrophage Activation Occurs Throughout the Peripheral Nervousmentioning

confidence: 99%

“…Degeneration of motor axons in the periphery is an early and significant pathological feature in ALS patients and mutant SOD1 mice (11,12). Mutant SOD1 also induces defects in peripheral axon transport, which may be a primary determinant of motor neuron death (13).…”

mentioning

confidence: 99%

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

Chiu

Phatnani

Kuligowski

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

177

176

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During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1؉ macrophages throughout the PNS in mutant SOD1 G93A and SOD1 G37R transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.innate immunity ͉ macrophage ͉ peripheral nervous system ͉ neuroimmunology ͉ amyotrophic lateral sclerosis

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“…1 Limited data from a number of healthy individuals at risk for ALS by virtue of their carrying a mutation in the SOD1 gene (SOD1ϩ) suggest a decline in motor unit numbers several months in advance of the appearance of symptoms. 2 Similarly, limited threshold tracking transcranial magnetic stimulation data from 3 presymptomatic SOD1ϩ individuals suggests an increase in cortical excitability within 3 months prior to the onset of symptoms. 3 Finally, a single prior study of 8 presymptomatic SOD1 mutation carriers reported decreased fractional anisotropy, increased tensor trace, and increased radial diffusivity in the posterior limb of the internal capsule.…”

mentioning

confidence: 99%

Presymptomatic spinal cord neurometabolic findings in SOD1 -positive people at risk for familial ALS

Carew¹,

Nair²,

Andersen³

et al. 2011

Neurology

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Objective: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure ratios of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1ϩ) and compare their neurometabolic ratios to patients with ALS and healthy controls. Methods:A cross-sectional study of 1 H-MRS of the cervical spine was performed on 24 presymptomatic SOD1ϩ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylaspartate (NAA) were determined.Results: NAA/Cr and NAA/Myo ratios are reduced in both SOD1ϩ subjects (39.7%, p ϭ 0.001 and 18.0%, p ϭ 0.02) and patients with ALS (41.2%, p Ͻ 0.001 and 24.0%, p ϭ 0.01) compared to controls. Myo/Cr is reduced (10.3%, p ϭ 0.02) in SOD1ϩ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p ϭ 0.002), but not in presymptomatic SOD1ϩ subjects compared to controls. It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neuronal degeneration precedes the appearance of clinical symptoms. Some evidence of this premanifest period has been derived from the superoxide dismutase (SOD1) mouse model of ALS in which there is a decline in the estimated motor unit number in advance of the appearance of symptoms. Conclusions:1 Limited data from a number of healthy individuals at risk for ALS by virtue of their carrying a mutation in the SOD1 gene (SOD1ϩ) suggest a decline in motor unit numbers several months in advance of the appearance of symptoms.

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Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation

Cited by 117 publications

References 10 publications

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice

Presymptomatic spinal cord neurometabolic findings in SOD1 -positive people at risk for familial ALS

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