Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation

Ng, Man-Cheuk; Ho, Jenny; Ho, Shu‐Leong; Lee, Raymand; Geng, Lanlan; Cheng, Tat-Sun; Song, You‐Qiang; Ho, Philip Wing-Lok; Fong, G.C.Y.; Mak, W; Chan, Koon‐Ho; Li, Leonard Sheung-Wai; Luk, K.D.K.; Hu, Yuming; Ramsden, D.; Leong, Lilian Ling-Yee

doi:10.1002/jmri.21217

Cited by 52 publications

(31 citation statements)

References 35 publications

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“…38 The lack of knowledge of the at-risk population and uncertainty over where the clinical horizon lies in relation to the start of the pathologic cascade currently hampers MRI study of the very earliest changes beyond rare familial cases. 39 Early peridiagnostic as well as longitudinal studies will be important for validation of the present findings.…”

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

confidence: 58%

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Filippini

Douaud²,

Mackay³

et al. 2010

Neurology

263

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: 58%

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Filippini

Douaud²,

Mackay³

et al. 2010

Neurology

263

241

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“…32 It is similarly believed that the neurodegenerative process in ALS may begin prior to the onset of symptoms, but there are relatively little human data to support this hypothesis. [2][3][4] An important reason for the paucity of human data is the practical difficulty of studying people at risk for ALS prior to the onset of symptoms. Pre-fALS is a prospective observational study of asymptomatic individuals from familial ALS pedigrees who harbor a mutation in an ALS susceptibility gene and are at high risk for developing ALS.…”

Section: Resultsmentioning

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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“…There are inconsistent reports of structural and functional MRI abnormalities prior to symptom onset in those at high genetic risk of ALS [Carew et al, 2011; Menke et al, 2016; Ng et al, 2008; Vucic et al, 2008; Walhout et al, 2015]. Evidence of cortical hyperexcitability in asymptomatic carriers of genetic mutations who are “at risk” of ALS is restricted to a very limited finding of reduced ligand [ 11 C]‐flumazenil binding in two individuals with the D90A SOD1 mutation [Turner et al, 2005a], and three SOD1 mutation carriers who demonstrated reduced or absent intra‐cortical inhibition within three months of symptom onset [Vucic et al, 2008].…”

Section: Discussionmentioning

confidence: 99%

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Proudfoot

Rohenkohl

Quinn

et al. 2016

Human Brain Mapping

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Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc.

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Abnormal diffusion tensor in nonsymptomatic familial amyotrophic lateral sclerosis with a causative superoxide dismutase 1 mutation

Cited by 52 publications

References 35 publications

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

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

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

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