Amyotrophic lateral sclerosis—Evolutionary and other perspectives

Eisen, Andrew

doi:10.1002/mus.21404

Cited by 60 publications

(56 citation statements)

References 113 publications

(95 reference statements)

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“…Specifi cally, our data corroborate the recent concept of the CC as a conduit for the spread of pathology from one hemisphere to the other (47). In agreement with our fi ndings, several clinical studies have demonstrated an impaired interhemispheric inhibition in ALS even at an early stage of disease progression, which could be mediated by CC impairment and associated with detection of mirror movements (48,49).…”

Section: Discussionsupporting

confidence: 93%

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

Trojsi¹,

Corbo²,

Caiazzo³

et al. 2013

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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In amyotrophic lateral sclerosis (ALS), diffusion weighted magnetic resonance imaging (DW-MRI) has produced mounting evidence of a widespread white matter (WM) damage within motor and extramotor pathways. To provide novel information about the degenerative process in ALS, overcoming some of the limitations imposed by diffusion tensor imaging (DTI), we performed a high angular resolution diffusion imaging (HARDI) analysis of DW-MRI data. Generalized fractional anisotropy (GFA) was evaluated in 19 patients with ALS and 19 matched control subjects, and was correlated with clinical scores of disability, pyramidal impairment by upper motor neuron (UMN) score and frontal dysfunction by the Frontal Systems Behaviour (FrSBe) scale. Results demonstrated that ALS patients showed a significant decrease of GFA in the WM tracts underneath the left and right precentral gyri and the body of the corpus callosum (p < 0.05, corrected), where GFA was significantly related to UMN scores (p < 0.001, uncorrected); and in the left superior longitudinal fasciculus (p < 0.05, corrected), where GFA was significantly related to FrSBe scale scores (p < 0.01, uncorrected). In conclusion, this study revealed a pattern of motor and extramotor frontal diffusivity abnormalities (probably related to behavioural and cognitive dysfunctions) showing a spatial distribution similar to what was previously described in ALS - frontotemporal dementia continuum.

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Section: Discussionsupporting

confidence: 93%

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

Trojsi¹,

Corbo²,

Caiazzo³

et al. 2013

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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“…Notwithstanding a need for dedicated studies in cases of pure PMA as well as in the earliest stages of typical ALS, we speculate, like others, 30 that ALS may be fundamentally a cortical neurodegenerative disorder. Rapid increase in human lifespan may have exposed a vulnerability of the aging brain for the specialized motor functions that have evolved on the basis of much shorter survival.…”

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

confidence: 52%

“…Hypotheses about focality of onset and spread of disease in ALS have indirectly implicated the CC (see figure in reference 13), and others have speculated that the CC might be a "conduit" for pathologic spread within a corticomotoneuronal model of ALS. 30 Although asymmetry of symptom onset is poorly understood, the observation of concordance for handedness and laterality of upper limb onset in ALS may provide further indirect support for an independent cortical vulnerability, when considered alongside studies that have noted greater cortical excitability and altered cerebral activation patterns in the dominant vs nondominant hand. 31 It is clear also that ALS pathology extends beyond the CST, sharing pathologic as well as clinical features with some forms of frontotemporal dementia (FTD).…”

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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“…There is evidence for greater connectivity in the dominant motor cortex with respect to handedness10; specifically, it has been noted that the production of movements in dominant and non-dominant hands involves distinct cerebral networks 11. Evolutionary aspects of neocortical function might have relevance to ALS pathogenesis, in that humans have evolved uniquely complex levels of corticomotoneuronal organisation and connectivity as part of the switch to bipedal locomotion and particularly the development of fine hand control through an opposable thumb 12. Such complexity may have come at a price and harbour a vulnerability in the ageing motor system unmasked by ALS.…”

Section: Discussionmentioning

confidence: 99%

Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis

Turner

Wicks

Brownstein

et al. 2010

Journal of Neurology, Neurosurgery & Psychiatry

122

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Background Focality of onset of amyotrophic lateral sclerosis (ALS) is not understood. Attempts to implicate physical exercise in the aetiology of ALS have provided inconsistent results. If physical use of a limb were important in defining the site of onset, then handedness might be expected to influence the side of upper limb-onset disease and footedness likewise in lower limb-onset ALS. Methods ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site of onset of symptoms and their dominant hand and foot. A binomial test of proportions was used to investigate the null hypothesis that handedness and footedness do not influence side of onset in upper and lower limb-onset ALS, respectively. Results 343 ALS patients with limb-onset disease were studied. For upper limb-onset patients, there was concordance for side of onset and handedness (64%; p<0.0006). For lower limb-onset patients, concordance for side of onset and footedness was absent. The frequency of left handedness was commensurate with that found in the general population. Interpretation These results are potentially consistent with the hypothesis that exercise influences pathogenesis in ALS since routine physical demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing or locomotion, which uses both legs equally. However, there may also be an inherent cortical vulnerability underlying upper limb-onset laterality, possibly influenced by changes in neuronal connectivity and cortical excitability in relation to handedness and reflected by the "split hand" phenomenon consistently observed in ALS.The site of onset of loss of function in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS) is approximately divided equally between upper limb, lower limb and bulbar territories, 1 with only a very small proportion (w3%) beginning in the respiratory or axial musculature. Although there are a number of active themes in the quest to understand pathogenesis in ALS, 3 very little is known about why the onset is focal, though it has been shown that upper (UMN) and lower motor neuron (LMN) signs (the hallmark of ALS) are maximal within this territory and show contiguous spread. 4 The inconsistent observations of relative athleticism among people with ALS 5e7 have led to continued debate about the possible role of physical exercise in the pathogenesis of ALS, 8 and putative direct effects via excitotoxicity and mitochondrial dysfunction.3 A more indirect association, whereby the genetic profiles that underlie ALS susceptibility and athleticism have common components, 9 currently seems equally, if not more, likely. If physical exercise is a direct determinant of motor neuron damage, then it might be expected that the site onset of symptoms in limb-onset ALS would be biased in favour of the dominant limb through relatively greater use. We attempted to confirm the null hypothesis that the side of initial symptoms i...

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Amyotrophic lateral sclerosis—Evolutionary and other perspectives

Cited by 60 publications

References 113 publications

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis

Concordance between site of onset and limb dominance in amyotrophic lateral sclerosis

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