Implications of ALS focality

Ravits, John; Laurie, Patrick; Fan, Yuxin; Moore, Dan H.

doi:10.1212/01.wnl.0000261045.57095.56

Cited by 143 publications

(121 citation statements)

References 49 publications

(56 reference statements)

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“…Furthermore, despite the lesion being present in every cell, ALS onset seems to occur in one neurological segment, spreading to neighbouring regions within a predictable portion of time (Roche, et al, 2012). The pattern of clinical spread is also predictable when using neuroanatomy as a framework (Ravits, et al, 2007). Neuropathologically, these findings suggest that ALS begins focally and spreads diffusely throughout the corticospinal, bulbar and spinal motor network.…”

Section: Introductionmentioning

confidence: 95%

Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

Jones

Troakes

King

et al. 2015

Neurobiology of Aging

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesised that analysing tissues by matching on degree of disease severity would identify different patterns of gene expression than a traditional case-control comparison. We analysed gene expression changes in four post-mortem CNS regions, stratified by severity of motor neuron loss. An overall case (n = 6) control (n = 3) comparison identified known ALS gene, SOX5 as showing differential expression (log2 fold-change = 0.09, p = 5.5x10

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Section: Introductionmentioning

confidence: 95%

Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes

Jones

Troakes

King

et al. 2015

Neurobiology of Aging

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“…Second, the disease process spreads via contiguity, with the rate of spread through each axis being central to determining phenotype. 11,12 If correct, these hypotheses would have profound implications for how we conceptualize ALS pathogenesis-e.g., providing some support for the theory that misfolded/ aggregated proteins recruit neighboring mutant or wild-type proteins in a prion-like fashion. 13 It has been difficult to test these hypotheses in a natural history study, however, due to the relatively advanced stage of disease at which patients with ALS emerge over the clinical horizon.…”

Section: Rationale Disease Biologymentioning

confidence: 99%

Presymptomatic studies in ALS

Benatar

Wuu

2012

Neurology

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It is now well-established that the disease process in many neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and Huntington disease, begins many years before the appearance of typical symptoms. Whether amyotrophic lateral sclerosis (ALS) is also characterized by a presymptomatic period, and if so how long this period lasts, is unclear. Answers to these questions will not only inform our understanding of disease biology and potential environmental risk factors for ALS, but also the design and implementation of early therapeutic and even preventative clinical trials. Moreover, the potential impact of studying people at genetic risk for ALS, the only population in which it is currently possible to study presymptomatic disease, is underscored by recent progress in our understanding of the shared genetic basis of familial and apparently sporadic ALS. Studying presymptomatic ALS, however, has proven difficult due to the challenge in identifying an at-risk population and various logistical and ethical considerations. In this article we present the rationale for studying presymptomatic ALS, summarize the early evidence supporting the existence of a presymptomatic phase of the disease, and discuss the challenges of studying presymptomatic ALS. We also use Pre-fALS a systematic and longitudinal investigation of a cohort of individuals at genetic risk for ALS, as an example to illustrate how one might approach these challenges. Neurology ® 2012;79:1732-1739 GLOSSARY ALS ϭ amyotrophic lateral sclerosis; DTI ϭ diffusion tensor imaging; fALS ϭ familial amyotrophic lateral sclerosis; FTD ϭ frontotemporal dementia; LMN ϭ lower motor neuron; MN ϭ motor neuron; MRS ϭ magnetic resonance spectroscopy; MUNE ϭ motor unit number estimation; Pre-fALS ϭ Pre-symptomatic Familial ALS study; UMN ϭ upper motor neuron.The last 15 years have witnessed a significant shift in our understanding of neurodegenerative diseases. We increasingly recognize that the degenerative process in disorders such as Alzheimer disease, 1 Huntington disease, 2 and Parkinson disease 3-5 begins years, if not decades, prior to the appearance of typical clinical manifestations. Whether ALS is also characterized by a prolonged presymptomatic period is unclear, but definitively answering this question is likely to have profound implications for understanding disease biology, uncovering environmental risk factors, developing effective therapies, and even disease prevention.To effectively study presymptomatic ALS, one must first identify people who are at risk for developing disease. Although advancing age is a risk factor for ALS, the broad range of age at symptom onset limits its utility in identifying at-risk individuals. Absent any known environmental risk factor, it is currently only possible to study individuals genetically predisposed to developing ALS-namely, presymptomatic gene mutation carriers.We begin this review with the rationale for studying presymptomatic ALS and a review of the relevant literature. We then turn to the ...

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“…Recent detailed autopsy studies of ALS patients have confirmed that loss of motor neurons is most pronounced at the site of onset and diminishes in a gradient fashion with further distance from that site. 3 While many aberrant phenomena including excitotoxicity, oxidative stress, mitochondrial dysfunction and altered axonal transport have been implicated in ALS pathogenesis, it is not easily apparent how any of these could explain the focal initiation or the progressive spread of the disease through the motor system. 4 While the majority of ALS occurs sporadically, approximately 5-10% of patients have a family history of the disorder, typically autosomal dominant.…”

Section: A Myotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%