Presymptomatic spinal cord neurometabolic findings in
            <i>SOD1</i>
            -positive people at risk for familial ALS

Carew, John D.; Nair, Govind; Andersen, Peter M.; Wuu, Joanne; Gronka, Susan; Hu, Xiaoping; Benatar, Michael

doi:10.1212/wnl.0b013e318231526a

Cited by 63 publications

(47 citation statements)

References 34 publications

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“…The pathological processes underlying ALS begin before the first clinical symptoms become apparent [34,35,36,37]. Our data imply that deficits in executive functioning, in those patients who develop them, emerge in this pre-symptomatic phase and, unlike motor impairments, remain relatively stable after the initial decline.…”

Section: Discussionmentioning

confidence: 76%

No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study

et al. 2015

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Background/Aims: A substantial proportion of amyotrophic lateral sclerosis (ALS) patients develop cognitive impairments. Longitudinal investigations of cognition in ALS have shown mixed results. While some authors report that cognitive performance remains stable as the disease progresses, others have found evidence for deterioration in various domains. Our objective was to investigate cognitive performance in ALS longitudinally, using the example of executive functions. Methods: 93 ALS patients and 73 age-, sex- and education-matched healthy controls underwent up to four neuropsychological evaluations, separated by 3- to 6-month intervals. We examined whether performance declined longitudinally on seven tests assessing various sub-components of executive functioning. Furthermore, we assigned an executive-performance-based ‘cognitive status' to each participant for every evaluation, examining whether cognitive deterioration (if present) was modulated by their baseline cognitive status and whether cognitive status changed over time. Results: Regardless of their cognitive status at baseline, ALS patients showed no significant decline in the sub-components of executive functioning. Conclusion: Our findings imply that the executive deficits which develop in some ALS patients emerge before motor symptoms and remain stable after an initial decline. The discrepancy between this trajectory and the progressive decline in motor functions may result from a differential vulnerability of motor and non-motor prefrontal neurons to the pathomechanism of ALS.

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Section: Discussionmentioning

confidence: 76%

No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study

et al. 2015

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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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“…23 Additionally, a recent cross-sectional MRS study of the cervical cord revealed differences in tissue metabolites (e.g., reduced NAA/Cr) in SOD1ϩ carriers compared to controls. 27 The expected heterogeneity of the study population with respect to the anticipated latency to onset of disease may underlie these varying cross-sectional findings.…”

Section: Environmental Risk Factorsmentioning

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

Cited by 63 publications

References 34 publications

No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study

No Change in Executive Performance in ALS Patients: A Longitudinal Neuropsychological Study

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

Presymptomatic studies in ALS

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