Cerebral degeneration in amyotrophic lateral sclerosis

Srivastava, Ojas; Hanstock, Chris; Chenji, Sneha; Mah, Dennell; Eurich, Dean T.; Ta, Daniel; Seres, Peter; Luk, Collin; Zinman, Lorne; Abrahão, Agessandro; Graham, Simon J.; Genge, Angela; Frayne, Richard; Kalra, Sanjay

doi:10.1212/cpj.0000000000000674

Cited by 12 publications

(16 citation statements)

References 37 publications

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“…The fact that GSH correlated with time from diagnosis but not with time from symptoms onset might be explained by the fact that ALS onset is insidious and the exact timing of it may be biased by patient recollection, while the time of diagnosis can be reliably ascertained from medical records. In contrast to GSH, the levels of NAA in the motor cortex correlated with the rate of disease progression, which supports the fact that NAA is a reliable neuronal marker as previously shown (18)(19)(20)(21)(46)(47)(48)(49) and can be used to probe the progressive neurodegeneration during ALS disease. Interestingly, the metabolic maps shown in the upper panel of Figure 1 indicate that there is more pronounced decrease in motor cortex for GSH than NAA at early stages of the disease, which have been found also at group level (Figure 2), suggesting that astrocytic changes might precede neurodegeneration or that the two processes may follow a different time course.…”

Section: Discussionsupporting

confidence: 80%

“…First, we investigated whether GSH levels in the corticospinal tract may correlate stronger with disease duration than GHS levels in the motor cortex. Second, we investigated the relation between clinical ALS progression and other neuro-metabolites ( 20 , 21 ) that are markers for neuronal health [N-acetyl-aspartate (NAA)], inflammation [myo-inositol (Ins)], and excitotoxicity [glutamate (Glu)]. Third, we investigated brain structural parameters ( 12 , 14 ), such as cortical thickness, from anatomical MRI and white matter tractography ( 22 ) from diffusion tensor imaging (DTI).…”

Section: Introductionmentioning

confidence: 99%

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Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients

et al. 2020

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Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients

et al. 2020

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“…Resting-state functional MRI (rs-fMRI) assesses functional connectivity. CALSNIC-1 includes single voxel magnetic resonance spectroscopy (MRS) for assessment of neuronal integrity and gliosis in the motor and prefrontal cortices; 15 this was not included in CALSNIC-2 due to time limitations. Instead, CALSNIC-2 added susceptibility weighted imaging (SWI) to quantify cerebral iron deposition, a second b -value of diffusion weighting to allow for diffusion kurtosis imaging, and multi-resolution 3D anatomical imaging.…”

Section: Methodsmentioning

confidence: 99%

The Canadian ALS Neuroimaging Consortium (CALSNIC) - a multicentre platform for standardized imaging and clinical studies in ALS

Kalra

Khan

Barlow

et al. 2020

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Background: Amyotrophic lateral sclerosis (ALS) is a disabling and rapidly progressive neurodegenerative disorder. Increasing age is an important risk factor for developing ALS, thus the societal impact of this devastating disease will become more profound as the population ages. A significant hurdle to finding effective treatment has been an inability to accurately quantify cerebral degeneration associated with ALS in humans. Advanced magnetic resonance imaging (MRI) techniques hold promise in providing a set of biomarkers to assist in aiding diagnosis and in efficiently evaluating new drugs to treat ALS. Methods: The Canadian ALS Neuroimaging Consortium (CALSNIC) was founded to develop and evaluate advanced MRI-based biomarkers that delineate biological heterogeneity, track disease progression, and predict survival in a large and heterogeneous sample of ALS patients. Findings: CALSNIC has launched two studies to date (CALSINC-1, CALSNIC-2), acquiring multimodal neuroimaging, neurological, neuropsychological data, and neuropathological data from ALS patients and healthy controls in a prospective and longitudinal fashion from multiple centres in Canada and, more recently, the United States. Clinical and MRI protocols are harmonized across research centres and different MR vendors. Interpretation: CALSNIC provides a multicentre platform for studying ALS biology and developing MRI-based biomarkers. Funding: Canadian Institutes of Health Research, ALS Society of Canada, Brain Canada Foundation, Shelly Mrkonjic Research Fund

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“…Several large studies examine specific neurodegenerative diseases [2][3][4][5] . These include cohort studies such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Parkinson Progression Marker Initiative (PPMI), which have advanced our understanding of prototypical Alzheimer's disease (AD) and Parkinson's disease (PD), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Translational neurodegenerative disease research recognizes the importance of multi-disciplinary team science, as shown through multiple prior initiatives [2][3][4][5] . Large scale and broadly accessible data encourages additional analyses on curated data but also allows researchers to merge data from multiple studies, leverage a constellation of initiatives, and accelerate discovery through broader integrations of data and wider collaborations of researchers 49 .…”

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confidence: 99%

The Ontario Neurodegenerative Disease Research Initiative

Sunderland¹,

Beaton²,

Arnott³

et al. 2020

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Objective: In individuals over the age of 65, concomitant neurodegenerative pathologies contribute to cognitive and/or motor decline and can be aggravated by cerebrovascular disease, but our understanding of how these pathologies synergize to produce the decline represents an important knowledge gap. The Ontario Neurodegenerative Disease Research Initiative (ONDRI), a multi-site, longitudinal, observational cohort study, recruited participants across multiple prevalent neurodegenerative diseases and cerebrovascular disease, collecting a wide array of data and thus allowing for deep investigation into common and unique phenotypes. This paper describes baseline features of the ONDRI cohort, understanding of which is essential when conducting analyses or interpreting results. Methods: Five disease cohorts were recruited: Alzheimer's disease/amnestic mild cognitive impairment (AD/MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and cerebrovascular disease (CVD). Assessment platforms included clinical, neuropsychology, eye tracking, gait and balance, neuroimaging, retinal imaging, genomics, and pathology. We describe recruitment, data collection, and data curation protocols, and provide a summary of ONDRI baseline characteristics. Results: 520 participants were enrolled. Most participants were in the early stages of disease progression. Participants had a median age of 69 years, a median Montreal Cognitive Assessment score of 25, a median percent of independence of 100 for basic activities of daily living, and a median of 93 for instrumental activities. Variation between disease cohorts existed for age, level of cognition, and geographic location. Conclusion: ONDRI data will enable exploration into unique and shared pathological mechanisms contributing to cognitive and motor decline across the spectrum of neurodegenerative diseases.

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Cerebral degeneration in amyotrophic lateral sclerosis

Cited by 12 publications

References 37 publications

Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients

Imaging Neurochemistry and Brain Structure Tracks Clinical Decline and Mechanisms of ALS in Patients

The Canadian ALS Neuroimaging Consortium (CALSNIC) - a multicentre platform for standardized imaging and clinical studies in ALS

The Ontario Neurodegenerative Disease Research Initiative

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