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

Authors :
James Chan
Kourosh Jafari-Khouzani
Eric A. Macklin
Wolfgang Bogner
Eva-Maria Ratai
Mark Levine-Weinberg
Bruce R. Rosen
Michael A. Schwarzschild
Christopher T. Breen
Sabrina Paganoni
Ovidiu C. Andronesi
Merit Cudkowicz
Jing Wang
Katharine Nicholson
Source :
Frontiers in Neurology, Vol 11 (2020), Frontiers in Neurology
Publication Year :
2020
Publisher :
Frontiers Media SA, 2020.

Abstract

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.

Details

ISSN :
16642295
Volume :
11
Database :
OpenAIRE
Journal :
Frontiers in Neurology
Accession number :
edsair.doi.dedup.....4c70ce4617a91e1df383c785a7326fa3
Full Text :
https://doi.org/10.3389/fneur.2020.590573