Interrogating the Metabolomic Profile of Amyotrophic Lateral Sclerosis in the Post-Mortem Human Brain by Infrared Matrix-Assisted Laser Desorption Electrospray Ionization (IR-MALDESI) Mass Spectrometry Imaging (MSI)

Abstract

Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal neurodegenerative disease characterized by progressive loss of motor function with an average survival time of 2–5 years after diagnosis. Due to the lack of signature biomarkers and heterogenous disease phenotypes, a definitive diagnosis of ALS can be challenging. Comprehensive investigation of this disease is imperative to discovering unique features to expedite the diagnostic process and improve diagnostic accuracy. Here, we present untargeted metabolomics by mass spectrometry imaging (MSI) for comparing sporadic ALS (sALS) and C9orf72 positive (C9Pos) post-mortem frontal cortex human brain tissues against a control cohort. The spatial distribution and relative abundance of metabolites were measured by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) MSI for association to biological pathways. Proteomic studies on the same patients were completed via LC-MS/MS in a previous study, and results were integrated with imaging metabolomics results to enhance the breadth of molecular coverage. Utilizing METASPACE annotation platform and MSiPeakfinder, nearly 300 metabolites were identified across the sixteen samples, where 25 were identified as dysregulated between disease cohorts. The dysregulated metabolites were further examined for their relevance to alanine, aspartate, and glutamate metabolism, glutathione metabolism, and arginine and proline metabolism. The dysregulated pathways discussed are consistent with reports from other ALS studies. To our knowledge, this work is the first of its kind, reporting on the investigation of ALS post-mortem human brain tissue analyzed by multiomic MSI.

Chronological and Biological Aging in Amyotrophic Lateral Sclerosis and the Potential of Senolytic Therapies

“…Signs and symptoms of ALS include features of muscle weakness and wasting as well as other features of upper motor neuron dysfunction including increased tone and spasticity [ 2 ]. Progression of ALS is often rapid, with an average survival of 2–5 years after onset [ 3 ], yet progression and prognosis vary by clinical presentation, such as bulbar onset, which denotes a more poor prognosis, as well as other factors including genetics [ 2 , 4 ].…”

Automatic z-Axis Correction for IR-MALDESI Mass Spectrometry Imaging of Uneven Surfaces

“…Desorbed neutrals are post-ionized in an ESI-like fashion before entering a mass spectrometer. 23 IR-MALDESI has been leveraged to detect different species, such as neurotransmitters, 24 metabolites, 25 lipids, 26 and glycans, 27 from tissue sections at a thickness of 3−30 μm. In these experiments, flat tissue sections are horizontally positioned at the focal plane of the laser given that the laser fires in the z dimension.…”

Predicting Sialic Acid Content of N-Linked Glycans Using the Isotopic Pattern of Chlorine

“…IR-MALDESI is coupled to an Orbitrap mass spectrometer to grant high resolving power and high mass measurement accuracy. This technique is capable of analyzing a large variety of biological samples, − and recent work has demonstrated the ability to analyze intact N- linked glycans . Unlike MALDI, IR-MALDESI can readily ionize N -linked glycans in negative-ionization mode without the dissociation of sialic acids .…”