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Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection.

ABSTRACT: We have applied nuclear magnetic resonance spectroscopy based plasma phenotyping to reveal diagnostic molecular signatures of SARS-CoV-2 infection via combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls (n = 26) with SARS-CoV-2 negative non-hospitalized respiratory patients and hospitalized respiratory patients (n = 23 and 11 respectively) with SARS-CoV-2 rRT-PCR positive respiratory patients (n = 17, with longitudinal sampling time-points). DIRE data were modelled using principal component analysis and orthogonal projections to latent structures discriminant analysis (O-PLS-DA), with statistical cross-validation indices indicating excellent model generalization for the classification of SARS-CoV-2 positivity for all comparator groups (area under the receiver operator characteristic curve = 1). DIRE spectra show biomarker signal combinations conferred by differential concentrations of metabolites with selected molecular mobility properties. These comprise the following: (a) composite N-acetyl signals from ?-1-acid glycoprotein and other glycoproteins (designated GlycA and GlycB) that were elevated in SARS-CoV-2 positive patients [p = 2.52 × 10^-10 (GlycA) and 1.25 × 10^-9 (GlycB) vs controls], (b) two diagnostic supramolecular phospholipid composite signals that were identified (SPC-A and SPC-B) from the -⁺N-(CH₃)₃ choline headgroups of lysophosphatidylcholines carried on plasma glycoproteins and from phospholipids in high-density lipoprotein subfractions (SPC-A) together with a phospholipid component of low-density lipoprotein (SPC-B). The integrals of the summed SPC signals (SPC_total) were reduced in SARS-CoV-2 positive patients relative to both controls (p = 1.40 × 10^-7) and SARS-CoV-2 negative patients (p = 4.52 × 10^-8) but were not significantly different between controls and SARS-CoV-2 negative patients. The identity of the SPC signal components was determined using one and two dimensional diffusional, relaxation, and statistical spectroscopic experiments. The SPC_total/GlycA ratios were also significantly different for control versus SARS-CoV-2 positive patients (p = 1.23 × 10^-10) and for SARS-CoV-2 negatives versus positives (p = 1.60 × 10^-9). Thus, plasma SPC_total and SPC_total/GlycA are proposed as sensitive molecular markers for SARS-CoV-2 positivity that could effectively augment current COVID-19 diagnostics and may have value in functional assessment of the disease recovery process in patients with long-term symptoms.

SUBMITTER: Lodge S

PROVIDER: S-EPMC7908063 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection.

Lodge Samantha S Nitschke Philipp P Kimhofer Torben T Wist Julien J Bong Sze-How SH Loo Ruey Leng RL Masuda Reika R Begum Sofina S Richards Toby T Lindon John C JC Bermel Wolfgang W Reinsperger Tony T Schaefer Hartmut H Spraul Manfred M Holmes Elaine E Nicholson Jeremy K JK

Analytical chemistry 20210212 8

We have applied nuclear magnetic resonance spectroscopy based plasma phenotyping to reveal diagnostic molecular signatures of SARS-CoV-2 infection via combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls (n = 26) with SARS-CoV-2 negative non-hospitalized respiratory patients and hospitalized respiratory patients (n = 23 and 11 respectively) with SARS-CoV-2 rRT-PCR positive respiratory patients (n = 17, with longitudi ...[more]

PMID: 33577736

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Project description:For many pathologies, early structural tissue changes occur at the cellular level, on the scale of micrometers or tens of micrometers. Magnetic resonance imaging (MRI) is a powerful non-invasive imaging tool used for medical diagnosis, but its clinical hardware is incapable of reaching the cellular length scale directly. In spite of this limitation, microscopic tissue changes in pathology can potentially be captured indirectly, from macroscopic imaging characteristics, by studying water diffusion. Here we focus on water diffusion and NMR relaxation in the human prostate, a highly heterogeneous organ at the cellular level. We present a physical picture of water diffusion and NMR relaxation in the prostate tissue, that is comprised of a densely-packed cellular compartment (composed of stroma and epithelium), and a luminal compartment with almost unrestricted water diffusion. Transverse NMR relaxation is used to identify fast and slow T 2 components, corresponding to these tissue compartments, and to disentangle the luminal and cellular compartment contributions to the temporal evolution of the overall water diffusion coefficient. Diffusion in the luminal compartment falls into the short-time surface-to-volume (S/V) limit, indicating that only a small fraction of water molecules has time to encounter the luminal walls of healthy tissue; from the S/V ratio, the average lumen diameter averaged over three young healthy subjects is measured to be 217.7±188.7 ?m. Conversely, the diffusion in the cellular compartment is highly restricted and anisotropic, consistent with the fibrous character of the stromal tissue. Diffusion transverse to these fibers is well described by the random permeable barrier model (RPBM), as confirmed by the dynamical exponent ? = 1/2 for approaching the long-time limit of diffusion, and the corresponding structural exponent p = -1 in histology. The RPBM-derived fiber diameter and membrane permeability were 19.8±8.1 ?m and 0.044±0.045 ?m/ms, respectively, in agreement with known values from tissue histology and membrane biophysics. Lastly, we revisited 38 prostate cancer cases from a recently published study, and found the same dynamical exponent ? = 1/2 of diffusion in tumors and benign regions. Our results suggest that a multi-parametric MRI acquisition combined with biophysical modeling may be a powerful non-invasive complement to prostate cancer grading, potentially foregoing biopsies.

Dataset Information

Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection.

Publications

Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection.

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