Methods to Discover and Validate Biofluid-Based Biomarkers in Neurodegenerative Dementias

Teunissen, Charlotte E.; Kimble, Leighann; Bayoumy, Sherif; Bolsewig, Katharina; Burtscher, Felicia; Coppens, Salomé; Das, Shreyasee; Gogishvili, Dea; Fernandes Gomes, Bárbara; Gómez de San José, Nerea; Mavrina, Ekaterina; Meda, Francisco J.; Mohaupt, Pablo; Mravinacová, Sára; Waury, Katharina; Wojdała, Anna Lidia; Abeln, Sanne; Chiasserini, Davide; Hirtz, Christophe; Gaetani, Lorenzo; Vermunt, Lisa; Bellomo, Giovanni; Halbgebauer, Steffen; Lehmann, Sylvain; Månberg, Anna; Nilsson, Peter; Otto, Markus; Vanmechelen, Eugeen; Verberk, Inge M.W.; Willemse, Eline; Zetterberg, Henrik

doi:10.1016/j.mcpro.2023.100629

Cited by 18 publications

(15 citation statements)

References 162 publications

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“…Highly sensitive, high-dimensional protein assays are now available which can assess a very wide range of proteins using small sample volumes. These novel antibody-based proteomic technologies, namely the OLINK® Proximity Extension 6 and the Alamar NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) 7 technologies, combine the sensitivity and specificity of immunoassay with the ability to detect a large breadth of targets 8 . This makes them ideal for discovery work, to characterise disease mechanisms and identify potential targets for intervention.…”

Section: Introductionmentioning

confidence: 99%

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

Li,

Kodosaki,

Heselgrave

et al. 2024

Preprint

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Pathophysiology and outcomes after Traumatic Brain Injury (TBI) are complex and highly heterogenous. Current classifications are uninformative about pathophysiology, which limits prognostication and treatment. Fluid-based biomarkers can identify pathways and proteins relevant to TBI pathophysiology. Proteomic approaches are well suited to exploring complex mechanisms of disease, as they enable sensitive assessment of an expansive range of proteins. We used novel high-dimensional, multiplex proteomic assays to study changes in plasma protein expression in acute moderate-severe TBI. We analysed samples from 88 participants in the longitudinal BIO-AX-TBI cohort (n=38 TBI within 10 days of injury, n=22 non-TBI trauma, n=28 non-injured controls) on two platforms: Alamar NULISA(TM) CNS Diseases and OLINK(R) Target 96 Inflammation. Participants also had data available from Simoa(R) (neurofilament light, GFAP, total tau, UCHL1) and Millipore (S100B). The Alamar panel assesses 120 proteins, most of which have not been investigated before in TBI, as well as proteins, such as GFAP, which differentiate TBI from non-injured and non-TBI trauma controls. A subset (n=29 TBI, n=24 non-injured controls) also had subacute 3T MRI measures of lesion volume and white matter injury (fractional anisotropy, scanned 10 days to 6 weeks after injury). Differential Expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin2, UCHL1, visinin-like protein1), astroglial markers (S100B, GFAP), tau and other neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid beta42, 14-3-3γ), inflammatory cytokines (IL16, CCL2, ficolin2), cell signalling (SFRP1), cell metabolism (MDH1) and autophagy related (sequestome1) proteins. Acute plasma levels of UCHL1, PSEN1, total tau and pTau231 correlated with subacute lesion volume, while sequestome1 was correlated with whole white matter skeleton fractional anisotropy and CCL2 was inversely correlated with corpus callosum FA. Neuronal, astroglial, tau and neurodegenerative proteins correlated with each other, and IL16, MDH1 and sequestome1. Clustering (k means) by acute protein expression identified 3 TBI subgroups which had differential injury patterns, but did not differ in age or outcome. Proteins that overlapped on two platforms had excellent (r>0.8) correlations between values. We identified TBI-specific changes in acute plasma levels of proteins involved in amyloid processing, inflammatory and cellular processes such as autophagy. These changes were related to patterns of injury, thus demonstrating that processes previously only studied in animal models are also relevant in human TBI pathophysiology. Our study highlights the potential of proteomic analysis to improve the classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.

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Section: Introductionmentioning

confidence: 99%

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

Li,

Kodosaki,

Heselgrave

et al. 2024

Preprint

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“…Most of the analytical assays for NDD biomarkers are based on antibodies, with enzyme-linked immunosorbent assay (ELISA) the most common assay used, in both research and clinical settings. 24 Various types of commercial ELISA kits including sandwich, competitive, direct, and indirect ELISA for NDD biomarkers utilize antibodies that are very specific to the target. Conventional ELISAs are widely used to quantify blood (plasma and serum) BDNF levels in the research setting.…”

Section: ■ Introductionmentioning

confidence: 99%

Isolation and Identification of the High-Affinity DNA Aptamer Target to the Brain-Derived Neurotrophic Factor (BDNF)

Chowdhury,

Collins,

Gell

et al. 2023

ACS Chem. Neurosci.

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Aptamers are functional oligonucleotide ligands used for the molecular recognition of various targets. The natural characteristics of aptamers make them an excellent alternative to antibodies in diagnostics, therapeutics, and biosensing. DNA aptamers are mainly single-stranded oligonucleotides (ssDNA) that possess a definite binding to targets. However, the application of aptamers to the fields of brain health and neurodegenerative diseases has been limited to date. Herein, a DNA aptamer against the brain-derived neurotrophic factor (BDNF) protein was obtained by in vitro selection. BDNF is a potential biomarker of brain health and neurodegenerative diseases and has functions in the synaptic plasticity and survival of neurons. We identified eight aptamers that have binding affinity for BDNF from a 50-nucleotide library. Among these aptamers, NV_B12 showed the highest sensitivity and selectivity for detecting BDNF. In an aptamer-linked immobilized sorbent assay (ALISA), the NV_B12 aptamer strongly bound to BDNF protein, in a dose-dependent manner. The dissociation constant (K d ) for NV_B12 was 0.5 nM (95% CI: 0.4−0.6 nM). These findings suggest that BDNF-specific aptamers could be used as an alternative to antibodies in diagnostic and detection assays for BDNF.

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“…This special issue of Molecular and Cellular Proteomics presents a wide range of primary research, reviews, and perspectives pertaining to clinical proteomics. The expanding scope of proteomics applications is reflected in the spectrum of disease foci represented, including neurodegenerative diseases ( 1 , 2 , 3 , 4 ), infectious disease ( 5 , 6 ), endocrinology ( 7 , 8 ), cardiovascular disease ( 9 ), inflammatory disease ( 10 ), kidney disease ( 11 ), and cancer ( 12 , 13 , 14 , 15 ), as well as in the burgeoning areas of health monitoring and exercise ( 16 , 17 ).…”

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confidence: 99%

“…The field of immunopeptidomics and its potential to inform biological understanding of immunological response to disease as well as to guide cancer and other vaccine development for precision medicine has expanded significantly owing to new technologies and their optimization ( 20 ). Mass spectrometry remains the workhorse of contemporary clinical proteomics, but improvements in the scale and sensitivity of array-based approaches make them an attractive alternative for select applications ( 1 , 16 ). Complex cross-sectional, longitudinal and multi-omic analyses are facilitated by accelerating computer speeds, storage capabilities, and the promulgation of computational methods focused on proteomics ( 17 , 18 ).…”

mentioning

confidence: 99%

“…While initially overhyped, there is now considerable evidence that biofluid-based proteomics using MS and other techniques has the depth, sensitivity and reproducibility required to identify promising candidate biomarkers to aid in diagnosis, prognosis, and clinically-actionable prediction ( 1 , 2 , 24 , 25 , 26 ). The needs for additional validation, assay refinement, health economics assessment, and viable reimbursement strategies remain challenges to the deployment of such biomarkers in the clinic.…”

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confidence: 99%

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Clinical Proteomics: A Promise Becoming Reality

Gillette,

Jimenez,

Carr

2024

Molecular & Cellular Proteomics

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Methods to Discover and Validate Biofluid-Based Biomarkers in Neurodegenerative Dementias

Cited by 18 publications

References 162 publications

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

High-dimensional proteomic analysis for pathophysiological classification of Traumatic Brain Injury

Isolation and Identification of the High-Affinity DNA Aptamer Target to the Brain-Derived Neurotrophic Factor (BDNF)

Clinical Proteomics: A Promise Becoming Reality

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