Diagnosis of ischemic stroke using circulating levels of brain-specific proteins measured via high-sensitivity digital ELISA

O’Connell, Grant; Alder, Megan L.; Smothers, Christine G.; Still, Carolyn H; Webel, Allison R.; Moore, Shirley M.

doi:10.1016/j.brainres.2020.146861

Cited by 17 publications

(18 citation statements)

References 34 publications

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“…We demonstrated, that blood T-tau and S100B levels were higher with AIS patients compared to that of patients with TIA. These results concur with those of previous studies, which demonstrated, that these biomarkers in CSF were elevated in patients with acute ischaemic stroke as a result of brain injury (14,37). All these blood biomarker levels associated with stroke severity were measured with NIHSS.…”

Section: Discussionsupporting

confidence: 92%

“…A significant correlation between NIHSS and T-tau levels in the blood has been shown in three earlier studies (8,14,37). Additionally, they also found a clear relationship between blood T-tau levels and infarction volume measured from CT or MRI.…”

Section: Discussionsupporting

confidence: 53%

“…The current study is the first to report the difference in T-tau levels between AIS and TIA patients and as a non-invasive method, blood T-tau measurements with SIMOA, might have the capacity to differentiate between ischemic events and stroke mimics. A recently published study demonstrated, that plasma T-Tau quantified with digital ELISA can discriminate AIS patients from normal control patients with 85.7% sensitivity/54.6% specificity (37). Patients in the current study suffered from mild strokes, which is reflected to low T-tau plasma levels at admission as well as low NIHSS values.…”

Section: Discussionmentioning

confidence: 54%

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Tau, S100B and NSE as Blood Biomarkers in Acute Cerebrovascular Events

Onatsu

Vanninen

Jäkälä

et al. 2020

In Vivo

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Background/Aim: We aimed to analyze the diagnostic value of total tau (T-tau), S-100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) as blood-based biomarkers in acute ischemic stroke (AIS) or transient ischemic attack (TIA), and their correlation with symptom severity, infarct size, etiology and outcome. Patients and Methods: A total of 102 patients with stroke and 35 with TIA were analyzed. Subacute (63.8±50.1 h) plasma T-tau was measured with the single-molecule array (Simoa) method and NSE and S100B were evaluated for comparison. We evaluated biomarkers associations with: (i) diagnosis of AIS or TIA, (ii) cerebral infarction volume in the brain computed tomography, (iii) stroke etiology, (iv) clinical stroke severity and (iv) functional outcome after three months. Results: T-tau was higher in patients with stroke [1.0 pg/ml (IQR=0.3-2.2)] than with TIA [0.5 pg/ml (IQR=0.2-1.0), p=0.02]. The levels of S100B were also increased in stroke [0.082 μg/l (IQR=0.049-0.157)] patients compared to TIA patients [0.045 μg/l (IQR=0.03-0.073), p<0.001]. However, when the results were adjusted for confounders, significance was lost. Serum levels of NSE among patients with AIS [11.85 μg/l (IQR=9.30-16.14)] compared to those with TIA [10.96 μg/l (IQR=7.98-15.33), p=0.30] were equal. T-tau and S100B concentrations significantly correlated with cerebral infarction volume (r=0.412, p<0.001) and (r=0.597, p<0.001), also after corrections (p<0.001). mRS scores at three-month follow-up correlated with T-tau (r=0.248, p=0.016) and S100B concentrations (r=0.205, p=0.045). Conclusion: For the diagnosis of TIA vs. AIS, blood T-tau and S100B concentrations discriminated only modestly. Additionally, groups were not separable after measuring of T-tau and S100B levels in the blood. T-tau and S100B concentrations correlated with the infarct size, but were not alone predictive for functional outcome at 3 months. T-tau protein is a microtubule-associated protein (MAP), expressed in the brain especially in the unmyelinated cortical axons (1). It is mostly found in neurons and to a lesser extent in astrocytes and oligodendrocytes. In nerve cells it has a critical role in the structural stabilization and formation of the neuronal cytoskeleton (2-4). Increased levels of tau protein have been detected in the cerebrospinal fluid (CSF) of patients with neurodegenerative diseases, e.g. Alzheimer's (5) and Creutzfeldt-Jakob disease (6), as well as in the CSF of those with severe head injuries (7). After neuro-axonal injury, such as acute ischemic stroke (AIS) or transient ischemic attack (TIA), tau proteins are also released to the extracellular space and can be detected both in CSF and 2577 This article is freely accessible online.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 54%

See 1 more Smart Citation

Tau, S100B and NSE as Blood Biomarkers in Acute Cerebrovascular Events

Onatsu

Vanninen

Jäkälä

et al. 2020

In Vivo

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“…While this did not hinder our ability to detect the presence of intergroup differences, it could have negatively impacted diagnostic performance. Thus, analysis of these markers in future work using more sensitive immunoassay techniques such as digital ELISA may reveal even higher levels of diagnostic performance than those which we have reported here (60,61). Furthermore, because the capacity of digital ELISA to support multiplexing is increasing (62), it possible that the future development of a multiplexed digital ELISA simultaneously targeting some or all of these proteins as a neuro panel could offer both high levels of analytical performance and convenience.…”

mentioning

confidence: 84%

Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage

O’Connell

Alder

Smothers

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The identification of precision blood biomarkers which can accurately indicate damage to brain tissue could yield molecular diagnostics with the potential to improve how we detect and treat neurological pathologies. However, a majority of candidate blood biomarkers for neurological damage that are studied today are proteins which were arbitrarily proposed several decades before the advent of high-throughput omic techniques, and it is unclear whether they represent the best possible targets relative to the remainder of the human proteome. Here, we leveraged mRNA expression data generated from nearly 12,000 human specimens to algorithmically evaluate over 17,000 protein-coding genes in terms of their potential to produce blood biomarkers for neurological damage based on their expression profiles both across the body and within the brain. The circulating levels of proteins associated with the top-ranked genes were then measured in blood sampled from a diverse cohort of patients diagnosed with a variety of acute and chronic neurological disorders, including ischemic stroke, hemorrhagic stroke, traumatic brain injury, Alzheimer’s disease, and multiple sclerosis, and evaluated for their diagnostic performance. Our analysis identifies several previously unexplored candidate blood biomarkers of neurological damage with possible clinical utility, many of which whose presence in blood is likely linked to specific cell-level pathologic processes. Furthermore, our findings also suggest that many frequently cited previously proposed blood biomarkers exhibit expression profiles which could limit their diagnostic efficacy.

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“…Meanwhile, for more acute neuronal injury, neurofilament may also have utility in stroke and traumatic brain injury prognostication. Following a stroke, blood NfL takes several hours to rise, limiting their utility in the hyperacute setting, however, the presence of elevated NfL may have utility in diagnosing subacute strokes as well as in the prognostication of outcomes [ 45 , 46 ]. Similarly, following traumatic brain injury, the extent of NfL increase acutely is predictive of the severity of injury, and while NfL decreases over time, it remains elevated relative to controls several years after the injury.…”

Section: Blood Nfl In Neurological Diseasesmentioning

confidence: 99%

Blood Neurofilament Light Chain: The Neurologist’s Troponin?

2020

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Blood neurofilament light chain (NfL) is a marker of neuro-axonal injury showing promising associations with outcomes of interest in several neurological conditions. Although initially discovered and investigated in the cerebrospinal fluid (CSF), the recent development of ultrasensitive digital immunoassay technologies has enabled reliable detection in serum/plasma, obviating the need for invasive lumbar punctures for longitudinal assessment. The most evidence for utility relates to multiple sclerosis (MS) where it serves as an objective measure of both the inflammatory and degenerative pathologies that characterise this disease. In this review, we summarise the physiology and pathophysiology of neurofilaments before focusing on the technological advancements that have enabled reliable quantification of NfL in blood. As the test case for clinical translation, we then highlight important recent developments linking blood NfL levels to outcomes in MS and the next steps to be overcome before this test is adopted on a routine clinical basis.

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Diagnosis of ischemic stroke using circulating levels of brain-specific proteins measured via high-sensitivity digital ELISA

Cited by 17 publications

References 34 publications

Tau, S100B and NSE as Blood Biomarkers in Acute Cerebrovascular Events

Tau, S100B and NSE as Blood Biomarkers in Acute Cerebrovascular Events

Large-scale informatic analysis to algorithmically identify blood biomarkers of neurological damage

Blood Neurofilament Light Chain: The Neurologist’s Troponin?

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