Dataset Information

Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke.

ABSTRACT:

Background

While neurogranin has no value as plasma biomarker for Alzheimer's disease, it may be a potential blood biomarker for traumatic brain injury. This evokes the question whether there are changes in neurogranin levels in blood in other conditions of brain injury, such as acute ischemic stroke (AIS).

Methods

We therefore explored neurogranin in paired cerebrospinal fluid (CSF)/plasma samples of AIS patients (n = 50) from a well-described prospective study. In parallel, we investigated another neuronal protein, i.e. tau, which has already been suggested as potential AIS biomarker in CSF and blood. ELISA as well as Single Molecule Array (Simoa) technology were used for the biochemical analyses. Statistical analyses included Shapiro-Wilk testing, Mann-Whitney analyses and Pearson's correlation analysis.

Results

In contrast to tau, of which high levels in both CSF and plasma were related to stroke characteristics like severity and long-term outcome, plasma neurogranin levels were only correlated with infarct volume. Likewise, CSF neurogranin levels were significantly higher in patients with an infarct volume > 5 mL than in patients with smaller infarct volumes. Finally, neurogranin and tau were significantly correlated in CSF, whereas a weaker relationship was observed in plasma.

Conclusions

These findings indicate that although plasma and CSF neurogranin may reflect the volume of acute cerebral ischemia, this synaptic protein is less likely to be a potential AIS biomarker. Levels of tau correlated with severity and outcome of stroke in both plasma and CSF, in the present study as well as previous reports, confirming the potential of tau as an AIS biomarker.

SUBMITTER: De Vos A

PROVIDER: S-EPMC5577791 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke.

De Vos Ann A Bjerke Maria M Brouns Raf R De Roeck Naomi N Jacobs Dirk D Van den Abbeele Lien L Guldolf Kaat K Zetterberg Henrik H Blennow Kaj K Engelborghs Sebastiaan S Vanmechelen Eugeen E

BMC neurology 20170830 1

<h4>Background</h4>While neurogranin has no value as plasma biomarker for Alzheimer's disease, it may be a potential blood biomarker for traumatic brain injury. This evokes the question whether there are changes in neurogranin levels in blood in other conditions of brain injury, such as acute ischemic stroke (AIS).<h4>Methods</h4>We therefore explored neurogranin in paired cerebrospinal fluid (CSF)/plasma samples of AIS patients (n = 50) from a well-described prospective study. In parallel, we i ...[more]

PMID: 28854881

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Project description:BackgroundIschemic stroke (IS) is more common every year, the condition is serious, and have a poor prognosis. New, efficient, and safe therapeutic targets are desperately needed as early treatment especially prevention and reperfusion is the key to lowering the occurrence of poorer prognosis. Generally circulating proteins are attractive therapeutic targets, this study aims to identify potential pharmacological targets among plasma and cerebrospinal fluid (CSF) proteins for the prevention and treatment of IS using a multicenter Mendelian randomization (MR) approach.MethodsFirst, the genetic instruments of 734 plasma and 151 CSF proteins were assessed for causative connections with IS from MEGASTROKE consortium by MR to identify prospective therapeutic targets. Then, for additional validation, plasma proteins from the deCODE consortium and the Fenland consortium, as well as IS GWAS data from the FinnGen cohort, the ISGC consortium and UK biobank, were employed. A thorough evaluation of the aforementioned possible pharmacological targets was carried out using meta-analysis. The robustness of MR results was then confirmed through sensitivity analysis using several techniques, such as bidirectional MR analysis, Steiger filtering, and Bayesian colocalization. Finally, methods like Protein-Protein Interaction (PPI) Networking were utilized to investigate the relationship between putative drug targets and therapeutic agents.ResultsThe authors discovered three proteins that may function as promising therapeutic targets for IS and meet the Bonferroni correction ( P <0.05/885=5.65×10 -5 ). Prekallikrein (OR=0.41, 95% CI: 0.27-0.63, P =3.61×10 -5 ), a protein found in CSF, has a 10-fold protective impact in IS, while the plasma proteins SWAP70 (OR=0.85, 95% CI: 0.80-0.91, P =1.64×10 -6 ) and MMP-12 (OR=0.92, 95% CI: 0.89-0.95, P =4.49×10 -6 ) of each SD play a protective role in IS. Prekallikrein, MMP-12, SWAP70 was replicated in the FinnGen cohort and ISGC database. MMP-12 (OR=0.93, 95% CI: 0.91-0.94, P <0.001), SWAP70 (OR=0.92, 95% CI: 0.90-0.94, P <0.001), and prekallikrein (OR=0.53, 95% CI: 0.33-0.72, P <0.001) may all be viable targets for IS, according to the combined meta-analysis results. Additionally, no evidence of reverse causality was identified, and Bayesian colocalization revealed MMP-12 (PPH 4 =0.995), SWAP70 (PPH 4 =0.987), and prekallikrein (PPH 4 =0.894) shared the same variant with IS, supporting the robustness of the aforementioned causation. Prekallikrein and MMP-12 were associated with the target protein of the current treatment of IS. Among them, Lanadelumab, a new drug whose target protein is a prekallikrein, may be a promising new drug for the treatment of IS.ConclusionThe prekallikrein, MMP-12, and SWAP70 are causally associated with the risk of IS. Moreover, MMP-12 and prekallikrein may be treated as promising therapeutic targets for medical intervention of IS.

Project description:Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.

Dataset Information

Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke.

Background

Methods

Results

Conclusions

Publications

Neurogranin and tau in cerebrospinal fluid and plasma of patients with acute ischemic stroke.

Similar Datasets

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