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Conventional ways of monitoring reperfusion in acute ischemic stroke have several limitations. In searching for an alternative, we evaluated biochemical serum markers of stroke change in relation to reperfusion. N-acetylaspartate (NAA) is a small amino acid synthesized by neuronal mitochondria, which can be released in the extracellular space after...
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... TCD could not be performed in these 2 patients because 1 patient died of intracranial hemorrhage, and 1 developed agitated delirium. Four patients demonstrated early recovery at 24 hours, 3 in group 3 and 1 in group 2. Figure 1 shows the mean NIHSS scores for all groups. Baseline NIHSS scores were not different between the groups (p=0,45). ...
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Two placebo-controlled trials have shown that early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischemic stroke improves outcomes up to 4.5 h after symptoms onset; however, six other trials contradict these results. We also know from analysis of the pooled data that benefits from treatment decrease as time f...
Background
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Background and purpose:
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Background and purpose:
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Citations
... Received 8 April 2020; Received in revised form 8 May 2020; Accepted 9 May 2020 concentration in T2D patients are scanty. NAA can be assayed in biological fluids by immunoassay [22], gas-chromatography and gaschromatography mass spectrometry [23,24,25,26], as well as by liquidchromatography mass spectrometry [19,27,28,29,30,31]. Interestingly, Sangaraju et al. [31] set up a valuable HPLC method to separate NAA from plasma components, based on the HILIC chromatographic technique, which allows the separation of small polar compounds in complex matrices [32]. ...
N-acetylaspartate is a human endogenous compound synthesized by neurons, which is involved in neuronal metabolism. It is used as a marker in brain magnetic resonance spectroscopy to investigate several neurological and metabolic disorders, that can be related to a variation of its concentration with respect to reference values. N-acetylaspartate is present also in biological fluids, such as plasma, urine, and cerebrospinal fluid, where it can be quantified. Here we describe the development and validation, in compliance with the EMA guidelines, of a novel assay method for the quantification of N-acetylaspartate in plasma based on tandem mass spectrometry coupled to liquid chromatography. Its peculiarity lies in the fact that sample preparation includes an esterification step, which significantly improves the chromatographic performances and, consequently, also the method sensitivity, reproducibility and accuracy. Instrumental LLOQ is 0.06 ng/mL, i.e. at least 300 times lower than the medium N-acetylaspartate concentration in samples, accuracy is in the range 98 - 103%, while precision lies between 1 and 3%. The method robustness was tested in about 1000 injections of plasma samples, 96 of which were used also to assess the reference ranges in control subjects (16.46-63.40 ng/mL). Controls were then compared to plasma samples from type 2 diabetic patients. Contrary to brain magnetic resonance spectroscopy, which demonstrated a decrease in the N-acetylaspartate levels in right frontal and parieto-temporal region of type 2 diabetic patients, plasma analysis showed no statistical difference with respect to controls. However, the method here described can be profitably used in studies concerning different disorders with CNS involvement, as confirmed by reports available in the literature.
... Biomarkers to monitor reperfusion in IS are scarce and nervous system-specific metabolite N-acetylaspartate (NAA) is, to our knowledge, the only reported blood-based biomarker of early reperfusion after brain ischemia. 33 Our findings may be translationally relevant in clinical scenarios where patients present with clinical syndromes, suggesting largevessel occlusion but unknown patency of the occluded artery. Alternatively, the identified cluster may have the potential to assess microcirculatory perfusion after successful vessel recanalization. ...
Background and purpose:
Circulating microRNAs (miRNAs) are emerging biomarkers for stroke because of their high stability in the bloodstream and association with pathophysiologic conditions. However, the circulating whole-genome miRNAs (miRNome) has not been characterized comprehensively in the acute phase of stroke.
Methods:
We profiled the circulating miRNome in mouse models of acute ischemic and hemorrhagic stroke by next-generation sequencing. Stroke models were compared with sham-operated and naive mice to identify deregulated circulating miRNAs. Top-ranked miRNAs were validated and further characterized by quantitative reverse transcription polymerase chain reaction.
Results:
We discovered 24 circulating miRNAs with an altered abundance in the circulation 3 hours after ischemia, whereas the circulating miRNome was not altered after intracerebral hemorrhage compared with sham-operated mice. Among the upregulated miRNAs in ischemia, the top-listed miR-1264/1298/448 cluster was strongly dependent on reperfusion in different ischemia models. A time course experiment revealed that the miR-1264/1298/448 cluster peaked in the circulation around 3 hours after reperfusion and gradually decreased thereafter.
Conclusions:
Alteration of the miRNome in the circulation is associated with cerebral ischemia/reperfusion, but not hemorrhage, suggesting a potential to serve as biomarkers for reperfusion in the acute phase. The pathophysiological role of reperfusion-inducible miR-1264/1298/448 cluster, which is located on chromosome X within the introns of the serotonin receptor HTR2C, requires further investigation.
... Indeed, altered expression of the primary inhibitor of tissue-type plasminogen activators, plasminogen activator inhibitor-1, promotes apoptotic sequence involving cytochrome c release from the mitochondria (Soeda et al., 2008). Moreover, the small amino acid N-acetylaspartate, synthesized by neuronal mitochondria, is released into serum following reperfusion in animal models of brain ischemia and in serum of patients following acute ischemic stroke (Elting et al., 2004). Additionally, DJ-1 promotes angiogenesis and osteogenesis by way of activating fibroblast growth factor receptor-1 signaling (Kim et al., 2012). ...
Oxidative stress is closely associated with secondary cell death in many disorders of the central nervous system including stroke, Parkinson's disease, Alzheimer's disease. Among many aberrant oxidative stress-associated proteins, DJ-1 has been associated with the oxidative stress cell death cascade primarily in Parkinson's disease. Although principally expressed in the cytoplasm and nucleus, DJ-1 can be secreted into the serum under pathological condition. Recently, a close pathological association between DJ-1 and oxidative stress in stroke has been implicated. To this end, we and others have demonstrated the important role of mitochondria in neuroprotection for stroke by demonstrating that the translocation of DJ-1 in the mitochondria could potentially mitigate mitochondrial injury. Here, we discuss our recent findings testing the hypothesis that DJ-1 not only functions as a form of intracellular protection from oxidative stress, but that it also utilizes paracrine and/or autocrine cues in order to accomplish extracellular signaling between neighboring neuronal cells, resulting in neuroprotection. This article highlights recent evidence supporting the status of DJ-1 as key anti-oxidative stress therapeutic target for stroke.
... Interestingly, altered expression of plasminogen activator inhibitor-1, which is the primary inhibitor of tissue-type plasminogen activators, has been shown to promote the apoptotic sequence involving cytochrome c release from mitochondria (Soeda et al., 2008). In addition, N-acetylaspartate is a small amino acid synthesized by neuronal mitochondria, which can be released in the extracellular space after reperfusion in animal models of brain ischemia and in serum of patients with acute ischemic stroke (Elting et al., 2004). Both these studies offer evidence on the critical role of mitochondria as a therapeutic target and biomarker for stroke. ...
... Magnetic resonance spectroscopy shows that NAA levels in ischemic injury continues to fall gradually for more than 1 week postinfarction, although any NAA detected beyond 24 h may simply be trapped in cellular debris [54,56,57]. Early reperfusion has been shown to cause a quick, transient increase in serum NAA concentration [58]. This may be due to resumed synthesis from restored metabolic function during a time of persistent BBB dysfunction, or simply from efficient clearance of NAA from the interstitium by restored regional blood flow. ...
Serum biomarkers related to the cascade of inflammatory, hemostatic, glial and neuronal perturbations have been identifed to diagnose and characterize intracerebral hemorrhage and cerebral ischemia. Interpretation of most markers is confounded by their latent rise, blood-brain barrier effects, the heterogeneity of etiologies and the wide range of normal values, limiting their application for early diagnosis, lesion size estimation and long-term outcome prediction. Certain hemostatic and inflammatory constituents have been found to predict response to thrombolysis and worsening due to infarct progression and secondary hemorrhage, offering a potential role for improved treatment selection and individualization of therapy. Biomarkers will become increasingly relevant for developing targets for neuroprotective therapies, monitoring response to treatment and as surrogate end points for treatment trials.
This article is aimed to current state of diagnostic and treatment of Canavan disease. Canavan disease is an inherited metabolic disease caused by the absence of enzyme aspartoacylase. Disruption of N-acetylaspartic acid metabolism results in its accumulation in the brain and subsequently in body fluids. It is characterized by spongy degeneration of the white matter in the brain resulting in severe psychomotor handicaps. An early diagnostic of Canavan disease is desirable to start a treatment before irreversible damage to slowing the progress and improving the quality of patient´s life. The present therapy consists of supportive basis and is focused on a symptomatic alleviation via drug treatment or dietary supplementation, and a gene therapy also seems to be a promising treatment for the future. Diagnostic methods are based on characteristic pathological changes of white matter examination, enzymatic assay for ASPA activity, molecular diagnostic approaches on gene level, and methods based on the determination of N-acetylaspartic acid as a marker of Canavan disease in various biological samples. Gas chromatography, liquid chromatography, and capillary electrophoresis are the most used analytical methods for the NAA determination mainly in urine and CSF. Hyphenated chromatographic and tandem mass spectrometric methods utilized recently provide more sensitive approach, advantageous for matrices with lower NAA levels.
