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Introduction: Previous studies have reported that YKL-40 can serve as a biomarker of infectious diseases and different stroke types. However, evidence supporting its role in diagnosing post-neurosurgical bacterial meningitis (PNBM) remains lacking., Methods: A total of 110 patients with stroke who underwent neurosurgical treatment were recruited. Among these, 36 were diagnosed with PNBM based on the results of bacterial culture/Gram staining or cerebrospinal fluid (CSF) characteristics. CSF levels of YKL-40 and other biomarkers with potential diagnostic utility for PNBM were statistically analysed using univariate and logistic regression models. Receiver operating characteristic (ROC) analysis was performed to investigate diagnostic efficiency., Results: According to univariate analysis, CSF levels of glucose, total protein, white blood cells, polymorphocytes, and YKL-40, as well as the CSF-to-blood glucose ratio, were significantly different between the PNBM and non-PNBM groups. Logistic regression analysis revealed that glucose (p = 0.026), total protein (p = 0.028), and YKL-40 (p = 0.006) levels in the CSF may have independent diagnostic utility for PNBM. Among the three biomarkers, CSF-to-blood glucose (area under the receiver operating characteristic curve [AUC] 0.9208) and YKL-40 (AUC 0.9587) demonstrated strong diagnostic utility., Conclusion: CSF levels of YKL-40, glucose, and total protein played independent roles in the diagnosis of PNBM in patients with stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Shedding light on less-known aspects of intracranial fluid dynamics may be helpful to understand the hydrocephalus mechanism. The present study suggests a mathematical framework based on in vivo inputs to compare the dynamic interaction of pulsatile blood, brain, and cerebrospinal fluid (CSF) between the healthy subject and the hydrocephalus patient., Method: The input data for the mathematical formulations was pulsatile blood velocity, which was measured using cine PC-MRI. Tube law was used to transfer the created deformation by blood pulsation in the vessel circumference to the brain domain. The pulsatile deformation of brain tissue with respect to time was calculated and considered to be inlet velocity in the CSF domain. The governing equations in all three domains were continuity, Navier-Stokes, and concentration. We used Darcy law with defined permeability and diffusivity values to define the material properties in the brain., Results: We validated the preciseness of the CSF velocity and pressure through the mathematical formulations with cine PC-MRI velocity, experimental ICP, and FSI simulated velocity and pressure. We used the analysis of dimensionless numbers including Reynolds, Womersley, Hartmann, and Peclet to evaluate the characteristics of the intracranial fluid flow. In the mid-systole phase of a cardiac cycle, CSF velocity had the maximum value and CSF pressure had the minimum value. The maximum and amplitude of CSF pressure, as well as CSF stroke volume, were calculated and compared between the healthy subject and the hydrocephalus patient., Conclusion: The present in vivo-based mathematical framework has the potential to gain insight into the less-known points in the physiological function of intracranial fluid dynamics and the hydrocephalus mechanism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Raised signal in cerebrospinal fluid (CSF) on fluid-attenuated inversion recovery (FLAIR) may indicate raised CSF protein or debris and is seen in inferior frontal sulci on routine MRI. To explore its clinical relevance, we assessed the association of inferior frontal sulcal hyperintensities (IFSH) on FLAIR with demographics, risk factors, and small vessel disease markers in three cohorts (healthy volunteers, n=44; mild stroke patients, n=105; older community-dwelling participants from Lothian birth cohort 1936, n=101). We collected detailed clinical data, scanned all subjects on the same 3T MRI scanner and 3-dimensional FLAIR sequence and developed a scale to rate IFSH. In adjusted analyses, the IFSH score increased with age (per 10-year increase; OR 1.69; 95% CI, 1.42-2.02), and perivascular spaces score in centrum semiovale in stroke patients (OR 1.73; 95% CI, 1.13-2.69). Since glymphatic CSF clearance declines with age and drains partially via the cribriform plate to the nasal lymphatics, IFSH on 3T MRI may be a non-invasive biomarker of altered CSF clearance and justifies further research in larger, more diverse samples., Competing Interests: Disclosure statement None., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke., Methods: We collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants., Results: After classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity., Conclusion: Serum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed., Competing Interests: NC, CM, GW and RS are listed as inventors on an International Patent Application entitled “Cerebrospinal fluid and blood-based biomarkers for the diagnosis of tuberculosis meningitis” (PCT/IB2019/054259), filing date: 23 May 2019. NC and GW are listed as inventors on another patent application entitled “Method for diagnosing tuberculous meningitis” (PCT/IB2015/052751), filing date: 15 April 2015. These applications do not generate any royalties for the inventors. These does not alter our adherence to PLOS ONE policies on sharing data and materials.

Human adipose-derived mesenchymal stem cells (hAMSCs) are capable of immunomodulation and regeneration after neural injury. For these reasons, hAMSCs have been investigated as a promising stem cell candidate for stroke treatment. However, noninvasive experiments studying the effects of grafted stem cells in the host brain have not yet been reported. Cerebrospinal fluid (CSF), which can be collected without sacrificing the subject, is involved in physiological control of the brain and reflects the pathophysiology of various neurological disorders of the central nervous system (CNS). Following stem cell transplantation in a stroke model, quantitative analysis of CSF proteome changes can potentially reveal the therapeutic effect of stem cells on the host CNS. We examined hAMSC-secreted proteins obtained from serum-free culture medium by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which identified several extracellular matrix proteins, supporting the well-known active paracrine function of hAMSCs. Subsequently, we performed label-free quantitative proteomic analysis on CSF samples from rat stroke models intravenously injected with hAMSC (experimental) or phosphate buffered saline (control). In total, 524 proteins were identified; among them, 125 and 91 proteins were increased and decreased with hAMSC treatment, respectively. Furthermore, gene set enrichment analysis revealed three proteins, 14-3-3 theta, MAG, and neurocan, that showed significant increases in the hAMSC-treated model; these proteins are core members of neurotrophin signaling, nerve growth factor (NGF) signaling, and glycosaminoglycan metabolism, respectively. Subsequent histological and neurologic function experiments validated proliferative neurogenesis in the hAMSC-treated stroke model. We conclude that (i) intravenous injection of hAMSCs can induce neurologic recovery in a rat stroke model and (ii) CSF may reflect the therapeutic effect of hAMSCs. Additionally, proteins as 14-3-3 theta, MAG, and neurocan could be considered as potential CSF biomarkers of neuroregeneration. These CSF proteome profiling results would be utilized as valuable resource in further stroke studies.

Background: Emergence of the novel corona virus (severe acute respiratory syndrome (SARS)-CoV-2) in December 2019 has led to the COVID-19 pandemic. The extent of COVID-19 involvement in the central nervous system is not well established, and the presence or the absence of SARS-CoV-2 particles in the cerebrospinal fluid (CSF) is a topic of debate., Case Description: We present two patients with COVID-19 and concurrent neurological symptoms. Our first patient is a 31-year-old man who had flu-like symptoms due to COVID-19 and later developed an acute-onset severe headache and loss of consciousness and was diagnosed with a Hunt and Hess grade 3 subarachnoid haemorrhage from a ruptured aneurysm. Our second patient is a 62-year-old woman who had an ischaemic stroke with massive haemorrhagic conversion requiring a decompressive hemicraniectomy. Both patients' CSF was repeatedly negative on real-time PCR analysis despite concurrent neurological disease., Conclusion: Our report shows that patients' CSF may be devoid of viral particles even when they test positive for COVID-19 on a nasal swab. Whether SARS-CoV-2 is present in CSF may depend on the systemic disease severity and the degree of the virus' nervous tissue tropism and should be examined in future studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Previously, brain volume (BV) and intracranial cerebrospinal fluid volume (CSFV) have been investigated regarding clinical outcomes of subgroups of ischemic stroke patients. This study aimed to examine if the preexisting, preischemic BV and CSFV have an impact on good functional outcome and mortality in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT)., Methods: Preischemic BV, CSFV, and CSFV/Total intracranial volume (TICV)-ratio were calculated with a fully automated segmentation platform. Univariate and multivariate analyses were used to study associations., Results: In this retrospective study 107 subsequent AIS patients of a prospective database were included. The segmentation results of the fully automated algorithm based on non-contrast computerized tomography scans (NCCT) correlated significantly with the segmentation results obtained from 3D T1 weighted magnetic resonance images (P < 0.001). In the univariate analysis a preexisting BV (P < 0.001), preexisting CSFV (P = 0.009), and the ratio CSFV/total intracranial volume (P < 0.001) each significantly correlated with good functional outcome and mortality. However, in the multivariate regression analysis, also correcting for patient age, none of these volumes remained to correlate with these outcome parameters., Conclusion: In summary, an association of BV, CSFV, and the CSFV/TICV-ratio with good functional outcome and mortality in AIS treated with MT could not be established. A fully automated segmentation algorithm based on NCCT was successfully developed in-house for calculating the volumes of interest., Competing Interests: Declaration of Competing Interest BF: Consultant for Stryker, speaker honoraria for Medtronic, Research grant from iSchemaView; CM: Consultant for Stryker and Penumbra. SM, DS, DH, TBB, MB, SW, CZ, and BW declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Central nervous system (CNS) ischemic events caused by fungal infections are rare, and clinical characteristics of these ischemic events are largely unknown. The objective of this manuscript is to highlight characteristics of fungal-related strokes and describe possible mechanistic differences between CNS mold and yeast infection-related strokes., Methods: We report a single-center retrospective case series of all adult patients who presented with concurrent CNS fungal infection and stroke between 2010 and 2018. Patients believed to have a stroke etiology due to cardioembolic, atheroembolic, or strokes nontemporally associated with a CNS fungal infection and those with incomplete stroke workups were excluded from analysis., Results: Fourteen patients were identified with ischemic stroke and concurrent CNS fungal infection without other known ischemic stroke etiology. Eight patients had a CNS yeast infection, and 6 had a CNS mold infection. All patients presented with recurrent or progressive stroke symptoms. Six patients were immune-compromised. Four patients admitted to intravenous drug use. All yeast infections were identified by cerebrospinal fluid culture or immunologic studies while all but one of the mold infections required identification by tissue biopsy. Leptomeningeal enhancement was only associated with CNS yeast infections, while basal ganglia stroke was only associated with CNS mold infections., Conclusion: Ischemic stroke secondary to CNS fungal infections should be considered in patients with recurrent or progressive cryptogenic stroke, regardless of immune status and cerebrospinal fluid profile. CNS yeast and mold infections have slightly different stroke and laboratory characteristics and should have a distinct diagnostic method. Depending on clinical suspicion, a thorough diagnostic approach including spinal fluid analysis and biopsy should be considered., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here, we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of poststroke edema needs to be revised, and these findings could provide a conceptual basis for development of alternative treatment strategies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Aims: Syphilis and stroke are high prevalent diseases in south Brazil and estimates of concomitance and possible role of syphilis in acute stroke are lacking. Our aims are to estimate the prevalence of syphilis and neurosyphilis (NS) in a cohort of tertiary stroke center., Methods: We reviewed all hospital records of stroke/transitory ischemic attack (TIA) using International Classification of Diseases, 10th revision, at discharge, frequency of syphilis screen, serology positivity, cerebrospinal fluid (CSF) analysis, and prevalence of NS in this stroke population applying CDC criteria., Results: Between 2015 and 2016, there were 1,436 discharges for cerebrovascular events and in 78% (1,119) of these cases, some syphilis screening was performed. We have found a frequency of positive serology for syphilis of 13% (143/1,119), and higher stroke severity was the main determinant for non-screening. Applying standard NS criteria, 4.7% (53/1,119) cases with CSF analysis had NS diagnosis: 8 based on CSF-Venereal Disease Research Laboratory (VDRL) positive and 45 based on abnormal CSF white cells or protein, but CSF VDRL negative. NS VDRL positive cases were younger, had higher serum VDRL title, had more frequent HIV infection, and received NS treatment more often. Demographic and clinical characteristics were not different between NS VDRL negative and non-NS cases., Conclusion: Positive syphilis serology is frequent in patients with acute stroke/TIA in our region. Acute post-stroke CSF abnormalities make the diagnosis of NS difficult in the context of CSF VDRL negative., (© 2020 S. Karger AG, Basel.)

Background and Purpose: Post-ischaemic immune cell invasion into the brain is well characterized in animal stroke models and contributes to neuronal damage. Therefore, it represents a promising therapeutic target. Cerebrospinal fluid (CSF) is easily accessible and may reflect cellular events within the parenchyma. However, comprehensive studies on CSF immune cells in patients with stroke are lacking., Methods: In a retrospective cohort study, we performed extensive immune-cell profiling in CSF and peripheral blood of patients with acute ischaemic stroke and healthy controls. In patients with stroke, infarct size was quantified on follow-up imaging., Results: Overall, 90 patients with ischaemic stroke and 22 controls were included in our study. After stroke, the total protein was increased (537.3 vs. 353.2 mg/L, P = 0.008) and the mean total white cell count was slightly but non-significantly elevated (1.76 vs. 0.50 cells/μL, P = 0.059). Proportions of CSF lymphocytes, monocytes and granulocytes and their respective subsets did not differ between patients with stroke and controls. In addition, there were no associations between proportions of major leukocyte subsets in CSF and the time from symptom onset to CSF sampling, infarct size or infarct localization., Conclusions: Ischaemic stroke induces only a very slight increase of CSF immune cells without changes in the composition of immune cell subsets, thus indicating that parenchymal inflammation is not sufficiently reflected in the CSF. Our findings suggest that CSF is not a major invasion route for immune cells and that CSF cell analyses are not suitable as biomarkers to guide future immune therapies for stroke., (© 2019 EAN.)

Background: Neurofilament light (NFL) is a well-validated biomarker for neuronal injury and neurodegeneration. Increased cerebrospinal fluid (CSF) levels have been shown after stroke, as well as in patients with a broad range of neurodegenerative and neuroinflammatory diseases. Neurofilament heavy (NFH) belongs to the same family of structural proteins but it is less extensively studied. The potential of phosphorylated NFH (pNFH) as a stroke biomarker and for the prediction of clinical outcome is unknown. In this study, we aimed to examine the temporal pattern of NFL and pNFH concentrations in serum and CSF after acute ischemic stroke., Materials and Methods: A quantitative Enzyme-Linked ImmunoSorbent Assay (ELISA) for pNFH was developed and tested on CSF and serum samples. NFL and pNFH were analysed in serum and CSF of acute ischemic stroke patients, who were followed over time (Day 0-1, Day 2-3, Day 7-9, three weeks, and 3-5 months after stroke)., Results: NFL and pNFH concentrations in serum and CSF increased after stroke, peaked during the 3rd week, and then decreased back to almost baseline levels at 3-5 months. CSF-NFL and serum-NFL correlated to the outcome measured by Barthel Index after 3-5 months, whilst no such association was seen for pNFH., Discussion: These findings suggest that NFL and pNFH in both CSF and serum reflect the temporal pattern of the post ischemic axonal injury and that this process does not seem to progress after 3-5 months., Conclusion: NFL and pNFH in CSF and serum are promising biomarkers for axonal injury following stroke. Further studies in larger populations are needed to fully understand the progression of the neuronal damage after acute ischemic stroke and to evaluate if these biomarkers can provide additive information and how they relate to outcome., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ischemic stroke is one of the most common causes of death worldwide and is a major cause of acquired disability in adults. However, there is still a need for an effective drug for its treatment. Buyang Huanwu decoction (BHD), a traditional Chinese medicine (TCM) prescription, has long been used clinically to aid neurological recovery after stroke. To establish potential clinical indicators of BHD efficacy in stroke treatment and prognosis, we conducted a combined proteomic and metabolomic analysis of cerebrospinal fluid (CSF) samples in a mouse stroke model. CSF samples were obtained from male mice with acute ischemic stroke induced by middle cerebral ischemic/reperfusion (CI/R) injury, some of which were then treated with BHD. Label-free quantitative proteomics was conducted using nano-LC-MS/MS on an LTQ Orbitrap mass and metabolomic analysis was performed using nanoprobe NMR and UHPLC-QTOF-MS. The results showed that several proteins and metabolites were present at significantly different concentrations in the CSF samples from mice with CI/R alone and those treated with BHD. These belonged to pathways related to energy demand, inflammatory signaling, cytoskeletal regulation, Wnt signaling, and neuroprotection against neurodegenerative diseases. In conclusion, our in silico data suggest that BHD treatment is not only protective but can also ameliorate defects in pathways affected by neurological disorders. These data shed light on the mechanism whereby BHD may be effective in the treatment and prevention of stroke-related neurodegenerative disease., Competing Interests: The authors have declared that no competing interests exist.

The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke.

Aim: Biomarkers are molecules measured in plasma, serum or other body fluids to characterize a disease. PARK7 and NDKA roles in the management of stroke are still on study. Therefore, their potentials need to be developed in totality. The aim of this review is to demonstrate that PARK7 and NDKA could present more clinical important information as biomarkers for management of stroke disease. Main contents: Four main aspects of PARK7 and NDKA are exploited in this review. First, their diagnostic value is discussed in order to demonstrate their possible role as stroke diagnosis markers. Second, this article will exploit the correlation of both markers with time, by showing their dynamic changes in serum and plasma. Third, it describes the observed relationship of their levels with NIH Stroke Scale. The last aspect visits the possibility of their implementation in stroke therapy., Conclusion: This article explores recent findings and proposes the potential roles that PARK7 and NDKA play in the management of acute stroke disease.

The objectives of this study were to investigate the relationship between cerebrospinal fluid lactate and serum concentrations in dogs with clinical signs of central nervous system disease and to establish if cerebrospinal fluid lactate (CSF) concentrations are higher in dogs with structural intracranial disease (Group Pos-MRI) compared to dogs that have clinical signs of intracranial disease but no structural brain disease (Group Neg-MRI) based on magnetic resonance imaging (MRI) findings. Using a prospective study canine blood and cerebrospinal fluid were collected in 24 dogs with neurological signs after undergoing brain MRI. Dogs were divided in 2 groups. No significant difference between serum lactate (1.57 ± 0.9 mmol/L) and CSF lactate concentration (1.34 ± 0.3 mmol/L) was detected. There was a direct correlation between CSF and serum lactate concentration ( R = 0.731; P = 0.01). No significant difference was found in CSF lactate concentration between the 2 groups of dogs ( P = 0.13).

Essentials Little is known of procarboxypeptidase U (proCPU) in cerebrospinal fluid (CSF) of stroke patients. ProCPU levels were studied in CSF of controls and non-thrombolyzed acute ischemic stroke patients. ProCPU is elevated in CSF of stroke patients compared with controls. ProCPU in CSF correlates with stroke progression, outcome, and blood-brain barrier dysfunction., Summary: Background Procarboxypeptidase U (proCPU, TAFI, proCPB2), the zymogen of CPU, which is a potent antifibrinolytic enzyme and a modulator of inflammation, has previously been investigated in plasma of stroke patients, but so far, no information on the proCPU levels in cerebrospinal fluid (CSF) during acute ischemic stroke (AIS) is available. Objectives This case-control observational study investigates proCPU in CSF of AIS patients compared with controls with an intact blood-brain barrier (BBB) and evaluates the relationship of CSF/plasma proCPU ratios with stroke parameters. Methods A sensitive HPLC-based enzymatic assay was used to determine proCPU levels in CSF of non-thrombolyzed patients in the hyperacute phase (< 24 h after onset) of AIS (n = 72). Individuals (n = 32) without stroke, an intact BBB and no apparent abnormalities in biochemical and microbiological tests, served as controls. Relations between the CSF/plasma proCPU ratio and (i) stroke severity, (ii) stroke progression/recurrence, (iii) stroke outcome and (iv) BBB dysfunction (CSF/serum albumin ratio) were assessed. Results Mean (SEM) proCPU levels were elevated in the CSF of stroke patients compared with controls (4.36 (0.23) U L -1 vs. 3.50 (0.23) U L -1 ). Higher median [IQR] CSF/plasma proCPU ratios were found in patients with stroke progression ((6.0 [4.2-6.9]) × 10 -3 ) and poor outcome ((6.4 [3.9-7.0]) × 10 -3 ) after 3 months (modified Rankin Scale; mRS > 3) compared with patients without progression ((3.9 [2.7-5.4]) × 10 -3 ) or better outcome ((4.0 [2.8-5.0]) × 10 -3 ). In stroke patients with a disrupted BBB, proCPU ratios were higher compared with stroke patients with an intact BBB ((6.4 [5.8-9.0]) × 10 -3 vs. (3.7 [2.8-5.0]) × 10 -3 ). Conclusions ProCPU is increased in CSF during hyperacute ischemic stroke and is associated with stroke progression and outcome after 3 months, most likely due to BBB dysfunction in the hyperacute phase of ischemic stroke., (© 2017 International Society on Thrombosis and Haemostasis.)

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.

A 73-year-old woman presented with sudden onset of right hemiparesis and was diagnosed as having cerebral infarction on the basis of diffusion-weighted brain MRI, which demonstrated lesions in the left parietal cortex. On the 3rd day, the patient developed right upper limb myoclonus, aphasia, and disturbance of consciousness with high fever. On the 6th day, she was transferred to our hospital with suspected viral encephalitis, and treatment with acyclovir was started. By the 6th day, the lesions detected by MRI had expanded to the gyrus cinguli, insula and thalamus, but not to the temporal lobe. At that time, the CSF cell count was 8/μl, and this later increased to 17/μl by the 13th day. Although herpes simplex virus DNA was detected in the CSF on the 6th day, there was no evidence of CSF pleocytosis or temporal lobe abnormalities demonstrable by brain MRI throughout the whole follow-up period. This was very atypical case of herpes simplex encephalitis characterized by a stroke-like episode, atypical MRI findings, and absence of cerebrospinal fluid pleocytosis. It is important to be mindful that herpes simplex encephalitis (HSE) can have an atypical presentation, and that sufficient acyclovir treatment should be initiated until HSE can be ruled out.

The aim of this study was to evaluate the prognostic value of serum and cerebrospinal fluid (CSF) free fatty acid (FFA) levels in a cohort of patients with an acute ischemic stroke (AIS). In a prospective study, FFA levels were measured using an enzyme cycling method on admission in serum and CSF of 252 consecutive patients with AIS. The prognostic value of FFA to predict the functional outcome and mortality within 90-day was compared with the National Institutes of Health Stroke Scale score and with other known outcome predictors. Serum and CSF levels of FFA increased with increasing severity of stroke as defined by the NIHSS score (all P < 0.001). Patients with an unfavorable outcomes and non-survivors had significantly increased FFA serum and CSF levels on admission (all P < 0.0001). Multivariate logistic regression analysis adjusted for common risk factors showed that serum FFA ≥0.71 mmol/L (third quarters) was an independent predictor of functional outcome (odds ratios (OR) = 4.86; 95 % confidence interval (CI) 2.26-10.48) and mortality (OR = 7.72; 95 % CI 3.01-21.48). The area under the receiver operating characteristic curve of serum FFA was 0.79 (95 % CI, 0.72-0.86) for functional outcome and 0.86 (95 % CI, 0.78-0.94) for mortality. Similarly, CSF FFA level also was an indicator for predicting of functional outcome and mortality. FFA levels in serum and CSF may serve as independent biomarkers in addition of the traditional methods for assessing the functional outcome and mortality of AIS.

Inflammatory cytokines are potential modulators of infarct progression in acute ischaemic stroke, and are therefore possible targets for future treatment strategies. Cytokine studies in animal models of surgically induced stroke may, however, be influenced by the fact that the surgical intervention itself contributes towards the cytokine response. Community-dwelling domestic dogs suffer from spontaneous ischaemic stroke, and therefore, offer the opportunity to study the cytokine response in a noninvasive set-up. The aims of this study were to investigate cytokine concentrations in plasma and cerebrospinal fluid (CSF) in dogs with acute ischaemic stroke and to search for correlations between infarct volume and cytokine concentrations. Blood and CSF were collected from dogs less than 72 h after a spontaneous ischaemic stroke. Infarct volumes were estimated on MRIs. Interleukin (IL)-2, IL-6, IL-8, IL-10 and tumour necrosis factor in the plasma, CSF and brain homogenates were measured using a canine-specific multiplex immunoassay. IL-6 was significantly increased in plasma (P=0.04) and CSF (P=0.04) in stroke dogs compared with healthy controls. The concentrations of other cytokines, such as tumour necrosis factor and IL-2, were unchanged. Plasma IL-8 levels correlated significantly with infarct volume (Spearman's r=0.8, P=0.013). The findings showed increased concentrations of IL-6 in the plasma and CSF of dogs with acute ischaemic stroke comparable to humans. We believe that dogs with spontaneous stroke offer a unique, noninvasive means of studying the inflammatory processes that accompany stroke while reducing confounds that are unavoidable in experimental models.

Diseases of the central nervous system that are caused by an underlying vascular pathology typically result in either hemorrhage or ischemia. Most prominent entities include spontaneous subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, and ischemic stroke. For anatomic reasons, cerebrospinal fluid (CSF) qualifies as body fluid for the exploration of biomarkers in these disorders. Even though in subarachnoid hemorrhage a few CSF parameters have been established for routine diagnostic purposes, there is still an unmet need and broad interest in the identification of molecules that would allow further insight into disease mechanisms and supplement patients' medical care. This chapter provides an overview on what is presently known about CSF biomarkers in spontaneous subarachnoid hemorrhage, spontaneous intracerebral hemorrhage, and ischemic stroke. We recapitulate current evidence on established diagnostic tests, discuss the role of various CSF molecules in the pathophysiology of these diseases, and illuminate their potential use in future clinical practice. Furthermore, we address methodologic aspects as well as shortcomings of research in this field., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cerebrospinal fluid (CSF) is an important biofluid for diagnosis of and research on neurological diseases. However, in-depth metabolomic profiling of CSF remains an analytical challenge due to the small volume of samples, particularly in small animal models. In this work, we report the application of a high-performance chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) workflow for CSF metabolomics in Gastrodia elata and Uncaria rhynchophylla water extract (GUW)-treated experimental cerebral ischemia model of rat. The GUW is a commonly used Traditional Chinese Medicine (TCM) for hypertension and brain disease. This study investigated the amine- and phenol-containing biomarkers in the CSF metabolome. After GUW treatment for 7 days, the neurological deficit score was significantly improved with infarct volume reduction, while the integrity of brain histological structure was preserved. Over 1957 metabolites were quantified in CSF by dansylation LC-MS. The analysis of this comprehensive list of metabolites suggests that metabolites associated with oxidative stress, inflammatory response, and excitotoxicity change during GUW-induced alleviation of ischemic injury. This work is significant in that (1) it shows CIL LC-MS can be used for in-depth profiling of the CSF metabolome in experimental ischemic stroke and (2) identifies several potential molecular targets (that might mediate the central nervous system) and associate with pharmacodynamic effects of some frequently used TCMs.

The aim of this study was to evaluate the association between cerebrospinal fluid (CSF) levels of free fatty acid (FFA) and functional outcome and stroke recurrence in patients with ischemic stroke. In a prospective study, CSF levels of FFA were measured using an enzyme cycling method on admission in 217 consecutive patients with first-ever ischemic stroke. Clinical information was collected. Functional outcome and stroke recurrence were evaluated at 1-year follow-up. Multivariate analyses were performed using logistic regression models. The CSF FFA level was obtained in all patients with a median value of 0.22 (IQR 0.12-0.33) mmol/l. At admission, 89 patients (41.0 %) had a minor stroke (NIHSS < 5). In these patients, the median FFA level was lower than that observed in patients with moderate-to-high clinical severity (0.16 vs 0.27 mmol/l, p < 0.001). Patients with unfavorable outcomes and stroke recurrence had significantly higher FFA CSF levels on admission (all p < 0.0001). Multivariate logistic regression analysis adjusted for common risk factors showed that CSF FFA ≥ 0.33 mmol/l (third quarters) was an independent predictor of functional outcome (OR = 2.825; 95 % CI 1.502-5.313, p = 0.001) and stroke recurrence (OR = 7.862; 95 % CI 3.248-19.031, p < 0.0001). Our results demonstrate that high FFA SCF levels were independently associated with both the poor functional prognosis and stroke recurrence in patients with ischemic stroke.

Angiitis of the central nervous system (CNS) is difficult to diagnose but potentially fatal. When stroke occurs in a younger individual or is associated with multiple infarcts on imaging, clinicians must decide how far to pursue a possible diagnosis of vasculitis. The aim of this study is to establish the prevalence of primary and secondary cerebral angiitis among patients presenting with stroke. Hospital attendances over a 10year period were surveyed by searching for diagnostic codes and key words specific for cerebral vasculitis/angiitis. Case notes were reviewed by the authors using two sets of criteria for angiitis of the CNS. Thirty-two patients were initially considered likely to have cerebral angiitis by treating physicians. Thirteen had been admitted to hospital with stroke. During this period, there were 7475 admissions for ischaemic and haemorrhagic stroke. Six patients had a final diagnosis of vasculitic stroke but only one had definite CNS angiitis with a first presentation as ischaemic stroke (0.02%). Most patients who did have cerebral vasculitis developed multifocal or subacute neurological deficits, or already had an immunological disorder known to be associated with secondary CNS angiitis. Of 19 patients given an alternative final diagnosis, the most common were atherosclerotic/embolic cerebrovascular disease (n=9) and reversible cerebral vasoconstriction syndrome (n=7). Stroke is rarely the first manifestation of cerebral vasculitis. Our findings suggest that routine screening for angiitis in stroke patients may not be warranted., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Herpes simplex virus (HSV) type-2 is known to cause meningitis and usually runs a benign course. Association of such infection with vasculitis of the central nervous system is not well known. Presented here is a case initially diagnosed as aseptic meningitis that subsequently evolved as stroke and exhibited angiographic evidence of widespread vasculitis of the intracranial vessels in association with a positive polymerase chain reaction (PCR) for HSV-2 in the cerebrospinal fluid (CSF).

The aim of this study is to determine the expression levels and clinical significance of circulating microRNAs (miRNAs), let-7e and miR-338 at different stages following ischemic stroke (IS). Seventy-two patients with IS at the acute stage were enrolled and monitored at different stages, and 51 healthy volunteers were served as the normal controls. Expression of let-7e and miR-338 in serum and cerebral spinal fluid (CSF) samples was analyzed by real-time quantitative PCR. The relationship between expression levels of let-7e and miR-338, National Institutes of Health Stroke Scale (NIHSS) scores, and the levels of serum CRP was analyzed, respectively. Compared to healthy controls, serum let-7e expression levels were significantly increased, while serum miR-338 expression levels were slightly increased in IS patients. Expression levels of Let-7e in serum varied at different stages in IS patients with the lowest expression in the recover stage and highest expression in the acute stage. However, serum miR-338 expression in IS patients was not significantly different in any stage. Compared to healthy controls and nonacute stages of IS groups, let-7e expression in CSF was markedly upregulated in IS patients at the acute stage. Different from that of let-7e, miR-338 expression in CSF was upregulated in IS patients only at the subacute stage but not in the acute stage. Meanwhile, let-7e, which was not significantly correlated with NIHSS scores (r = 0.29, P > 0.05), was positively correlated with the serum CRP levels (r = 0.67, P = 0.033). There is no significant correlation between the miR-338 expression levels and NIHSS scores or serum CRP levels. Moreover, let-7e, but not miR-338, had a high consistency in expression when tested both in CSF and serum samples. Finally, serum let-7e showed a specificity up to 73.4 % and a sensitivity of 82.8 % in IS patients at the acute stage, whereas serum miR-338 in IS patients showed a specificity up to 53.2 % and a sensitivity of 71.9 % in the acute stage. Expression levels of let-7e in serum may serve as a useful noninvasive circulating biomarker for the acute stage of ischemic stroke.

Background: Autophagy is demonstrated to be involved in acute ischemic stroke(AIS), which, however, is confined to cells and/or animals levels. The aim of this study was to determine two autophagy biomarkers, Beclin1 and LC3B, in cerebrospinal fluid (CSF) and serum of patients with AIS, and to evaluate a possible correlation between levels of Beclin1 and LC3B and severity of neurological deficit and clinical outcome of stroke patients., Methods: Levels of Beclin1 and LC3B were quantified by ELISA in CSF and serum collected from 37 AIS patients and 21 controls. The clinical severity at stroke onset was determined by the National Institute of Health Stroke Scale (NIHSS) and the neurological outcome was determined by the Modified Rankin Scale (mRs) and the improvement in NIHSS between stroke onset and 3 months later. Associations between autophagy biomarkers and infarct volume, NIHSS and mRs were assessed using Pearson analysis., Results: The levels of Beclin1 and LC3B were increased both in CSF and serum of AIS patients relative to controls. In CSF, they were positively correlated with infarct volume and NIHSS scores, and negatively correlated with mRs scores, but no significant association was observed in serum. Moreover, AIS patients with higher levels of Beclin1 and LC3B in CSF had significantly higher improvement in NIHSS., Conclusion: CSF and serum levels of autophagy biomarkers are altered in AIS patients. CSF levels of autophagy biomarkers are associated with infarct volume, clinical severity of and neurological outcome.

Objective: To assess the clinical significance of cerebrospinal fluid (CSF) free fatty acid (FFA) levels in Chinese patients with acute ischemic stroke., Methods: From December 2011 to October 2014, all patients with first-ever acute ischemic stroke were recruited to participate in the study. CSF levels of FFAs were assayed at 4 time points, and severity of stroke was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score on admission., Results: Median CSF FFA levels were significantly (P < 0.0001) higher in patients with stroke compared with control subjects. CSF FFA levels reflected the disease severity of acute ischemic stroke. There were significant positive associations between CSF FFA levels and NIHSS scores (r = 0.424, P < 0.0001) and infarct volume (r = 0.289, P < 0.0001). CSF FFA levels in patients with cardioembolic (CE) stroke were significantly higher compared with patients with non-CE stroke (0.34 mmol/L [interquartile range, 0.26-0.42] vs. 0.14 mmol/L [interquartile range, 0.08-0.23]; P < 0.0001). Based on the receiver operating characteristic curve, the optimal cutoff value of CSF FFA levels as an indicator for the diagnosis of CE stroke was projected to be 0.22 mmol/L, which yielded a sensitivity of 83.3% and a specificity of 75.3%, and the area under the curve was 0.873 (95% confidence interval, 0.810-0.935)., Conclusions: CSF FFA levels at the time of admission were associated with stroke severity and lesion volumes. In addition, CE stroke can be distinguished from other stroke etiologies by measuring CSF FFA levels very early., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The ectodomain of p75 neurotrophin receptor (p75NTR-ECD) has been suggested to play important roles in regulating beta-amyloid (Aβ) deposition and in protecting neurons from the toxicity of soluble Aβ. However, whether and how the serum and cerebrospinal fluid (CSF) levels of p75NTR-ECD change in patients with AD are not well documented. In the present study, we determined the concentrations of serum p75NTR-ECD in an AD group, a Parkinson disease group and a stroke group, as well as in a group of elderly controls without neurological disorders (EC). We also determined the levels of CSF p75NTR-ECD in a subset of the AD and EC groups. Our data showed that a distinct p75NTR-ECD profile characterized by a decreased CSF level and an increased serum level was present concomitantly with AD patients but not with other diseases. p75NTR-ECD levels in both the serum and CSF were strongly correlated with Mini-Mental State Examination (MMSE) scores and showed sound differential diagnostic value for AD. Moreover, when combining CSF Aβ42, CSF Aβ42/40, CSF ptau181 or CSF ptau181/Aβ42 with CSF p75NTR-ECD, the area under the receiver operating characteristic curve (AUC) and diagnostic accuracies improved. These findings indicate that p75NTR-ECD can serve as a specific biomarker for AD and the determination of serum and CSF p75NTR-ECD levels is likely to be helpful in monitoring AD progression.

Background: Brain injury is a medical emergency that needs to be diagnosed and treated promptly. Several proteins have been studied as biomarkers of this medical condition. The aims of this study were to: 1) evaluate the selectivity and precision of a commercial ELISA kit for neurofilament medium polypeptide (NFM) protein; and 2) evaluate the concentration in cerebrospinal fluid (CSF) and serum of healthy individuals and patients with brain damage., Methods: An ELISA from Elabscience was used. The selectivity was evaluated using size-exclusion chromatography and mass spectrometry. Intra- and inter-batch coefficients of variation (CV) were also studied. Fifty-one CSF samples from 36 age-matched patients with hemorrhagic stroke (HS) (n=30), ischemic stroke (IS) (n=11) and healthy individuals (n=10) were assayed. In addition, serum samples from healthy volunteers (n=47), 68 serum samples from seven patients with HS, 106 serum samples from 12 patients with traumatic brain injury (TBI) and 68 serum samples from 68 patients with mild traumatic brain injury (mTBI) were also analyzed., Results: NFM was identified in the chromatographic fraction with highest immunoreactivity. The intra- and inter-batch CVs were ≤10% and ≤13%, respectively. The CSF-NFM concentration in HS was significantly higher (p<0.0001) than in IS and controls. Serum NFM concentration ranged from 0.26 to 8.57 ng/mL in healthy individuals (median=2.29), from 0.97 to 42.4 ng/mL in HS (median=10.8) and from 3.48 to 45.4 ng/mL in TBI (median=14.7). Finally, 44% of patients with mTBI had increased NFM concentration, with significantly higher levels (p=0.01) in patients with polytrauma., Conclusions: To our knowledge this is the first study describing increased NFM levels in CSF and serum from patients with brain damage.

Cryptococcal meningitis is the most common manifestation of cryptococcosis and is caused by the encapsulated yeast organism Cryptococcus neoformans. It occurs most commonly in patients with impaired cell-mediated immunity such as in HIV infection; patients with hematological malignancies; patients post solid-organ transplantation; on chronic steroids or immunosuppressants. Clinically, stroke can arise as a complication of cryptococcal meningitis. While cerebrospinal fluid (CSF) examination is usually not indicated for evaluation of stroke patients, demonstration of cryptococcal yeast forms in CSF is valuable in guiding appropriate therapy in arterial stroke caused by Cryptococci. Herein, we describe the CSF and radiologic correlation in a female patient who presented with disseminated cryptococcosis, cryptococcal meninigitis and a middle cerebral artery infarct., (© 2014 Wiley Periodicals, Inc.)

Objective: Hyperintense acute reperfusion marker (HARM) without diffusion abnormalities is occasionally found in patients with an acute stroke. This study was to determine the prevalence and clinical implications of HARM without diffusion abnormalities., Materials and Methods: There was a retrospective review of magnetic resonance images 578 patients with acute strokes and identified those who did not have acute infarction lesions, as mapped by diffusion-weighted imaging (DWI). These patients were classified into an imaging-negative stroke and HARM without diffusion abnormalities groups, based on the DWI findings and postcontrast fluid attenuated inversion recovery images. The National Institutes of Health Stroke Scale (NIHSS) scores at admission, 1 day, and 7 days after the event, as well as clinical data and risk factors, were compared between the imaging-negative stroke and HARM without diffusion abnormalities groups., Results: Seventy-seven acute stroke patients without any DWI abnormalities were found. There were 63 patients with an imaging-negative stroke (accounting for 10.9% of 578) and 13 patients with HARM without diffusion abnormalities (accounting for 2.4% of 578). The NIHSS scores at admission were higher in HARM without diffusion abnormalities group than in the imaging-negative stroke group (median, 4.5 vs. 1.0; p < 0.001), but the scores at 7 days after the event were not significantly different between the two groups (median, 0 vs. 0; p = 1). The patients with HARM without diffusion abnormalities were significantly older, compared with patients with an imaging-negative stroke (mean, 73.1 years vs. 55.9 years; p < 0.001)., Conclusion: Patients with HARM without diffusion abnormalities are older and have similarly favorable short-term neurological outcomes, compared with the patients with imaging-negative stroke.

The aims of the study were (1) to determine whether miRNAs (microRNAs) can be detected in the cerebrospinal fluid (CSF) and blood of patients with ischemic stroke and (2) to compare these miRNA profiles with corresponding profiles from other neurological patients to address whether the miRNA profiles of CSF or blood have potential usefulness as diagnostic biomarkers of ischemic stroke. CSF from patients with acute ischemic stroke (n = 10) and patients with other neurological diseases (n = 10) was collected by lumbar puncture. Blood samples were taken immediately after. Expression profiles in the cell-free fractions of CSF and blood were analyzed by a microarray technique (miRCURY LNA™ microRNA Array, Exiqon A/S, Denmark) using a quantitative PCR (qPCR) platform containing 378 miRNA primers. In total, 183 different miRNAs were detected in the CSF, of which two miRNAs (let-7c and miR-221-3p) were found upregulated in relation to stroke. In the blood, 287 different miRNAs were detected of which two miRNAs (miR-151a-3p and miR-140-5p) were found upregulated and one miRNA (miR-18b-5p) was found downregulated in the stroke group. Some miRNAs occurred exclusively in the CSF including miR-523-3p which was detected in 50 % of the stroke patients, whereas it was completely absent in controls. Our preliminary results demonstrate that it is possible to detect and profile miRNAs in CSF and blood from patients with neurological diseases. Some miRNAs appear differentially expressed in the CSF and others in the blood of stroke patients. Currently, we are validating our results in larger groups of patients.

Background and Purpose: The aim of the present study was to investigate the impact of different stroke subtypes on the glymphatic system using MRI., Methods: We first improved and characterized an in vivo protocol to measure the perfusion of the glymphatic system using MRI after minimally invasive injection of a gadolinium chelate within the cisterna magna. Then, the integrity of the glymphatic system was evaluated in 4 stroke models in mice including subarachnoid hemorrhage (SAH), intracerebral hemorrhage, carotid ligature, and embolic ischemic stroke., Results: We were able to reliably evaluate the glymphatic system function using MRI. Moreover, we provided evidence that the glymphatic system was severely impaired after SAH and in the acute phase of ischemic stroke, but was not altered after carotid ligature or in case of intracerebral hemorrhage. Notably, this alteration in glymphatic perfusion reduced brain clearance rate of low-molecular-weight compounds. Interestingly, glymphatic perfusion after SAH can be improved by intracerebroventricular injection of tissue-type plasminogen activator. Moreover, spontaneous arterial recanalization was associated with restoration of the glymphatic function after embolic ischemic stroke., Conclusions: SAH and acute ischemic stroke significantly impair the glymphatic system perfusion. In these contexts, injection of tissue-type plasminogen activator either intracerebroventricularly to clear perivascular spaces (for SAH) or intravenously to restore arterial patency (for ischemic stroke) may improve glymphatic function., (© 2014 American Heart Association, Inc.)

The seemingly straightforward diagnosis of acute ischaemic stroke can be complicated by the presence of conditions presenting similarly to stroke, and atypical strokes presenting with confusing and non-classical signs. We present a diagnostic quest to disentangle the effects of a number of stroke mimics from those of an underlying bilateral cerebrovascular phenomena, where with appropriate treatment of the non-stroke conditions the patient was able to make a near complete neurological recovery., (2014 BMJ Publishing Group Ltd.)

Background: Post-varicella angiopathy is an important cause of childhood stroke and follows a particular pattern. Specific treatment guidelines have not been developed because of a lack of epidemiological, laboratory, and neuroimaging data. Prospective randomized controlled trials evaluating different treatment strategies have not been performed, and expert opinions on diagnostic criteria, prognosis, and treatment are diverging., Methods: This case series describes the clinical course, laboratory, and neuroimaging findings of four children with post-varicella angiopathy, who all underwent cerebrospinal fluid assessment and received antiviral, immunosuppressive, and antiplatelet treatment., Results: Cerebrospinal fluid analysis was positive for varicella-zoster virus markers in three children. At follow-up, three children had a mild hemiparesis and one child had no neurological symptoms. Neuroimaging showed complete vascular remission in three patients and improvement in one., Conclusions: Systematic search for virologic markers in cerebrospinal fluid will contribute to the understanding of the pathogenesis of idiopathic childhood stroke and can be considered as a prerequisite for the development of clear diagnostic criteria and relevant treatment strategies for post-varicella angiopathy. The role of antiviral and immunosuppressive medication needs to be clarified., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Studies in non-stroke patients have shown an association between dysregulation of the hypothalamic-pituitary-adrenal axis and morbidity and mortality. We conducted a systematic review to evaluate cortisol levels in acute stroke and their associations with outcome. We searched MEDLINE and EMBASE for articles up to April 2013 and PsychINFO for articles up to July 2013, using the keywords "cortisol" and "stroke" and associated terms or synonyms. We included studies published in peer-reviewed journals that recruited 10 or more participants and measured cortisol at least once in the first year following stroke. Data were extracted regarding cortisol levels, including changes over time and their relationship to stroke severity, and outcome. Of 11,240 abstracts, 101 full texts were obtained and 48 fulfilled our inclusion criteria. Cortisol levels were high in the first week after stroke in the majority of studies (26 studies, n = 1,340). Higher cortisol was associated with dependency (8/11 studies, n = 822), delirium (5/6 studies, n = 269) depression (3/5 studies n = 117) and mortality (8/10 studies, n = 856). Five studies adjusted for stroke severity; one found an association between higher cortisol and dependency, and three found an association between higher cortisol and mortality. Cortisol levels are high for at least 7 days after stroke. Elevated cortisol after stroke is associated with dependency, morbidity, and mortality; however, there is insufficient evidence to conclude that these relationships are independent of stroke severity.

The two primary categories of stroke, ischemic and hemorrhagic, both have fundamentally different mechanisms and thus different treatment options. These two stroke categories were applied to rat models to identify potential biomarkers that can distinguish between them. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO) without reperfusion while hemorrhagic stroke was induced by injecting collagenase IV into the striatum. Brain hemispheres and biofluids were collected at two time points: 3 and 6h after stroke. Known molecules were tested on the rat samples via quantitative immunoblotting (injured brain, CSF) and Banyan's proprietary ELISA assays (CSF, serum). The injured brain quantitative analyses revealed that αII-spectrin breakdown products (SBDP150, SBDP145) were strongly increased after 6h ischemia. In CSF, SBDP145 and ubiquitin C-terminal hydrolase-L1 (UCH-L1) levels were elevated after 6h ischemic stroke detected by Western blot and ELISA. In serum UCH-L1 levels were increased after 3 and 6h of ischemia detected by ELISA. However, levels of those proteins in hemorrhagic stroke remain normal. In summary, in both the brain and the biofluids, SBDPs and UCH-L1 were elevated after ischemic but not hemorrhagic stroke. These molecules behaved differently in the two stroke models and thus may be capable of being differentiated., (© 2013 Published by Elsevier B.V.)

Introduction: During the past decades there has been a great progress in neuroimaging methods. Cranial computed tomography is part of the daily routine now and its use allows a fast diagnosis of parenchymal hemorrhage. However, before the availability of computed tomography the differentiation between ischemic and hemorrhagic stroke was based on patient history, physical examination, percutan angiography and cerebrospinal fluid sampling, and the clinical utility could be evaluated by autopsy of deceased patients., Aim: The authors explored the diagnostic performance of cerebrospinal fluid examination for the diagnosis of ischemic and hemorrhagic stroke., Method: Data of 200 deceased stroke patients were retrospectively evaluated. All patients had liquor sampling at admission and all of them had brain autopsy., Results: Bloody or yellowish cerebrospinal fluid at admission had a positive predictive value of 87.5% for hemorrhagic stroke confirmed by autopsy, while clear cerebrospinal fluid had positive predictive value of 90.7% for ischemic stroke. Patients who had clear liquor, but autopsy revealed hemorrhagic stroke had higher protein level in the cerebrospinal fluid, but the difference was not statistically significant (p = 0.09)., Conclusions: The results confirm the importance of pathological evaluation of the brain in cases deceased from cerebral stroke. With this article the authors wanted to salute for those who contributed to the development of the Hungarian neuropathology. In this year we remember the 110th anniversary of the birth, and the 60th anniversary of the death of professor Kálmán Sántha. Professor László Molnár would be 90 years old in 2013.

Vascular factors are thought to contribute to the development of disease pathology in neurodegenerative dementia such as Alzheimer's disease (AD). Another entity, called vascular dementia (VaD), comprises a less defined group of dementia patients having various vascular diseases that especially emerge in the elderly population and require valid options for examination and differential diagnosis. In the context of a retrospective study, we analyzed the cerebrospinal fluid (CSF) biomarkers t-tau, p-tau and Aß42 of a total of 131 patients with AD (n = 47), mild cognitive impairment (MCI) (n = 22), VaD (n = 44) and stroke (n = 18). We found a remarkable alteration in CSF biomarker profile in AD, VaD and in acute ischemic events. CSF profile in AD patients was altered in a very similar way as in stroke patients, without statistical differences. In stroke, increase depend largely on size and duration after the initial event. Total tau levels were useful to differ between VaD and stroke. Aß42 decreased in a similar way in AD, VaD and stroke and had a trend to lower levels in MCI but not in controls.

Bradykinin (BK) was shown to stimulate the production of physiologically active metabolites, blood-brain barrier disruption, and brain edema. The aim of this prospective study was to measure BK concentrations in blood and cerebrospinal fluid (CSF) of patients with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and ischemic stroke and to correlate BK levels with the extent of cerebral edema and intracranial pressure (ICP). Blood and CSF samples of 29 patients suffering from acute cerebral lesions (TBI, 7; SAH,: 10; ICH, 8; ischemic stroke, 4) were collected for up to 8 days after insult. Seven patients with lumbar drainage were used as controls. Edema (5-point scale), ICP, and the GCS (Glasgow Coma Score) at the time of sample withdrawal were correlated with BK concentrations. Though all plasma-BK samples were not significantly elevated, CSF-BK levels of all patients were significantly elevated in overall (n=73) and early (≤72 h) measurements (n=55; 4.3±6.9 and 5.6±8.9 fmol/mL), compared to 1.2±0.7 fmol/mL of controls (p=0.05 and 0.006). Within 72 h after ictus, patients suffering from TBI (p=0.01), ICH (p=0.001), and ischemic stroke (p=0.02) showed significant increases. CSF-BK concentrations correlated with extent of edema formation (r=0.53; p<0.001) and with ICP (r=0.49; p<0.001). Our results demonstrate that acute cerebral lesions are associated with increased CSF-BK levels. Especially after TBI, subarachnoid and intracerebral hemorrhage CSF-BK levels correlate with extent of edema evolution and ICP. BK-blocking agents may turn out to be effective remedies in brain injuries.

Background and Purpose: There is limited information about changes in metabolism during acute ischemic stroke. The identification of changes in circulating plasma metabolites during cerebral infarction may provide insight into disease pathogenesis and identify novel biomarkers., Methods: We performed filament occlusion of the middle cerebral artery of Wistar rats and collected plasma and cerebrospinal fluid 2 hours after the onset of ischemia. Plasma samples from control and patients with acute stroke were also analyzed. All samples were examined using liquid chromatography followed by tandem mass spectrometry. Positively charged metabolites, including amino acids, nucleotides, and neurotransmitters, were quantified using electrospray ionization followed by scheduled multiple reaction monitoring., Results: The concentrations of several metabolites were altered in the setting of cerebral ischemia. We detected a reduction in the branched chain amino acids (valine, leucine, isoleucine) in rat plasma, rat cerebrospinal fluid, and human plasma compared with respective controls (16%, 23%, and 17%, respectively; P<0.01 for each). In patients, lower branched chain amino acids levels also correlated with poor neurological outcome (modified Rankin Scale, 0-2 versus 3-6; P=0.002)., Conclusions: Branched chain amino acids are reduced in ischemic stroke, and the degree of reduction correlates with worse neurological outcome. Whether branched chain amino acids are in a causal pathway or are an epiphenomenon of ischemic stroke remains to be determined.

The low-molecular-weight DNA appears in blood plasma of irradiated rats, and its content correlates directly with the irradiation dose. Cloning has shown, that enrichment of low-molecular-weight DNA with G+C content and features of its nucleotide sequences point to its ability to form rather stable nucleosomes. DNA obtained after irradiation of rats with principally different doses 8 and 100 Gy differed not only quantitatively, but also by content of the dinucleotides CpG and CpT; this suggests their origin from different sites of genome. For the first time it has been shown that exposure to low-frequency noise results in an increase of the contents of blood plasma low-molecular-weight DNA. In stroke patients blood concentrations of this DNA increased 3 days after the beginning of the acute period, and dynamics of its excretion differs in ischemic and hemorrhagic forms; in the case of ischemia low-molecular-weight DNA appears in cerebrospinal fluid. The chronic obstructive pulmonary disease in the state of remission is characterized by the decline of the level of low-molecular-weight DNA in the blood plasma unlike in the case of the chronic nonobstructive bronchitis. The clear dependence between formation and special features of the low-molecular-weight DNA fraction in blood plasma makes it possible to consider the low-molecular fraction as an universal index of apoptosis, which allows to distinguish basically different conditions of the body.

Stimulation of endogenous neural stem/progenitor cells (NSPCs) with therapeutic factors holds potential for the treatment of stroke. Cyclosporin A (CsA) is a particularly promising candidate molecule because it has been shown to act as a survival factor for these cells over a period of weeks both in vitro and in vivo; however, systemically-delivered CsA compromises the entire immune system, necessitating sustained localized delivery. Herein we describe a local delivery strategy for CsA using an epi-cortical hydrogel of hyaluronan-methylcellulose (HAMC) as the drug reservoir. Three methods of incorporating the drug into the hydrogel (solubilized, particulate, and poly(lactic-co-glycolic) acid (PLGA) microsphere-encapsulated) resulted in tunable release, spanning a period of hours to weeks. Importantly, PLGA-encapsulated CsA released from the hydrogel had equivalent bioactivity to fresh drug as measured by the neurosphere assay. Moreover, when CsA was released from the PLGA/HAMC composite that was injected on the cortex of adult mice, CsA was detected in the NSPC niche at a constant concentration for at least 24days post-implant. Thus this hydrogel composite system may be promising for the treatment of stroke., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Subventricular zone (SVZ) astrocytes and ependymal cells are both derived from radial glia and may have similar gliotic reactions after stroke. Diminishing SVZ neurogenesis worsens outcomes in mice, yet the effects of stroke on SVZ astrocytes and ependymal cells are poorly understood. We used mouse experimental stroke to determine if SVZ astrocytes and ependymal cells assume similar phenotypes and if stroke impacts their functions. Using lateral ventricular wall whole mount preparations, we show that stroke caused SVZ reactive astrocytosis, disrupting the neuroblast migratory scaffold. Also, SVZ vascular density and neural proliferation increased but apoptosis did not. In contrast to other reports, ependymal denudation and cell division was never observed. Remarkably, however, ependymal cells assumed features of reactive astrocytes post stroke, robustly expressing de novo glial fibrillary acidic protein, enlargening and extending long processes. Unexpectedly, stroke disrupted motile cilia planar cell polarity in ependymal cells. This suggested ciliary function was affected and indeed ventricular surface flow was slower and more turbulent post stroke. Together, these results demonstrate that in response to stroke there is significant SVZ reorganization with implications for both pathophysiology and therapeutic strategies.

Purpose: Cerebrospinal fluid (CSF) segmentation in computed tomography (CT) is a key step in computer-aided detection (CAD) of acute ischemic stroke. Because of image noise, low contrast and intensity inhomogeneity, CSF segmentation has been a challenging task. A region-based active contour model, which is insensitive to contour initialization and robust to intensity inhomogeneity, was developed for segmenting CSF in brain CT images., Methods: The energy function of the region-based active contour model is composed of a range domain kernel function, a space domain kernel function, and an edge indicator function. By minimizing the energy function, the region of edge elements of the target could be automatically identified in images with less dependence on initial contours. The energy function was optimized by means of the deepest descent method with a level set framework. An overlap rate between segmentation results and the reference standard was used to assess the segmentation accuracy. The authors evaluated the performance of the proposed method on both synthetic data and real brain CT images. They also compared the performance level of our method to those of region-scalable fitting (RSF) and global convex segment (GCS) models., Results: For the experiment of CSF segmentation in 67 brain CT images, their method achieved an average overlap rate of 66% compared to the average overlap rates of 16% and 46% from the RSF model and the GCS model, respectively., Conclusions: Their region-based active contour model has the ability to achieve accurate segmentation results in images with high noise level and intensity inhomogeneity. Therefore, their method has great potential in the segmentation of medical images and would be useful for developing CAD schemes for acute ischemic stroke in brain CT images.

Background: Approximately 10% to 14% of ischemic strokes occur in young adults., Objective: To investigate the yield of diagnostic tests, neuroimaging findings, and treatment of ischemic strokes in young adults., Design: We retrospectively reviewed data from our Get with the Guidelines-Stroke database from 2005 through 2010., Setting: University hospital tertiary stroke center., Patients: A total of 215 consecutive inpatients aged 18 to 45 years with ischemic stroke/transient ischemic attack. The mean (SD) age was 37.5 (7) years; 51% were male., Results: There were high incidence rates of hypertension (20%), diabetes mellitus (11%), dyslipidemia (38%), and smoking (34%). Relevant abnormalities were shown on cerebral angiography in 136 of 203 patients, on cardiac ultrasonography in 100 of 195, on Holter monitoring in 2 of 192; and on hypercoagulable panel in 30 of 189 patients. Multiple infarcts were observed in 31% and were more prevalent in individuals younger than age 35 years. Relevant arterial lesions were frequently detected in the middle cerebral artery (23%), internal carotid artery (13%), and vertebrobasilar arteries (13%). Cardioembolic stroke occurred in 47% (including 17% with isolated patent foramen ovale), and 11% had undetermined stroke etiology. The median National Institutes of Health Stroke Scale score was 3 (interquartile range, 0-9) and 81% had good outcome at hospital discharge. Of the 29 patients receiving thrombolysis (median National Institutes of Health Stroke Scale score, 14; interquartile range, 9-17), 55% had good outcome at hospital discharge and none developed symptomatic brain hemorrhage., Conclusions: This study shows the contemporary profile of ischemic stroke in young adults admitted to a tertiary stroke center. Stroke etiology can be determined in nearly 90% of patients with modern diagnostic tests. The causes are heterogeneous; however, young adults have a high rate of traditional vascular risk factors. Thrombolysis appears safe and short-term outcomes are favorable.