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Parkinson's disease (PD) is one of the most common neurodegenerative disorders globally and leads to an excessive loss of dopaminergic neurons in the substantia nigra of the brain. Circulating cell-free DNA (ccf-DNA) are double-stranded DNA fragments of different sizes and origins that are released into the serum and cerebrospinal fluid (CSF) due to cell death (i.e., necrosis and apoptosis) or are actively released by viable cells via exocytosis and NETosis. Using droplet digital polymerase chain reaction (ddPCR), we comprehensively analyzed and distinguished circulating cell-free mitochondrial DNA (ccf mtDNA) and circulating cell-free nuclear DNA (ccfDNA) in the serum and CSF of PD and control patients. The quantitative analysis of serum ccf-DNA in PD patients demonstrated a significant increase in ccf mtDNA and ccfDNA compared to that in healthy control patients and a significantly higher copy of ccf mtDNA when compared to ccfDNA. Next, the serum ccf mtDNA levels significantly increased in male PD patients compared to those in healthy male controls. Furthermore, CSF ccf mtDNA in PD patients increased significantly compared to ccfDNA, and ccf mtDNA decreased in PD patients more than it did in healthy controls. These decreases were not statistically significant but were in agreement with previous data. Interestingly, ccf mtDNA increased in healthy control patients in both serum and CSF as compared to ccfDNA. The small sample size of serum and CSF were the main limitations of this study. To the best of our knowledge, this is the first comprehensive study on serum and CSF of PD patients using ddPCR to indicate the distribution of the copy number of ccf mtDNA as well as ccfDNA. If validated, we suggest that ccf mtDNA has greater potential than ccfDNA to lead the development of novel treatments for PD patients.

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Purpose: Subependymoma is a slow-growing benign brain neoplasm, classified by the World Health Organization (WHO) as a grade I tumor, which typically presents in middle-aged male adults. Case description: A case of Bruns syndrome and an intraventricular subependymoma in a 49-year-old patient who presented with intractable headache and vertigo is discussed in this paper. Imaging revealed a well-delimited cystic and solid mass near the lateral ventricle. Comment: Complete surgical excision of the tumor resulted in the restoration of normal cerebrospinal fluid pathway and resolution of clinical symptoms with no signs of tumor recurrence in the 4-year follow-up period.

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Parkinson's disease (PD) is a major public health problem. Since currently there are no reliable diagnostic tools to reveal the early steps of PD, new methods should be developed, including those searching the variations in human metabolome. Alterations in human metabolites could help to establish an earlier and more accurate diagnosis. The presented research shows a targeted metabolomics study of both of the serum and CSF from PD patients, atypical parkinsonian disorders (APDs) patients, and the control. The use of the LC-MS/MS system enabled to quantitate 144 analytes in the serum and 51 in the CSF. This information about the concentration enabled for selection of the metabolites useful for differentiation between the studied group of patients, which should be further evaluated as candidates for markers of screening and differential diagnosis of PD and APDs. Among them, the four compounds observed to be altered in both the serum and CSF seem to be the most important: tyrosine, putrescine, trans-4-hydroxyproline, and total dimethylarginine. Furthermore, we indicated the metabolic pathways potentially related to neurodegeneration processes. Our studies present evidence that the proline metabolism might be related to neurodegeneration processes underlying PD and APDs. Further studies on the proposed metabolites and founded metabolic pathways may significantly contribute to understanding the molecular background of PD and improving the diagnostics and treatment in the future.

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BACKGROUND: Myelin basic protein (MBP) is the second most abundant protein in central nervous system myelin. Since the 1980s, it has been regarded as a marker of brain tissue injury in both trauma and disease. There have been no recent reports regarding MBP in aneurysmal subarachnoid haemorrhage (SAH). METHODS: One hundred four SAH patients with ruptured aneurysms underwent endovascular treatment within 24 h of rupture, and 156 blood samples were collected: 104 on days 0-3, 32 on days 4-6 and 20 on days 9-12 post-SAH. MBP levels were assayed using ELISA and compared with the clinical status on admission, laboratory results, imaging findings and treatment outcome at 3 months. RESULTS: MBP levels on days 0-3 post-SAH were significantly higher among poor outcome patients (p < 0.001), non-survivors (p = 0.005), patients who underwent intracranial intervention (p < 0.001) and patients with intracerebral haemorrhage (ICH; p < 0.001). On days 4-6 post-SAH, significantly higher levels were found following intracranial intervention (p = 0.009) and ICH (p = 0.039). There was clinically relevant correlation between MBP levels on days 0-3 post-SAH and 3-month Glasgow Outcome Scale (cc = - 0.42) and also ICH volume (cc = 0.48). All patients who made a full recovery had MBP levels below detection limit on days 0-3 post-SAH. Following endovascular aneurysm occlusion, there was no increase in MBP in 86 of the 104 patients investigated (83%). CONCLUSIONS: The concentration of MBP in peripheral blood after intracranial aneurysm rupture reflects the severity of the brain tissue injury (due to surgery or ICH) and correlates with the treatment outcome. Endovascular aneurysm occlusion was not followed by a rise in MBP in most cases, suggesting the safety of this technique.

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BACKGROUND: The pathophysiology of brain injury following aneurysmal subarachnoid haemorrhage (SAH) is associated with numerous mediators. The aim of the study is to analyse protein changes after SAH in cerebrospinal fluid (CSF) using mass spectrometry (MS). METHODS: CSF samples were obtained from forty-four control subjects, seven good outcome and ten poor outcome SAH patients. CSF samples were collected at specific time intervals after SAH (days 1, 5 and 10). MALDI-TOF (Matrix Assisted Laser Desorption/Ionization Time-of-Flight) and ClinProTools software were utilised for MS, MS/MS (Mass Spectrometry) spectra collection and analysis. Selected masses were identified. The MALDI-TOF profiling experiments allowed for the targeted selection of potential markers in SAH. The study was performed in three steps by comparison of CSF samples: (1) from the control group and SAH patients (both good and poor outcome groups); (2) collected on days 1, 5 and 10 within the groups of poor SAH and good SAH patients, respectively; (3) from poor outcome SAH and good outcome patients at days 1, 5 and 10. RESULTS: 15 new proteins whose CSF level is alternated by SAH presence, SAH treatment outcome and time passed since aneurysm rupture were identified. CONCLUSIONS: We demonstrated new proteins which might play a role in different stages of subarachnoid haemorrhage and could be a new target for further investigation.

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Accurate prognosis of outcome in subarachnoid haemorrhage (SAH) identifies salvageable poor-grade patients. Widely available and independent prognostic factors are needed, thus value of six routine blood tests is established. Prospectively collected database of 116 aneurysmal SAH patients was reviewed for white blood cell (WBC) count and concentration of C-reactive protein (CRP), sodium, potassium, glucose and haemoglobin on day 0, 1, 2, 3-4 and 5-7 post-SAH. All patients were admitted within 24 h, treated endovascularly within 48 h and assessed neurologically at admission and at three months post-SAH. Multivariate logistic regression and receiver operating curve were analyzed for each type of parameter assessed on specific day post-SAH. We have identified three different types of blood tests with the largest area under the curve (AUC). The three types of parameters identified as the most accurate, independent prognostic factors for mortality are WBC count on day 1 (p < 0.01 with AUC of 0.82); sodium level on day 2 (p < 0.05 with AUC of 0.81) and CRP level on day 3-4 (p < 0.05 with AUC of 0.74). Cut-off values of 12.88 × 103/µl, 155 mmol/l and 142.7 mg/l (respectively) exceeded on indicated time points predict patient's death with 96.7% specificity and 68.8% sensitivity. Early alterations in routine blood tests provide an accurate prognosis of death in SAH independently from well-established prognostic tools.

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[This corrects the article on p. 438 in vol. 8, PMID: 28894433.].

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BACKGROUND: The authors are aware of only one article investigating amino acid concentrations in cerebrospinal fluid (CSF) in patients with ruptured intracranial aneurysms, and this was published 31 years ago. Since then, both management of subarachnoid haemorrhage (SAH) and amino acid assay techniques have seen radical alterations, yet the pathophysiology of SAH remains unclear. OBJECTIVE: To analyse the pattern of concentrations of amino acids and related compounds in patients with different outcomes following aneurysmal SAH. METHODS: 49 CSF samples were collected from 23 patients on days 0-3, 5, and 10 post-SAH. Concentrations of 33 amino acids and related compounds were assayed by liquid chromatography tandem mass spectrometry in patients with good [Glasgow Outcome Scale (GOS) 1-3] and poor (GOS 4-5) outcome. RESULTS: Of the 33 compounds assayed, only hydroxyproline and 3-aminoisobutyric acid appeared not to increase significantly following SAH. In poor outcome patients, we found significantly higher concentrations of aspartic acid (p = 0.038), glutamic acid (p = 0.038), and seven other compounds on days 0-3 post-SAH; glutamic acid (p = 0.041) on day 5 post-SAH, and 2-aminoadipic acid (p = 0.033) on day 10 post-SAH. The most significant correlation with GOS at 3 months was found for aminoadipic acid on day 10 post-SAH (cc = -0.81). CONCLUSION: Aneurysmal rupture leads to a generalised increase of amino acids and related compounds in CSF. The patterns differ between good and poor outcome cases. Increased excitatory amino acids are strongly indicative of poor outcome.

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BACKGROUND: Inflammation following subarachnoid hemorrhage (SAH) involves numerous mediators with biomarker properties. Preliminary studies indicated that clusterin, a multifunctional chaperon protein, was a potential biomarker in SAH. We aimed to clarify the status of clusterin in SAH. METHODS: From 27 patients with severe SAH, 47 cerebrospinal fluid (CSF) samples were collected 0-3, 5-7, and 10-14 days after SAH. Control CSF was collected from 25 age- and sex-matched healthy control subjects undergoing spinal anesthesia for minor surgery. Clusterin concentrations were assayed using enzyme-linked immunosorbent assay and compared with inflammatory markers, imaging findings, and treatment outcome. RESULTS: In healthy control subjects, mean CSF clusterin level (1908.5 ng/mL ± 36.0) was significantly higher than in the patient group (P < 0.001). In the patient group, mean clusterin level was 741.1 ng/mL ± 759.2 0-3 days, 601.6 ng/mL ± 507.2 5-7 days, and 639.2 ng/mL ± 446.8 10-14 days after SAH. Clusterin level failed to differentiate between good (Glasgow Outcome Scale 4-5) and poor (Glasgow Outcome Scale 1-3) outcomes 0-3 days and 10-14 days after SAH (P = 0.238 and P = 0.225), but significantly higher levels of CSF clusterin were found 5-7 days after SAH in patients with good outcome (P = 0.017). There was a significant correlation between CSF clusterin level 5-7 days after SAH and Glasgow Outcome Scale at 3 months (correlation coefficient = 0.633). The best correlation was found for World Federation of Neurological Societies scale (correlation coefficient = -0.741). CONCLUSIONS: SAH is associated with immediate decrease in CSF clusterin concentrations. Clusterin level at one point was a good predictor of outcome, and it may serve as a biomarker.

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Receptors for advanced glycation end-products (RAGE) mediate the inflammatory reaction that follows aneurysmal subarachnoid haemorrhage. Soluble RAGE (sRAGE) may function as a decoy receptor. The significance of this endogenous anti-inflammatory mechanism in subarachnoid haemorrhage (SAH) remains unknown. The present study aims to analyse sRAGE levels in the cerebrospinal fluid (CSF) of SAH patients. sRAGE levels were assayed by ELISA kit in 47 CSF samples collected on post-SAH days 0-3, 5-7, and 10-14 from 27 SAH patients with acute hydrocephalus. CSF levels of sRAGE were compared with a control group and correlated with other monitored parameters. In the control group, the CSF contained only a trace amount of sRAGE. By contrast, the CSF of 20 SAH patients collected on post-SAH days 0-3 was found to contain statistically significant higher levels of sRAGE (mean concentration 3.91 pg/mL, p < 0.001). The most pronounced difference in CSF sRAGE levels between good and poor outcome patients was found on days 0-3 post-SAH but did not reach the significance threshold (p = 0.234). CSF sRAGE levels did not change significantly during hospitalisation (p = 0.868) and correlated poorly with treatment outcome, systemic inflammatory markers, and other monitored parameters. Our study revealed an early and constant increase of sRAGE level in the CSF of SAH patients.

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[This corrects the article DOI: 10.1371/journal.pone.0156171.].

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BACKGROUND: Toll-like receptor (TLR) signalling begins early in subarachnoid haemorrhage (SAH), and plays a key role in inflammation following cerebral aneurysm rupture. Available studies suggest significance of endogenous first-line blockers of a TLR pathway-soluble TLR2 and 4. METHODS: Eighteen patients with SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy; sTLR2 and 4 levels were assayed in cerebrospinal fluid (CSF) collected on post-SAH days 0-3, 5, and 10-12. Release kinetics were defined. CSF levels of sTLR2 and 4 were compared with a control group and correlated with the clinical status on admission, the findings on imaging, the degree of systemic inflammation and the outcome following treatment. RESULTS: None of study group showed detectable levels of sTLR2 and 4 on post-SAH day 0-3. 13 patients showed increased levels in subsequent samples. In five SAH patients sTLR2 and 4 levels remained undetectable; no distinctive features of this group were found. On post-SAH day 5 the strongest correlation was found between sTLR2 level and haemoglobin level on admission (cc = -0.498, P = 0.037). On post-SAH day 10-12 the strongest correlation was revealed between sTLR2 and treatment outcome (cc = -0.501, P = 0.076). Remaining correlations with treatment outcome, status at admission, imaging findings and inflammatory markers on post-SAH day 5 and 10-12 were negligible or low (-0.5 ≤ cc ≤ 0.5). CONCLUSIONS: In the majority of cases, rupture of a cerebral aneurysm leads to delayed release of soluble TLR forms into CSF. sTLR2 and 4 seem to have minor role in human post-SAH inflammation due to delayed release kinetics and low levels of these protein.

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BACKGROUND: Attempts to clarify mechanisms of early brain injury in subarachnoid hemorrhage (SAH) revealed a high-mobility group box 1 (HMGB1) protein involvement in sterile inflammation initiated by aneurysm rupture. This study aims at assessing the prognostic value of HMGB1 in comparison with traditional biomarkers. METHODS: Ten patients with Fisher grade 4 SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy. HMGB1 level was measured in cerebrospinal fluid (CSF) samples collected on first, fifth, and 10th day. HMGB1 level in first sample was correlated with treatment outcome assessed in Glasgow outcome scale (GOS) at 3 months. Obtained results were compared with plasma inflammatory markers, clinical grading scales, and imaging grading scales. HMGB1 level in consecutive samples was analyzed in search of concentration trends correlating with patients' outcome. RESULTS: HMGB1 level in CSF of SAH patients, in contrast to control group, is significantly elevated (P < .001). Good (GOS > 3) and poor (GOS ≤ 3) outcome patients differ significantly in HMGB1 level on admission (P < .01). The strongest correlation to patients' outcome was found for Hunt and Hess scale (R = -.887, P < .01), HMGB1 level (R = -.859, P < .01), and World Federation of Neurological Surgeons scale (R = -.832, P < .01). Constant and high HMGB1 level of 10 ng/mL or more in consecutive CSF samples identifies nonsurvivors. CONCLUSIONS: HMGB1 protein is elevated in SAH patients. Changes in the concentration of HMGB1 in consecutive samples of the CSF correlate with outcome. Our results encourage further proteomic investigation.

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BACKGROUND AND PURPOSE: Synovial cysts of the spine occur most frequently in the lumbosacral region. Methods of treatment vary, but in cases of chronic pain or neurological deficits surgical intervention is undertaken. The aim of this paper is to present indications, surgical technique and efficacy of surgical treatment in patients with synovial cyst of the spinal canal. MATERIAL AND METHODS: The retrospective analysis included 11 patients, aged from 47 to 72 years, treated at the Department of Neurosurgery and Neurotraumatology, Poznan University of Medical Sciences, between 2004 and 2009. The length of medical history ranged from 2 months to 6 years. Conservative treatment applied before surgery was not effective. Neurological examination revealed unilateral or bilateral sciatica, superficial sensory disturbance or lower limb paresis. RESULTS: Synovial cysts were located mainly at the L4-L5 level (9 cases). Magnetic resonance imaging (MRI) of the spine was performed in all patients and showed the cystic lesion attached to the intervertebral joint. Surgical treatment consisted of a unilateral fenestration using microsurgical techniques in most cases. Back pain relief was observed in 9 cases. In 10 patients, symptoms of sciatica disappeared. Neurological deficits disappeared in 5 patients. CONCLUSIONS: Surgical treatment of spinal synovial cysts is safe, effective and ensures a long-lasting effect. Surgical treatment is indicated in patients in whom the clinical symptoms correlate with the presence of synovial cyst in imaging studies and do not resolve after conservative treatment.

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Hemangioma is the most common primary tumor of the spine. Pregnancy is a risk factor increasing the possibility of disclosure or exacerbation of symptoms of spinal hemangioma. This paper presents a case of 32-year-old woman with hemangioma of Th6 vertebrae, which was revealed by paresis of the lower limbs and sphincters dysfunction at 34 weeks gestation. Pregnancy has ended with a cesarean section. Then posterolateral thoracotomy and removal of hemangioma were performed. Spinal cord was decompressed and stabilization of the spine with metal implants was carried out. Histological examination discovered cavernous hemangioma weaving. The patient is followed up in the outpatient clinic. Despite the improvement of neurological status--enhancement of the sensory function and development of bladder and rectal sphincter automatism--she did not regain the ability to walk alone.

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BACKGROUND AND PURPOSE: Vertebral haemangiomas are relatively common, benign vascular lesions; symptomatic ones that cause spinal cord compression are rare, however. Only 0.9-1.2% of all vertebral haemangiomas are symptomatic. The aim of the paper is to present indications, operative techniques and stabilization methods in patients with symptomatic vertebral haemangiomas. MATERIAL AND METHODS: Clinical analysis included 7 patients treated between 1995 and 2007. There were 4 females and 3 males, aged 24 to 63 yrs (average age 44 yrs). Symptomatic vertebral haemangiomas were diagnosed on the basis of neuroradiological studies. Surgery was applied in all cases. Implantation of internal stabilization followed vertebral haemangioma resection. RESULTS: Localization of vertebral haemangiomas included 1 case in the cervical, 5 cases in the thoracic and 1 case in the lumbar segment of the vertebral column. Symptoms of medulla compression were observed in 7 patients. Neurological symptoms were caused usually by hypertrophy or ballooning of the posterior cortex of the vertebral body into the vertebral canal. The anterior surgical approach was carried out in 2 cases, posterolateral in 3 cases and posterior in 2 cases. Spinal stability was secured by various implant systems and autogenic bone grafts. Bone defects in the vertebral body were filled with acrylic cement in 4 patients. In histological examinations, cavernous types were found in all patients. Neurological condition improved after the treatment in 5 patients. CONCLUSIONS: No standard therapy exists for symptomatic thoracic vertebral haemangiomas. However, immediate surgical intervention is necessary in cases with acute compressive myelopathy before the symptoms become irreversible.

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Giant "invasive" schwannomas of the spine occur occasionally, most frequently in the lumbar region. We present the case of a 46-year-old woman with giant "invasive" schwannoma of the lumbar spine, with a 12-year history of illness. The tu-mour originated in the vertebral canal and passed through the paraspinal muscles and retroperitoneal area to the abdominal cavity. The part of the tumour which was in the abdominal cavity was removed by means of laparotomy during the first operation. In the second one, the remaining part of the tumour was removed completely from the vertebral canal and retroperitoneal area through posterior-lateral access. The spine was stabilized with metal implants. Histological examination revealed cellular schwannoma. During the follow-up the pain resolved while paresis of the right quadriceps muscle of the thigh was still present. Cellular schwannoma is a benign form of schwannoma, but it may cause a local recurrence if not removed completely.

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