Publications by authors named "Janek Frantzén"

37 Publications

Admission Levels of Interleukin 10 and Amyloid β 1-40 Improve the Outcome Prediction Performance of the Helsinki Computed Tomography Score in Traumatic Brain Injury.

Front Neurol 2020 30;11:549527. Epub 2020 Oct 30.

Department of Specialities of Internal Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). To investigate whether admission levels of eight different protein biomarkers can improve the outcome prediction performance of the Helsinki computed tomography score (HCTS) without clinical covariates in TBI. Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42), glial fibrillary acidic protein, heart fatty acid-binding protein, interleukin 10 (IL-10), neurofilament light, S100 calcium-binding protein B, and total tau were measured within 24 h from admission. The patients were divided into favorable (Glasgow Outcome Scale-Extended 5-8, = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. The HCTS alone yielded a sensitivity of 97.0% (95% CI: 90.9-100) and specificity of 22.4% (95% CI: 10.2-32.7) and partial area under the curve of the receiver operating characteristic of 2.5% (95% CI: 1.1-4.7), in discriminating patients with favorable and unfavorable outcomes. The threshold to detect a patient with unfavorable outcome was an HCTS > 1. The three best individually performing biomarkers in outcome prediction were Aβ40, Aβ42, and neurofilament light. The optimal panel included IL-10, Aβ40, and the HCTS reaching a partial area under the curve of the receiver operating characteristic of 3.4% (95% CI: 1.7-6.2) with a sensitivity of 90.9% (95% CI: 81.8-100) and specificity of 59.2% (95% CI: 40.8-69.4). Admission plasma levels of IL-10 and Aβ40 significantly improve the prognostication ability of the HCTS after TBI.
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http://dx.doi.org/10.3389/fneur.2020.549527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661930PMC
October 2020

Diabetes is associated with familial idiopathic normal pressure hydrocephalus: a case-control comparison with family members.

Fluids Barriers CNS 2020 Sep 15;17(1):57. Epub 2020 Sep 15.

Department of Neurosurgery, Kuopio University Hospital, P.O.Box 100, 70029, Kuopio, KYS, Finland.

Background: The pathophysiological basis of idiopathic normal pressure hydrocephalus (iNPH) is still unclear. Previous studies have shown a familial aggregation and a potential heritability when it comes to iNPH. Our aim was to conduct a novel case-controlled comparison between familial iNPH (fNPH) patients and their elderly relatives, involving multiple different families.

Methods: Questionnaires and phone interviews were used for collecting the data and categorising the iNPH patients into the familial (fNPH) and the sporadic groups. Identical questionnaires were sent to the relatives of the potential fNPH patients. Venous blood samples were collected for genetic studies. The disease histories of the probable fNPH patients (n = 60) were compared with their ≥ 60-year-old relatives with no iNPH (n = 49). A modified Charlson Comorbidity Index (CCI) was used to measure the overall disease burden. Fisher's exact test (two-tailed), the Mann-Whitney U test (two-tailed) and a multivariate binary logistic regression analysis were used to perform the statistical analyses.

Results: Diabetes (32% vs. 14%, p = 0.043), arterial hypertension (65.0% vs. 43%, p = 0.033), cardiac insufficiency (16% vs. 2%, p = 0.020) and depressive symptoms (32% vs. 8%, p = 0.004) were overrepresented among the probable fNPH patients compared to their non-iNPH relatives. In the age-adjusted multivariate logistic regression analysis, diabetes remained independently associated with fNPH (OR = 3.8, 95% CI 1.1-12.9, p = 0.030).

Conclusions: Diabetes is associated with fNPH and a possible risk factor for fNPH. Diabetes could contribute to the pathogenesis of iNPH/fNPH, which motivates to further prospective and gene-environmental studies to decipher the disease modelling of iNPH/fNPH.
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http://dx.doi.org/10.1186/s12987-020-00217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493374PMC
September 2020

A comprehensive p75 neurotrophin receptor gene network and pathway analyses identifying new target genes.

Sci Rep 2020 09 11;10(1):14984. Epub 2020 Sep 11.

Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital and University of Turku, Hämeentie 11, P.O. Box 52, 20521, Turku, Finland.

P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n = 235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (p < 0.05, false discovery rate corrected). Gene network analyses showed multiple known and new targets in the p75NTR gene network. This study provides a comprehensive analysis and investigation into the current knowledge of p75NTR signaling networks and pathways. These results also identify several genes and their respective protein products as involved in the p75NTR network, which have not previously been clearly studied in this pathway. These results can be used to generate novel hypotheses to gain a greater understanding of p75NTR in acute brain injuries, neurodegenerative diseases and general response to cellular damage.
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http://dx.doi.org/10.1038/s41598-020-72061-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486379PMC
September 2020

Alterations in Microstructure and Local Fiber Orientation of White Matter Are Associated with Outcome after Mild Traumatic Brain Injury.

J Neurotrauma 2020 12 17;37(24):2616-2623. Epub 2020 Aug 17.

Department of Clinical Neurosciences, Intensive Care, Emergency Care and Pain Medicine, University of Turku, Turku, Finland.

Mild traumatic brain injury (mTBI) can have long-lasting consequences. We investigated white matter (WM) alterations at 6-12 months following mTBI using diffusion tensor imaging (DTI) and assessed if the alterations associate with outcome. Eighty-five patients with mTBI underwent diffusion-weighted magnetic resonance imaging (MRI) on average 8 months post-injury and patients' outcome was assessed at the time of imaging using the Glasgow Outcome Scale-Extended (GOS-E). Additionally, 30 age-matched patients with extracranial orthopedic injuries were used as control subjects. Voxel-wise analysis of the data was performed using a tract-based spatial statistics (TBSS) approach and differences in microstructural metrics between groups were investigated. Further, the susceptibility of the abnormalities to specific fiber orientations was investigated by analyzing the first eigenvector of the diffusion tensor in the voxels with significant differences. We found significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) and radial diffusivity (RD) in patients with mTBI compared with control subjects, whereas no significant differences were observed in axial diffusivity (AD) between the groups. The differences were present bilaterally in several WM regions and correlated with outcome. Moreover, multiple clusters were found in the principal fiber orientations of the significant voxels in anisotropy, and similar orientation patterns were found for the diffusivity metrics. These directional clusters correlated with patients' functional outcome. Our study showed that mTBI is associated with WM changes at the chronic stage and these alterations occur in several WM regions. In addition, several significant clusters of WM alterations in specific fiber orientations were found and these clusters were associated with outcome.
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http://dx.doi.org/10.1089/neu.2020.7081DOI Listing
December 2020

Cerebral autoregulation after aneurysmal subarachnoid haemorrhage. A preliminary study comparing dexmedetomidine to propofol and/or midazolam.

Acta Anaesthesiol Scand 2020 10 15;64(9):1278-1286. Epub 2020 Jul 15.

Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku, Turku, Finland.

Background: Cerebral autoregulation is often impaired after aneurysmal subarachnoid haemorrhage (aSAH). Dexmedetomidine is being increasingly used, but its effects on cerebral autoregulation in patients with aSAH have not been studied before. Dexmedetomidine could be a useful sedative in patients with aSAH as it enables neurological assessment during the infusion. The aim of this preliminary study was to compare the effects of dexmedetomidine on dynamic and static cerebral autoregulation with propofol and/or midazolam in patients with aSAH.

Methods: Ten patients were recruited. Dynamic and static cerebral autoregulation were assessed using transcranial Doppler ultrasound during propofol and/or midazolam infusion and then during three increasing doses of dexmedetomidine infusion (0.7, 1.0 and 1.4 μg/kg/h). Transient hyperaemic response ratio (THRR) and strength of autoregulation (SA) were calculated to assess dynamic cerebral autoregulation. Static rate of autoregulation (sRoR)% was calculated by using noradrenaline infusion to increase the mean arterial pressure 20 mm Hg above the baseline.

Results: Data from nine patients were analysed. Compared to baseline, we found no statistically significant changes in THRR or sROR%. THRR was (mean ± SD) 1.20 ± 0.14, 1.17 ± 0.13 (P = .93), 1.14 ± 0.09 (P = .72) and 1.19 ± 0.18 (P = 1.0) and sROR% was 150.89 ± 84.37, 75.22 ± 27.75 (P = .08), 128.25 ± 58.35 (P = .84) and 104.82 ± 36.92 (P = .42) at baseline and during 0.7, 1.0 and 1.4 μg/kg/h dexmedetomidine infusion, respectively. Dynamic SA was significantly reduced after 1.0 μg/kg/h dexmedetomidine (P = .02).

Conclusions: Compared to propofol and/or midazolam, dexmedetomidine did not alter static cerebral autoregulation in aSAH patients, whereas a significant change was observed in dynamic SA. Further and larger studies with dexmedetomidine in aSAH patients are warranted.
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http://dx.doi.org/10.1111/aas.13663DOI Listing
October 2020

Finnish study of intraoperative irrigation versus drain alone after evacuation of chronic subdural haematoma (FINISH): a study protocol for a multicentre randomised controlled trial.

BMJ Open 2020 06 21;10(6):e038275. Epub 2020 Jun 21.

Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Uusimaa, Finland.

Introduction: Chronic subdural haematomas (CSDHs) are one of the most common neurosurgical conditions. The goal of surgery is to alleviate symptoms and minimise the risk of symptomatic recurrences. In the past, reoperation rates as high as 20%-30% were described for CSDH recurrences. However, following the introduction of subdural drainage, reoperation rates dropped to approximately 10%. The standard surgical technique includes burr-hole craniostomy, followed by intraoperative irrigation and placement of subdural drainage. Yet, the role of intraoperative irrigation has not been established. If there is no difference in recurrence rates between intraoperative irrigation and no irrigation, CSDH surgery could be carried out faster and more safely by omitting the step of irrigation. The aim of this multicentre randomised controlled trial is to study whether no intraoperative irrigation and subdural drainage results in non-inferior outcome compared with intraoperative irrigation and subdural drainage following burr-hole craniostomy of CSDH.

Methods And Analysis: This is a prospective, randomised, controlled, parallel group, non-inferiority multicentre trial comparing single burr-hole evacuation of CSDH with intraoperative irrigation and evacuation of CSDH without irrigation. In both groups, a passive subdural drain is used for 48 hours as a standard of treatment. The primary outcome is symptomatic CSDH recurrence requiring reoperation within 6 months. The predefined non-inferiority margin for the primary outcome is 7.5%. To achieve a 2.5% level of significance and 80% power, we will randomise 270 patients per group. Secondary outcomes include modified Rankin Scale, rate of mortality, duration of operation, length of hospital stay, adverse events and change in volume of CSDH.

Ethics And Dissemination: The study was approved by the institutional review board of the Helsinki and Uusimaa Hospital District (HUS/3035/2019 §238) and duly registered at ClinicalTrials.gov. We will disseminate the findings of this study through peer-reviewed publications and conference presentations.

Trial Registration Number: NCT04203550.
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http://dx.doi.org/10.1136/bmjopen-2020-038275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311024PMC
June 2020

Admission Levels of Total Tau and β-Amyloid Isoforms 1-40 and 1-42 in Predicting the Outcome of Mild Traumatic Brain Injury.

Front Neurol 2020 13;11:325. Epub 2020 May 13.

Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Turku, Finland.

The purpose of this study was to investigate if admission levels of total tau (T-tau) and β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42) could predict clinical outcome in patients with mild traumatic brain injury (mTBI). A total of 105 patients with mTBI [Glasgow Coma Scale (GCS) ≥ 13] recruited in Turku University Hospital, Turku, Finland were included in this study. Blood samples were drawn within 24 h of admission for analysis of plasma T-tau, Aβ40, and Aβ42. Patients were divided into computed tomography (CT)-positive and CT-negative groups. The outcome was assessed 6-12 months after the injury using the Extended Glasgow Outcome Scale (GOSE). Outcomes were defined as complete (GOSE 8) or incomplete (GOSE < 8) recovery. The Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) was also used to assess mTBI-related symptoms. Predictive values of the biomarkers were analyzed independently, in panels and together with clinical parameters. The admission levels of plasma T-tau, Aβ40, and Aβ42 were not significantly different between patients with complete and incomplete recovery. The levels of T-tau, Aβ40, and Aβ42 could poorly predict complete recovery, with areas under the receiver operating characteristic curve 0.56, 0.52, and 0.54, respectively. For the whole cohort, there was a significant negative correlation between the levels of T-tau and ordinal GOSE score (Spearman ρ = -0.231, = 0.018). In a multivariate logistic regression model including age, GCS, duration of posttraumatic amnesia, Injury Severity Score (ISS), time from injury to sampling, and CT findings, none of the biomarkers could predict complete recovery independently or together with the other two biomarkers. Plasma levels of T-tau, Aβ40, and Aβ42 did not significantly differ between the outcome groups either within the CT-positive or CT-negative subgroups. Levels of Aβ40 and Aβ42 did not significantly correlate with outcome, but in the CT-positive subgroup, the levels of T-tau significantly correlated with ordinal GOSE score (Spearman ρ = -0.288, = 0.035). The levels of T-tau, Aβ40, and Aβ42 were not correlated with the RPCSQ scores. The early levels of T-tau are correlated with the outcome in patients with mTBI, but none of the biomarkers either alone or in any combinations could predict complete recovery in patients with mTBI.
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http://dx.doi.org/10.3389/fneur.2020.00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237639PMC
May 2020

Finnish Trial on Practices of Anterior Cervical Decompression and Fusion (FACADE): a protocol for a prospective randomised non-inferiority trial comparing outpatient versus inpatient care.

BMJ Open 2019 11 26;9(11):e032575. Epub 2019 Nov 26.

Finnish Centre for Evidence-Based Orthopedics (FICEBO), University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: Although a great majority of patients with cervical radiculopathy syndrome can successfully be treated non-operatively, a considerable proportion experience persistent symptoms, severe enough to require neurosurgical intervention. During the past decade, cervical spine procedures have increasingly been performed on an outpatient basis and retrospective database analyses have shown this to be feasible and safe. However, there are no randomised controlled studies comparing outpatient care with inpatient care, particularly with emphasis on the patients' perception of symptom relief and their ability to return to normal daily activities and work.

Methods And Analysis: This is a prospective, randomised, controlled, parallel group non-inferiority trial comparing the traditional hospital surveillance (inpatient, patients staying in the hospital for 1-3 nights after surgery) with outpatient care (discharge on the day of the surgery, usually within 6-8 hours after procedure) in patients who have undergone anterior cervical decompression and fusion procedure. To determine whether early discharge (outpatient care) is non-inferior to inpatient care, we will randomise 104 patients to these two groups and follow them for 6 months using the Neck Disability Index (NDI) as the primary outcome. We expect that early discharge is not significantly worse than the current care in terms of change in NDI. Non-inferiority will be declared if the mean improvement for outpatient care is no worse than the mean improvement for inpatient care, by a margin of 17.3%. We hypothesise that a shorter hospital stay results in more rapid return to normal daily activities, shorter duration of sick leave and decreased secondary costs to healthcare system. Secondary outcomes in our study are arm pain and neck pain using the Numeric Rating Scale, operative success (Odom's criteria), patient's satisfaction to treatment, general quality of life (EQ-5D-5L), Work Ability Score, sickness absence days, return to previous leisure activities and complications.

Ethics And Dissemination: The study was approved by the institutional review board of the Helsinki and Uusimaa Hospital District on 6 June 2019 (1540/2019) and duly registered at ClinicalTrials.gov. We will disseminate the findings of this study through peer-reviewed publications and conference presentations.

Trial Registration Number: NCT03979443.
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http://dx.doi.org/10.1136/bmjopen-2019-032575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886918PMC
November 2019

Correlation of Blood Biomarkers and Biomarker Panels with Traumatic Findings on Computed Tomography after Traumatic Brain Injury.

J Neurotrauma 2019 07 5;36(14):2178-2189. Epub 2019 Apr 5.

13 Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

The aim of the study was to examine the ability of eight protein biomarkers and their combinations in discriminating computed tomography (CT)-negative and CT-positive patients with traumatic brain injury (TBI), utilizing highly sensitive immunoassays in a well-characterized cohort. Blood samples were obtained from 160 patients with acute TBI within 24 h of admission. Levels of β-amyloid isoforms 1-40 (Aβ40) and 1-42 (Aβ42), glial fibrillary acidic protein (GFAP), heart fatty-acid binding protein (H-FABP), interleukin 10 (IL-10), neurofilament light (NF-L), S100 calcium-binding protein B (S100B), and tau were measured. Patients were divided into CT-negative ( = 65) and CT-positive ( = 95), and analyses were conducted separately for TBIs of all severities (Glasgow Coma Scale [GCS] score 3-15) and mild TBIs (mTBIs; GCS 13-15). NF-L, GFAP, and tau were the best in discriminating CT-negative and CT-positive patients, both in patients with mTBI and with all severities. In patients with all severities, area under the curve of the receiver operating characteristic (AUC) was 0.822, 0.817, and 0.781 for GFAP, NF-L, and tau, respectively. In patients with mTBI, AUC was 0.720, 0.689, and 0.676, for GFAP, tau, and NF-L, respectively. The best panel of three biomarkers for discriminating CT-negative and CT-positive patients in the group of all severities was a combination of GFAP+H-FABP+IL-10, with a sensitivity of 100% and specificity of 38.5%. In patients with mTBI, the best panel of three biomarkers was H-FABP+S100B+tau, with a sensitivity of 100% and specificity of 46.4%. Panels of biomarkers outperform individual biomarkers in separating CT-negative and CT-positive patients. Panels consisted mainly of different biomarkers than those that performed best as an individual biomarker.
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http://dx.doi.org/10.1089/neu.2018.6254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909751PMC
July 2019

Gadolinium retention in gliomas and adjacent normal brain tissue: association with tumor contrast enhancement and linear/macrocyclic agents.

Neuroradiology 2019 May 2;61(5):535-544. Epub 2019 Feb 2.

Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.

Purpose: To quantitate gadolinium deposits in gliomas and adjacent normal brain specimens, and to evaluate their association with tumor contrast enhancement and the type of gadolinium-based contrast agent (GBCA) used.

Methods: A total of 69 patients with primary glioma who underwent contrast-enhanced magnetic resonance imaging (MRI) prior to surgery were included in this retrospective study. Gadolinium was measured from histologically viable tumor, normal brain, and necrosis within the sample, when available, using inductively coupled plasma mass spectrometry (ICP-MS). Tumor contrast enhancement was categorized as none, minimal, or noticeable. Differences in gadolinium deposits by contrast enhancement and GBCA type were assessed.

Results: Seven patients received linear GBCA and 62 macrocyclic, respectively. At the time of surgery, gadolinium deposits were detected in 39 out of 69 (57%) tumor samples, 8 out of 13 (62%) normal brain, and 12 out of 14 (86%) necrotic specimens. Gadolinium was detected in both enhancing and non-enhancing tumors, but was greatest in gliomas with noticeable enhancement (p = 0.02). Administration of linear agents gadodiamide and gadopentetate dimeglumine resulted in significantly higher tumor gadolinium relative to macrocyclic gadoterate meglumine (p < 0.01 and p < 0.05, respectively). Normal brain and necrosis also showed higher gadolinium after exposure to linear gadodiamide (both p < 0.05). In multivariate regression, GBCA type (linear/macrocyclic) was the most powerful predictor of tumor gadolinium retention (p < 0.001).

Conclusion: Gadolinium can be detected in both enhancing and non-enhancing gliomas, neighboring normal brain, and necrosis. Gadolinium retention is higher after exposure to linear GBCAs compared with the macrocyclic gadoterate meglumine.
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http://dx.doi.org/10.1007/s00234-019-02172-6DOI Listing
May 2019

Risk Factors for Recurrent Hematoma After Surgery for Acute Traumatic Subdural Hematoma.

World Neurosurg 2019 Jan 10. Epub 2019 Jan 10.

Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital and University of Turku, Turku, Finland; Neurovascular Surgery Program, Section of Neurosurgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA. Electronic address:

Objective: The development of postcraniotomy hematoma (PCH) after surgery for acute traumatic subdural hematoma (aSDH) has been associated with an increased risk of a poor outcome. The risk factors contributing to PCH remain poorly understood. Our aim was to study the potential risk factors for PCH in a consecutive series of surgically evacuated patients with aSDH.

Methods: A total of 132 patients with aSDH treated at Turku University Hospital (Turku, Finland) from 2008 to 2012 were enrolled in the present retrospective cohort study. The demographic, clinical, laboratory, and imaging data were collected from the medical records. A comprehensive analysis of the data using 6 different univariate methods, including machine learning and multivariate analyses, was conducted to identify the factors related to PCH.

Results: The incidence of PCH after primary surgery for traumatic aSDH was 10.6%. The patients experiencing PCH were younger (P = 0.04). No difference was found in the use of anticoagulant or antiplatelet medication for the patients with and without PCH. Multivariate analyses identified alcohol inebriation at the time of injury (odds ratio [OR], 12.67; P = 0.041) and hypocapnia (OR, 26.09; P = 0.003) as independent risk factors for PCH. The patients with PCH had had hyponatremia (OR, 0.08; P = 0.018) less often, and their maximal systolic blood pressure was lower (OR, 0.94; P = 0.009). The area under the curve for the multivariate model was 0.96 (P = 0.049), with a Youden index of 0.88.

Conclusions: The results suggest that alcohol inebriation at the time of injury and hypocapnia during hospitalization are risk factors for the development of PCH.
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http://dx.doi.org/10.1016/j.wneu.2018.12.155DOI Listing
January 2019

Copy number loss in is common among Finnish and Norwegian patients with iNPH.

Neurol Genet 2018 Dec 3;4(6):e291. Epub 2018 Dec 3.

Department of Neurosurgery (V.E.K., A. Jokinen, I.J., J.-M.L., A. Junkkari, J.E.J., V.L.), Kuopio University Hospital and University of Eastern Finland; Institute of Clinical Medicine-Neurology (S.H., M.H., H. Soininen, A.M.K.), University of Eastern Finland, Kuopio; Department of Neurosurgery (M.O., K.L.), University of Helsinki and Helsinki University Hospital; Clinical Neurosciences (C.A., A.K., J.F., J.R.), Department of Neurosurgery, University of Turku and Turku University Hospital; Department of Neurosurgery (A.R.), Tampere University Hospital; Unit of Clinical Neuroscience (M. Kauppinen, V.L.), Neurosurgery, University of Oulu and Medical Research Center, Oulu University Hospital; Institute of Biomedicine (M.H.), University of Eastern Finland, Kuopio; Analytical and Translational Genetics Unit (M. Kurki), Department of Medicine, Massachusetts General Hospital; Program in Medical and Population Genetics (M. Kurki), Broad Institute of MIT and Harvard; Stanley Center for Psychiatric Research (M. Kurki), Broad Institute for Harvard and MIT; Department of Neurology (H. Sato, T.K.), Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Japan; Medical Research Center (A.M.R.), Oulu University Hospital, Finland; Unit of Clinical Neuroscience (A.M.R.), Neurology, University of Oulu, Finland; Department of Neurosurgery (P.K.E.), Oslo University Hospital-Rikshospitalet; and Institute of Clinical Medicine (P.K.E.), Faculty of Medicine, University of Oslo, Norway.

Objective: To evaluate the role of the copy number loss in in a Caucasian population.

Methods: Five hundred sixty-seven Finnish and 377 Norwegian patients with idiopathic normal pressure hydrocephalus (iNPH) were genotyped and compared with 508 Finnish elderly, neurologically healthy controls. The copy number loss in intron 2 of was determined using quantitative PCR.

Results: The copy number loss in intron 2 of was detected in 10% of Finnish (odds ratio [OR] = 1.9, = 0.0078) and in 21% of Norwegian (OR = 4.7, < 0.0001) patients with iNPH compared with 5.4% in Finnish controls. No copy number gains in were detected in patients with iNPH or healthy controls. The carrier status did not provide any prognostic value for the effect of shunt surgery in either population. Moreover, no difference was detected in the prevalence of hypertension or T2DM between copy number loss carriers and noncarriers.

Conclusions: This is the largest and the first multinational study reporting the increased prevalence of the copy number loss in intron 2 of among patients with iNPH, providing further evidence of its role in iNPH. The pathogenic role still remains unclear, requiring further study.
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http://dx.doi.org/10.1212/NXG.0000000000000291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283454PMC
December 2018

Early Levels of Glial Fibrillary Acidic Protein and Neurofilament Light Protein in Predicting the Outcome of Mild Traumatic Brain Injury.

J Neurotrauma 2019 05 8;36(10):1551-1560. Epub 2019 Jan 8.

1 Department of Neurosurgery, Turku University Hospital, Turku, Finland.

The purpose of this study was to correlate the early levels of glial fibrillary acidic protein (GFAP) and neurofilament light protein (NF-L) with outcome in patients with mild traumatic brain injury (mTBI). A total of 107 patients with mTBI (Glasgow Coma Scale ≥13) who had blood samples for GFAP and NF-L available within 24 h of arrival were included. Patients with mTBI were divided into computed tomography (CT)-positive and CT-negative groups. Glasgow Outcome Scale-Extended (GOSE) was used to assess the outcome. Outcomes were defined as complete (GOSE 8) versus incomplete (GOSE <8), and favorable (GOSE 5-8) versus unfavorable (GOSE 1-4). GFAP and NF-L concentrations in blood were measured using ultrasensitive single molecule array technology. Patients with incomplete recovery had significantly higher levels of NF-L compared with those with complete recovery ( = 0.005). The levels of GFAP and NF-L were significantly higher in patients with unfavorable outcome than in patients with favorable outcome ( = 0.002 for GFAP and  < 0.001 for NF-L). For predicting favorable outcome, the area under the receiver operating characteristic curve for GFAP and NF-L was 0.755 and 0.826, respectively. In a multi-variate logistic regression model, the level of NF-L was still a significant predictor for complete recovery (odds ratio [OR] = 1.008; 95% confidence interval [CI], 1.000-1.016). Moreover, the level of NF-L was a significant predictor for complete recovery in CT-positive patients (OR = 1.009; 95% CI, 1.001-1.016). The early levels of GFAP and NF-L are significantly correlated with the outcome in patients with mTBI. The level of NF-L within 24 h from arrival has a significant predictive value in mTBI also in a multi-variate model.
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http://dx.doi.org/10.1089/neu.2018.5952DOI Listing
May 2019

A Decision Support System for Diagnostics and Treatment Planning in Traumatic Brain Injury.

IEEE J Biomed Health Inform 2019 05 1;23(3):1261-1268. Epub 2018 Jun 1.

Traumatic brain injury (TBI) occurs when an external force causes functional or structural alterations in the brain. Clinical characteristics of TBI vary greatly from patient to patient, and a large amount of data is gathered during various phases of clinical care in these patients. It is hard for clinicians to efficiently integrate and interpret all of these data and plan interventions in a timely manner. This paper describes the technical architecture and functionality of a web-based decision support system (DSS), which not only provides advanced support for visualizing complex TBI data but also predicts a possible outcome by using a state-of-the-art Disease State Index machine-learning algorithm. The DSS is developed by using a three-layered architecture and by employing modern programming principles, software design patterns, and using robust technologies (C#, ASP.NET MVC, HTML5, JavaScript, Entity Framework, etc.). The DSS is comprised of a patient overview module, a disease-state prediction module, and an imaging module. After deploying it on a web-server, the DSS was made available to two hospitals in U.K. and Finland. Afterwards, we conducted a validation study to evaluate its usability in clinical settings. Initial results of the study indicate that especially less experience clinicians may benefit from this type of decision support software tool.
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http://dx.doi.org/10.1109/JBHI.2018.2842717DOI Listing
May 2019

Serum Metabolites Associated with Computed Tomography Findings after Traumatic Brain Injury.

J Neurotrauma 2018 11 21;35(22):2673-2683. Epub 2018 Aug 21.

1 Turku Centre for Biotechnology, University of Turku , Turku, Finland .

There is a need to rapidly detect patients with traumatic brain injury (TBI) who require head computed tomography (CT). Given the energy crisis in the brain following TBI, we hypothesized that serum metabolomics would be a useful tool for developing a set of biomarkers to determine the need for CT and to distinguish among different types of injuries observed. Logistical regression models using metabolite data from the discovery cohort (n = 144, Turku, Finland) were used to distinguish between patients with traumatic intracranial findings and those with negative findings on head CT. The resultant models were then tested in the validation cohort (n = 66, Cambridge, United Kingdom). The levels of glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 were also quantified in the serum from the same patients. Despite there being significant differences in the protein biomarkers in patients with TBI, the model that determined the need for a CT scan validated poorly (area under the curve [AUC] = 0.64: Cambridge patients). However, using a combination of six metabolites (two amino acids, three sugar derivatives, and one ketoacid) it was possible to discriminate patients with intracranial abnormalities on CT and patients with a normal CT (AUC = 0.77 in Turku patients and AUC = 0.73 in Cambridge patients). Further, a combination of three metabolites could distinguish between diffuse brain injuries and mass lesions (AUC = 0.87 in Turku patients and AUC = 0.68 in Cambridge patients). This study identifies a set of validated serum polar metabolites, which associate with the need for a CT scan. Additionally, serum metabolites can also predict the nature of the brain injury. These metabolite markers may prevent unnecessary CT scans, thus reducing the cost of diagnostics and radiation load.
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http://dx.doi.org/10.1089/neu.2017.5272DOI Listing
November 2018

A Comparative Ga-Citrate and Ga-Chloride PET/CT Imaging of Osteomyelitis in the Rat Tibia.

Contrast Media Mol Imaging 2018 25;2018:9892604. Epub 2018 Feb 25.

Turku PET Centre, University of Turku, Turku, Finland.

There may be some differences in the behavior of Ga-chloride and Ga-citrate leading to different accumulation profiles. This study compared Ga-citrate and Ga-chloride PET/CT imaging under standardized experimental models. Diffuse tibial osteomyelitis and uncomplicated bone healing rat models were used ( = 32). Two weeks after surgery, PET/CT imaging was performed on consecutive days using Ga-citrate or Ga-chloride, and tissue accumulation was confirmed by analysis. In addition, peripheral quantitative computed tomography and conventional radiography were performed. Osteomyelitis was verified by microbiological analysis and specimens were also processed for histomorphometry. In PET/CT imaging, the SUV of Ga-chloride and Ga-citrate in the osteomyelitic tibias (3.6 ± 1.4 and 4.7 ± 1.5, resp.) were significantly higher ( = 0.0019 and = 0.0020, resp.) than in the uncomplicated bone healing (2.7 ± 0.44 and 2.5 ± 0.49, resp.). In osteomyelitic tibias, the SUV of Ga-citrate was significantly higher than the uptake of Ga-chloride ( = 0.0017). In animals with uncomplicated bone healing, no difference in the SUV of Ga-chloride or Ga-citrate was seen in the operated tibias. This study further corroborates the use of Ga-citrate for PET imaging of osteomyelitis.
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http://dx.doi.org/10.1155/2018/9892604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845485PMC
July 2019

Regional brain morphometry in patients with traumatic brain injury based on acute- and chronic-phase magnetic resonance imaging.

PLoS One 2017 28;12(11):e0188152. Epub 2017 Nov 28.

Imperial College London, Department of Computing, London, United Kingdom.

Traumatic brain injury (TBI) is caused by a sudden external force and can be very heterogeneous in its manifestation. In this work, we analyse T1-weighted magnetic resonance (MR) brain images that were prospectively acquired from patients who sustained mild to severe TBI. We investigate the potential of a recently proposed automatic segmentation method to support the outcome prediction of TBI. Specifically, we extract meaningful cross-sectional and longitudinal measurements from acute- and chronic-phase MR images. We calculate regional volume and asymmetry features at the acute/subacute stage of the injury (median: 19 days after injury), to predict the disability outcome of 67 patients at the chronic disease stage (median: 229 days after injury). Our results indicate that small structural volumes in the acute stage (e.g. of the hippocampus, accumbens, amygdala) can be strong predictors for unfavourable disease outcome. Further, group differences in atrophy are investigated. We find that patients with unfavourable outcome show increased atrophy. Among patients with severe disability outcome we observed a significantly higher mean reduction of cerebral white matter (3.1%) as compared to patients with low disability outcome (0.7%).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0188152PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705131PMC
December 2017

Quantitative EEG Parameters for Prediction of Outcome in Severe Traumatic Brain Injury: Development Study.

Clin EEG Neurosci 2018 Jul 27;49(4):248-257. Epub 2017 Nov 27.

3 University of Turku, Turku, Finland.

Monitoring of quantitative EEG (QEEG) parameters in the intensive care unit (ICU) can aid in the treatment of traumatic brain injury (TBI) patients by complementing visual EEG review done by an expert. We performed an explorative study investigating the prognostic value of 59 QEEG parameters in predicting the outcome of patients with severe TBI. Continuous EEG recordings were done on 28 patients with severe TBI in the ICU of Turku University Hospital. We computed a set of QEEG parameters for each patient, and correlated these to patient outcome, measured by dichotomized Glasgow Outcome Scale (GOS) at a follow-up visit between 6 and 12 months, using area under receiver operating characteristic curve (AUC) as a nonlinear correlation measure. For 17 of the 59 QEEG parameters (28.8%), the AUC differed significantly from 0.5, most of these parameters measured EEG power or variability. The best QEEG parameters for outcome prediction were alpha power (AUC = 0.87, P < .01) and variability of the relative fast theta power (AUC = 0.84, P < .01). The results of this study indicate that QEEG parameters provide useful information for predicting outcome in severe TBI. Novel QEEG parameters with potential in outcome prediction were found, the prognostic value of these parameters should be confirmed in later studies. The results also provide further evidence of the usefulness of parameters studied in preexisting studies.
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http://dx.doi.org/10.1177/1550059417742232DOI Listing
July 2018

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination.

Stem Cells Transl Med 2017 10 23;6(10):1840-1851. Epub 2017 Sep 23.

Division of Clinical Immunology, Department of Laboratory Medicine, Finland.

Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRβ), CD73, CD271, alpha-smooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146 PDGFRβ Ki67 cells and CD73 CD271 PDGFRβ Ki67 cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146 PDGFRβ Ki67 and CD73 CD271 PDGFRβ Ki67 MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146 PDGFRβ Ki67 MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73 CD271 adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS. Stem Cells Translational Medicine 2017;6:1840-1851.
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http://dx.doi.org/10.1002/sctm.17-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430046PMC
October 2017

Accuracy of 837 pedicle screw positions in degenerative lumbar spine with conventional open surgery evaluated by computed tomography.

Acta Neurochir (Wien) 2017 10 10;159(10):2011-2017. Epub 2017 Aug 10.

Division of Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, Hämeentie 11, 20521, Turku, Finland.

Background: The spatial and directional accuracy of the positioning of pedicle screws in the lumbosacral spine with conventional open surgery assessed by computed tomography (CT) has been published in several studies, systematic reviews and meta-analyses with a short-term follow-up. Inaccurate pedicle screw insertion may cause neurologic symptoms and weakens the construct.

Methods: The data of 147 patients operated on with transpedicular screw fixation based on anatomical landmarks, supported by fluoroscopy, by a senior neurosurgeon in our clinic between 2000 and 2010 were analyzed retrospectively. The accuracy of the pedicle screw position was assessed by using postoperative CT images and graded in 2-mm increments up to 6 mm by two independent surgeons and partly by an independent radiologist.

Results: A total of 837 lumbosacral pedicle screws were inserted in 147 randomly selected patients by a senior neurosurgeon. A mean accuracy of 85.7% of the screws being inside the pedicles was identified by the surgeon observers, with 3.3% being perforated 4 mm or more outside the pedicles. Postoperative neurologic symptoms were observed on the side corresponding to the breach in an average of 25.9% of patients with pedicle perforations, and 89.2% of the misplaced screws were either medially or inferiorly inserted.

Conclusions: Screw application reached a mean accuracy of 85.7% based on anatomical landmarks supported by fluoroscopy, warranting computer-assisted navigation for increased accuracy. Our results of 24 patients (16.3%) with the breached screws indicate that the direction of the breach may be more important than the absolute deviation in causing new neurologic symptoms.
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http://dx.doi.org/10.1007/s00701-017-3289-7DOI Listing
October 2017

High angular resolution diffusion-weighted imaging in mild traumatic brain injury.

Neuroimage Clin 2017 17;13:174-180. Epub 2016 Nov 17.

Department of Neurology, University of Turku, Turku, Finland; Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland.

We sought to investigate white matter abnormalities in mild traumatic brain injury (mTBI) using diffusion-weighted magnetic resonance imaging (DW-MRI). We applied a global approach based on tract-based spatial statistics skeleton as well as constrained spherical deconvolution tractography. DW-MRI was performed on 102 patients with mTBI within two months post-injury and 30 control subjects. A robust global approach considering only the voxels with a single-fiber configuration was used in addition to global analysis of the tract skeleton and probabilistic whole-brain tractography. In addition, we assessed whether the microstructural parameters correlated with age, time from injury, patient's outcome and white matter MRI hyperintensities. We found that whole-brain global approach restricted to single-fiber voxels showed significantly decreased fractional anisotropy (FA) (p = 0.002) and increased radial diffusivity (p = 0.011) in patients with mTBI compared with controls. The results restricted to single-fiber voxels were more significant and reproducible than those with the complete tract skeleton or the whole-brain tractography. FA correlated with patient outcomes, white matter hyperintensities and age. No correlation was observed between FA and time of scan post-injury. In conclusion, the global approach could be a promising imaging biomarker to detect white matter abnormalities following traumatic brain injury.
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http://dx.doi.org/10.1016/j.nicl.2016.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144744PMC
November 2017

Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 Are Not Specific Biomarkers for Mild CT-Negative Traumatic Brain Injury.

J Neurotrauma 2017 Jan 27. Epub 2017 Jan 27.

2 Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital , Turku, Finland .

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) have been studied as potential biomarkers of mild traumatic brain injury (mTBI). We report the levels of GFAP and UCH-L1 in patients with acute orthopedic injuries without central nervous system involvement, and relate them to the type of extracranial injury, head magnetic resonance imaging (MRI) findings, and levels of GFAP and UCH-L1 in patients with CT-negative mTBI. Serum UCH-L1 and GFAP were longitudinally measured from 73 patients with acute orthopedic injury on arrival and on days 1, 2, 3, 7 after admission, and on the follow-up visit 3-10 months after the injury. The injury types were recorded, and 71% patients underwent also head MRI. The results were compared with those found in patients with CT-negative mTBI (n = 93). The levels of GFAP were higher in patients with acute orthopedic trauma than in patients with CT-negative mTBI (p = 0.026) on arrival; however, no differences were found on the following days. The levels of UCH-L1 were not significantly different between these two groups at any measured point of time. Levels of GFAP and UCH-L1 were not able to distinguish patients with CT-negative mTBI from patients with orthopedic trauma. Patients with orthopedic trauma and high levels of UCH-L1 or GFAP values may be falsely diagnosed as having a concomitant mTBI, predisposing them to unwarranted diagnostics and unnecessary brain imaging. This casts a significant doubt on the diagnostic value of GFAP and UCH-L1 in cases with mTBI.
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http://dx.doi.org/10.1089/neu.2016.4442DOI Listing
January 2017

Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury.

EBioMedicine 2016 Oct 15;12:118-126. Epub 2016 Jul 15.

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI-20520 Turku, Finland; Steno Diabetes Center A/S, DK-2820 Gentofte, Denmark; VTT Technical Research Centre of Finland, FI-02044, VTT, Espoo, Finland; Clinical Research Institute, Helsinki University Central Hospital, FI-00290 Helsinki, Finland; Department of Chemistry, Örebro University, 702 81 Örebro, Sweden. Electronic address:

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. TBI is an example of a medical condition where there are still major lacks in diagnostics and outcome prediction. Here we apply comprehensive metabolic profiling of serum samples from TBI patients and controls in two independent cohorts. The discovery study included 144 TBI patients, with the samples taken at the time of hospitalization. The patients were diagnosed as severe (sTBI; n=22), moderate (moTBI; n=14) or mild TBI (mTBI; n=108) according to Glasgow Coma Scale. The control group (n=28) comprised of acute orthopedic non-brain injuries. The validation study included sTBI (n=23), moTBI (n=7), mTBI (n=37) patients and controls (n=27). We show that two medium-chain fatty acids (decanoic and octanoic acids) and sugar derivatives including 2,3-bisphosphoglyceric acid are strongly associated with severity of TBI, and most of them are also detected at high concentrations in brain microdialysates of TBI patients. Based on metabolite concentrations from TBI patients at the time of hospitalization, an algorithm was developed that accurately predicted the patient outcomes (AUC=0.84 in validation cohort). Addition of the metabolites to the established clinical model (CRASH), comprising clinical and computed tomography data, significantly improved prediction of patient outcomes. The identified 'TBI metabotype' in serum, that may be indicative of disrupted blood-brain barrier, of protective physiological response and altered metabolism due to head trauma, offers a new avenue for the development of diagnostic and prognostic markers of broad spectrum of TBIs.
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http://dx.doi.org/10.1016/j.ebiom.2016.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078571PMC
October 2016

Familial idiopathic normal pressure hydrocephalus.

J Neurol Sci 2016 Sep 25;368:11-8. Epub 2016 Jun 25.

Department of Neurosurgery, Kuopio University Hospital, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. Electronic address:

Idiopathic normal pressure hydrocephalus (iNPH) is a late-onset surgically alleviated, progressive disease. We characterize a potential familial subgroup of iNPH in a nation-wide Finnish cohort of 375 shunt-operated iNPH-patients. The patients were questionnaired and phone-interviewed, whether they have relatives with either diagnosed iNPH or disease-related symptomatology. Then pedigrees of all families with more than one iNPH-case were drawn. Eighteen patients (4.8%) from 12 separate pedigrees had at least one shunt-operated relative whereas 42 patients (11%) had relatives with two or more triad symptoms. According to multivariate logistic regression analysis, familial iNPH-patients had up to 3-fold risk of clinical dementia compared to sporadic iNPH patients. This risk was independent from diagnosed Alzheimer's disease and APOE ε4 genotype. This study describes a familial entity of iNPH offering a novel approach to discover the potential genetic characteristics of iNPH. Discovered pedigrees offer an intriguing opportunity to conduct longitudinal studies targeting potential preclinical signs of iNPH.
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http://dx.doi.org/10.1016/j.jns.2016.06.052DOI Listing
September 2016

Injury profiles, demography and representativeness of patients with TBI attending a regional emergency department.

Brain Inj 2016 13;30(9):1062-7. Epub 2016 Jun 13.

a Department of Neurology , University of Turku , Finland.

Objectives: The aim of this study was to describe the demography and epidemiology of Finnish patients with TBI and to analyse the representativeness of a study sample.

Materials And Methods: This prospective multi-centre study was conducted as part of an international collaboration within the EU-funded TBIcare project. The study group was recruited from patients attending the regional emergency department (ED) of the Turku University Hospital, Finland. Pre-defined exclusion criteria included age < 18 years, more than 2 weeks from the injury and uncertain diagnosis of TBI. To be included, a need for an acute head CT (NICE-criteria) was required.

Results: Of the 620 patients with TBI or suspected TBI, 203 patients were recruited to the study. Falls were the most common injury mechanism. The study group included more males than the total eligible population (p = 0.011), but no other statistical differences were found. The most common cause for being excluded was lack of information available to the research group before discharge (34%).

Conclusion: This study supports previous findings that falls are the most common injury mechanism in the Western countries. Uncertainty about the diagnosis of TBI, lack of representativeness without continuous recruitment and poor information transfer about the ED attendees are major challenges for prospective TBI studies.
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http://dx.doi.org/10.3109/02699052.2016.1170880DOI Listing
January 2018

The Levels of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 During the First Week After a Traumatic Brain Injury: Correlations With Clinical and Imaging Findings.

Neurosurgery 2016 Sep;79(3):456-64

*Division of Clinical Neurosciences, Department of Neurosurgery and ‡Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital, Turku, Finland; §Department of Neurology, University of Turku, Turku, Finland; ¶Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital and University of Turku, Turku, Finland; ‖Systems Medicine, VTT Technical Research Centre of Finland, Tampere, Finland; #Division of Anaesthesia, Department of Medicine and **Department of Clinical Neurosciences, Neurosurgery Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.

Background: Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) are promising biomarkers of traumatic brain injury (TBI).

Objective: We investigated the relation of the GFAP and UCH-L1 levels to the severity of TBI during the first week after injury.

Methods: Plasma UCH-L1 and GFAP were measured from 324 consecutive patients with acute TBI and 81 control subject enrolled in a 2-center prospective study. The baseline measures included initial Glasgow Coma Scale (GCS), head computed tomographic (CT) scan at admission, and blood samples for protein biomarkers that were collected at admission and on days 1, 2, 3, and 7 after injury.

Results: Plasma levels of GFAP and UCH-L1 during the first 2 days after the injury strongly correlated with the initial severity of TBI as assessed with GCS. Additionally, levels of UCH-L1 on the seventh day after the injury were significantly related to the admission GCS scores. At admission, both biomarkers were capable of distinguishing mass lesions from diffuse injuries in CT, and the area under the curve of the receiver-operating characteristic curve for prediction of any pathological finding in CT was 0.739 (95% confidence interval, 0.636-0.815) and 0.621 (95% confidence interval, 0.517-0.713) for GFAP and UCH-L1, respectively.

Conclusion: These results support the prior findings of the potential role of GFAP and UCH-L1 in acute-phase diagnostics of TBI. The novel finding is that levels of GFAP and UCH-L1 correlated with the initial severity of TBI during the first 2 days after the injury, thus enabling a window for TBI diagnostics with latency.

Abbreviations: AUC, area under the curveCI, confidence intervalED, emergency departmentGCS, Glasgow Coma ScaleGRAP, glial fibrillary acidic proteinIMPACT, International Mission for Prognosis and Clinical TrialROC, receiver-operating characteristicTBI, traumatic brain injuryTRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain InjuryUCH-L1, ubiquitin C-terminal hydrolase-L1.
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http://dx.doi.org/10.1227/NEU.0000000000001226DOI Listing
September 2016

A glass fiber-reinforced composite - bioactive glass cranioplasty implant: A case study of an early development stage implant removed due to a late infection.

J Mech Behav Biomed Mater 2015 Mar 7;55:191-200. Epub 2015 Nov 7.

Department of Otorhinolaryngology - Head and Neck Surgery, Division of Surgery and Cancer Diseases, Turku University Hospital, PO Box 52, 20521 Turku, Finland; City of Turku Welfare Division, PO Box 670, 20101 Turku, Finland.

This case study describes the properties of an early development stage bioactive glass containing fiber-reinforced composite calvarial implant with histology that has been in function for two years and three months. The patient is a 33-year old woman with a history of substance abuse, who sustained a severe traumatic brain injury later unsuccessfully treated with an autologous bone flap and a custom-made porous polyethylene implant. She was thereafter treated with developmental stage glass fiber-reinforced composite - bioactive glass implant. After two years and three months, the implant was removed due to an implant site infection. The implant was analyzed histologically, mechanically, and in terms of chemistry and dissolution of bioactive glass. Mechanical integrity of the load bearing fiber-reinforced composite part of the implant was not affected by the in vivo period. Bioactive glass particles demonstrated surface layers of hydroxyapatite like mineral and dissolution, and related increase of pH was considerably less after two and three months period than that for fresh bioactive glass. There was a difference in the histology of the tissues inside the implant areas near to the margin of the implant that absorbed blood during implant installation surgery, showed fibrous tissue with blood vessels, osteoblasts, collagenous fibers with osteoid formation, and tiny clusters of more mature hard tissue. In the center of the implant, where there was less absorbed blood, only fibrous tissue was observed. This finding is in line with the combined positron emission tomography - computed tomography examination with (18F)-fluoride marker, which demonstrated activity of the mineralizing bone by osteoblasts especially at the area near to the margin of the implant 10 months after implantation. Based on these promising reactions found in the bioactive glass containing fiber-reinforced composite implant that has been implanted for two years and three months, calvarial reconstruction with the presented material appears to be a feasible method.
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http://dx.doi.org/10.1016/j.jmbbm.2015.10.030DOI Listing
March 2015

Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase-L1 as Outcome Predictors in Traumatic Brain Injury.

World Neurosurg 2016 Mar 10;87:8-20. Epub 2015 Nov 10.

Division of Clinical Neurosciences, Department of Rehabilitation and Brain Trauma, Turku University Hospital and University of Turku, Turku, Finland; Department of Neurology, University of Turku, Turku, Finland.

Objective: Biomarkers ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) may help detect brain injury, assess its severity, and improve outcome prediction. This study aimed to evaluate the prognostic value of these biomarkers during the first days after brain injury.

Methods: Serum UCH-L1 and GFAP were measured in 324 patients with traumatic brain injury (TBI) enrolled in a prospective study. The outcome was assessed using the Glasgow Outcome Scale (GOS) or the extended version, Glasgow Outcome Scale-Extended (GOSE).

Results: Patients with full recovery had lower UCH-L1 concentrations on the second day and patients with favorable outcome had lower UCH-L1 concentrations during the first 2 days compared with patients with incomplete recovery and unfavorable outcome. Patients with full recovery and favorable outcome had significantly lower GFAP concentrations in the first 2 days than patients with incomplete recovery or unfavorable outcome. There was a strong negative correlation between outcome and UCH-L1 in the first 3 days and GFAP levels in the first 2 days. On arrival, both UCH-L1 and GFAP distinguished patients with GOS score 1-3 from patients with GOS score 4-5, but not patients with GOSE score 8 from patients with GOSE score 1-7. For UCH-L1 and GFAP to predict unfavorable outcome (GOS score ≤ 3), the area under the receiver operating characteristic curve was 0.727, and 0.723, respectively. Neither UCHL-1 nor GFAP was independently able to predict the outcome when age, worst Glasgow Coma Scale score, pupil reactivity, Injury Severity Score, and Marshall score were added into the multivariate logistic regression model.

Conclusions: GFAP and UCH-L1 are significantly associated with outcome, but they do not add predictive power to commonly used prognostic variables in a population of patients with TBI of varying severities.
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http://dx.doi.org/10.1016/j.wneu.2015.10.066DOI Listing
March 2016

Serum levels of GFAP and EGFR in primary and recurrent high-grade gliomas: correlation to tumor volume, molecular markers, and progression-free survival.

J Neurooncol 2015 Sep 2;124(2):237-45. Epub 2015 Jun 2.

Department of Oncology and Radiotherapy, Turku University Hospital, Hämeentie 11, 20521, Turku, Finland.

Our aim was to study the association of two potential serum biomarkers glial fibrillary acidic protein (GFAP) and epidermal growth factor receptor (EGFR) with prognostic markers such as IDH1 mutation, tumor burden, and survival in patients with high-grade gliomas (HGG). Additionally, our objective was to evaluate the potential of serum EGFR as a surrogate marker for EGFR status in the tumor. Pre-operative serum samples were prospectively collected from patients with primary (n = 17) or recurrent (n = 10) HGG. Serum GFAP and EGFR levels were determined by ELISA and studied for correlation with molecular markers including EGFR amplification, tumor volume in contrast-enhanced T1-weighted MRI, and progression-free survival (PFS). Pre-operative serum GFAP level of ≥0.014 ng/ml was 86 % sensitive and 85 % specific for the diagnosis of glioblastoma. High GFAP was related to the lack of IDH1 mutation (P = 0.016), high Ki67 proliferation index (P < 0.001), and poor PFS (HR 5.9, CI 1.2-29.9, P = 0.032). Serum GFAP correlated with enhancing tumor volume in primary (r = 0.64 P = 0.005), but also in recurrent HGGs (r = 0.76 P = 0.011). In contrast, serum EGFR levels did not differ between HGG patients and 13 healthy controls, and were not related to EGFR status in the tumor. We conclude that high serum GFAP associates with IDH1 mutation-negative HGG, and poor PFS. Correlation with tumor burden in recurrent HGG implicates the potential of serum GFAP for detection of tumor recurrence. Our results suggest that circulating EGFR is not derived from glioma cells and cannot be used as a marker for EGFR status in the tumor.
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http://dx.doi.org/10.1007/s11060-015-1829-7DOI Listing
September 2015

Somatostatin receptor subtype 2 in high-grade gliomas: PET/CT with (68)Ga-DOTA-peptides, correlation to prognostic markers, and implications for targeted radiotherapy.

EJNMMI Res 2015 22;5:25. Epub 2015 Apr 22.

Department of Oncology and Radiotherapy, Turku University Hospital, Hämeentie 11, 20521 Turku, Finland.

Background: High-grade gliomas (HGGs) express somatostatin receptors (SSTR), rendering them candidates for peptide receptor radionuclide therapy (PRRT). Our purpose was to evaluate the potential of (68)Ga-DOTA-1-Nal(3)-octreotide ((68)Ga-DOTANOC) or (68)Ga-DOTA-Tyr(3)-octreotide ((68)Ga-DOTATOC) to target SSTR subtype 2 (SSTR2) in HGGs, and to study the association between SSTR2 expression and established biomarkers.

Methods: Twenty-seven patients (mean age 52 years) with primary or recurrent HGG prospectively underwent (68)Ga-DOTA-peptide positron emission tomography/computed tomography (PET/CT) before resection. Maximum standardized uptake values (SUVmax) and receptor binding potential (BP) were calculated on PET/CT and disruption of blood-brain barrier (BBB) from contrast-enhanced T1-weighted magnetic resonance imaging (MRI-T1-Gad). Tumor volume concordance between PET and MRI-T1-Gad was assessed by Dice similarity coefficient (DC) and correlation by Spearman's rank. Immunohistochemically determined SSTR2 status was compared to receptor imaging findings, prognostic biomarkers, and survival with Kruskal-Wallis, Pearson chi-square, and multivariate Cox regression, respectively.

Results: All 19 HGGs with disrupted BBB demonstrated tracer uptake. Tumor SUVmax (2.25 ± 1.33) correlated with MRI-T1-Gad (r = 0.713, P = 0.001) although DC 0.41 ± 0.19 suggested limited concordance. SSTR2 immunohistochemistry was regarded as positive in nine HGGs (32%) but no correlation with SUVmax or BP was found. By contrast, SSTR2 expression was associated with IDH1 mutation (P = 0.007), oligodendroglioma component (P = 0.010), lower grade (P = 0.005), absence of EGFR amplification (P = 0.021), and longer progression-free survival (HR 0.161, CI 0.037 to 0.704, P = 0.015).

Conclusions: In HGGs, uptake of (68)Ga-DOTA-peptides is associated with disrupted BBB and cannot be predicted by SSTR2 immunohistochemistry. Thus, PET/CT shows limited value to detect HGGs suitable for PRRT. However, high SSTR2 expression portends favorable outcome along with established biomarkers such as IDH1 mutation.

Trial Registration: ClinicalTrials.gov NCT01460706.
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http://dx.doi.org/10.1186/s13550-015-0106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420768PMC
May 2015