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  • Posti, Jussi P.; Takala, Riikka S. K.; Raj, Rahul; Luoto, Teemu M.; Azurmendi, Leire; Lagerstedt, Linnea; Mohammadian, Mehrbod; Hossain, Iftakher; Gill, Jessica; Frantzen, Janek; van Gils, Mark; Hutchinson, Peter J.; Katila, Ari J.; Koivikko, Pia; Maanpää, Henna-Riikka; Menon, David K.; Newcombe, Virginia F.; Tallus, Jussi; Blennow, Kaj; Tenovuo, Olli; Zetterberg, Henrik; Sanchez, Jean-Charles (2020)
    Background: Blood biomarkers may enhance outcome prediction performance of head computed tomography scores in traumatic brain injury (TBI). Objective: 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. Materials and methods: Eighty-two patients with computed tomography positive TBIs were included in this study. Plasma levels of beta-amyloid isoforms 1-40 (A beta 40) and 1-42 (A beta 42), 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, n = 49) and unfavorable (Glasgow Outcome Scale-Extended 1-4, n = 33) groups. The outcome was assessed 6-12 months after injury. An optimal predictive panel was investigated with the sensitivity set at 90-100%. Results: 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 A beta 40, A beta 42, and neurofilament light. The optimal panel included IL-10, A beta 40, 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). Conclusion: Admission plasma levels of IL-10 and A beta 40 significantly improve the prognostication ability of the HCTS after TBI.
  • Pekny, Milos; Wilhelmsson, Ulrika; Tatlisumak, Turgut; Pekna, Marcela (2019)
    Stroke is an acute insult to the central nervous system (CNS) that triggers a sequence of responses in the acute, subacute as well as later stages, with prominent involvement of astrocytes. Astrocyte activation and reactive gliosis in the acute stage of stroke limit the tissue damage and contribute to the restoration of homeostasis. Astrocytes also control many aspects of neural plasticity that is the basis for functional recovery. Here, we discuss the concept of intermediate filaments (nanofilaments) and the complement system as two handles on the astrocyte responses to injury that both present attractive opportunities for novel treatment strategies modulating astrocyte functions and reactive gliosis.
  • Peteri, Ulla-Kaisa; Niukkanen, Mikael; Castren, Maija L. (2019)
    To an increasing extent, astrocytes are connected with various neuropathologies. Astrocytes comprise of a heterogeneous population of cells with region- and species-specific properties. The frontal cortex exhibits high levels of plasticity that is required for high cognitive functions and memory making this region especially susceptible to damage. Aberrations in the frontal cortex are involved with several cognitive disorders, including Alzheimer's disease, Huntington's disease and frontotemporal dementia. Human induced pluripotent stem cells (iPSCs) provide an alternative for disease modeling and offer possibilities for studies to investigate pathological mechanisms in a cell type-specific manner. Patient-specific iPSC-derived astrocytes have been shown to recapitulate several disease phenotypes. Addressing astrocyte heterogeneity may provide an improved understanding of the mechanisms underlying neurodegenerative diseases.
  • Humaloja, Jaana; Ashton, Nicholas J.; Skrifvars, Markus B. (2022)
    This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2022. Other selected articles can be found online at Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.
  • COMACARE Study Groups; Humaloja, Jaana J; Lähde, Marika; Ashton, Nicholas J.; Reinikainen, Matti; Hästbacka, Johanna; Jakkula, Pekka; Friberg, Hans; Cronberg, Tobias; Pettilä, Ville; Blennow, Kaj; Zetterberg, Henrik; Skrifvars, Markus (2022)
    Aim: To determine the ability of serum glial fibrillary acidic protein (GFAp) and tau protein to predict neurological outcome after out-of-hospital cardiac arrest (OHCA). Methods: We measured plasma concentrations of GFAp and tau of patients included in the previously published COMACARE trial (NCT02698917) on intensive care unit admission and at 24, 48, and 72 h after OHCA, and compared them to neuron specific enolase (NSE). NSE concentrations were determined already during the original trial. We defined unfavourable outcome as a cerebral performance category (CPC) score of 3-5 six months after OHCA. We determined the prognostic accuracy of GFAp and tau using the receiver operating characteristic curve and area under the curve (AUROC). Results: Overall, 39/112 (35%) patients had unfavourable outcomes. Over time, both markers were evidently higher in the unfavourable outcome group (p < 0.001). At 48 h, the median (interquartile range) GFAp concentration was 1514 (886-4995) in the unfavourable versus 238 (135-463) pg/ ml in the favourable outcome group (p < 0.001). The corresponding tau concentrations were 99.6 (14.5-352) and 3.0 (2.2-4.8) pg/ml (p < 0.001). AUROCs at 48 and 72 h were 0.91 (95% confidence interval 0.85-0.97) and 0.91 (0.85-0.96) for GFAp and 0.93 (0.86-0.99) and 0.95 (0.89-1.00) for tau. Corresponding AUROCs for NSE were 0.86 (0.79-0.94) and 0.90 (0.82-0.97). The difference between the prognostic accuracies of GFAp or tau and NSE were not statistically significant. Conclusions: At 48 and 72 h, serum both GFAp and tau demonstrated excellent accuracy in predicting outcomes after OHCA but were not superior to NSE. Clinical trial registration: NCT02698917 (
  • Knuutinen, Oula; Kousi, Maria; Suo-Palosaari, Maria; Moilanen, Jukka S.; Tuominen, Hannu; Vainionpää, Leena; Joensuu, Tarja; Anttonen, Anna-Kaisa; Uusimaa, Johanna; Lehesjoki, Anna-Elina; Vieira, Päivi (2018)
    Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.
  • Mattila, Olli S.; Ashton, Nicholas J.; Blennow, Kaj; Zetterberg, Henrik; Harve-Rytsala, Heini; Pihlasviita, Saana; Ritvonen, Juhani; Sibolt, Gerli; Nukarinen, Tiina; Curtze, Sami; Strbian, Daniel; Pystynen, Mikko; Tatlisumak, Turgut; Kuisma, Markku; Lindsberg, Perttu J. (2021)
    BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) and tau are promising markers for differentiating acute cerebral ischemia (ACI) and hemorrhagic stroke (HS), but their prehospital dynamics and usefulness are unknown. METHODS: We performed ultra-sensitivite single-molecule array (Simoa((R))) measurements of plasma GFAP and total tau in a stroke code patient cohort with cardinal stroke symptoms [National Institutes of Health Stroke Scale (NIHSS) >= 3]. Sequential sampling included 2 ultra-early samples, and a follow-up sample on the next morning. RESULTS: We included 272 cases (203 ACI, 60 HS, and 9 stroke mimics). Median (IQR) last-known-well to sampling time was 53 (35-90) minutes for initial prehospital samples, 90 (67-130) minutes for secondary acute samples, and 21 (16-24) hours for next morning samples. Plasma GFAP was significantly higher in patients with HS than ACI (P410pg/mL, or prehospital GFAP 90-410pg/mL together with GFAP release >0.6pg/mL/minute) enabled ruling out HS with high certainty (NPV 98.4%) in 68% of patients with ACI (sensitivity for HS 96.6%, specificity 68%, PPV 50%). CONCLUSIONS: In comparison to single-point measurement, monitoring the prehospital GFAP release rate improves ultra-early differentiation of stroke subtypes. With serial measurement GFAP has potential to improve future prehospital stroke diagnostics.