Metylaatiostatus, neurodegeneraatio , kognitio

https://www.ncbi.nlm.nih.gov/pubmed/19679632

Clin Chem. 2009 Oct;55(10):1852-60. doi: 10.1373/clinchem.2009.125021. Epub 2009 Aug 13.

Methylation status and neurodegenerative markers in Parkinson disease.

Obeid R¹, Schadt A, Dillmann U, Kostopoulos P, Fassbender K, Herrmann W.Abstract  BACKGROUND:

Increased concentrations of plasma total homocysteine (tHcy) have been associated with age-related diseases, including dementia, stroke, and Parkinson disease (PD). Methylation status might link Hcy metabolism to neurodegenerative proteins in patients with PD.  METHODS:
We tested blood samples from 87 patients with PD (median age 68 years; 35 men) for tHcy, methylmalonic acid (MMA), vitamin B(12), vitamin B(6), folate, S-adenosyl methionine (SAM), S-adenosyl homocysteine (SAH), and amyloid-beta(1-42). We collected citrate blood from a subset of 45 patients to prepare platelet-rich plasma, and we used washed platelets to prepare cell extracts for amyloid precursor protein (APP) and alpha-synuclein assays. We used brain parenchyma sonography to estimate the substantia nigra echogenic area in a subset of 59 patients.  RESULTS:
Serum concentrations of tHcy were increased in PD patients (median 14.8 micromol/L). tHcy (beta coefficient = -0.276) and serum creatinine (beta = -0.422) were significant predictors of the ratio of SAM/SAH in plasma (P < 0.01). The plasma SAM/SAH ratio was a significant determinant for DemTect scores (beta = 0.612, P = 0.004). Significant negative correlations were found between concentrations of SAH in plasma and platelet APP and between SAM and platelet alpha-synuclein. A larger echogenic area of the substantia nigra was related to higher serum concentrations of MMA (P = 0.016).  CONCLUSIONS:
Markers of neurodegeneration (APP, alpha-synuclein) are related to markers of methylation (SAM, SAH) in patients with PD. Better cognitive function was related to higher methylation potential (SAM/SAH ratio). PMID: 19679632

DOI: 10.1373/clinchem.2009.125021

  [Indexed for MEDLINE]

Free full text

B12, Levodopa ja PD

https://www.ncbi.nlm.nih.gov/pubmed/20027219
 

PLoS One. 2009 Dec 21;4(12):e8268. doi: 10.1371/journal.pone.0008268.

Vitamin B12-impaired metabolism produces apoptosis and Parkinson phenotype in rats expressing the transcobalamin-oleosin chimera in substantia nigra.

Orozco-Barrios CE¹, Battaglia-Hsu SF, Arango-Rodriguez ML, Ayala-Davila J, Chery C, Alberto JM, Schroeder H, Daval JL, Martinez-Fong D, Gueant JL.AbstractBACKGROUND:

Vitamin B12 is indispensable for proper brain functioning and cytosolic synthesis of S-adenosylmethionine. Whether its deficiency produces effects on viability and apoptosis of neurons remains unknown. There is a particular interest in investigating these effects in Parkinson disease where Levodopa treatment is known to increase the consumption of S-adenosylmethionine. To cause deprivation of vitamin B12, we have recently developed a cell model that produces decreased synthesis of S-adenosylmethionine by anchoring transcobalamin (TCII) to the reticulum through its fusion with Oleosin (OLEO).
..
 In conclusion, the TCII-OLEO transfection was responsible for apoptosis in N1E-115 cells and rat substantia nigra and for Parkinson-like phenotype. This suggests evaluating whether vitamin B12 deficit could aggravate the PD in patients under Levodopa therapy by impairing S-adenosylmethionine synthesis in substantia nigra.

Neuroprotektiivinen E3 ubikitiiniligaasi MGRN1(RNF156) (16p13.3)

 RNF156, MGRN1 (16p13.3), Mahogunin Ring Finger-1
Expr. Spleen, brain.
https://www.ncbi.nlm.nih.gov/gene/?term=RNF156

Preferred Names

E3 ubiquitin-protein ligase MGRN1

Names

RING finger protein 156

RING-type E3 ubiquitin transferase MGRN1

mahogunin RING finger protein 1

mahogunin ring finger 1, E3 ubiquitin protein ligase

probable E3 ubiquitin-protein ligase MGRN1

Conserved Domains (3) summary

PHA02929
Location:232 → 331

PHA02929; N1R/p28-like protein; Provisional

• The poxviral RING protein p28 is a ubiquitin ligase that targets ubiquitin to viral replication factories.J. Virol. 2005 Jan ; 79(1):597-601
• Genome of deerpox virus.J. Virol. 2005 Jan ; 79(2):966-77
• Genome comparison of a nonpathogenic myxoma virus field strain with its ancestor, the virulent Lausanne strain.J. Virol. 2009 Mar ; 83(5):2397-403

TIGR00599
Location:273 → 449

rad18; DNA repair protein rad18.All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

pfam13920
Location:274 → 319

zf-C3HC4_3; Zinc finger, C3HC4 type (RING finger)

 

Related articles in PubMed

1. MGRN1-mediated ubiquitination of α-tubulin regulates microtubule dynamics and intracellular transport. Mukherjee R, et al. Traffic, 2017 Dec. PMID 28902452
2. Mahogunin ring finger-1 (MGRN1) suppresses chaperone-associated misfolded protein aggregation and toxicity. Chhangani D, et al. Sci Rep, 2013. PMID 23756845, Free PMC Article
3. Calmodulin regulates MGRN1-GP78 interaction mediated ubiquitin proteasomal degradation system. Mukherjee R, et al. FASEB J, 2019 Feb. PMID 30230921
4. Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival. Benvegnù S, et al. Mol Cell, 2017 May 4. PMID 28475871A decline in proteasome function is causally connected to neuronal aging and aging-associated neuropathologies. By using hippocampal neurons in culture and in vivo, we show that aging triggers a reduction and a cytoplasm-to-nucleus redistribution of the E3 ubiquitin ligase mahogunin (MGRN1). Proteasome impairment induces MGRN1 monoubiquitination, the key post-translational modification for its nuclear entry. One potential mechanism for MGRN1 monoubiquitination is via progressive deubiquitination at the proteasome of polyubiquitinated MGRN1. Once in the nucleus, MGRN1 potentiates the transcriptional cellular response to proteotoxic stress. Inhibition of MGRN1 impairs ATF3-mediated neuronal responsiveness to proteosomal stress and increases neuronal stress, while increasing MGRN1 ameliorates signs of neuronal aging, including cognitive performance in old animals. Our results imply that, among others, the strength of neuronal survival in a proteasomal deterioration background, like during aging, depends on the fine-tuning of ubiquitination-deubiquitination.
5. DNA methylation array analysis identifies breast cancer associated RPTOR, MGRN1 and RAPSN hypomethylation in peripheral blood DNA. Tang Q, et al. Oncotarget, 2016 Sep 27. PMID 27577081, Free PMC Article

1. depletion of MGRN1 activity may hamper physiologically important processes like mitochondrial movement in neuronal processes and intracellular transport of ligands through the endosomal pathway thereby contributing to the pathogenesis of neurodegeneration in certain types of prion diseases
2. In a heterologous expression system, MC1R-dependent Arrestins B ubiquitination was enhanced by overexpression of MGRN1 and was impaired by siRNA-mediated MGRN1 knockdown thus pointing to MGRN1 as the responsible E3-ligase.
3. Hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with breast cancer.
4. Regulation of Mfn1 by MGRN1 and the proteasome modulates mitochondrial fusion.
5. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy.
6. Mahogunin-mediated alpha-tubulin ubiquitination via noncanonical K6 linkage regulates microtubule stability and mitotic spindle orientation.
7. data suggest that MGRN1 selectively targets misfolded proteins for degradation and may exhibit viable therapeutic potential for the treatment of spongiform neurodegeneration
8. It therefore seems probable that the role of MGRN1 in the adrenal relates to the trafficking and/or degradation of the melanocortin 2 receptor.
9. Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)D

Select item 310898071.

Chronic and age-dependent effects of the spongiform neurodegeneration-associated MGRN1 E3 ubiquitin ligase (RFN156), Mahoquin Ring finger, Chr.11)    on mitochondrial homeostasis.

Gunn TM, Silvius D, Lester A, Gibbs B.

Mamm Genome. 2019 May 14. doi: 10.1007/s00335-019-09802-7. [Epub ahead of print]

Spongiform encephalopathy is an intriguing yet poorly understood neuropathology characterized by vacuoles, demyelination, and gliosis.
 It is observed

• in patients with prion disease, 
• primary mitochondrial disease,
•  HIV-1 infection of the brain, and 
• some inherited disorders,

 but the underlying mechanism of disease remains unclear. The brains of mice lacking the MGRN1 E3 ubiquitin ligase develop vacuoles by 9 months of age. MGRN1-dependent ubiquitination has been reported to regulate mitofusin 1 and GP78, suggesting MGRN1 may have a direct effect on mitochondrial homeostasis. Here, we demonstrate that some MGRN1 localizes to mitochondria, most likely due to N-myristoylation, and mitochondria in cells from Mgrn1 null mutant mice display fragmentation and depolarization without recruitment of the parkin E3 ubiquitin ligase. The late onset of pathology in the brains of Mgrn1 null mutant mice suggests that a further, age-dependent effect on mitochondrial homeostasis may be required to trigger vacuolation. Parkin protein and mRNA levels showed a significant decline in the brains of Mgrn1 null mutant mice by 12 months of age. To test whether loss of parkin triggers vacuolation through a synergistic effect, we generated Mgrn1; parkin double mutant mice. By 1 month of age, their brains demonstrated more severe mitochondrial dysfunction than Mgrn1 null mutants, but there was no effect on the age-of-onset of spongiform neurodegeneration. Expression of the ATF4 transcription factor, a key regulator of the mitochondrial stress response, also declined in the brains of aged Mgrn1 null mutant mice. Together, the data presented here indicate that loss of MGRN1 has early, direct effects on mitochondrial homeostasis and late, indirect effects on the ability of cells to respond to mitochondrial stress.DOI:10.1007/s00335-019-09802-7

Glioomatutkimuksesta väitöskirja 2019

https://biomedicine.gu.se/biomedicine/News_and_Events/event-detail/?eventId=70136894648

Susanna Larsson - Cell-based models for studying paediatric high grade gliomas

Dissertation

Thesis defense at the Sahlgrenska Academy, Institute of Biomedicine, dept of laboratory medicine

Opponent:
Silvia Marino, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Assessment committee:
Khalil Helou, dept. of oncology, inst. of clinical sciences
Elin Esbjörner Winters, dept. of Biology and Biological Engineering, Chemical Biology, Chalmers University of Technology

In this tttttttttttttt, three pre-clinical models were established which can be used to generate new knowledge and explore new treatment options for paediatric brain tumours. 

 Lapsuusiän  syöpää esiintyy 16:100 000 alle 15-vuotiaissa.
Alle 10-vuotiailla näistä on leukemioita 10% Akuutin lymfaattisen leukemian suhteen on kuitenkin nykyään 5- vuoden elossapysymisprosentti jomiltei 90%.
Keskushermostotuumoreita on 28%.
I
Neuroepiteliaalisesta kudoksesta lähteviä glioomia,
 astrosytoomia on  aivomaligniteeteista noin 45% ( niistä  matala-asteisesti maligneja  I-II noin 31% ja korkea-asteisesti maligneja III-IV asteisia  noin 6%).
Ependymoomia ( aivokammiosta alkuisin olevia) 10.5%,
Oligodendroglioomia 2,5 % ja ne alkavat oligodendrosyyteistä,
Aivorungon glioomia 2,6%.
II
Enbryonaalisia tuumoreita 18.8%
Näissä on medullobastoomia, pikkuaivosolusita lähteviä, 14.8%
ATRT  p,3 % ( atyyppiset teratoidit/rhabdoidit tuumorit)
PNET  (prim. neuroektodermaaliset tuumorit) on siirretty WHO-listalta toiseen ryhmään.
Pediatrista  GBM 2,3%
HGG (High-grade  glioma): anaplastista astrosytoomaa, diffuusia infiltroivaa pontista gliomaa.

Nämä jaetaan 6 ryhmään perustaen DNA-metylaatiotietoihin, ikään, jolloin tuumori alkoi,  tuumorin paikallistumiseen, geeni-ilmenntymiseen, onkogeenivaikuttajiin ja elossapysymisaikaan.
K27
G34
IDH, isositraattidehydrogenaasi
RTK1
Mesenkymaalinen
PXA, pleomorfinen xantoastrosytooma

Aivotuumorit ovat lapsilla suurin ryhmä solideja tuumoreita ja niiden tiliin  lasketaan  useimmat syövästä johtuvat kuolemantapaukset. Astrosytoomia on suurin ryhmä aivotuumoreista  ja korkean asteen gliooma HGG taas on niistä vaarallisin eikä siihen ole tehokkaita hoitoja.  Sen takia tämän taudin parempi käsittäminen on tarpeen ja uusia terapeuttisia  optioita tarvitaan kiireellisesti.
I. Tutkimuksien edistämiseksi  ensimmäisessä osatyössä valmistettiin  viljeltyjä gliooma kantasoluja(GCS), joilla   säilyi proliferoimiskyky ja joissa  esiintyi  hermonkantasolujen markkerit, ja ne antoivat vastetta  differentoiviin signaalilinjoihin.  Lisäksi koehiiriin istutettuina ne panivat alkuun tuumorinkasvun.
II. Toisessa osatyössä seurattiin GSC-transplantaatin aiheuttaman  tuumorin kasvua koehiirissä, xenograftituumoreiden  bistologisia ja molekulaarisia piirteitä. Eloonjääminen  hiirien tuumorista korreloi ihmisten eloonjäämiseen  Lisäksi xenograftituumoreilla  oli sama kasvumalli kuin potilaiden tuumoreilla, geneettiset ja epigeneettiset muuntumiset olivat samanlaisia kuin alkuperäistuumorilla  ja GSC-linjalla.
III. Kolmannessa työssä oli eläinmallina seeprakala, jolla  tätä  gliooma (HGG) laatua tutkittiin, tuumorin alkamispotentiaalia ja invasoivia ominaisuuksia. Kalakudos otti transplantoidut glioomasolut hyvin vastaan ja solut invasoituivat  ympäröivään aivokudokseen jo parissa päivässä.
Täten tässä väitöstyössä tehtiin kolme prekliinistä mallia, joita voidaan käyttää uuden tiedon esiinsaamiseen  lapsuuden aivotuumoreista  ja uusien hoito-optioiden  löytämiseen.
 ..
Kirjassa on runsas luettelo käytetyistä termeistä, niiden lyhennyksistä.(Kirjoitin Abbreviations  itselleni muistiin vihkoon. Niissä on tgerminologiaa , joihin  perehdyn siten ajan myötä)
Tänään luin  CHROMO-domeenin  omaavista proteiineista, jotka mainittiin kirjassa. Kirjoitin niistä geenit (9) Solusykli-blogiini. Kirjassa kerroti taustaosassa histonimodifikaatiosta.


Väitös on edessäpäin, toukokuun lopulla.
Muistiin 16-5- 2019

Aivojen biomarkkereista uusi väitöstyö tänään. Fokus: iskeminen aivohalvaus

https://gupea.ub.gu.se/handle/2077/59055
osatyöt ovat:
I. Pedersen A, Redfors P, Lundberg L, Gils A, Declerck PJ, Nilsson S, Jood K, Jern C. Haemostatic biomarkers are associated with long-term recurrent vascular events after ischaemic stroke. Thromb Haemost. 2016;116: 537-543.
VISA ARTIKEL

II. Pedersen A, Stanne TM, Redfors P, Viken J, Samuelsson H, Nilsson S, Jood K, Jern C. Fibrinogen concentrations predict long-term cognitive outcome in young ischemic stroke patients. Res Pract Thromb Haemost. 2018;2:339-346.
VISA ARTIKEL

III. Pedersen A, Stanne TM, Nilsson S, Klasson S, Rosengren L, Holmegaard L, Jood K, Blennow K, Zetterberg H, Jern C. Circulating neurofilament light in ischemic stroke: Temporal profile and outcome prediction. Submitted manuscript.

IV. Söderholm M*, Pedersen A*, Lorentzen E, Stanne TM, Bevan S, Olsson M, Cole JW, Fernandez-Cadenas I, Hankey GJ, Jimenez-Conde J, Jood K, Lee J-M, Lemmens R, Levi C, Mitchell BD, Norrving B, Rannikmäe K, Rost NS, Rosand J, Rothwell PM, Scott R, Strbian D, Sturm JW, Sudlow C, Traylor M, Thijs V, Tatlisumak T, Woo D, Worrall BB, Maguire JM**, Lindgren A**, Jern C**, on behalf of the International Stroke Genetics Consortium, the NINDS-SiGN Consortium, and the Genetics of Ischaemic Stroke Functional Outcome (GISCOME) network. Genome-wide association meta-analysis of functional outcome after ischemic stroke. Neurology, 2019;92:e1271-e1283. *These authors contributed equally to this work. **These authors jointly supervised this work.
VISA ARTIKEL
The overall aim of this thesis was to identify novel biomarkers for ischemic stroke outcomes. The specific aims were to test the hypotheses that circulating concentrations of hemostatic biomarkers predict the long-term post-stroke risk of recurrent vascular events/death (paper I) and/or cognitive impairment (paper II) and that circulating concentrations of a marker of neuronal damage (neurofilament light chain, NfL) predict post-stroke functional and neurological outcomes (paper III) as well as to identify genetic variants associated with post-stroke functional outcome through a genome wide association study (GWAS) approach (paper IV). Papers I-III are based on the first 600 cases and 600 controls recruited to the Sahlgrenska Academy Study on Ischemic Stroke, which includes consecutive ischemic stroke cases aged 18-69 years and sex- and age-matched population-based controls. In cases, blood sampling was performed in the acute phase, after three months, and in a subset also 7 years post-stroke. Controls were sampled once. These blood samples were used to analyze the protein and genetic biomarkers investigated in this thesis. Vascular events and death up to 14 years after inclusion were identified. In cases, functional and neurological outcomes were assessed at 3 months by the modified Rankin scale (mRS) and the NIH Stroke Scale (NIHSS), respectively. At 2 years, the mRS was assessed again, and in a subsample, long-term (7-year) outcomes were assessed by mRS and NIHSS. The 7-year follow-up also included cognitive testing with the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS) and Trailmaking Test. Paper IV was based on a GWAS approach, i.e. genetic variations spread throughout the entire genome were analyzed with respect to their association to 3-month post-stroke functional outcome in a hypothesis free manner. This study was performed within the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network, and included 6,165 ischemic stroke cases from 12 studies in Europe, USA and Australia. 
 In paper I, we found that plasma levels of hemostatic protein biomarkers were associated with vascular death and coronary events, but not with recurrent stroke.
 In paper II, we found that, in cases <50 at="" b="" index="" stroke="" years="">higher concentrations of the hemostatic protein fibrinogen were independently associated with worse cognitive outcome. 
 In paper III, we found that acute phase and 3-month serum levels of NfL were independently associated to NIHSS and mRS both in short- and long-term follow-up.
 In paper IV, we identified one genetic variant associated with functional outcome (mRS score 0-2 vs 3-6) at genome-wide significance. 
In addition, several genetic variants demonstrated suggestive associations, and some of these are located within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery.
 In conclusion, the results from this thesis demonstrate associations between circulating protein levels as well as genetic markers and ischemic stroke outcomes. These results add knowledge on potential mechanisms influencing outcomes after ischemic stroke and may in the long run contribute to a more personalized post-stroke management.

Kommentti: siis rheologisiä  tekijöitä 8gibrinogeenifunktio)  ja regeneraatiopotentiaalia  (sytoportektiivisuuden ylläpito) voidaan tarvitaessa  yksilöllisesti moduloida) . (Nrf2) 

Muita aivovamman biomarkkereita erikseen ja paneleina

. Duodecim 7/2019 kirjoittaa aiheesta
"Parempaa aivovammapotilaiden diagnostiikkaa ja hoitoa  verikokeen avulla?"
Siteeraan artikkelin  taustatekstiä:
(Jatkuu..)
 Edellä mainittujen proteiinibiomarkkereiden  (S100B, GFAP, UCH-L1) ohella  on tutkittu pieniä verestä mitattavia aineenvaihduntatuotteita kuten rasvahappoja ja glukoosijohdoksia aivovammadiagnostiikassa.    Toisin kuin usean proteiinin näiden aineenvaihduntabiomarkkereiden pääsy verenkiertoon  ei vaadi veri-aivoesteen vauriota.

Aivovammamarkkereiden tutkimuksessa metabolomiikan menetelmiä on toistaiseksi käytetty vileä vähän.
Hiljattain kuuden aineenvaihduntatuotteen yhdistelmän osoitettiin olevan suomalais-brittiläisessä kahden keskuksen tutkimuksessa jopa GFAP_UCH-L1- testiä tarkempi tunnistamaan TT-kuvantamista tarvitsevat potilaat.
Dickens AM, Posti JP, Takala RSK et al. Serum metabolites with computed tomography findings after traumatic brain injury. J neurotrauma 2018

Löydänkin paljon lähteitä hakemalla ylläolevalla tekstillä.  Tässä abstraktissa kerrotaan 8 eri biomarkkerin  tutkimuksesta akuutissa aivovammassa tarkoituksena  pystyä erottamaan  aivovamman eri vaikeusasteissa (Glascow Coma Scale)   TT- positiiviset ja TT negatiiviset aivovammat. 
Tutkimuksessa käytetyt proteiinibiomarkerit ovat:

• beta-amyloidiiisoformi 1-40(Abeta40) 
• beta-amyloidi-isoformi 1-42(Abeta42),
• gliaalinen fibrillaarinen asidinen proteiini GFAP,
• sydänrasvahappoa sitova proteiini H-FABP
• Interleukiini-10 (IL-10)
• kevyt neurofilamentti NF-L
• S100 kalsiumia sitova proteiini B (S100B) 
• Tau proteiini

 TT-negatiiviset ja TT-positiiviset potilaat erotti parhaiten biomarkkerit NF_L, GFAP ja tau  sekä lievien aivovammojen ryhmässä että kaikenasteisten aivovammojen ryhmissä.
Paras kolmen  panelikombinaatio kaikenasteisten aivovammojen ryhmissä oli GFAP +H-FABP + IL10 ja paras kolmen paneli  lievien vammojen ryhmässä oli H-FABP + S100B + tau.   Panelit koostuivat lähinnä eri biomarkkereista kuin niistä, jotka yksinään olivat parhaita erottamassa TT+ ja TT- potilaat.
https://www.liebertpub.com/doi/10.1089/neu.2018.6254 

Abstract

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 (n = 65) and CT-positive (n = 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.

GFAP-UCH-L1-testistä biomarkkeri akuutissa aivovammassa

. Duodecim 7/2019 kirjoittaa aiheesta
"Parempaa aivovammapotilaiden diagnostiikkaa ja hoitoa  verikokeen avulla?"
Siteeraan artikkelin  taustatekstiä:

"Verestä mitattavat aivovammamerkkiaineet ( biomarkkerit) tekevät tuloaan arkipäivän lääketieteeseen.  Yhdysvaltain lääkevalvontaviranopmainen(FDA) hyväksyi vuonna 2018 ensimmäisen testin aivovammapotilaiden kuvantamistarpeen seulontaan. Vuosikymmenien tutkimuksen  ja  odotuksen jälkeen biomarkkerit tuovat lähivuosina aivovammojen arviointiin toivottua objektiivisuutta".

"Väestötason vuosittainen aivovammojen ilmaantuvuus on jopa 790/ 100 000. Näistä vammoista valtaosa on lieviä. Lievien aivovammojen toipumisennuste on pääosin hyvä. Lievää vaikeampiin aivovammoihin liittyy puolestaan merkittävää invaliditeettia ja kuolleisuutta."

"Akuutin aivovamman arvioinnin haasteet voidaan jakaa karkeasti kolmeen teemaan:
(1) pään päivystyksellisen (akuutin)  tietokonekerroskuvauksen (TT, tietokonetomografia) tarve,
(2) lievien aivovammojen diagnostisten kriteerien subjektiivisuus
ja
(3) toipumisennusteen määrittäminen.
Näihin haasteisiin on pyritty löytämään ratkaisuja  tavallisesta verikokeesta, perifeerisestä verestä proteomiikan, genomiikan, metabolomiikan ja immunologian keinoin löydetyillä biomarkkereilla tai biomarkkeriyhdistelmillä. "

"Pään TT-kuvaus on muodostunut kultaiseksi standardiksi kallonsisäisten vammojen akuuttitutkimuksena. (Golden standard:  acute computer tomography)".

Kuvantamistarvetta vähentäville biomarkkereille on selkeä tarve, sillä valtaosa tapaturman vuoksi tehtävistä pään TT-kuvauksista (  jotka ovat kalliitat ja altistavat jonisoivalle säteilylle) on löydöksettömiä, siis aivan normaalilöytöjä.
 ( Tässä tarkoituksessa  2013  on otettu jo käyttöön S100B, muta se ei ole  yksiselitteinen ja riittävä).

Viime vuonna (2018) FDA:n hyväksynnän saanut testi sisältää gliasoluperäisen glial fibrillary acidic (GFAP) ja neuroniperäisen ubiquitin carboxy terminal hydrolase L1 (UCH-L1)-proteiinin pitoisuusmäärityksen.
Nämä biomarkkerit ovat varsin aivokudosspesifisiä:  kuvantaen todettaville aivokudoksen akuuteille vaurioille  ne ovat herkkiä eivätkä  puolestaan reagoi  S100B:n tavoin herkästi kallon ulkopuolisiin vammoihin. Testi validoitiin laajassa tutkimuksessa, joka osoitti testin ennustavan luotettavasti TT(+)-aivovammalöydöksiä lievän aivovamman saaneilla potilailla.
Mikä hidastaa testin kliinistä käyttöönottoa?
Puuttuu riittävän nopeaa laboratorioanalytiikkaa ja hoitopaikkamittauslaitteita ( point-of-care-test) sekä viitearvot:  tarkat potilasryhmäkohtaiset  (esimerkiksi monivamma-, lapsi-,vanhus- ja kroonisia aivosairauksia sairastavat potilaat)  viitearvot uupuvat".  katson mitä tästä testistä löytyy tietoa (Huomaan että UCH-L1 onkin tuttu  molekyyli, se on  deubikitinaasien DUB  yhdeestä alaryhmästä UCH, joten otan siitä erikseen  seuraavassa  geenitiedot ja löytöhistorian, nimet ja referenssit  talteen myös vihkooni DUB-luetteloon). Muitakin biomarkkereita  mainitaan  Duodecimin artikkelisas ja jatkan niistä erikseen.

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Items: 5

Select item 300541511.

GFAP-UCH-L1 test

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.

Bazarian JJ, Biberthaler P et al. 

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Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.

Bazarian JJ, Biberthaler P et al. 

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Löytyi suomalainen tutkimus. 

 

Select item 269633302.

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.

Posti JP, Takala RS, Runtti H, Newcombe VF, Outtrim J, Katila AJ, Frantzén J, Ala-Seppälä H, Coles JP, Hossain MI, Kyllönen A, Maanpää HR, Tallus J, Hutchinson PJ, van Gils M, Menon DK, Tenovuo O.

Neurosurgery. 2016 Sep;79(3):456-64. doi: 10.1227/NEU.0000000000001226. Abstract 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 curve
CI, confidence interval
ED, emergency department
GCS, Glasgow Coma Scale
GFAP, glial fibrillary acidic protein
IMPACT, International Mission for Prognosis and Clinical Trial
ROC, receiver-operating characteristic
TBI, traumatic brain injury
TRACK-TBI, Transforming Research and Clinical Knowledge in Traumatic Brain Injury
UCH-L1, ubiquitin C-terminal hydrolase-L1.

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