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)
Search results
Items: 9
1.
Vastagh C, Liposits Z.
Front Cell Neurosci. 2017 Jul 4;11:183. doi: 10.3389/fncel.2017.00183. eCollection 2017.
2. ( Tämä viite Luusto-blogiin luubiologiasta 12.3. 2019)
Nielson
CM, Liu CT, et al.
J Bone Miner Res. 2016 Dec;31(12):2085-2097. doi: 10.1002/jbmr.2913. Epub 2016 Sep 6.
- PMID:
- 27476799
4.
Yu X, Wang G, Gilmore A, Yee AX, Li X, Xu T, Smith SJ, Chen L, Zuo Y.
Neuron. 2013 Oct 2;80(1):64-71. doi: 10.1016/j.neuron.2013.07.014. Epub 2013 Oct 2.Refinement of mammalian neural circuits involves substantial
experience-dependent synapse elimination. Using in vivo two-photon
imaging, we found that experience-dependent elimination of postsynaptic
dendritic spines in the cortex was accelerated in ephrin-A2 knockout (KO) mice, resulting in fewer adolescent spines integrated into adult circuits. Such increased spine removal in ephrin-A2 KOs depended on activation of glutamate
receptors, as blockade of the N-methyl-D-aspartate (NMDA) receptors
eliminated the difference in spine loss between wild-type and KO mice.
We also showed that ephrin-A2 in the cortex colocalized with glial glutamate transporters, which were significantly downregulated in ephrin-A2 KOs. Consistently, glial glutamate transport was reduced in ephrin-A2 KOs, resulting in an accumulation of synaptic glutamate. Finally, inhibition of glial glutamate uptake promoted spine elimination in wild-type mice, resembling the phenotype of ephrin-A2 KOs. Together, our results suggest that ephrin-A2 regulates experience-dependent, NMDA receptor-mediated synaptic pruning through glial glutamate transport during maturation of the mouse cortex.
- PMID:
- 24094103
5.
Ong WY, Tanaka K, Dawe GS, Ittner LM, Farooqui AA.
J Alzheimers Dis. 2013;35(4):643-68. doi: 10.3233/JAD-121990. Review.Abstract
Progress is being
made in identifying possible pathogenic factors and novel genes in the
development of Alzheimer's disease (AD). Many of these could contribute
to 'slow excitotoxicity', defined as neuronal loss due to overexcitation
as a consequence of decreased energy production due, for instance, to
changes in insulin receptor signaling; or receptor abnormalities, such
as tau-induced alterations the N-methyl-D-aspartate (NMDA) receptor
phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate
in a tonic, rather than a phasic manner. Moreover, in prodromal AD
subjects, functional MRI reveals an increase in neural network
activities relative to baseline, rather than loss of activity. This may
be an attempt to compensate for reduced number of neurons, or reflect
ongoing slow excitotoxicity. This article reviews possible links between
AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes
including clusterin, phosphatidylinositol-binding clathrin assembly
protein, complement receptor 1, bridging integrator 1, ATP-binding
cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin
receptor A1; metabolic changes including insulin resistance and
hypercholesterolemia; lipid changes including alterations in brain
phospholipids, cholesterol and ceramides; glial changes affecting
microglia and astrocytes; alterations in brain iron metallome and
oxidative stress; and slow excitotoxicity. Better understanding of the
possible molecular links between pathogenic factors and slow
excitotoxicity could inform our understanding of the disease, and pave
the way towards new therapeutic strategies for AD.
- PMID:
- 23481689
- DOI:
- 10.3233/JAD-121990
- PMID:
- 23481689
6.
Bouvier
D, Tremblay ME, Riad M, Corera AT, Gingras D, Horn KE, Fotouhi M,
Girard M, Murai KK, Kennedy TE, McPherson PS, Pasquale EB, Fon EA,
Doucet G.
J Neurochem. 2010 Apr;113(1):153-65. doi: 10.1111/j.1471-4159.2010.06582.x. Epub 2010 Jan 12. Abstract
EphA4, a receptor
tyrosine kinase, is expressed in various pre-, post- and peri-synaptic
organelles and implicated in the regulation of morphological and
physiological properties of synapses. It regulates synaptic plasticity
by acting as a binding partner for glial ephrin-A3 and possibly other pre- or post-synaptic ephrins. Now, its trafficking mechanisms remain unknown. In this study, we examine the association of EphA4 with transport,
clathrin-coated and synaptic vesicles using cell fractionation, vesicle
immunoisolation and electron microscopy. EphA4 was found in highly
purified fractions of clathrin-coated or synaptic vesicles. It was also
detected in vesicles immuno-isolated with antibodies anti-synaptophysin,
anti-vesicular glutamate transporter or anti-vesicular GABA transporter; demonstrating its presence in synaptic vesicles. However, it was not detected in immuno-isolated piccolo-bassoon transport vesicles. In vivo and in dissociated cultures, EphA4 was localized by immunoelectron microscopy in vesicular glutamate transporter
1-(GLUT-1)positive terminals of hippocampal neurons. Remarkably, the cell
surface immunofluorescence of EphA4 increased markedly in cultured
hippocampal neurons following KCl depolarization. These observations
indicate that EphA4 is present in subsets of synapcltic vesies, can be
externalized during depolarization, and internalized within
clathrin-coated vesicles. This trafficking itinerary may serve to
regulate the levels of EphA4 in the synaptic plasma membrane and thereby
modulate signaling events that contribute to synaptic plasticity.
- PMID:
- 20067584
7.
Filosa
A, Paixão S, Honsek SD, Carmona MA, Becker L, Feddersen B, Gaitanos L,
Rudhard Y, Schoepfer R, Klopstock T, Kullander K, Rose CR, Pasquale EB,
Klein R.
Nat Neurosci. 2009 Oct;12(10):1285-92. doi: 10.1038/nn.2394. Epub 2009 Sep 6. Abstract
Astrocytes
are critical participants in synapse development and function, but
their role in synaptic plasticity is unclear. Eph receptors and their ephrin ligands have been suggested to regulate neuron-glia interactions, and EphA4-mediated ephrin
reverse signaling is required for synaptic plasticity in the
hippocampus. Here we show that long-term potentiation (LTP) at the
CA3-CA1 synapse is modulated by EphA4 in the postsynaptic CA1 cell and
by ephrin-A3, a ligand of EphA4 that is found in astrocytes. Lack of EphA4 increased the abundance of glial glutamate transporters (GLAST), and ephrin-A3 modulated transporter currents in astrocytes. Pharmacological inhibition of glial glutamate transporters rescued the LTP defects in EphA4 (Epha4) and ephrin-A3 (Efna3) mutant mice. Transgenic overexpression of ephrin-A3 in astrocytes reduces glutamate transporter levels and produces focal dendritic swellings possibly caused by glutamate excitotoxicity. These results suggest that EphA4/ephrin-A3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity.
- PMID:
- 19734893
8.
Carmona MA, Murai KK, Wang L, Roberts AJ, Pasquale EB.
Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12524-9. doi: 10.1073/pnas.0903328106. Epub 2009 Jul 10.Increasing evidence indicates the importance of neuron-glia
communication for synaptic function, but the mechanisms involved are not
fully understood. We reported that the EphA4 receptor tyrosine kinase
is in dendritic spines of pyramidal neurons of the adult hippocampus and
regulates spine morphology. We now show that the ephrin-A3
ligand, which is located in the perisynaptic processes of astrocytes,
is essential for maintaining EphA4 activation and normal spine
morphology in vivo. Ephrin-A3-knockout mice have spine irregularities similar to those observed in EphA4-knockout mice. Remarkably, loss of ephrin-A3 or EphA4 increases the expression of glial glutamate transporters. Consistent with this, glutamate transport is elevated in ephrin-A3-null hippocampal slices whereas Eph-dependent stimulation of ephrin-A3 signaling inhibits glutamate transport. Furthermore, some forms of hippocampus-dependent learning are impaired in the ephrin-A3-knockout mice. Our results suggest that the interaction between neuronal EphA4 and glial ephrin-A3 bidirectionally controls synapse morphology and glial glutamate transport, ultimately regulating hippocampal function.
- PMID:
- 19592509
9.
Ogawa Y, Takebayashi H, Takahashi M, Osumi N, Iwasaki Y, Ikenaka K.
Dev Neurosci. 2005;27(6):364-77.
- PMID:
- 16280634