| 1. |
- Ay, Hakan, et al.
(författare)
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Pathogenic Ischemic Stroke Phenotypes in the NINDS-Stroke Genetics Network
- 2014
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Ingår i: Stroke. - 0039-2499. ; 45:12, s. 3589-3596
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.
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| 2. |
- Lövkvist, Håkan, et al.
(författare)
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A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:7, s. 783-789
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Tidskriftsartikel (refereegranskat)abstract
- Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmo Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants <55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10 500 patients and 10 102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR=0.93; 95% confidence interval (CI): 0.83-1.05). Significant associations were not found for hypertensive participants or participants with age <55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR=0.96; 95% CI: 0.89-1.04) with significant heterogeneity for random effect (P=0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either. European Journal of Human Genetics (2012) 20, 783-789; doi: 10.1038/ejhg.2012.4; published online 25 January 2012
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| 3. |
- Lövkvist, Håkan, et al.
(författare)
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Are 25 SNPs from the CARDIoGRAM study associated with ischaemic stroke?
- 2013
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 20:9, s. 1284-1291
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Study (CARDIoGRAM) reported 25 single-nucleotide polymorphisms (SNPs) on 15 chromosomes to be associated with coronary artery disease (CAD) risk. Because common vascular risk factors are shared between CAD and ischaemic stroke (IS), these SNPs may also be related to IS overall or one or more of its pathogenetic subtypes. Methods: We performed a candidate gene study comprising 3986 patients with IS and 2459 control subjects. The 25 CAD-associated SNPs reported by CARDIoGRAM were examined by allelic association analysis including logistic regression. Weighted and unweighted genetic risk scores (GRSs) were also compiled and likewise analysed against IS. We furthermore considered the IS main subtypes large-vessel disease (LVD), small-vessel disease and cardioembolic stroke [according to Trial of Org 10172 in Acute Stroke Treatment (TOAST)] separately. Results: SNP rs4977574 on chromosome 9p21.3 was associated with overall IS [odds ratio (OR) = 1.12; 95% confidence interval (CI): 1.04-1.20; P = 0.002] as well as LVD (OR = 1.36; 95% CI: 1.13-1.64; P = 0.001). No other SNP was significantly associated with IS or any of its main subtypes. Analogously, the GRSs did not show any noticeable effect. Conclusions: Besides the previously reported association with SNPs on chromosome 9p21, this study did not detect any significant association between IS and CAD-susceptible genetic variants. Also, GRSs compiled from these variants did not predict IS or any pathogenetic IS subtype, despite a total sample size of 6445 participants.
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| 4. |
- Andsberg, Gunnar
(författare)
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Experimental Stroke and Neurotrophins: Regulation, function and gene transfer of neurotrophins in rat and mouse models of focal cerebral ischemia
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stroke caused by focal cerebral ischemia is a major cause of death and neurological disability in humans. The forebrain region most commonly affected by ischemic incidents is that supplied by the middle cerebral artery. In this thesis, neuronal cell death has been investigated using immunohistochemistry for identification of specific neurons and unbiased counting methods after transient occlusion of the middle cerebral artery (MCAO). Our studies show that striatal projection neurons and parvalbumin-containing interneurons are vulnerable, whereas cholinergic and NOS-containing interneurons are highly resistant to MCAO. The high potency of the neurotrophin family of neurotrophic factors to inhibit neuronal death in immature cell systems and the widespread expression of these factors throughout the adult brain, suggest that the neurotrophins might be critical regulators of neuronal survival. Rapid and profound increase of BDNF gene expression has been shown in the frontal and cingulate cortices after MCAO. We show here that also the BDNF protein levels are elevated in the same cortical regions after the ischemic insult, but also further dynamic changes in subcortical regions strongly suggesting anterograde transport of BDNF in forebrain neurons. In our further studies, the ability of the neurotrophins to change the vulnerability of striatal neurons to ischemic damage was investigated in the MCAO model. First, the resistant cholinergic interneurons in striatum respond to MCAO with expression of the p75 neurotrophin receptor (p75NTR). However, the vulnerability of the cholinergic interneurons to MCAO was not increased in a mice strain mutant for the P75NTR, which strongly argue against a major role of this receptor for the prominent resistance of these interneurons to ischemic insults. In order to directly investigate the neuroprotective properties of the neurotrophins, the vulnerability of striatal neurons to focal cerebral ischemia was determined after increasing the levels of BDNF and NGF by gene transfer to the striatum. Increased survival of striatal projection neurons was found after intrastriatal grafting of NGF-secreting genetically modified neural stem cells and after direct transfer of the BDNF gene to striatal cells using an adenoassociated viral (AAV) vector. Furthermore, viral transfer of the BDNF or NGF gene to striatal cells increased survival of parvalbumin-containing interneurons after MCAO. Our data support a role for the neurotrophins as a protective factor against ischemic damage. To assess the functional significance of increased neuronal survival in striatum after focal cerebral ischemia, we utilized different behavioral tests for striatal motor function. We found a strong correlation between scores from these behavioral tests and the extent of striatal damage, and in particular skilled forelimb use in the staircase paradigm was the best predictor of damage. Viral delivery of the neurotrophins lead to improvements in ischemia-induced motor impairments, which appeared to be due to increase in the survival of striatal neurons treated with BDNF. In conclusion, this thesis shows that focal cerebral ischemia causes dynamic changes of the BDNF and p75NTR levels. Gene transfer-induced elevation of neurotrophin levels increases the survival of striatal neurons to ischemic damage, which indicates a neuroprotective role for these factors in the mature brain.
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| 5. |
- Andsberg, Gunnar, et al.
(författare)
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Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats.
- 2002
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 9:2, s. 187-204
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Tidskriftsartikel (refereegranskat)abstract
- Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4-5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the deficits in a battery of behavioral tests designed to assess striatal function was highly correlated to the extent of ischemic damage determined by unbiased stereological estimations of striatal neuron numbers. The delivery of neurotrophins lead to mild functional improvements in the ischemia-induced motor impairments assessed 3-5 weeks after the insult, in agreement with a small but significant increase of the survival of dorsolateral striatal neurons. Detailed phenotypic analysis demonstrated that the parvalbumin-containing interneurons were spared to a greater extent by the neurotrophin treatment as compared to the projection neurons, which agreed with the specificity for interneuron transduction by the rAAV vector. These data show the advantage of the never previously performed combination of precise quantification of the ischemia-induced neuropathology along with detailed behavioural analysis for assessing neuroprotection after stroke. We observe that intrastriatal delivery of NGF and BDNF using a viral vector system can mitigate, albeit only moderately, neuronal death following stroke, which leads to detectable functional sparing. (c)2002 Elsevier Science (USA).
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| 6. |
- Andsberg, Gunnar, et al.
(författare)
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PreHospital Ambulance Stroke Test : pilot study of a novel stroke test
- 2017
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Ingår i: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. - London, UK : BioMed Central. - 1757-7241. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is a need for a prehospital stroke test that in addition to high sensitivity for stroke, also is able to communicate stroke severity similar to the National Institute of Health Stroke Scale (NIHSS).METHODS: The PreHospital Ambulance Stroke Test (PreHAST), an eight item test based on NIHSS, which scores stroke severity from 0-19 points, was designed and adapted for the ambulance services. In the pilot study the ambulance nurses used PreHAST to assess patients with suspected stroke in the prehospital setting. Regardless of the results after PreHAST testing the patients were triaged with a provisional stroke diagnosis. The PreHAST scores were compared with the final diagnosis and the ability to differentiate stroke and transient ischemic attacks (TIA) with ongoing symptoms at evaluation from non-stroke patients was analysed.RESULTS: 69 patients were included in the study, 26 had stroke/TIA and 43 other diagnoses. All stroke/TIA patients were identified by PreHAST (sensitivity 100% (95% CI; 87-100%)). The specificity increased with higher PreHAST scores and the discriminative capacity for PreHAST for different cut off values showed an area under the curve of 0.77 (95%CI; 0.66-0.88) in the receiver operating characteristic (ROC) analysis.DISCUSSION: PreHAST is designed for high sensitivity, screening for a broad range of stroke symptoms including most key components of NIHSS. The promising sensitivity between 87 and 100% in our study has to be confirmed in a larger study also including multiple centres. Higher PreHAST scores implied more typical patterns of stroke and accordingly the proportion of stroke mimics decrease with higher scores. However, also stroke mimics with epilepsy/seizure and patients with deficit after prior stroke could show higher PreHAST scores. Other prehospital stroke tests that evaluate stroke severity have been designed with the main purpose to screen for large vessel occlusion. The advantage of PreHAST is the dual purpose not only to evaluate stroke severity but also to screen for stroke in general.CONCLUSIONS: PreHAST is a new screening test of stroke adapted for ambulance services that in addition to high sensitivity for stroke, provides a grading system with increasing specificity with higher scores.
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| 7. |
- Andsberg, Gunnar, et al.
(författare)
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Upregulation of p75 neurotrophin receptor after stroke in mice does not contribute to differential vulnerability of striatal neurons
- 2001
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 169:2, s. 351-363
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Tidskriftsartikel (refereegranskat)abstract
- The survival of different neuron types and the expression of the p75 neurotrophin receptor (p75(NTR)) after focal cerebral ischemia were studied in the mouse striatum using immunocytochemical and histochemical techniques and stereological procedures. As assessed at 1 week after 30 min of middle cerebral artery occlusion, the order of vulnerability was projection neurons > parvalbumin-expressing interneurons > nitric oxide synthase-containing interneurons > cholinergic interneurons. Within the ischemic lesion, projection neurons were almost completely lost whereas cholinergic interneurons were spared. Calretinin-immunoreactive interneurons also seemed resistant to the insult. Expression of p75(NTR) was induced in cholinergic interneurons within the lesioned area, raising the possibility of a protective action. However, the number of cholinergic interneurons was unaffected in p75(NTR) knockout mice subjected to the same ischemic insult. These quantitative data demonstrate that striatal neurons in the mouse are differentially susceptible to ischemic damage and argue against a significant role of p75(NTR) for the high resistance of cholinergic interneurons.
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| 8. |
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| 9. |
- Gustafsson, Elin, et al.
(författare)
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Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.
- 2003
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 17:12, s. 2667-2678
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Tidskriftsartikel (refereegranskat)abstract
- o explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4–5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor–recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, γ-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.
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| 10. |
- Hall, Emma, et al.
(författare)
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Incidence of intracranial hemorrhagic complications after anterior circulation endovascular thrombectomy in relation to occlusion site : a nationwide observational register study
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Ingår i: Journal of NeuroInterventional Surgery. - 1759-8478.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Intracranial hemorrhage (ICH) is a potentially severe complication of endovascular thrombectomy (EVT). However, the relationship between the incidence and severity of ICH and vascular occlusion location is not well described.OBJECTIVE: To present a comprehensive analysis of subtypes of ICHs and their relationship to the occlusion site following EVT in the anterior circulation.METHODS: All patients with anterior circulation vessel occlusion stroke (internal carotid (ICA) and middle cerebral artery's first (M1) and later segments (M2 and beyond)) registered in the two Swedish national quality registers for stroke care and endovascular therapy during 2015-2020 were included. Hemorrhagic complications identified on imaging within 36 hours post-EVT were classified according to Heidelberg Bleeding Classification and further divided into symptomatic (sICH) or non-symptomatic (non-sICH).RESULTS: Of the 3077 patients, ICH frequency was 24.2%, which included 4.5% sICH. Subarachnoid hemorrhage (SAH) was the most frequent subtype of hemorrhage (10.9%). The hemorrhagic subtypes differed significantly by occlusion site, but the frequency of any bleed did not. EVT performed in and beyond the M2 more often resulted in SAH, frequently classified as non-sICH. EVT performed in the ICA was associated with more severe hemorrhages, such as intraventricular and large parenchymal hematomas, that were more often classified as sICH.CONCLUSION: In this nationwide unselected EVT cohort we found that ICH severity significantly differed between different vessel occlusion sites.
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