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  • 1
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 3 ( 2023-03-01), p. 977-990
    Abstract: Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P & lt; 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci ( & gt;90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 2
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 2 ( 2023-02-13), p. 600-611
    Abstract: Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/ or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 3
    In: International Journal of Stroke, SAGE Publications, Vol. 8, No. 8 ( 2013-12), p. 612-619
    Abstract: Detecting a benefit from closure of patent foramen ovale in patients with cryptogenic stroke is hampered by low rates of stroke recurrence and uncertainty about the causal role of patent foramen ovale in the index event. A method to predict patent foramen ovale-attributable recurrence risk is needed. However, individual databases generally have too few stroke recurrences to support risk modeling. Prior studies of this population have been limited by low statistical power for examining factors related to recurrence. Aims The aim of this study was to develop a database to support modeling of patent foramen ovale-attributable recurrence risk by combining extant data sets. Methods We identified investigators with extant databases including subjects with cryptogenic stroke investigated for patent foramen ovale, determined the availability and characteristics of data in each database, collaboratively specified the variables to be included in the Risk of Paradoxical Embolism database, harmonized the variables across databases, and collected new primary data when necessary and feasible. Results The Risk of Paradoxical Embolism database has individual clinical, radiologic, and echocardiographic data from 12 component databases, including subjects with cryptogenic stroke both with ( n = 1925) and without ( n = 1749) patent foramen ovale. In the patent foramen ovale subjects, a total of 381 outcomes (stroke, transient ischemic attack, death) occurred (median follow-up 2·2 years). While there were substantial variations in data collection between studies, there was sufficient overlap to define a common set of variables suitable for risk modeling. Conclusion While individual studies are inadequate for modeling patent foramen ovale-attributable recurrence risk, collaboration between investigators has yielded a database with sufficient power to identify those patients at highest risk for a patent foramen ovale-related stroke recurrence who may have the greatest potential benefit from patent foramen ovale closure.
    Type of Medium: Online Resource
    ISSN: 1747-4930 , 1747-4949
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2013
    detail.hit.zdb_id: 2211666-7
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  • 4
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: Introduction We aim to determine whether radiological findings are associated with patent foramen ovale (PFO) among patients with cryptogenic stroke (CS). Radiological findings associated with the presence of a PFO may represent stroke patterns typical of paradoxical embolism which may be distinct from other mechanisms of CS. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international collaboration that has combined individual-level data for subjects with CS and TIA who have known PFO status from 12 component studies (n=3665). For this study 7 databases (n=3023) were used that included subjects with and without PFO, and with radiologic data. Five variables were tested for their relationship with PFO status: 1) protocol-defined large vs. small infarct , 2) Index stroke seen on imaging, 3) superficial vs. deep infarct, 4) multiple index lesions, 5) Prior stroke, i.e. chronic infarct on index imaging. Results are presented in the table . Odds ratios and p-values are adjusted for age, database, sex, diabetes, hypertension, smoking, and history of stroke/TIA. This is the largest study to report the radiological characteristics of patients with CS who are known to have, or not to have, a PFO. Some prior studies had null findings but were limited by small sample size and low statistical power. Because CS unrelated to PFO may also be embolic, the radiological pattern of paradoxical embolism may not be expected to be different from other cryptogenic emboli. Despite this, PFOs were significantly more common in CS patients with large and with superficial infarcts. Conversely, infarcts that were small and deep were associated with PFO absence. This suggests that lacunar disease may account for some non-PFO related CS. Conclusion Participants were significantly more likely to have a PFO if they had 1) an index stroke seen on neuroimaging, 2) a large stroke, 3) a superficial stroke; there was no effect of the variables prior ( i.e. chronic) infarct or multiple vs. single infarcts. Further analyses may help to clarify the ability of neuroimaging to predict the finding of a PFO.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
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  • 5
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 3 ( 2013-03), p. 675-680
    Abstract: Patent foramen ovale (PFO) and cryptogenic stroke are commonly associated but some PFOs are incidental. Specific radiological findings associated with PFO may be more likely to indicate a PFO-related cause. We examined whether specific radiological findings are associated with PFO among subjects with cryptogenic stroke and known PFO status. Methods— We analyzed the Risk of Paradoxical Embolism(RoPE) Study database of subjects with cryptogenic stroke and known PFO status, for associations between PFO and: (1) index stroke seen on imaging, (2) index stroke size, (3) index stroke location, (4) multiple index strokes, and (5) prior stroke on baseline imaging. We also compared imaging with purported high-risk echocardiographic features. Results— Subjects (N=2680) were significantly more likely to have a PFO if their index stroke was large (odds ratio [OR], 1.36; P =0.0025), seen on index imaging (OR, 1.53; P =0.003), and superficially located (OR, 1.54; P 〈 0.0001). A prior stroke on baseline imaging was associated with not having a PFO (OR, 0.66; P 〈 0.0001). Finding multiple index strokes was unrelated to PFO status (OR, 1.21; P =0.161). No echocardiographic variables were related to PFO status. Conclusions— This is the largest study to report the radiological characteristics of patients with cryptogenic stroke and known PFO status. Strokes that were large, radiologically apparent, superficially located, or unassociated with prior radiological infarcts were more likely to be PFO-associated than were unapparent, smaller, or deep strokes, and those accompanied by chronic infarcts. There was no association between PFO and multiple acute strokes nor between specific echocardiographic PFO features with neuroimaging findings.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 6
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. suppl_1 ( 2012-02)
    Abstract: Background: A patent foramen ovale (PFO) discovered in the setting of a cryptogenic stroke (CS) may be incidental or pathogenic. Based on Bayes theorem, the proportion of CS that is PFO-attributable among patients found to have a PFO has been shown to be related to PFO prevalence in CS versus control patients. However, the prevalence of PFO in CS patients is itself dependent on the presence or absence of other risk factors. We exploited this relationship to create an index to stratify CS patients with PFO by their likelihood that the CS is PFO-attributable. Methods This project is part of the Risk of Paradoxical Embolism (RoPE) Study, an international, multicenter collaboration that has combined data for patients with CS and cryptogenic TIA who have known PFO status from 12 component studies (n=3665). For this study, we included those subjects within the 7 databases enrolling subjects both with and without PFO (n=3023). We used generalized linear mixed models to identify variables associated with the presence of a PFO, accounting for clustering within study. Based on this model, we created a simple index. Bayes theorem was used to estimate the PFO-attributable fraction in each stratum assuming a PFO prevalence in the general population of ∼25%. Results: Variables negatively associated with the presence of a PFO included: age (odds ratio [OR] = 0.97 per 1 year increase, p 〈 0.0001); diabetes (OR= 0.65, p 〈 0.001); hypertension (OR =0.68, p 〈 0.0001); smoking (OR = 0.70, p 〈 0.60); prior stroke or TIA (OR = 0.78, p=0.04). Cortical stroke on neuroimaging (OR = 1.46, p 〈 0.001) was also associated with PFO. Based on this, a simple index was created in which the absence of each stroke risk factor was assigned a point, with age dichotomized at 50 years. PFO prevalence in each stratum is shown in the table for patients 〈 age 60, i.e. the subset of patients likely to be considered for PFO closure trials. Conclusion: Even among CS patients in the younger age range considered eligible for closure trials, there is considerable heterogeneity in the distribution of risk factors for stroke and other characteristics that identify subgroups of CS patients with variation in PFO prevalence. This reflects substantial and clinically important variation in the probability that a discovered PFO is likely to be pathogenic rather than incidental. This score may be useful in selecting patients for closure trials, or for stratification within trials, particularly if combined with a recurrence risk model.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1467823-8
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  • 7
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background The “RoPE Score” is a predictive model created to stratify patients by the likelihood that a patent foramen ovale (PFO) is incidental or pathogenic using clinical variables. We hypothesized that the predictors of recurrent stroke differ between patients with pathogenic and incidental PFOs. Methods Patients in the Risk of Paradoxical Embolism (RoPE) database with cryptogenic stroke (CS) and PFO were classified as having a probable pathogenic PFO (RoPE Score of 〉 6, estimated PFO attributable fraction 72-99%, n=646) and others (RoPE Score of 〈 6 points estimated PFO attributable fraction 0-72%, n=678). We tested 15 clinical, 5 radiological, and 3 echo variables for associations with stroke recurrence using Cox survival models with component database as a stratification factor. An interaction with RoPE score was checked for the variables that were significant. Results Follow-up was available for 91%, 80%, and 58% at 1, 2, and 3 years. Overall, a higher recurrence risk was associated with an index TIA, not being on a statin at baseline, and having a prior radiological stroke. For the low RoPE score group, older age, male sex, high cholesterol and antiplatelet (vs warfarin) treatment predicted recurrence. For those with high RoPE scores, predictors were prior (clinical) stroke/TIA and 2 echo features: septal hypermobility and a small shunt ( 〈 10 bubbles). Conclusions Predictors of recurrence differ when PFO relatedness is classified by the RoPE Score. The hypothesis that patients with CS and PFO form a heterogenous group with different stroke mechanisms is supported. Conventional stroke risk factors were strong predictors among patients with lower RoPE scores. Echocardiographic features - including a counterintuitive association between smaller shunts and increased recurrence risk - were uniquely predictive in the high RoPE score group (likely pathogenic PFO).
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 8
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 11 ( 2020-6-4)
    Type of Medium: Online Resource
    ISSN: 1664-2295
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2564214-5
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  • 9
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. suppl_1 ( 2013-02)
    Abstract: Background Stroke databanks have consistently found a high ratio of anterior circulation (AC) to posterior circulation (PC) strokes without significant differences when compared for vascular risk factors, stroke etiology, treatments and outcome. One study suggested that there was a deviation from this consistent observation when comparing men and women with cryptogenic stroke (CS) and patent foramen ovale (PFO). We tested these associations using the RoPE database. Methods The Risk of Paradoxical Embolism (RoPE) Study is an international collaboration of 12 merged cohort studies of patients with CS and known PFO status (n=3674). This analysis was restricted to those subjects in the RoPE database with index strokes in the AC or PC (excluding both or unknown) from the 7 databases that had data for CS with, and without, PFO. We compared the effect of sex on infarct location among patients with versus without PFO. We used generalized linear mixed models to examine whether PFO status modified the gender effect on infarct location adjusting for study cohort as a random effect. Results Among cryptogenic stroke patients both with and without PFO, AC strokes were more common (61%) than PC overall (n=1535). Among patients with PFO, PC stroke was higher in men than in women (50% vs. 33%, OR 2.23, 95% CI: 1.58-3.13). This gender effect was attenuated in those without PFO (38% vs. 31%; OR 1.32, 95% CI: 0.98-1.77). The gender-by-PFO-status interaction was significant (p= 0.0224) and was highly consistent across study cohorts. Conclusions These data confirm that males with CS and PFO contravene the otherwise consistent pattern that AC strokes are more commonly observed than PC strokes in stroke populations. The potential mechanisms underlying this interaction between gender and PFO-status remain to be elucidated.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1467823-8
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  • 10
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 47, No. suppl_1 ( 2016-02)
    Abstract: Background: In patients with cryptogenic stroke (CS), a patent foramen ovale (PFO) can be incidental or pathogenic. The Risk of Paradoxical Embolism (RoPE) score has been developed to determine the likelihood that a PFO is pathogenic or incidental using clinical variables. We hypothesize that echocardiographic features and conditions promoting paradoxical embolism differ between patients with pathogenic and incidental PFOs. Methods: The International PFO Consortium collects clinical, radiological and echocardiographic data of patients with CS and PFO. In the original RoPE score, a value of 0-6 was classified as a low RoPE score and 7-10 as a high score. Since information on cortical versus deep stroke location (one of the items on the RoPE score) was not available, we used two alternative approaches to stratify for PFO pathogenicity. In a first approach, we used a 9-point score and lowered the cut-off for dichotomization by 1 point (RoPE score 0-5 vs 6-9). In a second approach, patients with a RoPE score of 6 were excluded since they could either be classified as low or high RoPE score depending on stroke location. The associations between RoPE stratum and echocardiographic features (atrial septal aneurysm (ASA), right-to-left shunt (RLS) at rest and large RLS) as well as conditions promoting paradoxical embolism (deep vein thrombosis (DVT), pulmonary embolism (PE) and Valsalva maneuver (VM) were studied. Results: We analyzed 1044 CS patients with a PFO. Average age was 55 (SD 16) and 635 patients (61%) were male. Preceding VM was more frequent in patients with a high vs low RoPE score in both analyses: 11% vs 5% (OR: 2.1 95%CI 1.3-4.3) and 10% vs 5% (OR: 2.0 95%CI 1.2-3.6). The distribution of ASA (35% vs 34% and 32% vs 34%, in the first and the second analysis respectively), RLS at rest (28% vs 28% and 29% vs 28%), large RLS (67% vs 66% and 65% vs 66%), PE (2% vs 2% and 1% vs 2%), and DVT (4% vs 4% and 3% vs 4%) did not differ by RoPE stratum. Conclusion: In patients with CS, preceding VM was significantly associated with pathogenic PFO, while echocardiographic features or conditions promoting paradoxical embolism were not. The formation of a significant right-to-left pressure gradient at the atrial septum level appears to play a substantial role in the pathogenicity of PFO.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    RVK:
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467823-8
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