The clinical epidemiology of immune thrombocytopenia (ITP) is not well known in adults. This study was aimed at assessing the clinical epidemiology of incident ITP adults, the factors associated with ...chronicity and exposure to treatments. This study was conducted in the CARMEN registry, a multicentric prospective cohort aimed at including all newly diagnosed ITP adults in the French Midi‐Pyrénées region, South of France (3 million inhabitants) from June 2013. Descriptive analyses and multivariate logistic regression models were conducted. Out of 121 newly diagnosed ITP until December 2014, 113 patients were followed in the region and gave informed consent. Median age was 65 years. Half of the patients were female, 20.3% had a secondary ITP, 50.4% had a Charlson's score ≥1, median platelet count was 17 × 109/L; 50.9% had bleeding symptoms, including 2 severe gastrointestinal tract and 1 intracranial bleedings; 21.4% had another autoimmune disease and 20.3% experienced an infection within the six weeks before ITP onset. Persistency and chronicity rates were 68.2% and 58.7%, respectively. Antinuclear antibodies were associated with chronicity (OR: 2.89, 95% CI: 1.08‐7.74). Sixty‐eight (60.2%) patients were treated during the week following the diagnosis. Factors associated with the use of intravenous corticosteroids were secondary ITP and high bleeding score. Those associated with the use of intravenous immunoglobulin (IVIg) were a high bleeding score and low platelet count. In conclusion, severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections were frequent. Antinuclear antibodies seem predictors of chronicity. Intravenous corticosteroids and IVIg were frequently used.
Impaired platelet production is a mechanism of immune thrombocytopenia (ITP). Morphological abnormalities of megakaryocytes (MKs) are sometimes observed in this disease. Two studies have suggested an ...association between MK abnormalities and response to corticosteroids in primary ITP, but none have investigated this association for thrombopoietin-receptor agonists (TPO-RAs). This was the aim of this study. The source of population was the French CARMEN registry with prospective follow-up of adult patients with incident ITP. We included patients with primary ITP, treated by TPO-RA and with a bone marrow smear before initiating TPO-RA. MK abnormalities were categorized by the presence of dysplasia and by the stage of maturation. Among 451 patients screened, 38 were included in the analysis. There was no difference in the median percentage of dysplastic MKs between responders to TPO-RA (4.0%, 95% confidence interval - CI: 2.3-6.4) and non-responders (4.5%, 95% CI: 0.7-7.1). There was a slightly higher proportion of granular MKs (4.5%, 95% CI: 3-6) and basophilic MKs (30.1%, 95% CI: 21.9-39.1) in non-responders compared to responders (granular: 2.0%, 95% CI: 0-4.1; basophilic: 21.3%, 95% CI: 11.4-40.7). In conclusion, MK abnormalities were not associated with response achievement in ITP patients treated with TPO-RA in this series of 38 patients.
The relationship between neuroinflammation and cognition remains uncertain in early Alzheimer’s disease (AD). We performed a cross-sectional study to assess how neuroinflammation is related to ...cognition using TSPO PET imaging and a multi-domain neuropsychological assessment. A standard uptake value ratio (SUVR) analysis was performed to measure
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F-DPA-714 binding using the cerebellar cortex or the whole brain as a (pseudo)reference region. Among 29 patients with early AD, the pattern of neuroinflammation was heterogeneous and exhibited no correlation with cognition at voxel-wise, regional or whole-brain level. The distribution of the SUVR values was independent of sex, APOE phenotype, early and late onset of symptoms and the presence of cerebral amyloid angiopathy. However, we were able to demonstrate a complex dissociation as some patients with similar PET pattern had opposed neuropsychological profiles while other patients with opposite PET profiles had similar neuropsychological presentation. Further studies are needed to explore how this heterogeneity impacts disease progression.
•Glial activation, synaptic and axonal damage are not affected by TSPO genotype in AD.•Studies can combine TSPO PET and CSF biomarkers for a selected TSPO phenotype in AD.•Results from one TSPO ...phenotype might be generalizable to an entire AD population.
PET imaging of the translocator protein (TSPO) is used to assess in vivo brain inflammation. One of the main methodological issues with this method is the allelic dependence of the radiotracer affinity. In Alzheimer’s disease (AD), previous studies have shown similar clinical and patho-biological profiles between TSPO genetic subgroups. However, there is no evidence regarding the effect of the TSPO genotype on cerebrospinal-fluid biomarkers of glial activation, and synaptic and axonal damage.
We performed a trans-sectional study in early AD to compare cerebrospinal-fluid levels of GFAP, YKL-40, sTREM2, IL-6, IL-10, NfL and neurogranin between TSPO genetic subgroups.
We recruited 33 patients with early AD including 16 (48%) high affinity binders, 13 (39%) mixed affinity binders, and 4/33 (12%) low affinity binders. No difference was observed in terms of demographics, and cerebrospinal fluid levels of each biomarker for the different subgroups.
TSPO genotype is not associated with a change in glial activation, synaptic and axonal damage in early AD. Further studies with larger numbers of participants will be needed to confirm that the inclusion of specific TSPO genetic subgroups does not introduce selection bias in studies and trials of AD that combine TSPO imaging with cerebrospinal fluid biomarkers.
Mutations in the human X-linked doublecortin gene (DCX) cause major neocortical disorganization associated with severe intellectual disability and intractable epilepsy. Although Dcx knockout (KO) ...mice exhibit normal isocortical development and architecture, they show lamination defects of the hippocampal pyramidal cell layer largely restricted to the CA3 region. Dcx-KO mice also exhibit interneuron abnormalities. As well as the interest of testing their general neurocognitive profile, Dcx-KO mice also provide a relatively unique model to assess the effects of a disorganized CA3 region on learning and memory. Based on its prominent anatomical and physiological features, the CA3 region is believed to contribute to rapid encoding of novel information, formation and storage of arbitrary associations, novelty detection, and short-term memory. We report here that Dcx-KO adult males exhibit remarkably preserved hippocampal- and CA3-dependant cognitive processes using a large battery of classical hippocampus related tests such as the Barnes maze, contextual fear conditioning, paired associate learning and object recognition. In addition, we show that hippocampal adult neurogenesis, in terms of proliferation, survival and differentiation of granule cells, is also remarkably preserved in Dcx-KO mice. In contrast, following social deprivation, Dcx-KO mice exhibit impaired social interaction and reduced aggressive behaviors. In addition, Dcx-KO mice show reduced behavioral lateralization. The Dcx-KO model thus reinforces the association of neuropsychiatric behavioral impairments with mouse models of intellectual disability.
Background: The clinical epidemiology of immune thrombocytopenia (ITP) is not well known. Some issues (bleeding events at diagnosis, association to other autoimmune diseases, rate of infection prior ...to ITP onset) are not well described in adults. Little is known as regards first-line treatment choice in the real-life practice.
Aim: The aims of this study were to assess i) the clinical epidemiology of incident ITP adults; ii) the use of first-line treatments in this population; and iii) the factors associated with the initial use of intravenous (IV) corticosteroids (CS) and of intravenous immunoglobulin (IVIg) in a real-life setting. This study was carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology.
Methods: Study population was the patients included between June 2013 and December 2014 in the CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) multicenter registry. This multicenter registry is carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology. The originalities of this registry are: the prospective follow-up of newly diagnosed ITPs, aimed at completeness of recording in the French Midi-Pyrénées region, South of France (3 million inhabitants), and the detailed recording of ITP treatment exposures. All the physicians in charge of ITP patients in the region, belonging to the netwotk of the regional center for autoimmune cytopenia, prospectively follow every patient newly diagnosed for ITP during routine visit or hospital stay. ITP is defined in accordance with French guidelines: platelet count <150 x 109/L and exclusion of other causes of thrombocytopenia. In this study, we assessed the clinical epidemiology at ITP onset, as well as ITP treatment use during the week following the diagnosis. Logistic regression models were performed to assess the factors associated with the use of IV CS and of IVIg. The following covariates were included: age, gender, Charlson's comorbidity score, secondary vs. primary ITP, bleeding score and platelet count.
Results: Out of 121 newly diagnosed ITP, 113 patients were followed in the region and gave informed consent. Median age was 65 years (range: 18-95). Half of the patients were female, 24 (21.3%) had a secondary ITP, 57 (50.4%) had a Charlson's score ≥1, median platelet count was 17 x109/L (range: 1-126); 57 (50.9%) had bleeding symptoms, including 2 severe gastro-intestinal tract and 1 intracranial bleeding. Median Khellaf's bleeding score was 5 (range: 0-35). Twenty-five (21.4%) patients had another autoimmune disease (mostly: Hashimoto's thyroiditis, n=6, Sjögren syndrome, n=5, Evans syndrome, n=3) and 23 (20.3%) experienced an infection within the six weeks before ITP onset (including 8 influenza-like and 3 gastro-enteritis like syndromes, the others being various bacterial infections). Sixty-eight (60.2%) patients were treated during the week following the diagnosis. Among them, 66 (98.5%) received CS (median dose: 0.99 mg/kg/d), including 21 (31.3%) IV CS, 29 (43.3%) IVIg, 8 (11,9%) platelet transfusion, 2 romiplostim and 1 rituximab. The factors associated with the use of IV CS were secondary ITP (OR: 5.91; 95% CI: 1.78-19.71) and Khellaf's bleeding score >8 (OR: 4.09; 95% CI 0.96-17.35). Those associated with the use of IVIg were Khellaf's bleeding score >8 (OR: 7.30; 95% CI 1.36-32.27) and platelet count <10 x 109/L (OR: 3.95; 95% CI 1.77-13.29).
Conclusions: This prospective cohort of newly diagnosed ITP adults confirms that severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections are frequent. IVIg and IV CS were frequently used, particularly in case of severe bleeding.
Godeau:Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adoue:LFB: Other: Symposium presentations ; OCTAPHARMA: Other: Symposium presentations ; ACTELION: Other: Symposium presentations ; PFIZER: Other: Symposium presentations ; AMGEN: Other: Symposium presentations ; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Other: Symposium presentations.
Patients with Doublecortin (DCX) mutations have severe cortical malformations associated with mental retardation and epilepsy. Dcx knockout (KO) mice show no major isocortical abnormalities, but have ...discrete hippocampal defects. We questioned the functional consequences of these defects and report here that Dcx KO mice are hyperactive and exhibit spontaneous convulsive seizures. Changes in neuropeptide Y and calbindin expression, consistent with seizure occurrence, were detected in a large proportion of KO animals, and convulsants, including kainate and pentylenetetrazole, also induced seizures more readily in KO mice. We show that the dysplastic CA3 region in KO hippocampal slices generates sharp wave-like activities and possesses a lower threshold for epileptiform events. Video-EEG monitoring also demonstrated that spontaneous seizures were initiated in the hippocampus. Similarly, seizures in human patients mutated for DCX can show a primary involvement of the temporal lobe. In conclusion, seizures in Dcx KO mice are likely to be due to abnormal synaptic transmission involving heterotopic cells in the hippocampus and these mice may therefore provide a useful model to further study how lamination defects underlie the genesis of epileptiform activities.
OBJECTIVE. 7-Tesla MRI of the hippocampus enhances the visualization of its internal substructures. Among these substructures, the cornu Ammonis and subiculum form a contiguous folded ribbon of gray ...matter. Here, we propose a method to analyze local thickness measurements of this ribbon. METHODS. We introduce an original approach based upon the estimation of a diffeomorphic vector field that traverses the ribbon. The method is designed to handle specificities of the hippocampus and corresponding 7-Tesla acquisitions: highly convoluted surface, non closed ribbon, incompletely defined inner/outer boundaries, anisotropic acquisitions. We furthermore propose to conduct group comparisons using a population template built from the central surfaces of individual subjects. RESULTS. We first assessed the robustness of our approach to anisotropy, as well as to inter-rater variability, on a post-mortem scan and on in vivo acquisitions respectively. We then conducted a group study on a dataset of in vivo MRI from temporal lobe epilepsy (TLE) patients and healthy controls. The method detected local thinning patterns in patients, predominantly ipsilaterally to the seizure focus, which is consistent with medical knowledge. CONCLUSION. This new technique allows measuring the thickness of the hippocampus from 7-Tesla MRI. It shows good robustness with respect to anisotropy and inter-rater variability and has the potential to detect local atrophy in patients. SIGNIFICANCE. As 7-Tesla MRI is increasingly available, this new method may become a useful tool to study local alterations of the hippocampus in brain disorders. It is made freely available to the community (code: https://github.com/aramis-lab/hiplay7-thickness, postmortem segmentation: https://doi.org/10.5281/zenodo.3533264).
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