A Reliable and Rapid Language Tool for the Diagnosis, Classification, and Follow-Up of Primary Progressive Aphasia Variants

International audienceBackground: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking. Methods: We developed and evaluated a rapid language test for PPA ("PARIS") assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia ("LAST", "ART"). Results: The application duration of the "PARIS" was ∼10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the "PARIS" reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the "LAST" and "ART," the "PARIS" also had the highest sensitivity for detecting language decline. Conclusions: The "PARIS" is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing

Prevalence and incidence of postpartum depression and environmental factors: the IGEDEPP cohort

Background: IGEDEPP (Interaction of Gene and Environment of Depression during PostPartum) is a prospective multicenter cohort study of 3,310 Caucasian women who gave birth between 2011 and 2016, with follow-up until one year postpartum. The aim of the current study is to describe the cohort and estimate the prevalence and cumulative incidence of early and late postpartum depression (PPD). Methods: Socio-demographic data, personal and family psychiatric history, as well as stressful life events during childhood and pregnancy were evaluated at baseline. Early and late PPD were assessed at 8 weeks and 1 year postpartum respectively, using DSM-5 criteria. Results: The prevalence of early PPD was 8.3% (95%CI 7.3-9.3), and late PPD 12.9% (95%CI 11.5-14.2), resulting in an 8-week cumulative incidence of 8.5% (95%CI 7.4-9.6) and a one-year cumulative incidence of PPD of 18.1% (95%CI: 17.1-19.2). Nearly half of the cohort (N=1571, 47.5%) had a history of at least one psychiatric or addictive disorder, primarily depressive disorder (35%). Almost 300 women in the cohort (9.0%) reported childhood trauma. During pregnancy, 47.7% women experienced a stressful event, 30.2% in the first 8 weeks and 43.9% between 8 weeks and one year postpartum. Nearly one in five women reported at least one stressful postpartum event at 8 weeks. Conclusion: Incident depressive episodes affected nearly one in five women during the first year postpartum. Most women had stressful perinatal events. Further IGEDEPP studies will aim to disentangle the impact of childhood and pregnancy-related stressful events on postpartum mental disorders.Comment: 34 pages, 6 table

Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis

Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72–74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S(1 )alleles for the sequences A-RAA or E-RAA; S(2 )for Q or D-K-RAA; S(3D )for D-R-RAA; S(3P )for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S(2 )and S(3P )alleles were significantly over-transmitted and the S(1), S(3D )and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S(2)/S(3P), S(2)/S(2), S(3P)/S(3P), S(2)/L and S(3P)/L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S(2)/S(3P )[OR 22.2, 95% confidence interval 9.9–49.7]) to the lowest (S(3P)/L [OR 4.4, 95% confidence interval 2.3–8.4])

Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Meta-Analysis of Treatment Outcome and Predictors of Response

Background Deep brain stimulation (DBS) has been proposed as an alternative to ablative neurosurgery for severe treatment-resistant Obsessive-Compulsive Disorder (OCD), although with partially discrepant results probably related to differences in anatomical targetting and stimulation conditions. We sought to determine the efficacy and tolerability of DBS in OCD and the existence of clinical predictors of response using meta-analysis. Methods We searched the literature on DBS for OCD from 1999 through January 2014 using PubMed/MEDLINE and PsycINFO. We performed fixed and random-effect meta-analysis with score changes (pre-post DBS) on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as the primary-outcome measure, and the number of responders to treatment, quality of life and acceptability as secondary measures. Findings Thirty-one studies involving 116 subjects were identified. Eighty-three subjects were implanted in striatal areas anterior limb of the internal capsule, ventral capsule and ventral striatum, nucleus accumbens and ventral caudate 27 in the subthalamic nucleus and six in the inferior thalamic peduncle. Global percentage of Y-BOCS reduction was estimated at 45.1% and global percentage of responders at 60.0%. Better response was associated with older age at OCD onset and presence of sexual/religious obsessions and compulsions. No significant differences were detected in efficacy between targets. Five patients dropped out, but adverse effects were generally reported as mild, transient and reversible. Conclusions Our analysis confirms that DBS constitutes a valid alternative to lesional surgery for severe, therapy-refractory OCD patients. Well-controlled, randomized studies with larger samples are needed to establish the optimal targeting and stimulation conditions and to extend the analysis of clinical predictors of outcome

Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

Background: The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. Methods: We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. Results: For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. Conclusions: These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.This study was supported by grants EUROSCA/LSHM-CT-2004-503304 from the European Union, grant from the European Community's Seventh Framework Programme (FP7/2007-2013 n° 2012-305121 NEUROMICS), GeneMove/01 GM 0503 from the German Ministry of Education and Research, within the framework of the ERA-Net for Research Programmes on Rare Diseases, grant 3 PO5B 019 24 from the Polish Ministry of Scientific Research and Information Technology, and grant No 674N—RISCA/2010—2014 from Polish Ministry of Science and Higher Education. The research leading to these results has received funding from the programme ‘Investissements d'avenir’ ANR-10-IAIHU-06. BPvdW is supported by research grants from the Netherlands Brain Foundation, the Royal Dutch Society for Physical Therapy, BBMRI-NL, and the Radboud University Medical Centre. MB is supported by the grant OTKA K 103983. AF was supported by a grant from POR CREME 2007-20013. AB was supported by the grant EUROSCA/LSHM-CT-2004-503304 and by the grant NEUROMICS (7th framework programme) from the European Union. AB, AD and GS received funding from the VERUM Foundation. AD received support from ANR (French Research Agency) and Eranet for the Risca project, PG and AC work at University College London Hospitals/University College London which receives a proportion of its funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. Paola Giunti receives funding from the EC (HEALTH-F2-2010-242193; FP7 Grant). DeNDRoN, Ataxia UK and NIHR, Department of Health

Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings

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Consensus Recommendations for Clinical Outcome Assessments and Registry Development in Ataxias: Ataxia Global Initiative (AGI) Working Group Expert Guidance

To accelerate and facilitate clinical trials, the Ataxia Global Initiative (AGI) was established as a worldwide research platform for trial readiness in ataxias. One of AGI's major goals is the harmonization and standardization of outcome assessments. Clinical outcome assessments (COAs) that describe or reflect how a patient feels or functions are indispensable for clinical trials, but similarly important for observational studies and in routine patient care. The AGI working group on COAs has defined a set of data including a graded catalog of COAs that are recommended as a standard for future assessment and sharing of clinical data and joint clinical studies. Two datasets were defined: a mandatory dataset (minimal dataset) that can ideally be obtained during a routine clinical consultation and a more demanding extended dataset that is useful for research purposes. In the future, the currently most widely used clinician-reported outcome measure (ClinRO) in ataxia, the scale for the assessment and rating of ataxia (SARA), should be developed into a generally accepted instrument that can be used in upcoming clinical trials. Furthermore, there is an urgent need (i) to obtain more data on ataxia-specific, patient-reported outcome measures (PROs), (ii) to demonstrate and optimize sensitivity to change of many COAs, and (iii) to establish methods and evidence of anchoring change in COAs in patient meaningfulness, e.g., by determining patient-derived minimally meaningful thresholds of change