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To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β(1-42)) and evaluated the specificity of 14-3-3 in Creutzfeldt-Jakob disease diagnosis for the years 1998-2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt-Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt-Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt-Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95-97%) and non-neurological conditions (91-97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82-87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt-Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin. [ABSTRACT FROM AUTHOR]

Human prion diseases are rare, transmissible and often rapidly progressive dementias. The most common type, sporadic Creutzfeldt-Jakob disease (sCJD), is highly variable in clinical duration and age at onset. Genetic determinants of late onset or slower progression might suggest new targets for research and therapeutics. We assembled and array genotyped sCJD cases diagnosed in life or at autopsy. Clinical duration (median:4, interquartile range (IQR):2.5-9 (months)) was available in 3,773 and age at onset (median:67, IQR:61-73 (years)) in 3,767 cases. Phenotypes were successfully transformed to approximate normal distributions allowing genome-wide analysis without statistical inflation. 53 SNPs achieved genome-wide significance for the clinical duration phenotype; all of which were located at chromosome 20 (top SNP rs1799990, pvalue = 3.45x10-36, beta = 0.34 for an additive model; rs1799990, pvalue = 9.92x10-67, beta = 0.84 for a heterozygous model). Fine mapping, conditional and expression analysis suggests that the well-known non-synonymous variant at codon 129 is the obvious outstanding genome-wide determinant of clinical duration. Pathway analysis and suggestive loci are described. No genome-wide significant SNP determinants of age at onset were found, but the HS6ST3 gene was significant (pvalue = 1.93 x 10-6) in a gene-based test. We found no evidence of genome-wide genetic correlation between case-control (disease risk factors) and case-only (determinants of phenotypes) studies. Relative to other common genetic variants, PRNP codon 129 is by far the outstanding modifier of CJD survival suggesting only modest or rare variant effects at other genetic loci., Competing Interests: Stéphane Haik reports grants from Santé Publique France, during the conduct of the study; grants from LFB Biomedicaments, grants from Institut de Recherche Servier, grants from MedDay Pharmaceuticals, outside the submitted work; In addition, Stéphane Haik has a patent Method for treating prion diseases (PCT/EP2019/070457) pending. Brian Appleby has received funding from CDC, NIH, CJD Foundation, Alector, and Ionis. He has served as a consultant for Ionis, Sangamo, and Gate Biosciences. He has received royalties from Wolter Kluwers. Karl Fronztek reports grants from Ono Pharmaceuticals outside the submitted work. Simon Mead reports grants from Medical Research Council (UK) and grants from National Institute of Health Research’s Biomedical Research Centre at University College London Hospitals NHS Foundation Trust during the conduct of the study. Gabor G Kovacs reports personal fees from Biogen, outside the submitted work. John Collinge reports grants from Medical Research Council, grants from NIHR UCLH Biomedical Research Centre, during the conduct of the study; and is a Director and shareholder of D-Gen Limited, an academic spinout in the field of prion disease diagnostics, decontamination and therapeutics. Inga Zerr reports grants from the Bundesministerium für Gesundheit via Robert Koch institute, JPND and personal fees (not related to the content of the manuscript) from Ferring Pharmaceuticals and IONIS, speaking honoraria for medical lectures from Lilly, Biogen, Medfora, DGLN (German Society for cerebrospinal fluid diagnostics in Neurology). Maurizio Pocchiari reports personal fees from Ferring Pharmaceuticals, personal fees from CNCCS (Collection of National Chemical Compounds and Screening Center), non-financial support from Fondazione Cellule Staminali, outside the submitted work. Michael D Geschwind has consulted for3D Communications, Adept Field Consulting, Advanced Medical Inc., Best Doctors Inc., Second Opinion Inc., Gerson Lehrman Group Inc., Guidepoint Global LLC, InThought Consulting Inc., Market Plus, Trinity Partners LLC, Biohaven Pharmaceuticals, Quest Diagnostics and various medical-legal consulting. He has received speaking honoraria for various medical center lectures and from Oakstone publishing. He has received past research support from Alliance Biosecure, CurePSP, the Tau Consortium, and Quest Diagnostics. Michael D Geschwind serves on the board of directors for San Francisco Bay Area Physicians for Social Responsibility and on the editorial board of Dementia & Neuropsychologia., (Copyright: © 2024 Hummerich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The blood-brain barrier (BBB) is pivotal for the maintenance of brain homeostasis and it strictly regulates the cerebral transport of a wide range of endogenous compounds and drugs. While fasting is increasingly recognized as a potential therapeutic intervention in neurology and psychiatry, its impact upon the BBB has not been studied. This study was designed to assess the global impact of fasting upon the repertoire of BBB transporters., Methods: We used a combination of in vivo and in vitro experiments to assess the response of the brain endothelium in male rats that were fed ad libitum or fasted for one to three days. Brain endothelial cells were acutely purified and transcriptionaly profiled using RNA-Seq. Isolated brain microvessels were used to assess the protein expression of selected BBB transporters through western blot. The molecular mechanisms involved in the adaptation to fasting were investigated in primary cultured rat brain endothelial cells. MCT1 activity was probed by in situ brain perfusion., Results: Fasting did not change the expression of the main drug efflux ATP-binding cassette transporters or P-glycoprotein activity at the BBB but modulated a restrictive set of solute carrier transporters. These included the ketone bodies transporter MCT1, which is pivotal for the brain adaptation to fasting. Our findings in vivo suggested that PPAR δ, a major lipid sensor, was selectively activated in brain endothelial cells in response to fasting. This was confirmed in vitro where pharmacological agonists and free fatty acids selectively activated PPAR δ, resulting in the upregulation of MCT1 expression. Moreover, dosing rats with a specific PPAR δ antagonist blocked the upregulation of MCT1 expression and activity induced by fasting., Conclusions: Altogether, our study shows that fasting affects a selected set of BBB transporters which does not include the main drug efflux transporters. Moreover, we describe a previously unknown selective adaptive response of the brain vasculature to fasting which involves PPAR δ and is responsible for the up-regulation of MCT1 expression and activity. Our study opens new perspectives for the metabolic manipulation of the BBB in the healthy or diseased brain., (© 2024. The Author(s).)

Suicide attempts (SA) are prevalent in substance use disorders (SUD). Epigenetic mechanisms may play a pivotal role in the molecular mechanisms of environmental effects eliciting suicidal behaviour in this population. Hypothalamic-pituitary-adrenal axis (HPA), oxytocin and neurotrophin pathways have been consistently involved in SA, yet , their interplay with childhood adversity remains unclear, particularly in SUD. In 24 outpatients with SUDs, we examined the relation between three parental dysfunctional styles and history of SA with methylation of 32 genes from these pathways, eventually analysing 823 methylation sites. Extensive phenotypic characterization was obtained using a semi-structured interview. Parental style was patient-reported using the Measure of Parental Style (MOPS) questionnaire, analysed with and without imputation of missing items. Linear regressions were performed to adjust for possible confounders, followed by multiple testing correction. We describe both differentially methylated probes (DMPs) and regions (DMRs) for each set of analyses (with and without imputation of MOPS items). Without imputation, five DMRs in OXTR, CRH and NTF3 significantly interacted with MOPS father abuse to increase the risk for lifetime SA, thus covering the three pathways. After imputation of missing MOPS items, two other DMPs from FKBP5 and SOCS3 significantly interacted with each of the three father styles to increase the risk for SA. Although our findings must be interpreted with caution due to small sample size, they suggest implications of stress reactivity genes in the suicidal risk of SUD patients and highlight the significance of father dysfunction as a potential marker of childhood adversity in SUD patients., (© 2024 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening., (© 2024. The Author(s).)

BackgroundPrion diseases are rare, fatal disorders that have repeatedly raised public health concerns since the early 1990s. An active prion disease surveillance network providing national level data was implemented in France in 1992.AimWe aimed to describe the epidemiology of sporadic, genetic and infectious forms of prion diseases in France since surveillance implementation.MethodsWe included all suspected cases notified from January 1992 to December 2016, and cases who died during the period with a definite or probable prion disease diagnosis according to EuroCJD criteria. Demographic, clinical, genetic, neuropathological and biochemical data were collected.ResultsIn total, 25,676 suspected cases were notified and 2,907 were diagnosed as prion diseases, including 2,510 (86%) with sporadic Creutzfeldt-Jakob disease (sCJD), 240 (8%) genetic and 157 (6%) with infectious prion disease. Suspected cases and sCJD cases increased over time. Younger sCJD patients (≤ 50 years) showed phenotypes related to a distinct molecular subtype distribution vs those above 50 years. Compared to other European countries, France has had a higher number of cases with iatrogenic CJD after growth hormone treatment and variant CJD (vCJD) linked to bovine spongiform encephalopathy (second after the United Kingdom), but numbers slowly decreased over time.ConclusionWe observed a decrease of CJD infectious forms, demonstrating the effectiveness of measures to limit human exposure to exogenous prions. However, active surveillance is needed regarding uncertainties about future occurrences of vCJD, possible zoonotic potential of chronic wasting diseases in cervids and increasing trends of sCJD observed in France and other countries.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of prion diseases. The causes of sCJD are still unknown and exogenous factors may play a role. Worldwide, the number of patients with sCJD has progressively increased over time. This increase can be partly explained by increasing life expectancy and better case ascertainment, but a true increase in the number of sCJD cases cannot be excluded. We estimated mortality rates from sCJD in France (1992-2016) and studied variation in mortality rates by age, period, and time.We included all cases aged 45-89 years old who died with a probable/definite sCJD diagnosis based on the French national surveillance network. We used age-period-cohort (APC) Poisson regression models to study variation in mortality rates by sex, age, period, and time.A total of 2475 sCJD cases aged 45-89 years were included. Mortality rates increased with age, reached a peak between 75 and 79 years, and decreased thereafter. Mortality rates were higher in women than men at younger ages and lower at older ages. The full APC model with a sex×age interaction provided the best fit to the data, thus in favour of sex, age, period, and cohort effects on mortality rates. In particular, mortality rates increased progressively with successive birth cohorts.Based on 25 years of active surveillance in France, we show evidence for sex, age, period, and cohort effects on sCJD mortality. The identification of cohort effects suggests that environmental exposures may play a role in sCJD etiology., (© 2023. The Author(s).)

Objectives: An accelerated cellular ageing has been observed in bipolar disorder (BD) using biomarkers such as telomere length (TL) and mitochondrial DNA copy number (mtDNAcn). Several risk factors might drive premature ageing in individuals with BD, including a familial predisposition. This study compared TL and mtDNAcn between individuals with BD and their (un)-affected siblings, and explored factors that may explain proband-sibling differences., Methods: Sixty individuals with BD and seventy-four siblings (34 affected with BD or mood disorders and 40 unaffected) were included. Quantitative polymerase chain reaction (qPCR) was used to measure TL and mtDNAcn from peripheral blood genomic DNA., Results: TL and mtDNAcn did not significantly differ between probands and their siblings, whatever these latter were affected or not with mood disorders. However, the correlation plots of TL or mtDNAcn in proband-sibling pairs suggested that some pairs were discordant. The within proband-sibling pairs differences for TL and mtDNAcn were not explained by differences in all tested factors., Conclusions: This study shows that probands with BD and their siblings are concordant for TL and mtDNAcn suggesting that they may share some environmental or genetic determinants of these two biomarkers of cellular ageing.

In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10 -3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10 -3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal., (© 2022 Society for the Study of Addiction.)

Background: Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology., Aims: Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm., Methods: A cocaine-CPP paradigm in male Sprague-Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference., Results: Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between -85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes ( Fos , Egr2 , Nr4a1 , and Zbtb37 ) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP., Conclusion: These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine's rewarding effects.

Introduction: The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests., Methods: We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients., Results: The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis., Discussion: This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: To elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging., Methods: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF β-amyloid (Aβ) peptide biomarkers. These Aβ cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients., Results: A total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%., Discussion: The proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The 10-15-years decrease in life expectancy observed in individuals with bipolar disorder (BD) has been linked to the concept of accelerated cellular aging. Telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) have been proposed as markers of cellular aging and comparisons between individuals with BD and healthy controls (HC) sometimes led to conflicting results. Previous studies had moderate sample sizes and studies combining these two markers into a single analysis are scarce. Using quantitative polymerase chain reaction, we measured both TL and mtDNAcn in DNA (peripheral blood) in a sample of 130 individuals with BD and 78 HC. Regression analyses, receiver operating characteristic (ROC), and clustering analyses were performed. We observed significantly lower TL and mtDNAcn in individuals with BD as compared to HC (respective decrease of 26.5 and 35.8%). ROC analyses showed that TL and mtDNAcn highly discriminated groups (AUC = 0.904 for TL and AUC = 0.931 for mtDNAcn). In the whole population, clustering analyses identified a group of young individuals (age around 36 years), with accelerated cellular aging (both shorter TL and lower mtDNAcn), which consisted mostly of individuals with BD (85.5%). The subgroup of patients with young age but accelerated aging was not characterized by specific clinical variables related to the course of BD or childhood maltreatment. However, patients in this subgroup were more frequently treated with anticonvulsants. Further characterization of this subgroup is required to better understand the molecular mechanisms and the risk factors of accelerated cellular aging in BD., (© 2022. The Author(s).)

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity., Methods: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately., Results: Cocaine dependence (p occurrence = 6.18 × 10 -5 , p severity = 9.25 × 10 -8 ), number of cocaine dependence DSM IV-Tr criteria (p occurrence = 1.22 × 10 -7 , p severity = 5.09 × 10 -6 ), and frequency of intake during the worst period of misuse (p occurrence = 8.51 × 10 -04 , p severity = 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs., Conclusion: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Suicide attempts have been associated with both cocaine use disorder (CocUD) and childhood trauma. We investigated how childhood trauma is an independent risk factor for serious and recurrent suicide attempts in CocUD. Method : 298 outpatients (23% women) with CocUD underwent standardized assessments of substance dependence (Diagnostic and Statistical Manual-mental disorders, fourth edition, text revised), impulsiveness, resilience, and childhood trauma, using validated tools. Suicide attempts history was categorized as single vs. recurrent or non-serious vs. serious depending on the lifetime number of suicide attempts and the potential or actual lethality of the worst attempt reported, respectively. Bivariate and multinomial regression analyses were used to characterize which childhood trauma patterns were associated with the suicide attempts groups. Results : 58% of CocUD patients reported childhood trauma. Recurrent and serious suicide attempts clustered together and were thus combined into "severe SA." Severe suicide attempt risk increased proportionally to the number of childhood traumas (test for trend, p  = 9 × 10 -7 ). Non-severe suicide attempt risk increased with impulsiveness and decreased with resilience. In multinomial regression models, a higher number of traumas and emotional abuse were independently and only associated with severe vs. non-severe suicide attempts (effect size = 0.82, AUC = 0.7). The study was limited by its cross-sectional design. Conclusion : These preferential associations between childhood trauma and severe suicide attempts warrant specific monitoring of suicide attempts risk in CocUD, regardless of the severity of addiction profiles.

Malnutrition has been reported in alcohol use disorder patients as having a possible influence on cognitive function. The aim of this study was to analyse the prevalence of ascorbic acid (AA) deficiency in inpatients admitted for alcohol detoxification and the associated factors, including cognitive impairment in the early period of abstinence. A retrospective chart review was conducted. The AA level was categorised into three groups: deficiency (AAD) (<2 mg/L), insufficiency (AAI) (2-5 mg/L) and normal level. The cognitive impairment was screened using the Montreal Cognitive Assessment (MoCA). Ninety-six patients were included (74 men; mean age 49.1 years (±11.5)). Twenty-seven AAD (28.1%) and twenty-two AAI (22.9%) were observed. In multivariate analysis, risk factors for AAD versus normal AA level were men (OR 17.8, 95%CI (1.63-194)), compensated cirrhosis (OR 9.35, 95%CI (1.60-54.6)) and street homelessness (OR 5.76, 95%CI (1.24-26.8) versus personal housing). The MoCA score was available for 53 patients (mean MoCA score: 25.7 (±3.3)). In multivariate analysis, the natural logarithm of AA (β = 1.18, p = 0.037) and sedative use disorder (β = -2.77, p = 0.046) were associated with the MoCA score. AAD and AAI are frequent in inpatients admitted for alcohol detoxification. A low level of AA was associated with cognitive impairment in the early period of abstinence.

Human prion diseases are fatal neurodegenerative disorders that include sporadic, infectious and genetic forms. Inherited Creutzfeldt-Jakob disease due to the E200K mutation of the prion protein-coding gene is the most common form of genetic prion disease. The phenotype resembles that of sporadic Creutzfeldt-Jakob disease at both the clinical and pathological levels, with a median disease duration of 4 months. To date, there is no available treatment for delaying the occurrence or slowing the progression of human prion diseases. Existing in vivo models do not allow high-throughput approaches that may facilitate the discovery of compounds targeting pathological assemblies of human prion protein or their effects on neuronal survival. Here, we generated a genetic model in the nematode Caenorhabditis elegans, which is devoid of any homologue of the prion protein, by expressing human prion protein with the E200K mutation in the mechanosensitive neuronal system. Expression of E200K prion protein induced a specific behavioural pattern and neurodegeneration of green fluorescent protein-expressing mechanosensitive neurons, in addition to the formation of intraneuronal inclusions associated with the accumulation of a protease-resistant form of the prion protein. We demonstrated that this experimental system is a powerful tool for investigating the efficacy of anti-prion compounds on both prion-induced neurodegeneration and prion protein misfolding, as well as in the context of human prion protein. Within a library of 320 compounds that have been approved for human use and cross the blood-brain barrier, we identified five molecules that were active against the aggregation of the E200K prion protein and the neurodegeneration it induced in transgenic animals. This model breaks a technological limitation in prion therapeutic research and provides a key tool to study the deleterious effects of misfolded prion protein in a well-described neuronal system., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Cocaine users often present with repetitive events of cocaine-associated chest pain (CACP), clinically resembling acute coronary syndromes. The aim of the study is to describe the specific risk factors for CACP. Method: Cocaine users ( n = 316) were recruited for a multicenter cross-sectional study. Lifetime CACP history, sociodemographic factors, and lifetime use of cocaine and other substances were assessed. Thirty single nucleotide polymorphisms (SNPs) of NOS3, ROCK2, EDN1, GUCY1A3 , and ALDH2 genes, suggested by the literature on coronary spasms, were selected. The associations with CACP history were tested using the chi-square test, Student's t -test and logistic regression. Results: Among the 316 subjects [78.5% men, mean age 37.5 years, (standard-deviation ±8.7)], 190 (60.1%) were daily cocaine users and 103 (32.6%) reported a lifetime CACP history. Among those with a lifetime CACP history, the median was 10 events per individual. In multivariate analysis, lifetime CACP history was associated with daily cocaine use [odds-ratio (OR) 3.24; 95% confidence intervals (1.29-9.33)], rapid route of cocaine use [OR 2.33 (1.20-4.64) vs. intranasal use], and lifetime amphetamine use [daily amphetamine use: OR 2.80 (1.25-6.32) and non-daily amphetamine use: OR 2.14 (1.15-4.04) vs. never used]. Patients with lifetime opioid maintenance treatment (OMT) reported significantly less lifetime CACP history [OR 0.35 (0.16-0.76)]. None of the selected SNPs was associated with CACP history after multiple testing corrections. Conclusions: Clinical variables describing the intensity of stimulant use were positively associated with lifetime CACP history, while OMT was negatively associated with it. Specific harm reduction strategies can target these risk factors., Competing Interests: In the past 5 years, FV had congress fees paid by CAMURUS AB (2018, 2019), and RECORDATI (2020). FV gave a single lecture for RECORDATI (2020) and served in advisory boards for CAMURUS AB (2019), and ACCORD HEALTH CARE (2021). All payments were made to a research entity and not directly to FV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Clergue-Duval, Nicolas-Sacy, Karsinti, Zerdazi, Laplanche, Brousse, Marees, Derks, Henry, Bellivier, Vorspan and Bloch.)

Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.

Motor disturbances strongly increase the burden of cocaine use disorder (CUDs). The objective of our translational study was to identify the genes and biological pathways underlying the tolerance to cocaine-induced motor effects. In a 5-day protocol measuring motor tolerance to cocaine in rats (N = 40), modeling the motor response to cocaine in patients, whole-genome RNA sequencing was conducted on the ventral and dorsal striatum to prioritize a genetic association study in 225 patients with severe CUD who underwent thorough phenotypic (cocaine-induced hyperlocomotion, CIH; and cocaine-induced stereotypies, CIS) and genotypic [571,000 polymorphisms (SNPs)] characterization. We provide a comprehensive description of the rat striatal transcriptomic response to cocaine in our paradigm. Repeated vs. acute cocaine binge administration elicited 27 differentially expressed genes in the ventral striatum and two in the dorsal striatum. One gene, Lrp1b, was differentially expressed in both regions. In patients, LRP1B was significantly associated with both CIS and CIH. CIH was also associated with VPS13A, a gene involved in a severe neurological disorder characterized by hyperkinetic movements. The LRP1B minor allele rs7568970 had a significant protective effect against CIS (558 SNPs, Bonferroni-corrected p = 0.02) that resisted adjustment for confounding factors, including the amount of cocaine use (adjusted beta = -0.965 and -2.35 for heterozygotes and homozygotes, respectively, p < 0.01). Using hypothesis-free prioritization of candidate genes along with thorough methodology in both the preclinical and human analysis pipelines, we provide reliable evidence that LRP1B and VPS13A are involved in the motor tolerance to cocaine in CUD patients, in line with their known pathophysiology.

Background: Amyloid pathology, which is one of the characteristics of Alzheimer's disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1-42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aβ1-40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aβ40 in the context of AD studied in several studies has yielded conflicting results., Methods: Here, we analyzed the levels of Aβ1-40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aβ1-42 and Aβ1-40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular)., Results: Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aβ40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aβ1-40 and p-tau (181) in CSF, particularly in control patients., Conclusions: These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aβ40 and the development of the disease.

Background: Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms., Methods: We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country., Findings: Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10 -15 ; heterozygous model p=1·01 × 10 -135 ), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10 -9 ), and GAL3ST1 (rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10 -10 ). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions., Interpretation: We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders., Funding: Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Wilson disease is an autosomal recessive metabolic disorder resulting from accumulation of excess copper especially in the liver and brain. This disease is mainly characterized by hepatic disorders and less frequently by neuro-psychiatric disturbances. This recessive disease is due to mutation in ATP7B, which codes for an ATPase involved in copper-transport across the plasma membrane. Molecular diagnosis of WD is positive in approximately 98% of cases. Also, in few cases, WD patients present a single deleterious mutation (heterozygous) or no mutation after sanger and NGS standard sequencing analysis of ATP7B. Therefore, in these problematic WD cases, we hypothesized that deleterious mutations reside in intronic regions of ATP7B., Methods: Complete ATP7B gene was sequenced by Next Generation Sequencing including its promoter., Results: Five unrelated families with Wilson disease shared the same novel, deep intronic NG&#95;008806.1 (ATP7B&#95;v001):c.2866-1521G>A variant in ATP7B. Analysis of RNA transcripts from primary fibroblasts of one patient confirmed the deleterious impact of the intronic variant on splicing and its likely pathologic effect in this compound heterozygote., Conclusion: This discovery of a novel intronic mutation in ATP7B has improved the molecular diagnosis of WD in the French patient cohort to greater than 98%. Thus, we recommend complete sequencing of ATP7B gene, including introns, as a molecular diagnostic approach in cases of clinically confirmed WD which lack pathogenic exon or promoter variants in one or both alleles., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Acute kidney injury (AKI) is the major complication of rhabdomyolysis. We aimed to identify the predictive factors for AKI and renal replacement therapy (RRT) requirement in poisoning-associated rhabdomyolysis. We conducted a cohort study including 273 successive poisoned patients (median age, 41 years) who developed rhabdomyolysis defined as creatine kinase (CK) >1000 IU/L. Factors associated with AKI and RRT requirement were identified using multivariate analyses. Poisonings mainly involved psychotropic drugs. AKI occurred in 88 patients (37%) including 43 patients (49%) who required RRT. Peak serum creatinine and CK were weakly correlated ( R 2 = 0.17, p < 0.001). Death (13%) was more frequent after AKI onset (32% vs. 2%, p < 0.001). On admission, lithium overdose (OR, 44.4 (5.3-371.5)), serum calcium ≤2.1 mmol/L (OR, 14.3 (2.04-112.4)), female gender (OR, 5.5 (1.8-16.9)), serum phosphate ≥1.5 mmol/L (OR, 2.0 (1.0-4.2)), lactate ≥ 3.3 mmol/L (OR, 1.2 (1.1-1.4)), serum creatinine ≥ 125 µmol/L (OR, 1.05 (1.03-1.06)) and age (OR, 1.04 (1.01-1.07)) independently predicted AKI onset. Calcium-channel blocker overdose (OR, 14.2 (3.8-53.6)), serum phosphate ≥ 2.3 mmol/L (OR, 1.6 (1.1-2.6)), Glasgow score ≤ 5 (OR, 1.12; (1.02-1.25)), prothrombin index ≤ 71% (OR, 1.03; (1.01-1.05)) and serum creatinine ≥ 125 µmol/L (OR, 1.01; (1.00-1.01)) independently predicted RRT requirement. We identified the predictive factors for AKI and RRT requirement on admission to improve management in poisoned patients presenting rhabdomyolysis.

Background: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD., Methods and Findings: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD., Conclusions: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level., Competing Interests: No conflicts of interest with regards to this paper. Outside the submitted work, TG reported having received consulting fees from Actelion, Biogen, Eli Lilly, Iqvia/ Quintiles; MSD; Novartis, Quintiles, Roche Pharma, lecture fees from Biogen, Lilly, Parexel, Roche Pharma, and grants to his institution from Actelion and PreDemTech.

Rationale: The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences., Objective: To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use., Methods: We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100 mg/kg in mice. We investigated the effects of single (30 mg/kg; acute injection) versus repeated (30 mg/kg ×3/day for 3 days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship., Results: Both naphyrone administration patterns induced time-dependent increases in locomotor activity (p < 0.001 and p < 0.0001, respectively) and social interaction (p < 0.05 and p < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior (p < 0.01) and reduced resignation (p < 0.01) whereas binge administration induced non-anxiety-like behavior (p < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine (p < 0.0001) and norepinephrine (p < 0.05 and p < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3 h. The naphyrone concentration/locomotor effect relationship was described by an additive E max model with an EC 50 of 672 μg/L., Conclusions: Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.

Objectives: Lithium is the leading mood stabiliser for maintenance treatment in bipolar disorder (BD). However, response to lithium is heterogeneous with more than 60% of patients experiencing partial or no response. In vitro and in vivo molecular studies have reported the implication of kinases in the pathophysiology of BD. Methods: Since kinases are putative targets for lithium therapeutic action, we conducted the first pilot study using kinase array technology to evaluate the global serine/threonine kinases (STK) profiles in cell lines from BD I subtype patients classified as lithium excellent-responders (ER) and non-responder (NR) to lithium treatment. Results: We found significant differences in the basal STK profiles between ER and NR to lithium. We also tested lithium influence on the global STK profile and found no significant difference between ER vs NR cell lines. Conclusions: The results obtained in this exploratory study suggest that multiplex kinase activity profiling could provide a complementary approach in the study of biomarkers of therapeutic response in BD.

Purpose: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly., Methods: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish., Results: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives., Conclusion: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.

Because quantitative reverse transcription PCR (RT-qPCR) gene expression data are compositional, amounts of quantified RNAs must be normalized using reference genes. However, the two most used methods to select reference genes (NormFinder and geNorm) ignore the compositional nature of RT-qPCR data, and often lead to different results making reliable reference genes selection difficult. We propose a method, based on all pairwise equivalence tests on ratio of gene expressions, to select genes that are stable enough to be used as reference genes among a set a candidate genes. This statistical procedure controls the error of selecting an inappropriate gene. Application to 30 candidate reference genes commonly used in human studies, assessed by RT-qPCR in RNA samples from lymphoblastoid cell lines of 14 control subjects and 26 patients with bipolar disorder, allowed to select 7 reference genes. This selection was consistent with geNorm's ranking, less with NormFinder's ranking. Our results provide an important fundamental basis for reference genes identification using sound statistics taking into account the compositional nature of RT-qPCR data. The method, implemented in the SARP.compo package for R (available on the CRAN), can be used more generally to prove that a set of genes shares a common expression pattern.

Purpose: Presymptomatic testing for susceptibility to genetic prion diseases is often delivered in difficult circumstances, as the index case is often dying when a genetic diagnosis is obtained. Since test requests in these diseases are very rare, the factors underlying decisions of relatives to be tested or not and the long-term psychological consequences are not reported. Methods: We contacted subjects who had consulted between 2004 and 2017 because a relative carried a pathological PRNP variant. Standardized psychological scales and semistructured interviews were proposed. Results: We did contact 19 of the 30 subjects who had consulted: 6 of 10 who did not undergo testing, 10 of 12 noncarriers, and 3 of 8 mutation carriers. Anxiety rates were high and similar between noncarriers and untested subjects. Conclusions: Living in a family with inherited prion disease produced psychological burden, regardless of the decision to undergo testing and its results. Decisions in favor of being testing did not allow relief of anxiety about the family disease. The dilemmatic decision not to know remained a burden to be coped with. Genetic counseling procedures should take into account all these situations, even that of noncarriers and that of untested., (Copyright © 2019 Schwartz, Brandel, Babonneau, Boucher, Schaerer, Haik, Laplanche, Gargiulo and Durr.)

High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine that emerges as a promising peripheral marker of inflammation. HMGB1 and C-reactive protein levels were assessed in plasma of control subjects and remitted patients with bipolar disorder (BD). HMGB1 levels were significantly higher in patients with BD as compared to control subjects whereas C-reactive protein levels did not differ between the two groups. No significant effect of potential covariates was identified. The results of this pilot study suggest that HMGB1 might be a specific peripheral marker of inflammation in BD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Protein misfolding cyclic amplification assay (PMCA) and real-time quaking-induced conversion (RT-QuIC) are two amplification techniques based on the ability of PrPsc to induce a conformational change in PrP allowing the detection of minute amounts of PrPsc in body fluids or tissues. PMCA and RT-QuIC have different ability to amplify PrPsc from sporadic, variant and genetic forms of Creutzfeldt-Jakob disease (CJD). PMCA readily amplifies PrPsc from variant CJD (vCJD) tissue while RT-QuIC easily amplifies PrPsc from sporadic CJD (sCJD) patient tissues. In terms of diagnosis, this implies the possibility of distinguishing vCJD from sCJD and explains the wider use of RT-QuIC given the respective frequencies of vCJD and sCJD. The sensitivity values of RT-QuIC for the diagnosis of sCJD are comparable or higher than those of the other tests (EEG, MRI, detection of 14-3-3 or tau proteins in cerebrospinal fluid) but with a specificity close to 100%. These new diagnostic methods could also be useful for the diagnosis of other neurodegenerative diseases., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Context: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling., Patients and Methods: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aβ 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis., Results: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aβ1-42 and Aβ1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aβ1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aβ1-42 concentrations <550 pg/mL or pTau>60 pg/mL., Conclusion: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease., Methods: We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene ( PRNP ) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials., Results: Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials., Conclusion: The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit., (© 2019 American Academy of Neurology.)

Treacher Collins syndrome (TCS) is a frequent cause of mandibulofacial dysostosis. To date, TCS-causing mutations in three genes, namely TCOF1, POLR1D, and POLR1C have been identified. TCS is usually inherited in an autosomal dominant manner, with a high clinical variability and no phenotype-genotype correlation. Up-to now, five families have been reported with an autosomal recessive mode of inheritance due to mutations in POLR1D or POLR1C. We report here a new family with two sisters affected by mild TCS carrying compound POLR1C heterozygous mutations, and review the literature on mild forms of TCS, autosomal recessive inheritance in this syndrome and POLR1C mutations., (© 2019 Wiley Periodicals, Inc.)

Objective: To investigate the relationship between cerebrospinal fluid (CSF) β-amyloid peptide (Aβ42) and CSF Tau in a large population of patients referred to memory clinics for investigation of cognitive dysfunction., Methods: We analyzed Alzheimer's disease (AD) biomarkers in CSF taken from 3565 patients referred to 18 French memory clinics. Patients were classified into four profiles according to levels of CSF biomarkers (A: amyloidosis, N: neurodegeneration). The association between CSF Tau and CSF Aβ42 were analyzed using general linear regression models, in the overall population and stratified by biomarkers profiles. We compared linear and quadratic models using Akaike information criterion. We also assessed change in biomarker profiles in a subset of patients who had 2 assessments of biomarkers., Results: CSF Tau was negatively associated with CSF Aβ42 in the overall population, following a non-linear quadratic model. However, the nature of this association was different in the 4 profiles: positive association in A-N- profile, negative association in A-N+ and A+N+ profiles, lack of association in A+N- patients. When considering patients with longitudinal data on profiles, 36% of those initially classified as A-N+ evolved to an A+N+ profile., Conclusions: The nature of the association between CSF Aβ42 and CFS Tau depends on the A/N profiles of patients. These results suggest an increase in CSF Aβ42 early in the disease before its decline while tau pathology progresses, this pattern is particularly observed in non-APOE4 subjects. This phenomenon may explain why some patients with neurodegeneration only markers convert to an AD profile (A+N+) over time., Competing Interests: The authors have declared that no competing interests exist.

Objective: Alzheimer's disease (AD) is the sixth leading cause of death, with an average survival estimated between 5 and 10 years after diagnosis. Despite recent advances in diagnostic criteria of AD, few studies have used biomarker-based diagnostics to determine the prognostic factors of AD. We investigate predictors of death and institutionalization in a population of AD patients with high probability of AD physiopathology process assessed by positivity of three CSF biomarkers., Methods: Three hundred twenty-one AD patients with abnormal values for CSF beta-amyloid peptide (Aβ42), tau, and phosphorylated tau levels were recruited from a memory clinic-based registry between 2008 and 2017 (Lariboisiere hospital, Paris, France) and followed during a median period of 3.9 years. We used multivariable Cox models to estimate the hazard ratio (HR) of death and institutionalization for baseline clinical data, genotype of the apolipoprotein E (APOE), and levels of CSF biomarkers., Results: A total of 71 (22%) patients were institutionalized and 57 (18%) died during the follow-up. Greater age, male sex, lower MMSE score, and lower CSF Aβ42 level were associated with an increased risk of mortality. One standard deviation lower CSF Aβ42 (135 pg/mL) was associated with a 89% increased risk of death (95% CI = 1.25-2.86; p = 0.002). This association was not modified by age, sex, education, APOE ε4, and disease severity. There was no evidence of an association of tau CSF biomarkers with mortality. None of the CSF biomarkers were associated with institutionalization., Conclusions: Lower CSF Aβ42 is a strong prognostic marker of mortality in AD patients, independently of age or severity of the disease. Whether drugs targeting beta-amyloid peptide could have an effect on mortality of AD patients should be investigated in future clinical trials.