Intérêt des bandes oligoclonales dans le liquide céphalo-rachidien comme facteur pronostique de conversion des syndromes cliniquement isolés en sclérose en plaques cliniquement définie en pratique quotidienne

Devant un syndrome cliniquement isolé évocateur d'un 1er évènement de sclérose en plaques, les critères de McDonald de 2005 acceptent 2 méthodes pour prouver la dissémination dans l'espace : la présence de 3 des 4 critères de Barkhof (CB) sur l'imagerie par résonance magnétique (IRM) initiale, ou l'association de bandes oligoclonales (BOC) et de 2 lésions à l'IRM. En pratique quotidienne, l'IRM est dvenue l'examen complémentaire pronostique de conversion en SEP cliniquement définie (SEP-CD) le plus important. L'analyse du liquide céphalo-rachidien (LCR) semble être passée au second plan. L'objectif est d'évaluer comme facteur pronostique de conversion des SCI en SEP-CD, la présence de BOC dans la ponction lombaire (PL). Nous avons sélectionné de façon prospective les patients ayant présenté un SCI entre le 01/01/03 et le 31/12/05, hospitalisés au CHU de Clermont-Ferrand, où ils ont eu une PL avec recherche de BOC en isoélectrofocalisation dans le LCR, une IRM encéphalique et médullaire, sur laquelle les CB ont été appliqués rétrspectivement. La conversion en SEP-CD était définie par la mesure avant mars 2008 d'un 2ème évènement neurologique. Nous avons comparé les performances statistiques des BOC, des CB et de 2 lésions T2 associées à des BOC positives. 72 patients ont été inclus dans l'étude (sex ratio F/H=4,5 ; âge moyen=35 ans). Après un suivi de 55 mois, la sensibilité du critère utilisant les BOC est de 62%, versus 50% pour les CB. La spécificité des CB est de 100%, versus 66,5% pour l'autre méthode. Notre travail retrouve un risque de conversion des SCI en SEP-CD plus important chez les patients validant les CB que chez ceux qui présentent 2 lésions à l'IRM associées à la présence de BOC. Dans la population validant les CB, la présence de BOC dans le LCR n'apporte pas d'élément supplémentaire pronostique de conversion en SEP-CD. La PL ne semble donc pas utile chez les patients ayant 3 ou 4 CB. Dans la population aux données d'IRM équivoques, la valeur pronostique de la présence de BOC augmente avec l'allongement de la durée de suivi. Son intérêt comme facteur pronostique de conversion en SEP-CD n'apparaît qu'après un long délai, nous incitant à suivre plus longtemps les patients.CLERMONT FD-BCIU-Santé (631132104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Phenotype and imaging features associated with APP duplications

Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

International audienceThe SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications