CRMP5 Regulates Generation and Survival of Newborn Neurons in Olfactory and Hippocampal Neurogenic Areas of the Adult Mouse Brain

The Collapsin Response Mediator Proteins (CRMPs) are highly expressed in the developing brain, and in adult brain areas that retain neurogenesis, ie: the olfactory bulb (OB) and the dentate gyrus (DG). During brain development, CRMPs are essentially involved in signaling of axon guidance and neurite outgrowth, but their functions in the adult brain remain largely unknown. CRMP5 has been initially identified as the target of auto-antibodies involved in paraneoplasic neurological diseases and further implicated in a neurite outgrowth inhibition mediated by tubulin binding. Interestingly, CRMP5 is also highly expressed in adult brain neurogenic areas where its functions have not yet been elucidated. Here we observed in both neurogenic areas of the adult mouse brain that CRMP5 was present in proliferating and post-mitotic neuroblasts, while they migrate and differentiate into mature neurons. In CRMP5−/− mice, the lack of CRMP5 resulted in a significant increase of proliferation and neurogenesis, but also in an excess of apoptotic death of granule cells in the OB and DG. These findings provide the first evidence that CRMP5 is involved in the generation and survival of newly generated neurons in areas of the adult brain with a high level of activity-dependent neuronal plasticity

Neurology

The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.Observatoire Français de la Sclérose en Plaque

A Genome-Scale DNA Repair RNAi Screen Identifies SPG48 as a Novel Gene Associated with Hereditary Spastic Paraplegia

We have identified a novel gene in a genome-wide, double-strand break DNA repair RNAi screen and show that is involved in the neurological disease hereditary spastic paraplegia

CARACTERISTIQUES ELECTROPHYSIOLOGIQUES DES NEUROPATHIES PERIPHERIQUES PARANEOPLASIQUES ASSOCIEES A L'ANTICORPS ANTI-HU (ETUDE RETROSPECTIVE D'UNE SERIE DE 17 PATIENTS)

ST ETIENNE-BU Médecine (422182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Expression de CRMP5 dans le nerf périphérique et rôle dans le syndrome neurologique paraneoplasique CV2

Les syndromes neurologiques paranéoplasiques dépendent de mécanismes auto-immuns dirigés contre des antigènes onconeuronaux communs du cancer et au système nerveuX. Ils sont des modèles utiles pour la compréhension de l'immuniité anti-tumorale et des affections neuro-immunologiques. De plus, ils ont permis l'identification de proteines neurales impliquées dans des mécanismes fondamentaux en neuroscience. CRMP5, est un antigène onconeural associé à une neuropathie périphéique et au thymome. Dans ce travail, nous avons montré que CRMP5 était exprimée dans des cellules de Schwann non myélinésantes sous l'action de signaux axonaux lors du développement et de la régénérescence axonale. Une tentative de développement d'un modèle animal de neuropathie périphérique par immunisation anti-CRMP5 a par ailleurs montré que les anticorps anti-CRMP5 n'étaient sans doute pas les acteurs principaux de la réponse immunitaire. enfin, nous avons étudié l'expression de CRMP5 dans le thymus et les thymomes. nos résultats montrent que la rupture de la tolérance du soi dans le syndrome anti-CRMP5 es différente selon le type de tumeur. Ils suggèrent aussi que l'expression des antigènes onconeuronaux dans le thymus pourrait être un facteur de la tolérance vis-à-vis de ces antigènesLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Retrospective study of 203 ALS patients followed in a reference center between 2003 and 2011 (interests and limits of our practice)

La sclérose latérale amyotrophique (SLA) est une maladie neuro-dégénérative des motoneurones rapidement progressive et fatale. Nous avons étudié les patients pris en charge par l'équipe multidisciplinaire du centre hospitalier universitaire de Saint-Etienne entre 2003 et 2011 pour évaluer notre pratique. Nous avons comparé nos données à la littérature. A partir du registre du centre, 203 patients sur 306 ont été sélectionnés. Toutes les données disponibles du dossier médical ont été colligées et analysées : sociales, cliniques, survie, décès. Trente et un pourcents des patients SLA ont débuté par la forme bulbaire. Trente-quatre virgule cinq pourcents des patients ont eu une gastrostomie et 29.6% une ventilation non invasive avec une tendance à l'allongement de la survie pour ces derniers. La médiane de survie a été de 28.9 mois La cause de décès la plus fréquente était respiratoire. Le suivi sur 9 ans des patients montre des résultats proches de la littérature et permet de réfléchir à l'évolution de nos pratiques qui devront encore plus être axées sur l'anticipation notamment en cas de signes mêmes discrets d'atteinte respiratoireST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

A clinical screening tool for objective and subjective cognitive disorders in multiple sclerosis

International audienceBACKGROUND: Cognitive dysfunction is common in multiple sclerosis (MS). Deficits can affect attention, concentration, planning, and memory. They can have severe functional consequences in many domains. Cognitive complaints are frequently associated with other confounding factors (fatigue, anxiety, depression, or treatment side effects). In most cases, cognitive assessment is proposed after a spontaneous complaint, but determining the extent of discomfort perceived by the patient, the influence of coexisting factors, or the optimal timing for a more complete neuropsychological assessment is difficult. OBJECTIVE: The objective of this work was to evaluate the feasibility and relevance of a fast global assessment of both objective and subjective cognitive dysfunction in MS. METHODS: MS patients underwent a brief cognitive assessment including 7 visual analogue scales (VASs) asking about the patient's subjective level of discomfort in various domains, a memory test (Barbizet's lion story), a commonly used test of information processing speed (Symbol Digit Modalities Test [SDMT]) and self-reporting questionnaires for fatigue and mood (Fatigue Severity Scale [FSS] and Hospital Anxiety and Depression Scale [HADS]). Spearman correlation coefficients among scores were estimated. RESULTS: The mean age of the 73 patients included was 48.3 (SD 11.1) years; 78% were females and 52.8% had the remittent-recurrent MS form, 8.3% the primary progressive form, and 38.9% the secondary progressive form. In less than 20min, this brief cognitive assessment was able to identify symptoms and quantify discomfort level. Symptoms of fatigue and anxiety frequently coexisted with cognitive complaints. We found modest correlations between scores on the VAS fatigue and the FSS and between scores on the VAS mood and the HADS. Analytical evaluation revealed that most patients had similar SDMT and recall profiles; however, a small proportion showed a dissociation between these 2 tests, which validated the inclusion of both tests in the assessment. Accounting for coexisting factors (e.g., anxiety and fatigue) and their functional repercussions is essential for prioritizing these problems within the context of multidisciplinary patient treatment. CONCLUSION: Considering the possible multifactorial character of cognitive dysfunction in MS, it is essential to ask patients about their experiences and to take into account cognitive complaints in the follow-up of patients. The assessment tool we propose is simple and easy to use in a clinical setting and provides the information necessary for requesting (or not) a more complete neuropsychological assessment

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

International audienceOBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. Interpretation: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour