Intracisternal delivery of NFκB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment.

We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFκB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic kainic acid (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self-complementary AAV2/9 (scAAV2/9) delivery in the adult rat cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, AAV2/9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFκB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the CD11b marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug-induced or transgenic disease models. However, further improvements are required to enhance viral particles penetration into the brain

Gamma knife radiosurgery for arteriovenous malformations: general principles and preliminary results in a Swiss cohort.

Arteriovenous malformations (AVMs) are a type of vascular malformation characterised by an abnormal connection between arteries and veins, bypassing the capillary system. This absence of capillaries generates an elevated pressure (hyperdebit), in both the AVM and the venous drainage, increasing the risk of rupture. Management modalities are: observation, microsurgical clipping, endovascular treatment and radiosurgery. The former can be used alone or in the frame of a multidisciplinary approach. We review our single-institution experience with gamma knife radiosurgery (GKR) over a period of 5 years. The study was open-label, prospective and nonrandomised. Fifty-seven consecutive patients, benefitting from 64 GKR treatments, were included. All were treated with Leksell Gamma Knife Perfexion (Elekta Instruments, AB, Sweden) between July 2010 and August 2015. All underwent stereotactic multimodal imaging: standard digital subtraction angiography, magnetic resonance imaging and computed tomography angiography. We report obliteration rates, radiation-induced complications and haemorrhages during follow-up course. The mean age was 46 years (range 13-79 years). The mean follow-up period was 36.4 months (median 38, range 12-75 months). Most common pretherapeutic clinical presentation was haemorrhage (50%). The most common Pollock-Flickinger score was between 1.01 and 1.5 (46%) and Spetzler-Martin grade III (46%). In 39 (60.1%) of cases, GKR was performed as upfront therapeutic option. The mean gross target volume (GTV) was 2.3 ml (median 1.2, range 0.03-11.3 ml). Mean marginal dose was 22.4 Gy (median 24, range 18-24 Gy). The mean prescription isodose volume (PIV) was 2.9 ml (median 1.8, range 0.065-14.6 ml). The overall obliteration rates (all treatments combined) at 12, 24, 36, 48 and 60 months were 4.8, 16.9%, 37.4, 63.6 and 78.4%, respectively. The main predictive factors for complete obliteration were: higher mean marginal dose (23.3 vs 21.0 Gy), lower GTV (mean 1.5 vs 3.5 ml) and absence of previous embolisation (at 60 months 61.8% prior embolisation compared with 82.4% without prior embolisation) (for all p <0.05). Eight (14%) patients experienced complications after GKR. Overall definitive morbidity rate was 3.1%. No patient died from causes related to GKR. However, during the obliteration period, one case of extremely rare fatal haemorrhage occurred. Radiosurgery is a safe and effective treatment modality for intracranial AVMs in selected cases. It can be used as upfront therapy or in the frame of a combined management. Obliteration rates are high, with minimal morbidity. The treatment effect is progressive and subsequent and regular clinical and radiological follow-up is needed to evaluate this effect

Preserving normal facial nerve function and improving hearing outcome in large vestibular schwannomas with a combined approach: planned subtotal resection followed by gamma knife radiosurgery.

To perform planned subtotal resection followed by gamma knife surgery (GKRS) in a series of patients with large vestibular schwannoma (VS), aiming at an optimal functional outcome for facial and cochlear nerves. Patient characteristics, surgical and dosimetric features, and outcome were collected prospectively at the time of treatment and during the follow-up. A consecutive series of 32 patients was treated between July 2010 and June 2016. Mean follow-up after surgery was 29 months (median 24, range 4-78). Mean presurgical tumor volume was 12.5 cm3 (range 1.47-34.9). Postoperative status showed normal facial nerve function (House-Brackmann I) in all patients. In a subgroup of 17 patients with serviceable hearing before surgery and in which cochlear nerve preservation was attempted at surgery, 16 (94.1%) retained serviceable hearing. Among them, 13 had normal hearing (Gardner-Robertson class 1) before surgery, and 10 (76.9%) retained normal hearing after surgery. Mean duration between surgery and GKRS was 6.3 months (range 3.8-13.9). Mean tumor volume at GKRS was 3.5 cm3 (range 0.5-12.8), corresponding to mean residual volume of 29.4% (range 6-46.7) of the preoperative volume. Mean marginal dose was 12 Gy (range 11-12). Mean follow-up after GKRS was 24 months (range 3-60). Following GKRS, there were no new neurological deficits, with facial and hearing functions remaining identical to those after surgery in all patients. Three patients presented with continuous growth after GKRS, were considered failures, and benefited from the same combined approach a second time. Our data suggest that large VS management, with planned subtotal resection followed by GKRS, might yield an excellent clinical outcome, allowing the normal facial nerve and a high level of cochlear nerve functions to be retained. Our functional results with this approach in large VS are comparable with those obtained with GKRS alone in small- and medium-sized VS. Longer term follow-up is necessary to fully evaluate this approach, especially regarding tumor control

Sympathetic activity and early mobilization in patients in intensive and intermediate care with severe brain injuries: a preliminary prospective randomized study.

Patients who experience severe brain injuries are at risk of secondary brain damage, because of delayed vasospasm and edema. Traditionally, many of these patients are kept on prolonged bed rest in order to maintain adequate cerebral blood flow, especially in the case of subarachnoid hemorrhage. On the other hand, prolonged bed rest carries important morbidity. There may be a clinical benefit in early mobilization and our hypothesis is that early gradual mobilization is safe in these patients. The aim of this study was to observe and quantify the changes in sympathetic activity, mainly related to stress, and blood pressure in gradual postural changes by the verticalization robot (Erigo®) and after training by a lower body ergometer (MOTOmed-letto®), after prolonged bed rest of minimum 7 days. Thirty patients with severe neurological injuries were randomized into 3 groups with different protocols of mobilization: Standard, MOTOmed-letto® or Erigo® protocol. We measured plasma catecholamines, metanephrines and blood pressure before, during and after mobilization. Blood pressure does not show any significant difference between the 3 groups. The analysis of the catecholamines suggests a significant increase in catecholamine production during Standard mobilization with physiotherapists and with MOTOmed-letto® and no changes with Erigo®. This preliminary prospective randomized study shows that the mobilization of patients with severe brain injuries by means of Erigo® does not increase the production of catecholamines. It means that Erigo® is a well-tolerated method of mobilization and can be considered a safe system of early mobilization of these patients. Further studies are required to validate our conclusions. The study was registered in the ISRCTN registry with the trial registration number ISRCTN56402432 . Date of registration: 08.03.2016. Retrospectively registered

Robust thalamic nuclei segmentation method based on local diffusion magnetic resonance properties.

The thalamus is an essential relay station in the cortical-subcortical connections. It is characterized by a complex anatomical architecture composed of numerous small nuclei, which mediate the involvement of the thalamus in a wide range of neurological functions. We present a novel framework for segmenting the thalamic nuclei, which explores the orientation distribution functions (ODFs) from diffusion magnetic resonance images at 3 T. The differentiation of the complex intra-thalamic microstructure is improved by using the spherical harmonic (SH) representation of the ODFs, which provides full angular characterization of the diffusion process in each voxel. The clustering was performed using the k-means algorithm initialized in a data-driven manner. The method was tested on 35 healthy volunteers and our results show a robust, reproducible and accurate segmentation of the thalamus in seven nuclei groups. Six of them closely matched the anatomy and were labeled as anterior, ventral anterior, medio-dorsal, ventral latero-ventral, ventral latero-dorsal and pulvinar, while the seventh cluster included the centro-lateral and the latero-posterior nuclei. Results were evaluated both qualitatively, by comparing the segmented nuclei to the histological atlas of Morel, and quantitatively, by measuring the clusters' extent and the clusters' spatial distribution across subjects and hemispheres. We also showed the robustness of our approach across different sequences and scanners, as well as intra-subject reproducibility of the segmented clusters using additional two scan-rescan datasets. We also observed an overlap between the path of the main long-connection tracts passing through the thalamus and the spatial distribution of the nuclei identified with our clustering algorithm. Our approach, based on SH representations of the ODFs, outperforms the one based on angular differences between the principle diffusion directions, which is considered so far as state-of-the-art method. Our findings show an anatomically reliable segmentation of the main groups of thalamic nuclei that could be of potential use in many clinical applications

Introducing a nationwide registry: the Swiss study on aneurysmal subarachnoid haemorrhage (Swiss SOS)

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is a haemorrhagic form of stroke and occurs in a younger population compared with ischaemic stroke or intracerebral haemorrhage. It accounts for a large proportion of productive life-years lost to stroke. Its surgical and medical treatment represents a multidisciplinary effort. Due to the complexity of the disease, the management remains difficult to standardise and quality of care is accordingly difficult to assess. Objective: To create a registry to assess management parameters of patients treated for aSAH in Switzerland. Methods: A cohort study was initiated with the aim to record characteristics of patients admitted with aSAH, starting January 1st 2009. Ethical committee approval was obtained or is pending from the institutional review boards of all centres. In the study period, seven Swiss hospitals (five university [U], two non-university medical centres) harbouring a neurosurgery department, an intensive care unit and an interventional neuroradiology team so far agreed to participate in the registry (Aarau, Basel [U], Bern [U], Geneva [U], Lausanne [U], St. Gallen, Zürich [U]). Demographic and clinical parameters are entered into a common database. Discussion: This database will soon provide (1) a nationwide assessment of the current standard of care and (2) the outcomes for patients suffering from aSAH in Switzerland. Based on data from this registry, we can conduct cohort comparisons or design diagnostic or therapeutic studies on a national level. Moreover, a standardised registration system will allow healthcare providers to assess the quality of car

Microsurgical resection of intracranial meningiomas in patients aged 80 years old or more: A systematic review and meta-analysis.

The incidence of intracranial meningiomas rises with advancing age, raising the question of whether similar surgical outcomes in morbidity and mortality can be expected compared to younger population. We conducted a systematic review and meta-analysis of research examining microsurgical outcomes in those aged 80 years or older. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we reviewed articles published between January 1995 and January 2024, referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies of series reporting microsurgical resection of intracranial meningiomas in patients aged 80 years or more, written in English. Primary outcome was EOR (extend of resection), classified as tumor total resection versus partial resection. Secondary outcomes were morbidity and mortality. Ten studies reported 690 patients. Total tumor resection was achieved in 88% of cases (range 85-91; I <sup>2</sup> = 56; p heterogeneity = 0.02; p < 0.01). Tumor partial resection was achieved in 12% (range 9-15; I^2 = 56; p heterogeneity = 0.02 and p < 0.001). Postsurgical intracerebral hemorrhage was encountered in 1% of cases (range 0-2; I^2 = 69; p heterogeneity = < 0.01). Surgical mortality was encountered in 5% of cases (range 3-7; I^2 = 61; p heterogeneity = < 0.01). Current data suggests that achieving high total resection rates, up to 88%, is feasible. The surgical mortality rate was 5%. A key unresolved neurosurgical dilemma is whether to operate on patients over 80 years old. Future studies are essential to assess all relevant risk factors comprehensively

Incidence du processus de vieillissement et des traits d'histoire de vie sur l'évolution de l'ADN mitochondrial chez les bivalves

RÉSUMÉ: Les bivalves sont de bons modèles biologiques pour l’étude du vieillissement cellulaire en raison de leurs grandes variations de longévités. L’objectif principal de la maîtrise était de comprendre le mode d’évolution de l’ADN mitochondrial (ADNmt) en lien avec le vieillissement cellulaire chez les bivalves. Pour répondre à cet objectif, deux études ont été réalisées. La première étude a permis de décrire les génomes mitochondriaux de neuf espèces de la sous-classe des Heterodonta, de reconstituer la phylogénie des Heterodonta et d’étudier la répartition génétique de l’espèce Arctica islandica. La deuxième étude a permis d’étudier le mode d’évolution de l’ADNmt par rapport à trois traits d’histoire de vie (longévité, temps de génération et température maximale létale). La composition des génomes mitochondriaux des neuf espèces d’Heterodonta correspond à celle retrouvée généralement chez les animaux : 13 gènes codant pour les protéines, 2 gènes ribonucléiques ribosomiques et 22 gènes ribonucléiques de transfert ; même si quelques particularités propres aux bivalves ont été observées (duplication du gène COX2, addition de gènes tRNA-Met, absence du gène ATP8 et configuration du gène CYTB en deux cadres de lecture). Les phylogénies des Heterodonta réalisées à partir de la concaténation des séquences nucléotidiques de 12 gènes mitochondriaux codant pour les protéines ont permis de confirmer les précédentes phylogénies et d’établir une relation de parenté solide entre les espèces Arctica islandica et Corbicula fluminea. L’étude sur la répartition génétique de l’espèce Arctica islandica montre que la population du golfe du Saint-Laurent est génétiquement plus proche de la population de la mer Baltique, que des populations de la mer du Nord et d’Islande. Le vieillissement, représenté par la longévité dans la deuxième étude, est expliqué à 68% par le temps de génération et à 22% par la température. Le taux de substitution synonyme est expliqué en partie (entre 9 et 30%) par la longévité. Les autres traits d’histoire de vie étudiés (temps de génération et température maximale létale) n’influencent pas l’évolution de l’ADNmt chez les bivalves. Nous présentons ici, la première étude sur l’impacte de la longévité sur le mode d’évolution de l’ADNmt chez des invertébrés. -- Mot(s) clé(s) en français : vieillissement, génome mitochondrial, bivalve, phylogénie Bayésienne, évolution des traits d'histoire de vie, taux de substitution, Arctica islandica. -- ABSTRACT: Bivalves are good model for studying evolutionary processes related to aging as they exhibit great variations in longevities among species. The aim of this Master was to understand how mitochondrial DNA (mtDNA) has evolved in relation to aging in bivalves. Two studies were performed to answer this question. The first chapter examines the description of the mitochondrial genomes of nine species of the subclass Heterodonta, provides a new Heterodonta phylogeny, and examines intraspecific variation in Arctica islandica using the full mitochondria genomes. The second study focus on the evolution of mtDNA relative to three life-history traits (longevity, generation time, and maximum lethal temperature). Mitochondrial genome cartography for the nine Heterodonta species corresponds to what is generally found in animals: 13 protein-coding genes, 2 ribosomal RNA genes and 22 transfer RNA genes. Some characters specific to bivalves were observed (duplication of COX2 gene, addition of tRNA-Met genes, lack of ATP8 gene and two reading frames for CYTB gene). Heterodonta phylogenies performed from the concatenation of 12 protein-coding genes nucleotide sequences confirmed previous phylogenies and established a strong relationship between the species Arctica islandica and Corbicula fluminea. Results on genetics repartition of Arctica islandica showed that the population from the Gulf of St. Lawrence was genetically closer to Baltic Sea population than to populations from the North Sea and Iceland. Aging, represented by longevity in the second chapter, was explained by generation time (68%) and by temperature (22%). The synonymous substitution rate is explained in part (between 9 and 30%) by longevity. Other life history traits studied (generation time and maximum lethal temperature) did not influence mtDNA evolution in bivalves. We present here, the first study on the evolution of mtDNA relative to longevity in invertebrates. -- Mot(s) clé(s) en anglais : aging, mitochondrial genome, bivalve, Bayesian phylogeny, life-history evolution, substitution rates, Arctica islandica