Human pegivirus identified in severe myelitis and optic neuritis in immunocompromised patients: A pathogenic role for a forgotten virus?

The role of Human pegivirus (HPgV) in patients with encephalitis has been recently questioned. We present cases of 4 patients with similar clinical, biological, and radiological characteristics, including a past history of transplantation with long-term immunosuppression and a progressive course of severe and predominantly myelitis, associated in 3 cases with optic neuropathy causing blindness. Extensive workup was negative but analysis of the CSF by use of pan-microorganism DNA- and RNA-based shotgun metagenomics was positive for HPgV. This case series further supports the hypothesis of HPgV CNS infection and highlights the utility of metagenomic next-generation sequencing of CSF in immunocompromised patients.

High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 2: putative scenarios and timeline in case of approval, recommendations for use, implementation, and ethical considerations in France.

In 2021, aducanumab, an immunotherapy targeting amyloid-ß, was approved for Alzheimer's disease (AD) by the US Food and Drug Administration thanks to positive results on a putative biological surrogate marker. This approval has raised an unprecedented controversy. It was followed by a refusal of the European Medicine Agency, which does not allow the marketing of drugs solely on biological arguments and raised safety issues, and important US coverage limitations by the Centers for Medicare & Medicaid Services. Two other anti-amyloid immunotherapies showed significant results regarding a clinical outcome in phase II trials, and five drugs are being studied in phase III trials. Lecanemab is currently under examination for an 'Accelerated Approval' in the US, with an expected decision in January 2023. The common feature and novelty of these anti-amyloid immunotherapies, compared to those tested in previous trials of the 2010s, is their ability to induce a high clearance of amyloid load, as measured with positron emission tomography, in the brain of early-stage biomarker-proven AD patients. In the first part of this review, we underlined through a meta-analysis that the pooled data from high-clearance anti-amyloid immunotherapies trials demonstrated a significant but slight clinical effect after 18 months. Still, safety remains an issue with serious and symptomatic amyloid-related imaging abnormalities, which are seldom (∼1 per 200 treated patients) but occur beyond chance. In the second part of this review, we hypothesized that there is a high probability that some phase III trials of high-clearance anti-amyloid immunotherapies in early AD will finally be unarguably positive on clinical outcomes in the next five years with acceptable safety data. This may, in turn, lead to approval by the European Medicine Agency if the risk-benefit profile is deemed favorable. Such approval would be a game-changer in managing AD patients and for the organization of memory clinics in France. We review the possible timeline and scenarios for putative approval in France and make propositions regarding putative use in clinical practice, putative implementation in a real-life setting, and ethical considerations.

High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects.

In 2021, aducanumab, an immunotherapy targeting amyloid-ß, was approved for Alzheimer's disease (AD) by the US Food and Drug Administration thanks to positive results on a putative biological surrogate marker. This approval has raised an unprecedented controversy. It was followed by a refusal of the European Medicine Agency, which does not allow the marketing of drugs solely on biological arguments and raised safety issues, and important US coverage limitations by the Centers for Medicare & Medicaid Services. Two other anti-amyloid immunotherapies showed significant results regarding a clinical outcome in phase 2 trials, and five drugs are being studied in phase 3 trials. Compared to those tested in previous trials of the 2010s, the common feature and novelty of these anti-amyloid immunotherapies is their ability to induce a high clearance of amyloid load, as measured with positron emission tomography, in the brain of early-stage biomarker-proven AD patients. Here, we review the available evidence regarding efficacy and safety data and medico-economical aspects for high-clearance anti-amyloid immunotherapies. We also perform frequentist and Bayesian meta-analyses of the clinical efficacy and safety of the highest dose groups from the two aducanumab phase 3 trials and the donanemab and lecanemab phase 2 trials. When pooled together, the data from high-clearance anti-amyloid immunotherapies trials confirm a statistically significant clinical effect of these drugs on cognitive decline after 18 months (difference in cognitive decline measured with CDR-SB after 18 months between the high dose immunotherapy groups vs. placebo = -0.24 points; P=0.04, frequentist random-effect model), with results on ADAS-Cog being the most statistically robust. However, this effect remains below the previously established minimal clinically relevant values. In parallel, the drugs significantly increased the occurrence of amyloid-related imaging abnormalities-edema (ARIA-E: risk ratio=13.39; P<0.0001), ARIA-hemorrhage (risk ratio=2.78; P=0.0002), and symptomatic and serious ARIA (7/1321=0.53% in the high dose groups versus 0/1446 in the placebo groups; risk ratio=6.44; P=0.04). The risk/benefit ratio of high-clearance immunotherapies in early AD is so far questionable after 18 months. Identifying subgroups of better responders, the perspective of combination therapies, and a longer follow-up may help improve their clinical relevance. Finally, the preliminary evidence from medico-economical analyses seems to indicate that the current cost of aducanumab in the US is not in reasonable alignment with its clinical benefits.

Therapeutic news in Alzheimer's disease: Soon a disease-modifying therapy?

Research on disease-modifying treatments for Alzheimer's disease has resulted in a series of failures over the past 20 years. However, in the last three years, four molecules have shown significant effects on clinical endpoints in phase II or III clinical trials (i.e., slowing of cognitive decline). Among these four molecules, three are anti-amyloid immunotherapies: aducanumab, donanemab, and lecanemab, responsible for a significant clearance of cerebral beta-amyloid deposits. These provisional data are still awaiting confirmation to put an end to the controversy surrounding the 2021 Food and Drug Administration's decision to give conditional approval to aducanumab, which is considered premature by many specialists. Confirmation is also necessary to assess the benefit (magnitude of the slowing of cognitive decline) and risk (edema and cerebral hemorrhage induced by these treatments) balance of these molecules. Masitinib, a treatment whose probable mechanism of action is neuroinflammation, has also shown positive effects that need to be confirmed. Therapies targeting the tau protein are less advanced and have yet to be proven. Patients have renewed hope since it may not be unreasonable that these disease-modifying therapies will be part of the French therapeutic arsenal within the next five years.

Pseudoxanthoma elasticum overlaps hereditary spastic paraplegia type 56.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. METHODS: First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. RESULTS: 6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. CONCLUSION: CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

[Toward a preventive management Alzheimer's disease]. / Pour une prise en charge préventive de la maladie d'Alzheimer.

Dementias, and Alzheimer's disease (AD) in particular, will increasingly become a public health issue. However, three major data may change the severity of these pathologies: in young adults, simple measures of healthy lifestyle (control of vascular risk factors, physical activity and cognitive stimulation), have an impact on a future cognitive decline; the same lifestyle interventions may delay the start of the disease for elderly people potentially at-risk; finally, and for the first time, a monoclonal antibody directed against amyloid lesions has just shown a significant effect on the progression of AD in patients at an early stage of the disease. According to these results, we will have to reconsider the strategy for managing minor or severe cognitive disorders and particularly AD. Nowadays, patients start the care process too late. The solution is to act earlier, even preventively. It is necessary to improve a care offer adapted to this new situation in order to impact on the disease as soon as possible, even before the onset of symptoms, based on: 1) predictive algorithms aimed at establishing whose cognitively unimpaired individuals may further develop the disease; these algorithms will be based on demographic, family, cognitive, genomic and biological data, such as in the "Santé Cerveau" project developed in partnership with the Health Regional Agency (ARS) and the general practitioners; 2)and on some expert centers which must become "dementia prevention clinics" to test prevention measures, initiate and validate multi-domain therapeutic education programs; to disclose about the risk in response to the request of worried patients; and to propose early pharmacological treatments if these individuals are on the way to declare AD in the coming months, taking into account competition between risks. This will allow to prepare to make use of new pharmacological treatments that might be discovered.

Automatic knee meniscus tear detection and orientation classification with Mask-RCNN.

PURPOSE: This work presents our contribution to a data challenge organized by the French Radiology Society during the Journées Francophones de Radiologie in October 2018. This challenge consisted in classifying MR images of the knee with respect to the presence of tears in the knee menisci, on meniscal tear location, and meniscal tear orientation. MATERIALS AND METHODS: We trained a mask region-based convolutional neural network (R-CNN) to explicitly localize normal and torn menisci, made it more robust with ensemble aggregation, and cascaded it into a shallow ConvNet to classify the orientation of the tear. RESULTS: Our approach predicted accurately tears in the database provided for the challenge. This strategy yielded a weighted AUC score of 0.906 for all three tasks, ranking first in this challenge. CONCLUSION: The extension of the database or the use of 3D data could contribute to further improve the performances especially for non-typical cases of extensively damaged menisci or multiple tears.

Kidney cortex segmentation in 2D CT with U-Nets ensemble aggregation.

PURPOSE: This work presents our contribution to one of the data challenges organized by the French Radiology Society during the Journées Francophones de Radiologie. This challenge consisted in segmenting the kidney cortex from coronal computed tomography (CT) images, cropped around the cortex. MATERIALS AND METHODS: We chose to train an ensemble of fully-convolutional networks and to aggregate their prediction at test time to perform the segmentation. An image database was made available in 3 batches. A first training batch of 250 images with segmentation masks was provided by the challenge organizers one month before the conference. An additional training batch of 247 pairs was shared when the conference began. Participants were ranked using a Dice score. RESULTS: The segmentation results of our algorithm match the renal cortex with a good precision. Our strategy yielded a Dice score of 0.867, ranking us first in the data challenge. CONCLUSION: The proposed solution provides robust and accurate automatic segmentations of the renal cortex in CT images although the precision of the provided reference segmentations seemed to set a low upper bound on the numerical performance. However, this process should be applied in 3D to quantify the renal cortex volume, which would require a marked labelling effort to train the networks.

Carotid contrast-enhanced ultrasonography and multimodal imaging in a case of TIPIC syndrome.

Transient perivascular inflammation of the carotid artery (TIPIC) syndrome, previously referred to as 'carotidynia', is an unclassified clinicoradiological entity associating atypical acute neck pain, eccentric perivascular infiltration on imaging and improvement of symptoms either spontaneously or with anti-inflammatory treatment. This case report presents a patient with TIPIC syndrome who underwent five different types of imaging modality, including contrast-enhanced ultrasonography (CEUS) of the carotids, and describes the CEUS appearances of TIPIC syndrome.

Body mass loss correlates with cognitive performance in primates under acute caloric restriction conditions.

Brain functions are known to consume high levels of energy, thus, the integrity of cognitive performance can be drastically impacted by acute caloric restriction. In this study, we tested the impact of a 40% caloric restriction on the cognitive abilities of the grey mouse lemur (Microcebus murinus). Twenty-three male mouse lemurs were divided into two groups: 13 control animals (CTL) that were fed with 105kJ/day and 10calorie restricted (CR) animals that received 40% less food (63kJ/day) than the CTL animals. The animals were fed according to their group for 19days. Before treatment, we assessed baseline associative learning capacities, resting metabolic rates and locomotor performance of both animal groups. After treatment, we tested the same functions as well as long-term memory. Our results showed that CR animals had lower learning performance following caloric restriction. The effects of caloric restriction on memory recall varied and depended on the metabolism of the individual animal. Body mass loss was linked to memory test performance in the CR group, and lower performance was observed in individuals losing the most weight. While CR was observed to negatively impact learning, locomotor capacities were preserved in CR animals, and there were higher resting metabolic rates in the CR group. Our data reinforce the strong link between energy allocation and brain function, and suggest that in the context of food shortage, learning capacities could be a limiting parameter in the adaptation to a changing environment.

[Contribution of arterial spin labeling to the diagnosis of sudden and transient neurological deficit]. / Apport de la séquence de marquage des spins artériels (ASL) devant un déficit neurologique brutal et transitoire.

MRI is the gold standard exploration for sudden transient neurological events. If diffusion MRI is negative, there may be a diagnostic doubt between transient ischemic attack and other causes of transient neurological deficit. We illustrate how sequence arterial spin labeling (ASL), which evaluates cerebral perfusion, contributes to the exploration of transient neurological events. An ASL sequence was performed in seven patients with a normal diffusion MRI explored for a transient deficit. Cortical hyperperfusion not systematized to an arterial territory was found in three and hypoperfusion systematized to an arterial territory in four. ASL helped guide early management of these patients.

Accelerated cortical atrophy in cognitively normal elderly with high ß-amyloid deposition.

OBJECTIVE: Given the recent and growing interest in the concepts of prodromal and presymptomatic Alzheimer disease, it is crucial to determine whether the presence of ß-amyloid (Aß) in the brain of asymptomatic elderly individuals is a pathologic condition associated with accelerated neuronal and synaptic loss. The aim of the present study was to assess whether Aß influences the rate of atrophy in cognitively normal elderly individuals. METHODS: Seventy-four healthy elderly individuals underwent an MRI scan and a 11C-Pittsburgh compound B (PiB) PET scan at baseline and a second MRI scan 18 months later. Voxel-wise analyses were performed using maps of annual rate of atrophy generated from the serial MRI scans, including comparison between individuals with high vs low neocortical PiB and correlation with baseline neocortical PiB. RESULTS: The rate of atrophy was significantly higher in the normal elderly individuals with high PiB compared with those with low PiB and was significantly correlated with baseline neocortical PiB, with the highest significance in the temporal neocortex and the posterior cingulate cortex. CONCLUSIONS: Our findings show that the presence of Aß in the brain, known to occur in about one-third of asymptomatic elderly individuals, is actually a pathologic state associated with accelerated atrophy. They also suggest that therapy aimed to reduce the neurodegenerative process should be commenced in presymptomatic individuals with high PiB.

Inhibition of L-homocysteic acid and buthionine sulphoximine-mediated neurotoxicity in rat embryonic neuronal cultures with alpha-lipoic acid enantiomers.

In the present report, we have set out to investigate the potential capacity of both the oxidised and reduced forms of RS-alpha-lipoic acid, and its separate R-(+) and S-(-)enantiomers, to prevent cell death induced with L-homocysteic acid (L-HCA) and buthionine sulphoximine (BSO) in rat primary cortical and hippocampal neurons. L-HCA induced a concentration-dependent neurotoxic effect, estimated by cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction, in primary neurons, but was significantly more toxic for hippocampal (EC(50)=197 microM) compared with cortical neurons (EC(50)=1016 microM) whereas D-HCA demonstrated only moderate (<20%) toxicity. On the other hand, cortical and hippocampal cultures were equally susceptible (341 and 326 microM, respectively) to the neurotoxic action of BSO. Antioxidants including butylated hydroxyanisole, propyl gallate and vitamin E protected cells against the neurotoxic effect of L-HCA and BSO. However, N-acetyl-cysteine and tert-butylphenyl nitrone, although capable of abrogating L-HCA-mediated cell death showed no protective effect against BSO-mediated toxicity. RS-alpha-lipoic acid, RS-alpha-dihydrolipoic acid and the enantiomers R-alpha-lipoic acid and S-alpha-lipoic acid protected cells against L-HCA-mediated toxicity with EC(50) values between 3.1-8.3 microM in primary hippocampal neurons and 2.6-16.8 microM for cortical neurons. However, RS-alpha-lipoic acid, RS-alpha-dihydrolipoic acid, and S-alpha-lipoic acid failed to protect cells against the degeneration induced by prolonged exposure to BSO, whereas the natural form, R-alpha-lipoic, was partially active under the same conditions. The present results indicate a unique sensitivity of hippocampal neurons to the effect of L-HCA-mediated toxicity, and suggest that RS-alpha-lipoic acid, and in particular the R-alpha-enantiomeric form is capable of preventing oxidative stress-mediated neuronal cell death in primary cell culture.