In 2021, aducanumab, an immunotherapy targeting amyloid-β, 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.
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.
In 2018, the US National Institute on Aging and the Alzheimer's Association proposed a purely biological definition of Alzheimer's disease that relies on biomarkers. Although the intended use of this ...framework was for research purposes, it has engendered debate and challenges regarding its use in everyday clinical practice. For instance, cognitively unimpaired individuals can have biomarker evidence of both amyloid β and tau pathology but will often not develop clinical manifestations in their lifetime. Furthermore, a positive Alzheimer's disease pattern of biomarkers can be observed in other brain diseases in which Alzheimer's disease pathology is present as a comorbidity. In this Personal View, the International Working Group presents what we consider to be the current limitations of biomarkers in the diagnosis of Alzheimer's disease and, on the basis of this evidence, we propose recommendations for how biomarkers should and should not be used for diagnosing Alzheimer's disease in a clinical setting. We recommend that Alzheimer's disease diagnosis be restricted to people who have positive biomarkers together with specific Alzheimer's disease phenotypes, whereas biomarker-positive cognitively unimpaired individuals should be considered only at-risk for progression to Alzheimer's disease.
La définition de la maladie d’Alzheimer a connu des évolutions majeures depuis les premiers critères diagnostiques de 1984. La caractérisation neuropsychologique précise des différentes présentations ...syndromiques communes de la maladie, ainsi que le développement de nombreux biomarqueurs ont permis de définir la phase prodromique de la maladie, au stade du trouble neurocognitif léger. Cette définition prodromique clinicobiologique de la maladie permet aujourd’hui une prise en charge optimisée des patients, et sous-tend l’émergence actuelle de stratégies médicamenteuses possiblement disease-modifier. La définition de la phase préclinique de la maladie n’est en revanche aujourd’hui pas consensuellement admise au niveau international, du fait notamment d’incertitudes persistantes quant à la capacité des biomarqueurs actuels à prédire l’évolution vers la démence chez des sujets asymptomatiques.
The definition of Alzheimer's disease (AD) has undergone major developments since the initial 1984 diagnostic criteria. The precise neuropsychological characterization of specific syndromic presentations of the disease, along with the development of numerous biomarkers, has allowed for the definition of prodromal AD, at the stage of mild cognitive impairment. This clinico-biological prodromal definition of the disease now enables optimized patient management and supports the current emergence of potentially disease-modifying therapies. On the other hand, the definition of preclinical AD is currently not universally accepted, mainly due to persistent uncertainties regarding the ability of current biomarkers to predict the progression to dementia in asymptomatic individuals.
In 2021, aducanumab, an immunotherapy targeting amyloid-β, 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.
In early Alzheimer's disease (AD), the hippocampal region is the area most severely affected by cellular and structural alterations, yet glucose hypometabolism predominates in the posterior ...association cortex and posterior cingulate gyrus. One prevalent hypothesis to account for this discrepancy is that posterior cingulate hypometabolism results from disconnection from the hippocampus through disruption of the cingulum bundle. However, only partial and indirect evidence currently supports this hypothesis. Thus, using structural magnetic resonance imaging and 2-(18)Ffluoro-2-deoxy-D-glucose positron emission tomography in 18 patients with early AD, we assessed the relationships between hippocampal atrophy, white matter integrity, and gray matter metabolism by means of a whole-brain voxel-based correlative approach. We found that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated to hypometabolism of the posterior cingulate cortex but also of the middle cingulate gyrus, thalamus, mammillary bodies, parahippocampal gyrus, and hippocampus (all part of Papez's circuit), as well as the right temporoparietal associative cortex. These results provide the first direct evidence supporting the disconnection hypothesis as a major factor contributing to the early posterior hypometabolism in AD. Disruption of the cingulum bundle also appears to relate to hypometabolism in a large connected network over and above the posterior cingulate cortex, encompassing the whole memory circuit of Papez (consistent with the key location of this white matter tract within this loop) and also, but indirectly, the right posterior association cortex.
Given the recent and growing interest in the concepts of prodromal and presymptomatic Alzheimer disease, it is crucial to determine whether the presence of β-amyloid (Aβ) 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 Aβ influences the rate of atrophy in cognitively normal elderly individuals.
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.
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.
Our findings show that the presence of Aβ 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.
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.
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.
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.
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.
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