This scientific commentary refers to ‘Natural history of motor symptoms in Parkinson’s disease and the long-duration response to levodopa’, by Cilia etal. (doi:10.1093/brain/awaa181).
Donanemab in Early Alzheimer’s Disease Espay, Alberto J; Mintun, Mark A; Wessels, Alette M ...
The New England journal of medicine,
08/2021, Letnik:
385, Številka:
7
Journal Article
Recenzirano
To the Editor:
The results of the placebo-controlled trial of donanemab conducted by Mintun et al. (May 6 issue)
1
may be misleading on three points. First, although donanemab therapy induced a ...marked reduction in the amyloid plaque level as measured by positron-emission tomography with
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F-florbetapir tracing, the primary outcome — the change in the composite score on the Integrated Alzheimer’s Disease Rating Scale (iADRS; scores range from 0 to 144, with lower scores indicating a greater cognitive deficit and greater impairment of the ability to perform activities of daily living) — showed a between-group difference of only 3.20 points in . . .
Protein aggregation into amyloid fibrils affects many proteins in a variety of diseases, including neurodegenerative disorders, diabetes, and cancer. Physicochemically, amyloid formation is a phase ...transition process, where soluble proteins are transformed into solid fibrils with the characteristic cross-β conformation responsible for their fibrillar morphology. This phase transition proceeds via an initial, rate-limiting nucleation step followed by rapid growth. Several well-defined nucleation pathways exist, including homogenous nucleation (HON), which proceeds spontaneously; heterogeneous nucleation (HEN), which is catalyzed by surfaces; and seeding via preformed nuclei. It has been hypothesized that amyloid aggregation represents a protein-only (nucleic-acid free) replication mechanism that involves transmission of structural information via conformational templating (the prion hypothesis). While the prion hypothesis still lacks mechanistic support, it is also incompatible with the fact that proteins can be induced to form amyloids in the absence of a proteinaceous species acting as a conformational template as in the case of HEN, which can be induced by lipid membranes (including viral envelopes) or polysaccharides. Additionally, while amyloids can be formed from any protein sequence and via different nucleation pathways, they invariably adopt the universal cross-β conformation; suggesting that such conformational change is a spontaneous folding event that is thermodynamically favorable under the conditions of supersaturation and phase transition and not a templated replication process. Finally, as the high stability of amyloids renders them relatively inert, toxicity in some amyloid pathologies might be more dependent on the loss of function from protein sequestration in the amyloid state rather than direct toxicity from the amyloid plaques themselves.
Given the past two decades of over 40 failed trials of amyloid-lowering therapies in Alzheimer's Disease (AD), many of which succeeded in lowering amyloid as designed, we present an ethical argument ...for emptying the drug pipeline of tests of amyloid-lowering agents so as to end the historical dominance of the amyloid-reducing therapeutic approach in AD.
A biomedical hypothesis is a theoretical assumption amenable to being tested in a randomized clinical trial. The main hypotheses in neurodegenerative disorders are based on the concept that proteins ...accumulate in an aggregated fashion and trigger toxicity. The toxic proteinopathy hypothesis posits that neurodegeneration is caused by toxicity of aggregated amyloid in Alzheimer's disease (toxic amyloid hypothesis), aggregated α-synuclein in Parkinson's disease (toxic synuclein hypothesis), and aggregated tau in progressive supranuclear palsy (toxic tau hypothesis). To date, we have accumulated 40 negative anti-amyloid randomized clinical, 2 anti-synuclein trials, and 4 anti-tau trials. These results have not prompted a major reconsideration of the toxic proteinopathy hypothesis of causality. Imperfections in trial design and execution (incorrect dosage, insensitive endpoints, too-advanced population) but not in the underlying hypotheses have prevailed as explaining the failures. We review here the evidence suggesting that the threshold of hypothesis falsifiability may be too high and advocate in favor of a minimal set of rules that facilitate the interpretation of negative clinical trials as falsifying the driving hypotheses, in particular if the desirable change in surrogate endpoints has been achieved. We propose four steps to refute a hypothesis in future-negative surrogate-backed trials and argue that for the actual rejection to take place, refutation must be accompanied by the proposal of an alternative hypothesis. The absence of alternative hypotheses may be the single greatest reason why there remains hesitancy in rejecting the toxic proteinopathy hypothesis: in the absence of alternatives, we have no clear guidance as to where to redirect or focus.
The dominant protein-lowering strategy in Alzheimer's Disease (AD) has failed to provide a clinically-meaningful treatment for patients. We hypothesize that the loss of functional, soluble Aβ42 ...during the process of aggregation into amyloid is more detrimental to the brain than the corresponding accrual of insoluble amyloid.The dominant protein-lowering strategy in Alzheimer's Disease (AD) has failed to provide a clinically-meaningful treatment for patients. We hypothesize that the loss of functional, soluble Aβ42 during the process of aggregation into amyloid is more detrimental to the brain than the corresponding accrual of insoluble amyloid.
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