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- Jönsson, Linus, et al.
(författare)
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Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer’s disease
- 2024
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer’s disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes. Methods: We simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale–sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years. Results: The PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease. Conclusion: PMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.
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| 2. |
- Mastenbroek, Sophie E., et al.
(författare)
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Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer’s disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.
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