Quantitative detection and staging of presymptomatic cognitive decline in familial Alzheimer's disease: a retrospective cohort analysis.
Event-based modelling
Familial Alzheimer’s disease
Neuropsychology
Preclinical
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
06 10 2020
06 10 2020
Historique:
received:
09
07
2020
accepted:
17
09
2020
entrez:
7
10
2020
pubmed:
8
10
2020
medline:
25
6
2021
Statut:
epublish
Résumé
Understanding the earliest manifestations of Alzheimer's disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer's disease (FAD) cohort to characterise preclinical cognitive change. Data included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline. Cognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum. Data-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer's disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.
Sections du résumé
BACKGROUND
Understanding the earliest manifestations of Alzheimer's disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer's disease (FAD) cohort to characterise preclinical cognitive change.
METHODS
Data included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline.
RESULTS
Cognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum.
CONCLUSIONS
Data-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer's disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.
Identifiants
pubmed: 33023653
doi: 10.1186/s13195-020-00695-2
pii: 10.1186/s13195-020-00695-2
pmc: PMC7539456
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
126Subventions
Organisme : Medical Research Council
ID : G0900421
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M003108/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S03546X/1
Pays : United Kingdom
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