A Disease Progression Model to Quantify the Nonmotor Symptoms of Parkinson's Disease in Participants With Leucine-Rich Repeat Kinase 2 Mutation.
Adult
Age Factors
Aged
Aged, 80 and over
Antiparkinson Agents
/ administration & dosage
Databases, Factual
Disease Progression
Female
Glucosylceramidase
/ genetics
Heterozygote
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ genetics
Longitudinal Studies
Male
Middle Aged
Models, Theoretical
Mutation
/ genetics
Parkinson Disease
/ genetics
Predictive Value of Tests
Severity of Illness Index
alpha-Synuclein
/ genetics
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
27
10
2020
accepted:
12
03
2021
pubmed:
25
4
2021
medline:
28
8
2021
entrez:
24
4
2021
Statut:
ppublish
Résumé
Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson's disease (PD). Understanding the rate of progression in PD as measured by both motor and nonmotor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson's Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I (nonmotor aspects of experiences of daily living) in 158 participants with PD who were carriers and 598 participants with PD who were noncarriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, or R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in noncarriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is ~ 60% lower in carriers as compared with noncarriers of LRRK2 gene mutations.
Substances chimiques
Antiparkinson Agents
0
SNCA protein, human
0
alpha-Synuclein
0
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
GBA protein, human
EC 3.2.1.45
Glucosylceramidase
EC 3.2.1.45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
508-518Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R007446/1
Pays : United Kingdom
Organisme : FDA HHS
ID : U18 FD005320
Pays : United States
Informations de copyright
© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.
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