Journal
NEUROIMAGE-CLINICAL
Volume 18, Issue -, Pages 456-466Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.nicl.2018.01.009
Keywords
Parkinson disease; LAG3; Alpha-synuclein; Trans-synaptic spread; Atrophy; Genetic analysis
Categories
Funding
- Michael J. Fox Foundation
- Abbvie
- Avid Radiopharmaceuticals
- Biogen Idec
- BioLegend
- Bristol-Myers Squibb
- Eli Lilly and Company
- F. Hoffmann-La Roche Ltd.
- GE Healthcare
- Genentech
- GlaxoSmithKline
- Lundbeck Foundation
- Merck
- MesoScale Discovery
- Piramal
- Pfizer
- Sanofi Genzyme
- Servier
- Takeda
- Teva
- UCB
- NIH [R01NS092802]
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Multiple genes have been implicated in Parkinson disease pathogenesis, but the relationship between regional expression of these genes and regional dysfunction across the brain is unknown. We address this question by joint analysis of high resolution magnetic resonance imaging data from the Parkinson's Progression Markers Initiative and regional genetic microarray expression data from the Allen Brain Atlas. Regional brain atrophy and genetic expression was co-registered to a common 86 region brain atlas and robust multivariable regression analysis was performed to identify genetic predictors of regional brain atrophy. Top candidate genes from GWAS analysis, as well as genes implicated in trans-synaptic alpha-synuclein transfer and autosomal recessive PD were included in our analysis. We identify three genes with expression patterns that are highly significant predictors of regional brain atrophy. The two most significant predictors are LAG3 and RAB5A, genes implicated in transsynaptic synuclein transfer. Other well-validated PD-related genes do not have expression patterns that predict regional atrophy, suggesting that they may serve other roles such as disease initiation factors.
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