title: Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.
abstract: There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Locascio
authors.affiliation: 3 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Shirley
authors.initials: S
authors.lastname: Eberly
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Liao
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Ganqiang
authors.initials: G
authors.lastname: Liu
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Hoesing
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Duong
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Trisini-Lipsanopoulos
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Kaltra
authors.initials: K
authors.lastname: Dhima
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Hung
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA 6 Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Alice W
authors.initials: AW
authors.lastname: Flaherty
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
authors.affiliation: 7 Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hayes
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Wills
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: U
authors.initials: U
authors.lastname: Shivraj Sohur
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Nicte I
authors.initials: NI
authors.lastname: Mejia
authors.affiliation: 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 7 Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: 3 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: David
authors.initials: D
authors.lastname: Oakes
authors.affiliation: 8 Program for Regulatory Science and Medicine, Department of Neurology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Shoulson
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Dong
authors.affiliation: 8 Program for Regulatory Science and Medicine, Department of Neurology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Marek
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ivinson
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.affiliation: 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Growdon
authors.affiliation: 7 Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Sudarsky
authors.affiliation: 9 Institute for Neurodegenerative Disorders, New Haven, CT 06510, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
authors.affiliation: 10 Program in Neuroscience, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario K1H8M5, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ravina
authors.affiliation: 1 Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Cambridge, MA 02139, USA 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA 4 Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA 5 Biomarkers Program, Harvard NeuroDiscovery Center, Boston, MA 02115, USA 7 Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA cscherzer@rics.bwh.harvard.edu.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
mesh_terms: D000368:Aged; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005820:Genetic Testing; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D059906:Neuroimaging; D010300:Parkinson Disease / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D011877:Radionuclide Imaging; D012720:Severity of Illness Index; D014326:Tropanes; D051844:alpha-Synuclein / Q000097:blood* / Q000235:genetics*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D014326:Tropanes; D051844:alpha-Synuclein; C087552:2-carbomethoxy-8-(3-fluoropropyl)-3-(4-iodophenyl)tropane
keywords: biobank; biomarker; cognitive decline; gene expression; mitochondria; α-synuclein