TY - JOUR
T1 - SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function during Aging
AU - Seddighi, Sahba
AU - Varma, Vijay R.
AU - An, Yang
AU - Varma, Sudhir
AU - Beason-Held, Lori L.
AU - Tanaka, Toshiko
AU - Kitner-Triolo, Melissa H.
AU - Kraut, Michael A.
AU - Davatzikos, Christos
AU - Thambisetty, Madhav
N1 - Funding Information:
The study was approved by the Institutional Review Board and the National Institute on Aging. Human research at the National Institutes of Health (NIH) is implemented in accord with the U.S. Department of Health and Human Services (45 CFR46) and U.S. Food and Drug Administration (21 CFR 50 and 56) regulations for the protection of human subjects. The NIA IRB is part of the Human Subject Protection Program of the NIH. All participants provided written informed consent at each visit [38, 39].
Funding Information:
This research was supported by the Intramural Research Program of the NIH, National Institute on Aging, and by Research and Development Contract N01-AG-3-2124.
Funding Information:
aClinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA bLaboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA cHiThru Analytics, Laurel, MD, USA dTranslational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA eDepartment of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA fDepartment of Radiology, Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, USA
Funding Information:
The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 & DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina – Chapel Hill (MH090936 & MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 06/10/2015.
PY - 2018
Y1 - 2018
N2 - We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.
AB - We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.
KW - Alzheimer's disease
KW - magnetic resonance imaging
KW - positron emission tomography
KW - single nucleotide polymorphism
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U2 - 10.3233/JAD-170557
DO - 10.3233/JAD-170557
M3 - Article
C2 - 29154276
AN - SCOPUS:85036503694
SN - 1387-2877
VL - 61
SP - 401
EP - 414
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -