Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline

Kim, Namhee; Yu, Lei; Dawe, Robert; Petyuk, Vladislav A.; Gaiteri, Chris; De Jager, Philip L.; Schneider, Julie A.; Arfanakis, Konstantinos; Bennett, David A.

doi:10.1016/j.neurobiolaging.2019.07.013

Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline

Journal Article · Fri Jul 26 00:00:00 EDT 2019 · Neurobiology of Aging

DOI:https://doi.org/10.1016/j.neurobiolaging.2019.07.013· OSTI ID:1615003

^[1]; Yu, Lei ^[1]; Dawe, Robert ^[1]; ^[2]; Gaiteri, Chris ^[1]; De Jager, Philip L. ^[3]; Schneider, Julie A. ^[1]; Arfanakis, Konstantinos ^[4]; Bennett, David A. ^[1]

Rush Univ. Medical Center, Chicago, IL (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Columbia Univ. Medical Center, New York, NY (United States); Broad Inst., Cambridge, MA (United States)
Rush Univ. Medical Center, Chicago, IL (United States); Illinois Inst. of Technology, Chicago, IL (United States)

The associations of 4 proteins-AK4, ITPK1, HSPB2, and IGFBP5-with cognitive function in older adults were largely unexplained by known brain pathologies. We examined the extent to which individual protein associations with cognitive decline were attributable to microstructural changes in the brain. This study included 521 participants (mean age 90.3, 65.9-108.3) with the postmortem reciprocal of transverse relaxation time (R₂) magnetic resonance image. All participants came from one of the 2 ongoing longitudinal cohorts of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project. Higher abundance of AK4, HSPB2, and IGFBP5 was associated with faster cognitive decline and mediated through lower postmortem R₂ in the frontal and temporal white matter regions. In contrast, higher abundance of ITPK1 was associated with slower cognitive decline and mediated through higher postmortem R₂ in the frontal and temporal white matter regions. Lastly, the associations of 4 proteins-AK4, ITPK1, IGFBP5, and HSPB2-with cognition in late life were explained via microstructural changes in the brain.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1615003

Report Number(s):: PNNL-SA-147569

Journal Information:: Neurobiology of Aging, Journal Name: Neurobiology of Aging Journal Issue: C Vol. 84; ISSN 0197-4580

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

References (47)

Association of Cardiovascular Risk Factors With MRI Indices of Cerebrovascular Structure and Function and White Matter Hyperintensities in Young Adults Williamson, Wilby; Lewandowski, Adam J.; Forkert, Nils D. JAMA, Vol. 320, Issue 7 https://doi.org/10.1001/jama.2018.11498	journal	August 2018
Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline Yu, Lei; Dawe, Robert J.; Boyle, Patricia A. JAMA Neurology, Vol. 74, Issue 12 https://doi.org/10.1001/jamaneurol.2017.2807	journal	December 2017
A unified statistical approach for determining significant signals in images of cerebral activation Worsley, K. J.; Marrett, S.; Neelin, P. Human Brain Mapping, Vol. 4, Issue 1 https://doi.org/10.1002/(SICI)1097-0193(1996)4:1<58::AID-HBM4>3.0.CO;2-O	journal	January 1996
The neuropathology of probable Alzheimer disease and mild cognitive impairment Schneider, Julie A.; Arvanitakis, Zoe; Leurgans, Sue E. Annals of Neurology, Vol. 66, Issue 2 https://doi.org/10.1002/ana.21706	journal	August 2009
Relation of neuropathology to cognition in persons without cognitive impairment Bennett, David A.; Wilson, Robert S.; Boyle, Patricia A. Annals of Neurology, Vol. 72, Issue 4 https://doi.org/10.1002/ana.23654	journal	October 2012
Much of late life cognitive decline is not due to common neurodegenerative pathologies: Cognitive Decline Boyle, Patricia A.; Wilson, Robert S.; Yu, Lei Annals of Neurology, Vol. 74, Issue 3 https://doi.org/10.1002/ana.23964	journal	July 2013
Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease: HS and TDP-43 in Aging and AD Nag, Sukriti; Yu, Lei; Capuano, Ana W. Annals of Neurology, Vol. 77, Issue 6 https://doi.org/10.1002/ana.24388	journal	April 2015
Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia: Targeted Proteomics in Alzheimer's Dementia Yu, Lei; Petyuk, Vladislav A.; Gaiteri, Chris Annals of Neurology, Vol. 84, Issue 1 https://doi.org/10.1002/ana.25266	journal	July 2018
Assessing the significance of focal activations using their spatial extent Friston, K. J.; Worsley, K. J.; Frackowiak, R. S. J. Human Brain Mapping, Vol. 1, Issue 3 https://doi.org/10.1002/hbm.460010306	journal	January 1994
1.4T study of proton magnetic relaxation rates, iron concentrations, and plaque burden in Alzheimer's disease and control postmortem brain tissue House, Michael J.; St. Pierre, Timothy G.; McLean, Catriona Magnetic Resonance in Medicine, Vol. 60, Issue 1 https://doi.org/10.1002/mrm.21586	journal	June 2008
Postmortem MRI of human brain hemispheres:T₂relaxation times during formaldehyde fixation Dawe, Robert J.; Bennett, David A.; Schneider, Julie A. Magnetic Resonance in Medicine, Vol. 61, Issue 4 https://doi.org/10.1002/mrm.21909	journal	April 2009
Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy Simon, Christian M.; Rauskolb, Stefanie; Gunnersen, Jennifer M. Acta Neuropathologica, Vol. 130, Issue 3 https://doi.org/10.1007/s00401-015-1446-8	journal	May 2015
Investigating the Medial Temporal Lobe in Alzheimer’s Disease and Mild Cognitive Impairment, with Turboprop Diffusion Tensor Imaging, MRI-volumetry, and T 2-relaxometry Arfanakis, Konstantinos; Gui, Minzhi; Tamhane, Ashish A. Brain Imaging and Behavior, Vol. 1, Issue 1-2 https://doi.org/10.1007/s11682-007-9001-4	journal	May 2007
Cognitive activity, cognitive function, and brain diffusion characteristics in old age Arfanakis, Konstantinos; Wilson, Robert S.; Barth, Christopher M. Brain Imaging and Behavior, Vol. 10, Issue 2 https://doi.org/10.1007/s11682-015-9405-5	journal	May 2015
Gene expression and DNA methylation are extensively coordinated with MRI-based brain microstructural characteristics Gaiteri, Chris; Dawe, Robert; Mostafavi, Sara Brain Imaging and Behavior, Vol. 13, Issue 4 https://doi.org/10.1007/s11682-018-9910-4	journal	June 2018
Prolongation of magnetic resonance T2 time in hippocampus of human patients marks the presence and severity of Alzheimer's disease Kirsch, Steven J.; Jacobs, Roland W.; Butcher, Larry L. Neuroscience Letters, Vol. 134, Issue 2 https://doi.org/10.1016/0304-3940(92)90513-7	journal	January 1992
Identification of a novel adenylate kinase system in the brain: Cloning of the fourth adenylate kinase Yoneda, Takunari; Sato, Makoto; Maeda, Mitsuyo Molecular Brain Research, Vol. 62, Issue 2 https://doi.org/10.1016/S0169-328X(98)00249-6	journal	November 1998
The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study Bennett, David A.; Schneider, Julie A.; Tang, Yuxiao The Lancet Neurology, Vol. 5, Issue 5 https://doi.org/10.1016/S1474-4422(06)70417-3	journal	May 2006
Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study Arvanitakis, Zoe; Capuano, Ana W.; Leurgans, Sue E. The Lancet Neurology, Vol. 15, Issue 9 https://doi.org/10.1016/S1474-4422(16)30029-1	journal	August 2016
Expression of inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) and its role in neural tube defects Majerus, Philip W.; Wilson, David B.; Zhang, Chunfen Advances in Enzyme Regulation, Vol. 50, Issue 1 https://doi.org/10.1016/j.advenzreg.2009.10.017	journal	January 2010
Enzymatically inactive adenylate kinase 4 interacts with mitochondrial ADP/ATP translocase Liu, Rujuan; Ström, Anna-Lena; Zhai, Jianjun The International Journal of Biochemistry & Cell Biology, Vol. 41, Issue 6 https://doi.org/10.1016/j.biocel.2008.12.002	journal	June 2009
Prolongation of T2 relaxation times of hippocampus and amygdala in Alzheimer's disease Wang, Huali; Yuan, Huishu; Shu, Liang Neuroscience Letters, Vol. 363, Issue 2 https://doi.org/10.1016/j.neulet.2004.03.061	journal	June 2004
Ex vivo T2 relaxation: associations with age-related neuropathology and cognition Dawe, Robert J.; Bennett, David A.; Schneider, Julie A. Neurobiology of Aging, Vol. 35, Issue 7 https://doi.org/10.1016/j.neurobiolaging.2014.01.144	journal	July 2014
APOE and cerebral amyloid angiopathy in community-dwelling older persons Yu, Lei; Boyle, Patricia A.; Nag, Sukriti Neurobiology of Aging, Vol. 36, Issue 11 https://doi.org/10.1016/j.neurobiolaging.2015.08.008	journal	November 2015
Vascular risk factors and progression of white matter hyperintensities in the Lothian Birth Cohort 1936 Dickie, David Alexander; Ritchie, Stuart J.; Cox, Simon R. Neurobiology of Aging, Vol. 42 https://doi.org/10.1016/j.neurobiolaging.2016.03.011	journal	June 2016
Postmortem MRI: a novel window into the neurobiology of late life cognitive decline Dawe, Robert J.; Yu, Lei; Leurgans, Sue E. Neurobiology of Aging, Vol. 45 https://doi.org/10.1016/j.neurobiolaging.2016.05.023	journal	September 2016
Postmortem brain MRI is related to cognitive decline, independent of cerebral vessel disease in older adults Dawe, Robert J.; Yu, Lei; Schneider, Julie A. Neurobiology of Aging, Vol. 69 https://doi.org/10.1016/j.neurobiolaging.2018.05.020	journal	September 2018
Heat shock proteins: Cellular and molecular mechanisms in the central nervous system Stetler, R. Anne; Gan, Yu; Zhang, Wenting Progress in Neurobiology, Vol. 92, Issue 2 https://doi.org/10.1016/j.pneurobio.2010.05.002	journal	October 2010
Neurodevelopmental effects of insulin-like growth factor signaling O’Kusky, John; Ye, Ping Frontiers in Neuroendocrinology, Vol. 33, Issue 3 https://doi.org/10.1016/j.yfrne.2012.06.002	journal	August 2012
Mapping protein abundance patterns in the brain using voxelation combined with liquid chromatography and mass spectrometry Petyuk, Vladislav A.; Qian, Wei-Jun; Smith, Richard D. Methods, Vol. 50, Issue 2 https://doi.org/10.1016/j.ymeth.2009.07.009	journal	February 2010
Label-Free Quantitative LC–MS Proteomics of Alzheimer’s Disease and Normally Aged Human Brains Andreev, Victor P.; Petyuk, Vladislav A.; Brewer, Heather M. Journal of Proteome Research, Vol. 11, Issue 6 https://doi.org/10.1021/pr3001546	journal	May 2012
A draft map of the human proteome Kim, Min-Sik; Pinto, Sneha M.; Getnet, Derese Nature, Vol. 509, Issue 7502 https://doi.org/10.1038/nature13302	journal	May 2014
A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease Mostafavi, Sara; Gaiteri, Chris; Sullivan, Sarah E. Nature Neuroscience, Vol. 21, Issue 6 https://doi.org/10.1038/s41593-018-0154-9	journal	May 2018
Neural tube defects in mice with reduced levels of inositol 1,3,4-trisphosphate 5/6-kinase Wilson, Monita P.; Hugge, Christopher; Bielinska, Malgorzata Proceedings of the National Academy of Sciences, Vol. 106, Issue 24 https://doi.org/10.1073/pnas.0904172106	journal	June 2009
Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain Krienen, Fenna M.; Yeo, B. T. Thomas; Ge, Tian Proceedings of the National Academy of Sciences, Vol. 113, Issue 4 https://doi.org/10.1073/pnas.1510903113	journal	January 2016
A transcriptional signature of hub connectivity in the mouse connectome Fulcher, Ben D.; Fornito, Alex Proceedings of the National Academy of Sciences, Vol. 113, Issue 5 https://doi.org/10.1073/pnas.1513302113	journal	January 2016
Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies Schneider, J. A.; Arvanitakis, Z.; Yu, L. Brain, Vol. 135, Issue 10 https://doi.org/10.1093/brain/aws234	journal	October 2012
Statistical mediation analysis with a multicategorical independent variable Hayes, Andrew F.; Preacher, Kristopher J. British Journal of Mathematical and Statistical Psychology, Vol. 67, Issue 3 https://doi.org/10.1111/bmsp.12028	journal	November 2013
The Relationship of Cerebral Vessel Pathology to Brain Microinfarcts: Cerebral Vessel Pathology and Microinfarcts Arvanitakis, Zoe; Capuano, Ana W.; Leurgans, Sue E. Brain Pathology, Vol. 27, Issue 1 https://doi.org/10.1111/bpa.12365	journal	April 2016
Correlated gene expression supports synchronous activity in brain networks Richiardi, J.; Altmann, A.; Milazzo, A. -C. Science, Vol. 348, Issue 6240 https://doi.org/10.1126/science.1255905	journal	June 2015
Microinfarct Pathology, Dementia, and Cognitive Systems Arvanitakis, Zoe; Leurgans, Sue E.; Barnes, Lisa L. Stroke, Vol. 42, Issue 3 https://doi.org/10.1161/STROKEAHA.110.595082	journal	March 2011
The TMEM106B locus and TDP-43 pathology in older persons without FTLD Yu, L.; De Jager, P. L.; Yang, J. Neurology, Vol. 84, Issue 9 https://doi.org/10.1212/WNL.0000000000001313	journal	February 2015
Physical activity, motor function, and white matter hyperintensity burden in healthy older adults Fleischman, D. A.; Yang, J.; Arfanakis, K. Neurology, Vol. 84, Issue 13 https://doi.org/10.1212/WNL.0000000000001417	journal	March 2015
Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons Boyle, Patricia A.; Yu, Lei; Nag, Sukriti Neurology, Vol. 85, Issue 22 https://doi.org/10.1212/WNL.0000000000002175	journal	November 2015
Insulin-like growth factor binding protein 5 and apoptosis in mammary epithelial cells Marshman, E. Journal of Cell Science, Vol. 116, Issue 4 https://doi.org/10.1242/jcs.00263	journal	December 2002
Cerebral white matter hyperintensities (WMH): an analysis of cerebrovascular risk factors in Lebanon Gebeily, Souheil; Fares, Youssef; Kordahi, Manal International Journal of Neuroscience, Vol. 124, Issue 11 https://doi.org/10.3109/00207454.2014.884087	journal	February 2014
Religious Orders Study and Rush Memory and Aging Project Bennett, David A.; Buchman, Aron S.; Boyle, Patricia A. Journal of Alzheimer's Disease, Vol. 64, Issue s1 https://doi.org/10.3233/JAD-179939	journal	June 2018

Cited By (1)

Insulin-like growth factor 5 associates with human Aß plaques and promotes cognitive impairment Rauskolb, Stefanie; Andreska, Thomas; Fries, Sophie Acta Neuropathologica Communications, Vol. 10, Issue 1 https://doi.org/10.1186/s40478-022-01352-5	journal	May 2022

Figures / Tables (13)

Similar Records

Cognition may link cortical IGFBP5 levels with motor function in older adults

Journal Article · Sun Aug 11 20:00:00 EDT 2019 · PLoS ONE · OSTI ID:1642067

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
AK4
HSPB2
IGFBP5
ITPK1
brain pathology
brain protein
cognitive decline
mediation analysis
microstructural changes
postmortem brain
transverse relaxation time

Microstructural changes in the brain mediate the association of AK4, IGFBP5, HSPB2, and ITPK1 with cognitive decline

Citation Formats

References (47)

Cited By (1)

Figures / Tables (13)

Similar Records

Related Subjects