TY - JOUR
T1 - Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers
AU - Cogswell, Petrice M.
AU - Wiste, Heather J.
AU - Senjem, Matthew L.
AU - Gunter, Jeffrey L.
AU - Weigand, Stephen D.
AU - Schwarz, Christopher G.
AU - Arani, Arvin
AU - Therneau, Terry M.
AU - Lowe, Val J.
AU - Knopman, David S.
AU - Botha, Hugo
AU - Graff-Radford, Jonathan
AU - Jones, David T.
AU - Kantarci, Kejal
AU - Vemuri, Prashanthi
AU - Boeve, Bradley F.
AU - Mielke, Michelle M.
AU - Petersen, Ronald C.
AU - Jack, Clifford R.
N1 - Funding Information:
R.C.P. has consulted for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Eisai, Inc. and is on a Data and Safety Monitoring Committee for Genentech, Inc. He receives research support from the National Institute on Aging, the GHR Foundation and the Alzheimer's Association.
Funding Information:
M.M.M. receives support from the NIH, unrestricted research grants from Biogen, and consults for Brain Protection Company.
Funding Information:
K.K. serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc.; receives research support from Avid Radioparmaceuticals and Eli Lilly, and receives funding from NIH and Alzheimer's Drug Discovery Foundation.
Funding Information:
B.B.B. has served as an investigator for a clinical trial sponsored for Biogen. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr Lewy Body Dementia Program, and the Little Family Foundation,
Funding Information:
V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI).
Funding Information:
We would like to greatly thank AVID Radiopharmaceuticals, Inc. for their support in supplying AV-1451 precursor, chemistry production advice and oversight, and FDA regulatory cross-filing permission and documentation needed for this work. This work was supported by the National Institutes of Health [U01 AG006786, P50 AG016574, P30 AG062677, RO1 NS097495, RO1 AG056366, R37 AG011378 and RO1 AG041851]. The funding sources had no role in study design, analysis and interpretation or data, writing the manuscript, or the decision to submit the article for publication.
Funding Information:
This work was supported by the National Institutes of Health [U01 AG006786, P50 AG016574, P30 AG062677, RO1 NS097495, RO1 AG056366, R37 AG011378 and RO1 AG041851]. The funding sources had no role in study design, analysis and interpretation or data, writing the manuscript, or the decision to submit the article for publication.
Publisher Copyright:
© 2020 The Authors
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34–97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.
AB - Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34–97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM.
KW - Alzheimer's disease
KW - Beta amyloid PET
KW - Quantitative susceptibility mapping
KW - Tau PET
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U2 - 10.1016/j.neuroimage.2020.117433
DO - 10.1016/j.neuroimage.2020.117433
M3 - Article
C2 - 33035667
AN - SCOPUS:85092895768
SN - 1053-8119
VL - 224
JO - NeuroImage
JF - NeuroImage
M1 - 117433
ER -