Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals.
Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ1-42and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations within vivomeasures of amyloid pathology. With the recent advent ofin vivoTau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aβ+) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ+individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD.SIGNIFICANCE STATEMENTThis article offers a first look at the relationship between Tau-PET imaging with F18-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimer's disease.
Departments of Neurology and.|Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts 02129.
Aaron P
0000-0002-0418-0999
AP
Schultz
Departments of Neurology and.|Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts 02129.
Jasmeer P
0000-0002-7792-1698
JP
Chhatwal
Radiology, and.|Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts 02129.
Trey
T
Hedden
Departments of Neurology and.|Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown HealthCare Center, Charlestown, Massachusetts 02129.
Elizabeth C
EC
Mormino
Departments of Neurology and.|Radiology, and.
Bernard J
0000-0002-3102-6778
BJ
Hanseeuw
Radiology, and.
Jorge
0000-0002-4199-2304
J
Sepulcre
Departments of Neurology and.|Jheronimus Academy of Data Science, Cognitive Science and Artificial Intelligence, Tilburg University, 5211 DA, 's-Hertogenbosch, The Netherlands.
Willem
W
Huijbers
Departments of Neurology and.
Molly
M
LaPoint
Departments of Neurology and.|Florey Institute of Neuroscience and Mental Health, Parkville 3052, Victoria, Australia, and.|Melbourne School of Psychological Sciences, University of Melbourne, Melbourne 3010, Victoria, Australia, and.
Rachel F
RF
Buckley
Radiology, and.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Keith A
0000-0002-5916-6043
KA
Johnson
Departments of Neurology and reisa@bwh.harvard.edu.|Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Reisa A
0000-0003-1535-6133
RA
Sperling
D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000502:physiology*; D063132:Connectome; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009415:Nerve Net / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism*; D049268:Positron-Emission Tomography; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
AV1451; DMN; PiB; Tau; amyloid; fcMRI