The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging.
The two primary molecular pathologies in Alzheimer's disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices.
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA bagordon@wustl.edu.
Brian A
BA
Gordon
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Karl
K
Friedrichsen
3 Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Matthew
M
Brier
4 Division of Biology and Biomedical Sciences, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Tyler
T
Blazey
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Yi
Y
Su
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Jon
J
Christensen
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Patricia
P
Aldea
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Jonathan
J
McConathy
2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA 3 Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 4 Division of Biology and Biomedical Sciences, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 5 The Hope Center for Neurological Disorders, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
David M
DM
Holtzman
2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA 3 Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 5 The Hope Center for Neurological Disorders, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Nigel J
NJ
Cairns
2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA 3 Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
John C
JC
Morris
2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA 3 Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 5 The Hope Center for Neurological Disorders, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Anne M
AM
Fagan
2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA 3 Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 5 The Hope Center for Neurological Disorders, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
Beau M
BM
Ances
1 Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA 2 Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, Missouri 63110, USA 6 Department of Neurological Surgery, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, Missouri 63108, USA.
Tammie L S
TL
Benzinger
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000378:metabolism; D002243:Carbolines; D005260:Female; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D049268:Positron-Emission Tomography / Q000379:methods*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D002243:Carbolines; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C000591008:7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole
Alzheimer’s disease; cerebrospinal fluid; positron emission tomography; preclinical; tau imaging