title: Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET.
abstract: Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer disease (AD) comes primarily from rodent models. However, unlike rodents, in which predominant extracranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Dynamic PET with18F-THK5117, a tracer for tau pathology, was used to estimate the ventricular CSF time-activity as a biomarker for CSF clearance. We tested 3 hypotheses: extracranial CSF is detected at the superior turbinates; CSF clearance is reduced in AD; and CSF clearance is inversely associated with amyloid deposition.Methods:Fifteen subjects, 8 with AD and 7 normal control volunteers, were examined with18F-THK5117. Ten subjects additionally underwent11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were11C-PiB-positive. Ventricular time-activity curves of18F-THK5117 were used to identify highly correlated time-activity curves from extracranial voxels.Results:For all subjects, the greatest density of CSF-positive extracranial voxels was in the nasal turbinates. Tracer concentration analyses validated the superior nasal turbinate CSF signal intensity. AD patients showed ventricular tracer clearance reduced by 23% and 66% fewer superior turbinate CSF egress sites. Ventricular CSF clearance was inversely associated with amyloid deposition.Conclusion:The human nasal turbinate is part of the CSF clearance system. Lateral ventricle and superior nasal turbinate CSF clearance abnormalities are found in AD. Ventricular CSF clearance reductions are associated with increased brain amyloid depositions. These data suggest that PET-measured CSF clearance is a biomarker of potential interest in AD and other neurodegenerative diseases.
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York mony.deleon@nyumc.org.
authors.forename: Mony J
authors.initials: MJ
authors.lastname: de Leon
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Tohoku University School of Medicine, Tohoku, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.
authors.forename: Wai H
authors.initials: WH
authors.lastname: Tsui
authors.affiliation: Manhattan Diagnostic Radiology, New York, New York.
authors.forename: Les A
authors.initials: LA
authors.lastname: Saint-Louis
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.|Department of Radiology, New York University Center School of Medicine, New York, New York.
authors.forename: Lidia
authors.initials: L
authors.lastname: Glodzik
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Osorio
authors.affiliation: Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Fortea
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.
authors.forename: Tracy
authors.initials: T
authors.lastname: Butler
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pirraglia
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.|Department of Neurology, New York University School of Medicine, New York, New York.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fossati
authors.affiliation: Department of Psychiatry, New York University School of Medicine, Center for Brain Health, New York, New York.|Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Roxana O
authors.initials: RO
authors.lastname: Carare
authors.affiliation: Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York.|Center for Basic and Translational Neuroscience, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
authors.affiliation: Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Helene
authors.initials: H
authors.lastname: Benveniste
authors.affiliation: Department of Radiology, New York University Center School of Medicine, New York, New York.
authors.forename: Henry
authors.initials: H
authors.lastname: Rusinek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging* / Q000378:metabolism; D000814:Aniline Compounds / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D052160:Benzothiazoles / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; C000604726:6-((3-fluoro-2-hydroxy)propoxy)-2-(4-methylaminophenyl)quinoline; D000814:Aniline Compounds; D052160:Benzothiazoles; D011804:Quinolines; D013844:Thiazoles
keywords: Alzheimer disease; CSF clearance; PET/CT; THK5117; dynamic PET; neurology; research methods