Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET

Mony J. De Leon; Yi Li; Nobuyuki Okamura; Wai H. Tsui; Les A. Saint-Louis; Lidia Glodzik; Ricardo S. Osorio; Juan Fortea; Tracy Butler; Elizabeth Pirraglia; Silvia Fossati; Hee Jin Kim; Roxana O. Carare; Maiken Nedergaard; Helene Benveniste; Henry Rusinek

doi:10.2967/jnumed.116.187211

Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET

Mony J. De Leon^*, Yi Li, Nobuyuki Okamura, Wai H. Tsui, Les A. Saint-Louis, Lidia Glodzik, Ricardo S. Osorio, Juan Fortea, Tracy Butler, Elizabeth Pirraglia, Silvia Fossati, Hee Jin Kim, Roxana O. Carare, Maiken Nedergaard, Helene Benveniste, Henry Rusinek

^*Corresponding author for this work

53 Citations (Scopus)

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 with ¹⁸F-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 with ¹⁸F-THK5117. Ten subjects additionally underwent ¹¹C-Pittsburgh compound B (¹¹C-PiB) PET scanning, and 8 were ¹¹C-PiB-positive. Ventricular time-activity curves of ¹⁸F-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.

Original language	English
Journal	Journal of Nuclear Medicine
Volume	58
Issue number	9
Pages (from-to)	1471-1476
Number of pages	6
ISSN	0161-5505
DOIs	https://doi.org/10.2967/jnumed.116.187211
Publication status	Published - 2017

Keywords

Alzheimer disease
CSF clearance
Dynamic PET
Neurology
PET/CT
Research methods
THK5117

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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De Leon, M. J., Li, Y., Okamura, N., Tsui, W. H., Saint-Louis, L. A., Glodzik, L., Osorio, R. S., Fortea, J., Butler, T., Pirraglia, E., Fossati, S., Kim, H. J., Carare, R. O., Nedergaard, M., Benveniste, H., & Rusinek, H. (2017). Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET. Journal of Nuclear Medicine, 58(9), 1471-1476. https://doi.org/10.2967/jnumed.116.187211

De Leon, MJ, Li, Y, Okamura, N, Tsui, WH, Saint-Louis, LA, Glodzik, L, Osorio, RS, Fortea, J, Butler, T, Pirraglia, E, Fossati, S, Kim, HJ, Carare, RO, Nedergaard, M, Benveniste, H & Rusinek, H 2017, 'Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET', Journal of Nuclear Medicine, vol. 58, no. 9, pp. 1471-1476. https://doi.org/10.2967/jnumed.116.187211

@article{f3613286f8a64b2b9aae6eb791d2bd28,

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 with 18F-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 with 18F-THK5117. Ten subjects additionally underwent 11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were 11C-PiB-positive. Ventricular time-activity curves of 18F-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.",

keywords = "Alzheimer disease, CSF clearance, Dynamic PET, Neurology, PET/CT, Research methods, THK5117",

author = "{De Leon}, {Mony J.} and Yi Li and Nobuyuki Okamura and Tsui, {Wai H.} and Saint-Louis, {Les A.} and Lidia Glodzik and Osorio, {Ricardo S.} and Juan Fortea and Tracy Butler and Elizabeth Pirraglia and Silvia Fossati and Kim, {Hee Jin} and Carare, {Roxana O.} and Maiken Nedergaard and Helene Benveniste and Henry Rusinek",

year = "2017",

doi = "10.2967/jnumed.116.187211",

language = "English",

volume = "58",

pages = "1471--1476",

journal = "The Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "Society of Nuclear Medicine",

number = "9",

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TY - JOUR

T1 - Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET

AU - De Leon, Mony J.

AU - Li, Yi

AU - Okamura, Nobuyuki

AU - Tsui, Wai H.

AU - Saint-Louis, Les A.

AU - Glodzik, Lidia

AU - Osorio, Ricardo S.

AU - Fortea, Juan

AU - Butler, Tracy

AU - Pirraglia, Elizabeth

AU - Fossati, Silvia

AU - Kim, Hee Jin

AU - Carare, Roxana O.

AU - Nedergaard, Maiken

AU - Benveniste, Helene

AU - Rusinek, Henry

PY - 2017

Y1 - 2017

N2 - 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 with 18F-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 with 18F-THK5117. Ten subjects additionally underwent 11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were 11C-PiB-positive. Ventricular time-activity curves of 18F-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.

AB - 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 with 18F-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 with 18F-THK5117. Ten subjects additionally underwent 11C-Pittsburgh compound B (11C-PiB) PET scanning, and 8 were 11C-PiB-positive. Ventricular time-activity curves of 18F-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.

KW - Alzheimer disease

KW - CSF clearance

KW - Dynamic PET

KW - Neurology

KW - PET/CT

KW - Research methods

KW - THK5117

U2 - 10.2967/jnumed.116.187211

DO - 10.2967/jnumed.116.187211

M3 - Journal article

C2 - 28302766

AN - SCOPUS:85028021300

SN - 0161-5505

VL - 58

SP - 1471

EP - 1476

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

IS - 9

ER -

Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET

Abstract

Keywords

UN SDGs

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