Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein

Chulhyoung Lyoo, Masamichi Ikawa, Jeih San Liow, Sami S. Zoghbi, Cheryl L. Morse, Victor W. Pike, Masahiro Fujita, Robert B. Innis, William Charles Kreisl

Research output: Contribution to journalArticle

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Abstract

Alzheimer disease (AD) is associated with an increase in the brain of the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because a reference region devoid of TSPO does not exist in the brain. We sought to determine whether a simple ratio method could substitute for absolute quantitation of binding with 11C-PBR28, a second-generation radioligand for TSPO. Methods: 11C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment, and 25 AD patients. Group differences in 11C-PBR28 binding were compared using 2 methods. The first was the gold standard method of calculating total distribution volume (VT), using the 2-tissue-compartment model with the arterial input function, corrected for plasma-free fraction of radiotracer (fP). The second method used a ratio of brain uptake in target regions to that in cerebellum - that is, standardized uptake value ratio (SUVR). Results: Using absolute quantitation, we confirmed that TSPO binding (VT/fP) was greater in AD patients than in healthy controls in expected temporoparietal regions and was not significantly different among the 3 groups in the cerebellum. When the cerebellum was used as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in 1 additional region, suggesting SUVR may have greater sensitivity. Coefficients of variation of SUVR measurements were about two-thirds lower than those of absolute quantification, and the resulting statistical significance was much higher for SUVR when comparing AD and healthy controls (e.g., P < 0.0005 for SUVR vs. P = 0.023 for VT/fP in combined middle and inferior temporal cortex). Conclusion: To measure TSPO density in AD patients and control subjects, a simple ratio method SUVR can substitute for, and may even be more sensitive than, absolute quantitation. The SUVR method is expected to improve subject tolerability by allowing shorter scanning time and not requiring arterial catheterization. In addition, this ratio method allows smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values.

Original languageEnglish
Pages (from-to)701-706
Number of pages6
JournalJournal of Nuclear Medicine
Volume56
Issue number5
DOIs
Publication statusPublished - 2015 May 1

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Cerebellum
Alzheimer Disease
Proteins
Brain
Microglia
Temporal Lobe
Protein Binding
Catheterization
Astrocytes
Sample Size
(methyl-(11)C)N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Lyoo, Chulhyoung ; Ikawa, Masamichi ; Liow, Jeih San ; Zoghbi, Sami S. ; Morse, Cheryl L. ; Pike, Victor W. ; Fujita, Masahiro ; Innis, Robert B. ; Kreisl, William Charles. / Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. In: Journal of Nuclear Medicine. 2015 ; Vol. 56, No. 5. pp. 701-706.
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abstract = "Alzheimer disease (AD) is associated with an increase in the brain of the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because a reference region devoid of TSPO does not exist in the brain. We sought to determine whether a simple ratio method could substitute for absolute quantitation of binding with 11C-PBR28, a second-generation radioligand for TSPO. Methods: 11C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment, and 25 AD patients. Group differences in 11C-PBR28 binding were compared using 2 methods. The first was the gold standard method of calculating total distribution volume (VT), using the 2-tissue-compartment model with the arterial input function, corrected for plasma-free fraction of radiotracer (fP). The second method used a ratio of brain uptake in target regions to that in cerebellum - that is, standardized uptake value ratio (SUVR). Results: Using absolute quantitation, we confirmed that TSPO binding (VT/fP) was greater in AD patients than in healthy controls in expected temporoparietal regions and was not significantly different among the 3 groups in the cerebellum. When the cerebellum was used as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in 1 additional region, suggesting SUVR may have greater sensitivity. Coefficients of variation of SUVR measurements were about two-thirds lower than those of absolute quantification, and the resulting statistical significance was much higher for SUVR when comparing AD and healthy controls (e.g., P < 0.0005 for SUVR vs. P = 0.023 for VT/fP in combined middle and inferior temporal cortex). Conclusion: To measure TSPO density in AD patients and control subjects, a simple ratio method SUVR can substitute for, and may even be more sensitive than, absolute quantitation. The SUVR method is expected to improve subject tolerability by allowing shorter scanning time and not requiring arterial catheterization. In addition, this ratio method allows smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values.",
author = "Chulhyoung Lyoo and Masamichi Ikawa and Liow, {Jeih San} and Zoghbi, {Sami S.} and Morse, {Cheryl L.} and Pike, {Victor W.} and Masahiro Fujita and Innis, {Robert B.} and Kreisl, {William Charles}",
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Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. / Lyoo, Chulhyoung; Ikawa, Masamichi; Liow, Jeih San; Zoghbi, Sami S.; Morse, Cheryl L.; Pike, Victor W.; Fujita, Masahiro; Innis, Robert B.; Kreisl, William Charles.

In: Journal of Nuclear Medicine, Vol. 56, No. 5, 01.05.2015, p. 701-706.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein

AU - Lyoo, Chulhyoung

AU - Ikawa, Masamichi

AU - Liow, Jeih San

AU - Zoghbi, Sami S.

AU - Morse, Cheryl L.

AU - Pike, Victor W.

AU - Fujita, Masahiro

AU - Innis, Robert B.

AU - Kreisl, William Charles

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Alzheimer disease (AD) is associated with an increase in the brain of the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because a reference region devoid of TSPO does not exist in the brain. We sought to determine whether a simple ratio method could substitute for absolute quantitation of binding with 11C-PBR28, a second-generation radioligand for TSPO. Methods: 11C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment, and 25 AD patients. Group differences in 11C-PBR28 binding were compared using 2 methods. The first was the gold standard method of calculating total distribution volume (VT), using the 2-tissue-compartment model with the arterial input function, corrected for plasma-free fraction of radiotracer (fP). The second method used a ratio of brain uptake in target regions to that in cerebellum - that is, standardized uptake value ratio (SUVR). Results: Using absolute quantitation, we confirmed that TSPO binding (VT/fP) was greater in AD patients than in healthy controls in expected temporoparietal regions and was not significantly different among the 3 groups in the cerebellum. When the cerebellum was used as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in 1 additional region, suggesting SUVR may have greater sensitivity. Coefficients of variation of SUVR measurements were about two-thirds lower than those of absolute quantification, and the resulting statistical significance was much higher for SUVR when comparing AD and healthy controls (e.g., P < 0.0005 for SUVR vs. P = 0.023 for VT/fP in combined middle and inferior temporal cortex). Conclusion: To measure TSPO density in AD patients and control subjects, a simple ratio method SUVR can substitute for, and may even be more sensitive than, absolute quantitation. The SUVR method is expected to improve subject tolerability by allowing shorter scanning time and not requiring arterial catheterization. In addition, this ratio method allows smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values.

AB - Alzheimer disease (AD) is associated with an increase in the brain of the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because a reference region devoid of TSPO does not exist in the brain. We sought to determine whether a simple ratio method could substitute for absolute quantitation of binding with 11C-PBR28, a second-generation radioligand for TSPO. Methods: 11C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment, and 25 AD patients. Group differences in 11C-PBR28 binding were compared using 2 methods. The first was the gold standard method of calculating total distribution volume (VT), using the 2-tissue-compartment model with the arterial input function, corrected for plasma-free fraction of radiotracer (fP). The second method used a ratio of brain uptake in target regions to that in cerebellum - that is, standardized uptake value ratio (SUVR). Results: Using absolute quantitation, we confirmed that TSPO binding (VT/fP) was greater in AD patients than in healthy controls in expected temporoparietal regions and was not significantly different among the 3 groups in the cerebellum. When the cerebellum was used as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in 1 additional region, suggesting SUVR may have greater sensitivity. Coefficients of variation of SUVR measurements were about two-thirds lower than those of absolute quantification, and the resulting statistical significance was much higher for SUVR when comparing AD and healthy controls (e.g., P < 0.0005 for SUVR vs. P = 0.023 for VT/fP in combined middle and inferior temporal cortex). Conclusion: To measure TSPO density in AD patients and control subjects, a simple ratio method SUVR can substitute for, and may even be more sensitive than, absolute quantitation. The SUVR method is expected to improve subject tolerability by allowing shorter scanning time and not requiring arterial catheterization. In addition, this ratio method allows smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values.

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