title: Cerebellum Can Serve As a Pseudo-Reference Region in Alzheimer Disease to Detect Neuroinflammation Measured with PET Radioligand Binding to Translocator Protein.
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 (11)C-PBR28, a second-generation radioligand for TSPO.
  
  
  METHODS
  (11)C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment, and 25 AD patients. Group differences in (11)C-PBR28 binding were compared using 2 methods. The first was the gold standard method of calculating total distribution volume (V(T)), using the 2-tissue-compartment model with the arterial input function, corrected for plasma-free fraction of radiotracer (f(P)). 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 (V(T)/f(P)) 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Chul Hyoung
authors.initials: CH
authors.lastname: Lyoo
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Morse
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York kreislw@mail.nih.gov.
authors.forename: William Charles
authors.initials: WC
authors.lastname: Kreisl
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011743:Pyrimidines / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism*; D012015:Reference Standards
chemical_list: C526315:(methyl-(11)C)N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine; D008024:Ligands; D011743:Pyrimidines; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: 11C-PBR28; Alzheimer disease; neuroinflammation; positron emission tomography; ratio method