title: Reference tissue normalization in longitudinal (18)F-florbetapir positron emission tomography of late mild cognitive impairment.
abstract: BACKGROUND
  Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation of amyloid-β (Aβ) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest (18)F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions.
  
  
  METHODS
  We calculated the correlation between (18)F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Aβ1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique-the weighted two-point correlation function (wS2)-to capture potentially more subtle changes in Aβ-PET data.
  
  
  RESULTS
  Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Aβ1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Aβ1-42 levels across all time points and reference regions, including the cerebellar gray matter.
  
  
  CONCLUSIONS
  The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical (18)F-florbetapir uptake in longitudinal studies.
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN, 37232-2310, USA. sepideh.shokouhi@vanderbilt.edu.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Shokouhi
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN, 37232-2310, USA. john.w.mckay@vanderbilt.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Mckay
authors.affiliation: Center of Functional Imaging, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA, 94720, USA. slbaker@lbl.gov.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Baker
authors.affiliation: Department of Biostatistics, Vanderbilt University, 2525 West End Avenue, 11th Floor, Suite 11000, Nashville, TN, 37203-1738, USA. h.kang@vanderbilt.edu.
authors.forename: Hakmook
authors.initials: H
authors.lastname: Kang
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN, 37232-2310, USA. aaron.brill@Vanderbilt.Edu.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Brill
authors.affiliation: Department of Psychiatry, Vanderbilt University, 1601 23rd Avenue South, Nashville, TN, 37212, USA. harry.gwirtsman@Vanderbilt.Edu.
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gwirtsman
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN, 37232-2310, USA. bill.riddle@Vanderbilt.Edu.
authors.forename: William R
authors.initials: WR
authors.lastname: Riddle
authors.affiliation: Department of Neurology, Vanderbilt University, A-0118 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2551, USA. daniel.claassen@Vanderbilt.Edu.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Claassen
authors.affiliation: Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 1161 21st Avenue South, Medical Center North, AA-1105, Nashville, TN, 37232-2310, USA. baxter.rogers@vanderbilt.edu.
authors.forename: Baxter P
authors.initials: BP
authors.lastname: Rogers
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000000981:diagnostic imaging / Q000378:metabolism*; D005026:Ethylene Glycols; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D049268:Positron-Emission Tomography / Q000379:methods*; D012015:Reference Standards; D015203:Reproducibility of Results
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D005026:Ethylene Glycols; D010446:Peptide Fragments; C497285:amyloid beta-protein (1-41); C545186:florbetapir