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).

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.

Trial registration: ClinicalTrials.gov NCT00613119.

Keywords: 11C-PBR28; Alzheimer disease; neuroinflammation; positron emission tomography; ratio method.

© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figures

FIGURE 1

In the combined middle and inferior temporal cortex, total distribution volume corrected for free fraction of radioligand (VT/fP), standardized uptake value ratio (SUVR), and distribution volume ratio (DVR) values were greater for Alzheimer’s disease (AD) patients than for mild cognitive impairment (MCI) patients or controls. Error bars denote mean ± SD. The SD bars have similar heights for VT/fP and SUVR due to different scales on the two y-axes. The coefficient of variation of VT/fP was three to four times greater than that for SUVR and DVR, as shown by coefficient of variation (%COV) values above the SD bars.

FIGURE 2

In the cerebellum, 11C-PBR28 binding did not differ between controls and patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD). 11C-PBR28 binding values in total distribution volume corrected for free fraction of radioligand (VT/fP) and standardized uptake value (SUV) are shown. Error bars denote mean ± SD. Coefficient of variation (%COV) values are shown above the vertical bars.

FIGURE 3

Correlation between the binding values and the severity of cognitive impairment measured by the sum-of-boxes of clinical dementia rating (CDR) score. Total volume of distribution corrected for plasma free fraction (VT/fP), standardized uptake value ratio (SUVR), and distribution volume ratio (DVR) of combined middle and inferior temporal cortex similarly correlated with the severity of cognitive impairment. Non-invasive ratio method did not deteriorate correlation with clinical severity.