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

Abstract

Alzheimer’s disease (AD) is associated with increase in brain of the 18 kDa translocator protein (TSPO), which is over-expressed 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 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 (MCI), and 25 AD patients. Group differences in ¹¹C-PBR28 binding were compared using two methods. First, the “gold standard” method of calculating total distribution volume (V_T), using the two-tissue compartmental model with the arterial input function, corrected for plasma free fraction of radiotracer (f_P). Second, a ratio of brain uptake in target regions to that in cerebellum—i.e., standardized uptake value ratio (SUVR). Results: Using absolute quantitation, we confirmed that TSPO binding (V_T/f_P): 1) was greater in AD patients than in healthy controls in expected temporo-parietal regions, and 2) was not significantly different among the three groups in cerebellum. Using the cerebellum 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 one 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 V_T/f_P in combined middle and inferior temporal cortex). Conclusion: To measure TSPO density in AD 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 scan 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.