Can target-to-pons ratio be used as a reliable method for the analysis of [¹¹C]PIB brain scans?

Abstract

Rationale

¹¹C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be present in genetic Alzheimer's (AD), cerebral amyloid angiopathy and prion diseases. Therefore, we investigated whether the pons could be used as an alternative reference region for the analysis of [¹¹C]PIB binding in AD. The aims of the study were to: 1) Evaluate the pons as a reference region using arterial plasma input function and Logan graphical analysis of binding. 2) Assess the power of target-to-pons ratios to discriminate controls from AD subjects. 3) Determine the test-retest reliability in AD subjects. 4) Demonstrate the application of target-to-pons ratio in subjects with elevated cerebellar [¹¹C]PIB binding.

Methods

12 sporadic AD subjects aged 65 ± 4.5 yrs with a mean MMSE 21.4 ± 4 and 10 age-matched control subjects had [¹¹C]PIB PET with arterial blood sampling. Three additional subjects (two subjects with pre-symptomatic presenilin-1 mutation carriers and one probable familial AD) were also studied. Object maps were created by segmenting individual MRIs and spatially transforming the gray matter images into standard stereotaxic MNI space and then superimposing a probabilistic atlas. Cortical [¹¹C]PIB binding was assessed with an ROI (region of interest) analysis. Parametric maps of the volume of distribution (V_T) were generated with Logan analysis. Additionally, parametric maps of the 60–90 min target-to-cerebellar ratio (RATIO_CER) and the 60–90 min target-to-pons ratio (RATIO_PONS) were computed.

Results

All three approaches were able to differentiate AD from controls (p < 0.0001, nonparametric Wilcoxon rank sum test) in the target regions with RATIO_CER and RATIO_PONS differences higher than V_T with use of an arterial input function. All methods had a good reproducibility (intraclass correlation coefficient > 0.83); RATIO_CER performed best closely followed by RATIO_PONS. The two subjects with presenilin-1 mutations and the probable familial AD case showed no significant differences in cortical binding using RATIO_CER, but the RATIO_PONS approach revealed higher [¹¹C]PIB binding in cortex and cerebellum.

Conclusion

This study established 60–90 min target-to-pons RATIOs as a reliable method of analysis in [¹¹C]PIB PET studies where cerebellum is not an appropriate reference region.