Relative ¹¹C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session ¹⁵O-Water and ¹¹C-PiB PET

Abstract

The primary goal of this study was to assess the suitability of 11C-Pittsburgh compound B (11C-PiB) blood–brain barrier delivery (K1) and relative delivery (R1) parameters as surrogate indices of cerebral blood flow (CBF), with a secondary goal of directly examining the extent to which simplified uptake measures of 11C-PiB retention (amyloid-β load) may be influenced by CBF, in a cohort of controls and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Methods Nineteen participants (6 controls, 5 AD, 8 MCI) underwent MR imaging, 15O-water PET, and 11C-PiB PET in a single session. Fourteen regions of interest (including cerebellar reference region) were defined on MR imaging and applied to dynamic coregistered PET to generate time–activity curves. Multiple analysis approaches provided regional 15O-water and 11C-PiB measures of delivery and 11C-PiB retention that included compartmental modeling distribution volume ratio (DVR), arterial- and reference-based Logan DVR, simplified reference tissue modeling 2 (SRTM2) DVR, and standardized uptake value ratios. Spearman correlation was performed among delivery measures (i.e., 15O-water K1 and 11C-PiB K1, relative K1 normalized to cerebellum [Rel-K1-Water and Rel-K1-PiB], and 11C-PiB SRTM2-R1) and between delivery measures and 11C-PiB retention, using the Bonferroni method for multiple-comparison correction. Results Primary analysis showed positive correlations (ρ ≈0.2–0.5) between 15O-water K1 and 11C-PiB K1 that did not survive Bonferroni adjustment. Significant positive correlations were found between Rel-K1-Water and Rel-K1-PiB and between Rel-K1-Water and 11C-PiB SRTM2-R1 (ρ ≈0.5–0.8, P < 0.0036) across primary cortical regions. Secondary analysis showed few significant correlations between 11C-PiB retention and relative 11C-PiB delivery measures (but not 15O-water delivery measures) in primary cortical areas that arose only after accounting for cerebrospinal fluid dilution. Conclusion 11C-PiB SRTM2-R1 is highly correlated with regional relative CBF, as measured by 15O-water K1 normalized to cerebellum, and cross-sectional 11C-PiB retention did not strongly depend on CBF across primary cortical regions. These results provide further support for potential dual-imaging assessments of regional brain status (i.e., amyloid-β load and relative CBF) through dynamic 11C-PiB imaging.

Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

“…Good spatial correlations were found between CBF estimates and FDG, including in regions affected by hypometabolism in symptomatic sporadic AD [8,10,12]. The gold standard for CBF measurement is 15 O-H 2 O PET [13,14]; however, its 2-minute half-life prevents its widespread use [13]. 15 O-H 2 O has been used to validate perfusion weighted measurements derived from PiB PET [15] based upon influx of the PiB tracer into the brain [16] using either the early frames of the PiB scan (ePiB) or a relative tracer influx rate (PiB-R1) [15,17].…”

“…Longitudinal analyses were performed on a subset of 30 participants with at least one follow-up session including dynamic PiB and FDG scans (see demographics in Table 2). Of the 110 participants with baseline dynamic data, 30 participants at the Washington University site additionally underwent an 15 O-H 2 O PET scan for CBF assessment (see demographics in Supplementary Table S1).…”

“…The gold standard for CBF measurement is 15 O-H 2 O PET [13,14]; however, its 2-minute half-life prevents its widespread use [13]. 15 O-H 2 O has been used to validate perfusion weighted measurements derived from PiB PET [15] based upon influx of the PiB tracer into the brain [16] using either the early frames of the PiB scan (ePiB) or a relative tracer influx rate (PiB-R1) [15,17]. Several studies on sporadic AD showed that a perfusion image with ePiB, in addition to a common Ab burden PiB image, improves discrimination between AD pathology and other Ab-and tau-related clinical disorders [10,18,19].…”

“…Here, we compared PiB-R1 and ePiB with FDG in a model of AD progression to evaluate their utility in clinical research and trials of dynamic Ab PET measures as markers of neuronal injury. A validation substudy compared PiB-R1 and ePiB with the perfusion gold standard, 15 O-H 2 O PET.…”

Early Phase PIB‐PET as a Surrogate for Global and Regional Cerebral Blood Flow Measures

“…Reports have compared CBF to estimates derived from the summed early phase [ 11 C]PIB images (6 minutes, 1‐4 minutes), and WARM (washout allometric reference method) and the normalized CBF (to cerebellum) to the R1 parameter from the standard reference tissue model . These techniques are generally computationally demanding (eg, R1 or WARM) or produce relative CBF measures only . It was the purpose of this research to explore the potential of readily derived, early PIB‐based parameters and demographic information to model absolute global and regional CBF as determined by the gold‐standard, quantitative [ 15 O]water PET imaging.…”