Reference region automatic extraction in dynamic [(11)C]PIB

Abstract

The positron emission tomography (PET) radiotracer [(11)C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [(11)C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [(11)C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [(11)C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [(11)C]PIB studies.

Figure 1

Normalized time–activity curve of the predefined three classes; normal gray matter, specific-binding gray matter, and blood pool.

Figure 2

Maps of normal gray matter ratio (A), specific-binding gray matter ratio (B), blood-pool ratio (C) estimated by supervised algorithm, and extracted reference region (D) superimposed on magnetic resonance imaging for an idiopathic Alzheimer's disease subject.

Figure 3

Example of cerebellar segmentation for the idiopathic Alzheimer's disease subject that demonstrated the higher non-reference percentage of voxels in the cerebellum; reference (A; REF), non-reference with high specific-binding fraction (B; NREF-Binding), and non-reference with high blood-pool fraction (C; NREF-Blood) superimposed on magnetic resonance imaging (upper), and averaged time–activity curve of the whole cerebellum and each cerebellar segment (D) (lower).

Figure 4

Parametric V_T map of the same idiopathic Alzheimer's disease subject obtained using a plasma input function (left) and histogram of V_T estimates for voxels within each cerebellar segment identified by the supervised algorithm. REF, reference; NREF-Binding, non-reference region with high specific-binding fraction; NREF-Blood, non-reference with high blood-pool fraction.

Figure 5

Relationship of binding potential (BP_ND) estimates between the plasma input graphical analysis using the supervised clustering extracted region and using the cerebellum as a reference region (A), relationship of BP_ND estimates between the plasma input graphical analysis and reference input graphical analysis using the supervised clustering extracted reference region (B), and Bland–Altman plots between BP_ND estimates with the plasma input and the supervised clustering extracted reference input (C).

Figure 6

Binding potential (BP_ND) values of prefrontal cortex estimated by the reference input graphical analysis with cerebellum or supervised clustering extracted region as a reference for controls, idiopathic Alzheimer's disease (AD), and familial AD subjects.