New method of quantification of tau pathology with ¹¹C-PBB3 PET using reference tissue extracted from cerebral cortical gray matter

Objectives Quantitative visualization of tau pathology improves diagnostic accuracy and facilitates evaluation of disease-modifying drugs targeting tau in tauopathies. Tau pathology can be accurately quantified by reference tissue models when reference tissue devoid of target binding sites is available. However, in tauopathies such as progressive supranuclear palsy and corticobasal degeneration, unlike in Alzheimer’s disease, tau accumulation can be found throughout brain regions including the cerebellum. This makes it difficult to select a distinctive brain region devoid of tau binding as reference tissue. The purpose of study was to develop a new method to quantify the tau pathology with ¹¹C-PBB3 using extracted reference voxels in cortical gray matter, which have a low likelihood of containing tau accumulations.

Methods ¹¹C-PBB3 PET data of 7 mild AD patients (ADs) and 7 elderly healthy control subjects (HCs) enrolled in a previous study was reanalyzed (3 men/4 women for both groups, age: 76 ± 7 y for ADs and 70 ± 6 y for HCs, mean ± SD). Parametric images of binding potential (BP^[asterisk]_ND) were generated using the reference tissue defined in two ways, standard (the cerebellar cortex) and new methods. Our new method was to define the reference tissue consisting of a pool of cortical gray matter voxels that have a low likelihood of tau binding using a frequency histogram of BP^[asterisk]_ND values in the parametric images generated by the standard method.

Results The reference tissue voxels by our new method for ADs and HCs spread through the cortical gray matter, which was considered to have a low likelihood of tau accumulation. The BP^[asterisk]_ND values by our new method correlated very well to those by the standard method (r² = 0.94), although the values with the current method were slightly higher by ~0.14 than those by the standard method (Figure).

Conclusions We developed a new method of ¹¹C-PBB3 quantification for tau pathology using cortical gray matter as reference tissue. This method should be applicable in patients with tauopathies lacking any distinctive brain regions devoid of tau accumulation. $$graphic_FC949AB5-5154-4113-A6AF-E86E5FA95485$$

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