Assessing THK523 selectivity for tau deposits in Alzheimer's disease and non-Alzheimer's disease tauopathies

Abstract

Introduction: The introduction of tau imaging agents such as (18)F-THK523 offers new hope for the in vivo assessment of tau deposition in tauopathies such as Alzheimer's disease (AD), where preliminary (18)F-THK523-PET studies have demonstrated significantly higher cortical retention of (18)F-THK523 in AD compared to age-matched healthy individuals. In addition to AD, tau imaging with PET may also be of value in assessing non-AD tauopathies, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease (PiD).

Methods: To further investigate the ability of THK523 to recognize tau lesions, we undertook immunohistochemical and fluorescence studies in serial brain sections taken from individuals with AD (n = 3), CBD (n = 2), PSP (n = 1), PiD (n = 2) and Parkinson's disease (PD; n = 2). In addition to the neuropathological analysis, one PSP patient had undergone a (18)F-THK523 PET scan 5 months before death.

Results: Although THK523 labelled tau-containing lesions such as neurofibrillary tangles and neuropil threads in the hippocampus and frontal regions of AD brains, it failed to label tau-containing lesions in non-AD tauopathies. Furthermore, though THK523 faintly labelled dense-cored amyloid-β plaques in the AD frontal cortex, it failed to label α-synuclein-containing Lewy bodies in PD brain sections.

Conclusion: The results of this study suggest that (18)F-THK523 selectively binds to paired helical filament tau in AD brains but does not bind to tau lesions in non-AD tauopathies, or to α-synuclein in PD brains.

Figure 1

THK523 binds to neurofibrillary tangles in an Alzheimer’s disease patient. Microscopy of 5-μm serial sections from the hippocampus of a representative Alzheimer’s disease patient. The left image (tau) is the first of three serial sections. It is immunostained with tau polyclonal antibody to detect tau lesions in the hippocampus. The black arrow indicates the positioning of neurofibrillary tangles (NFTs). The positioning of the NFTs indicated by the black arrow was transferred to subsequent adjacent serial sections that were either stained with THK523 (middle image, THK523) or immunostained with a monoclonal antibody raised to amyloid-β (Aβ) to identify senile plaques in the tissue section (right image, Aβ). Fluorescence staining of THK523 (middle) appears to colocalise and resemble tau NFTs, indicated by the yellow arrow, in the absence of Aβ immunoreactivity in the same tissue region (right, red arrow). Tissue section images were obtained using a Zeiss microscope and an AxioCam digital camera (Carl Zeiss Microscopy, North Ryde, Australia). Scale bars, 100 μm.

Figure 2

THK523 does not bind to tau lesions in corticobasal degeneration or Pick’s disease. Microscopy of 5-μm serial sections from the striatum of a corticobasal degeneration (CBD) patient (top panel) and the frontal cortex of a Pick’s disease (PiD) patient (bottom panel). The left side (Tau) shows the first of two serial sections immunostained with tau polyclonal antibodies to detect tau lesions. The arrows indicate the positioning of brown immunostained globose tangles (GT) and coiled bodies (CB; top panel) in a CBD patient and Pick’s bodies and dystrophic neurites (DN) (bottom panel). The same region of tissue was subsequently imaged for the adjacent section, which was stained with THK523 (right, THK523). The positioning of the tau lesion arrows was transferred to the adjacent stained serial section and is indicated by yellow arrows (THK523). The absence of fluorescence suggests that THK523 does not bind to CBD or PiD tau lesions. Tissue sections were imaged using a Zeiss microscope and an AxioCam digital camera at 5× (CBD) and 20× (PiD) original magnification.

Figure 3

THK523 does not bind to globose tangles in a progressive supranuclear palsy patient. Microscopy of 5-μm serial sections taken from the pons (top panels) and the striatum (bottom panels) of a representative progressive supranuclear palsy (PSP) patient. Left (Tau) images show the first of two serial sections immunostained with a tau polyclonal antibody to detect globose tangles (GB). The black arrows indicate the positioning of brown immunostained GBs in the tissue section examined. The same region of tissue was subsequently imaged for the adjacent section, which was treated with THK523 (right, THK523). The positioning of the tau lesion black arrows was transferred to the adjacent stained serial section and is indicated by the yellow arrows (THK523). The absence of fluorescence suggests that THK523 did not bind to the tau lesions of the PSP patients examined. Tissue sections were imaged using a Zeiss microscope and an AxioCam digital camera at 5× original magnification.

Figure 4

¹⁸F-THK523 and ¹¹⁸F-florbetaben positron emission tomography scans in a progressive supranuclear palsy patient. Representative ¹⁸F-florbetaben (¹⁸F-FBB, left) and ¹⁸F-THK523 (¹⁸F-THK, right) transaxial images at three different brain levels of a 79–year-old PSP patient with a Mini Mental State Examination score of 26. Visual inspection reveals no cortical retention of either ¹⁸F-THK523 or ¹⁸F-florbetaben, despite a postmortem immunohistological examination (see Figure 3 5 months after PET evaluation), confirming the presence of tau lesions. SUVR, Standardised uptake value ratio.

Figure 5

THK523 does not bind to Lewy bodies in Parkinson’s disease patient. Microscopy of 5-μm serial sections from the substantia nigra of a Parkinson’s disease patient. The left image (α-syn shows the first of two serial sections. It immunostained with an α-synuclein antibody to detect Lewy bodies (LB) in the substantia nigra. The black arrows indicate the positioning of LBs. The same region of tissue was subsequently imaged for the adjacent sections, which were treated with THK523. The positions indicated by the black arrows in the left panel were transferred to the adjacent THK523 serial section and are indicated by the yellow arrows (THK523). The absence of fluorescence staining indicates that THK523 does not bind to α-synuclein containing Lewy bodies in the same tissue region. Tissue sections were imaged using a Zeiss microscope and an AxioCam digital camera at 5× original magnification.