Correlation of In Vivo [18F]Flortaucipir With Postmortem Alzheimer Disease Tau Pathology

Ruben Smith,Moa Wibom,Elisabet Englund,Oskar Hansson,Daria Pawlik

doi:10.1001/jamaneurol.2018.3692

Ruben Smith, Moa Wibom + Show 3 more

Open Access

https://doi.org/10.1001/jamaneurol.2018.3692

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Abstract

In Alzheimer disease (AD), tau filaments form neuronal inclusions in neurites (neuropil threads) and in somata (neurofibrillary tangles), and neurite tau pathology constitutes the most common pathology. Positron emission tomography (PET) ligands have been developed to detect in vivo tau pathology in AD. However, the association of AD tau pathology post mortem with in vivo tau PET retention has not been established. Therefore, there is a need to investigate the associations of tau PET with postmortem tau pathology in AD. To study the association of regional in vivo retention of the tau PET ligand [18F]flortaucipir (previously known as AV1451) with the density of tau neuropathology in the corresponding brain regions in a patient with AD. The patient was a man in his 40s with AD caused by a PSEN1 mutation. Between May 2015 and December 2016, he underwent 2 [18F]flortaucipir PET scans at Lund University Hospital, Lund, Sweden. Postmortem analysis was performed 12 months after the last PET scan. Tau pathology was assessed using phosphorylated tau (AT8) immunohistochemistry and Gallyas silver staining. In addition to the regional total tau pathology burden, the density of tau-positive neurites and intrasomal tau tangles were quantified using a stereology-based method. Further, β-amyloid-containing plaques were detected using 4G8 immunohistochemistry. Data were analyzed between January 2018 and August 2018. Regional standardized uptake value ratios of [18F]flortaucipir were compared with the amount of tau pathology in the corresponding brain areas. In this patient, the clinical disease symptoms progressed rapidly in life, paralleled with an annual increase of tau PET retention of 20% to 40% in many cortical regions. Compared with postmortem immunohistochemistry, regional in vivo uptake of [18F]flortaucipir was correlated with the density of tau-positive neurites (AT8: rs = 0.87; P < .001; Gallyas: rs = 0.92; P < .001), intrasomal tau tangles (AT8: rs = 0.65; P = .01; Gallyas: rs = 0.84; P < .001), and total tau burden (AT8: rs = 0.84; P < .001; Gallyas: rs = 0.82; P < .001). No correlations between [18F]flortaucipir and β-amyloid pathology were found. These results indicate that [18F]flortaucipir PET retention is a robust in vivo measure of the total AD tau burden.

Highlights

S everal tau positron emission tomography (PET) radiotracers have been recently developed for detection of tau pathology in Alzheimer disease (AD).[1]
We quantified the regional tau and β-amyloid (Aβ) pathology in a patient with early-onset AD caused by a mutation in the PSEN1 gene and correlated the intensity of the pathology with the retention of [18F]flortaucipir in corresponding brain regions of the Positron emission tomography (PET) scan
In addition to the total tau burden, we quantified both the number of neurites and the number of intrasomal tau tangles shown to be positive on phosphorylated tau (AT8) immunohistochemistry and Gallyas silver staining using a method based on modified unbiased stereology

Summary

Methods

Study Participant All procedures were reviewed and approved by the Regional Ethical Review Board of Lund and the regional radiation safety committee. Written informed consent was obtained from the patient prior to enrollment in the study. The clinical characteristics of the patient have been described in detail before.[6] In brief, the patient was diagnosed with early-onset AD caused by a PSEN1 mutation (Thr116Asn) and fulfilled the Diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised)[13] criteria for dementia combined with the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for AD.[14] The postmortem neuropathological examination confirmed the AD diagnosis. Magnetic Resonance Imaging and PET Imaging procedures for this patient have been described in detail previously.[6] In brief, [18F]flortaucipir PET scans were performed on a Discovery 690 PET scanner (GE Healthcare) in LIST mode after a bolus injection of 370 MBq of [18F]flortaucipir.

Results

Discussion

Conclusion