Diagnosing Alzheimer's disease is challenging, partly due to the closely related pathological features shared with other neurodegenerative diseases. Presently, a definite diagnosis of Alzheimer's disease can only be established by post mortem pathological examination focusing on two main pathological hallmarks: (i) amyloid plaques consisting of aggregated amyloid beta (Aβ) peptides, and (ii) neurofibrillary tangles made of abnormally phosphorylated tau protein.In living individuals, Alzheimer's disease diagnosis relies on two main approaches: (i) imaging of the accumulation of tau tangles and Aβ plaques in the brain using positron emission tomography (PET), and (ii) measuring brain-specific biochemical changes in CSF reflecting tau and Aβ pathophysiology. However, tau PET is expensive and only available in specialised medical centres. In 1995, our group developed two immunoassays for quantifying tau in CSF, one for measuring pathological tau phosphorylated at threonine-181 (p-tau181) and the other for the neuronal injury marker "total tau." These assays, targeting mid-region tau species, were subsequently developed into commercial kit assays, and have recently been approved by the United States Food and Drugs Administration to support diagnosis and candidate drug testing.The assays have been used in hundreds of published independent clinical studies. In reviewing

Background 18F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18F-THK5351 brain uptake using PET and autoradiography.MethodsEight participants (five mild cognitive impairment, two Alzheimer’s disease, and one progressive supranuclear palsy) had baseline 18F-AZD4694 and 18F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18F-THK5351 scan 9–28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline.ResultsAt baseline, 18F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9–28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18F-THK5351 uptake.ConclusionsThese results indicate that the interpretation of 18F-THK5351 PET images, with respect to tau, is confounded by the high MAO-B availability across the entire brain. In addition, the heterogeneous MAO-B availability across the cortex may limit the interpretation of 18F-THK5351 scans using reference region methods.

The present results highlight complexities underlying brain adaptations during the aging process, and support the notion that certain aspects of neurotransmission remain stable during the adult life span.