NEUROFIBRILLARY TANGLE FORMATION AND SYNAPTIC LOSS: WHICH COMES FIRST?

Abstract

Neurofibrillary tangles (NFT) are known as the pathologic hallmark of Alzheimer's disease (AD) along with amyloid plaques. Neurofibrillary tangle formation is known to parallel neuronal loss and synaptic loss. Recently, a novel tau PET tracer, [18F]THK5351 was developed. The aim of this study was to evaluate the clinical usefulness of [18F]THK5351 PET as an early diagnostic marker for Alzheimer's disease (AD) and to examine the correlation between tau uptake and synaptic loss in AD. We included the 22 patients with AD dementia, 13 patients with amnestic mild cognitive impairment (aMCI) and 15 age-matched control with normal cognition (NC). All participants underwent [18F]THK5351 PET, [18F]FDG PET, 3D magnetic resonance imaging and detailed neuropsychological tests. To compare the distribution of tau deposition among the three groups (AD, aMCI and normal controls), regional of interest (ROI)-based statistical analyses and voxel-based statistical analyses were performed. Correlation analyses between THK5351 retention and glucose metabolism were performed in the 82 ROI of the cerebral cortices. Global tau retention was significantly greater in AD compared to NC. The regions with higher tau uptake in AD compared to NC were frontal, inferior temporal, superior and inferior parietal, occipital, anterior cingulate cortex, posteior cingulate cortex, and striatum. The patients with aMCI showed higher uptake in the inferior temporal lobe compared to NC. In the correlation analyses, THK5351 retention showed negative correlation with glucose metabolism, in the patients with AD dementia. Meanwhile, in the amnestic MCI patients, there were a few regions with positive correlation between THK5351 retention and glucose metabolism, which is known as regions where NFT deposit at the early stage. THK5351 PET reflects symptoms and disease severity. THK5351 retention in inferior temporal cortex may indicate the increase risk of AD. These study suggests synaptic loss may follow tau uptake in the AD spectrum disease. In addition, positive correlation between THK5351 retention and glucose metabolism in the patients with aMCI may suggest that it may be related to secondary compensation mechanism of synaptic changes following tau uptake.