Early Brainstem ([18f])Thk5351 Uptake Is Inked To Cortical Hyperexcitability In Healthy Aging

BACKGROUND. Neuronal hyperexcitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-beta (A beta) protein accumulation - both central to AD neuropathology - promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and A beta aggregates are first detected, respectively, in the brainstem and frontomedia I and temporobasal cortices. decades prior to the onset of A beta cognitive symptoms. Whether cortical excitability is related to early brainstem tau - and its associated neuroinflammation - and cortical A beta aggregations remains unknown.METHODS. We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late-middle-aged individuals (50-69 years; 45 women and 19 men). We assessed whole-brain( [18F])THK5351 PET uptake as a proxy measure of tau/neuroinflammation, and we assessed whole-brain A beta burden with ([18F])Flutemetamol or( [18F])Florbetapir radiotracers.RESULTS. We found that higher ([18F])THK5351 uptake in a brainstem monoaminergic compartment was associated with increased cortical excitability {r = 0.29, P = 0.02). By contrast, ([18F])THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole- brain voxel-based quantification analyses (P value corrected for family-wise error [PFWE-corrected] < 0.001), was not significantly associated with cortical excitability (r = 0.14, P = 0.25). Importantly, no significant association was found between early A beta cortical deposits and cortical excitability (r = -0.20, P = 0.11).CONCLUSION. These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans.