Early brainstem [18F]THK5351 uptake is linked to cortical hyperexcitability in healthy aging.
BACKGROUNDNeuronal hyperexcitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-β (Aβ) protein accumulation - both central to AD neuropathology - promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau - and its associated neuroinflammation - and cortical Aβ aggregations remains unknown.METHODSWe 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 Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers.RESULTSWe 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 Aβ cortical deposits and cortical excitability (r = -0.20, P = 0.11).CONCLUSIONThese 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.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGF.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.
['Van Egroo|Maxime|M|', 'Chylinski|Daphne|D|', 'Narbutas|Justinas|J|', 'Besson|Gabriel|G|', 'Muto|Vincenzo|V|', 'Schmidt|Christina|C|', 'Marzoli|Davide|D|', 'Cardone|Paolo|P|', 'Vandeleene|Nora|N|', 'Grignard|Martin|M|', 'Luxen|André|A|', 'Salmon|Eric|E|', 'Lambert|Christian|C|', 'Bastin|Christine|C|', 'Collette|Fabienne|F|', 'Phillips|Christophe|C|', 'Maquet|Pierre|P|', 'Bahri|Mohamed Ali|MA|', 'Balteau|Evelyne|E|', 'Vandewalle|Gilles|G|']
D000368:Aged D000544:Alzheimer Disease D000631:Aminopyridines D016229:Amyloid beta-Peptides D001933:Brain Stem D002540:Cerebral Cortex D003430:Cross-Sectional Studies D042241:Early Diagnosis D004569:Electroencephalography D005260:Female D005462:Fluorine Radioisotopes D059907:Functional Neuroimaging D000073656:Healthy Aging D006801:Humans D008279:Magnetic Resonance Imaging D008297:Male D008875:Middle Aged D049268:Positron-Emission Tomography D011804:Quinolines D019275:Radiopharmaceuticals D050781:Transcranial Magnetic Stimulation D016875:tau Proteins
Aging Alzheimer’s disease Neuroimaging Neuroscience