Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism.
Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
Fruzsina
F
Soltész
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, United Kingdom.
John
J
Suckling
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
Phil
P
Lawrence
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, United Kingdom.
Roger
R
Tait
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, United Kingdom.
Cinly
C
Ooi
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
Graham
G
Bentley
Department of Psychology, University of Exeter, Exeter, United Kingdom.
Chris M
CM
Dodds
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
Sam R
SR
Miller
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
David R
DR
Wille
Queensland Brain Institute, University of Queensland, Queensland, Australia.
Misha
M
Byrne
Clinical Unit Cambridge, GlaxoSmithKline, Cambridge, United Kingdom.
Simon M
SM
McHugh
School of Psychology and Psychiatry, Monash University, Melbourne, Australia.
Mark A
MA
Bellgrove
Queensland Brain Institute, University of Queensland, Queensland, Australia.
Rodney J
RJ
Croft
Tsinghua University Medical School, Beijing, China.
Bai
B
Lu
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, United Kingdom.
Edward T
ET
Bullmore
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, United Kingdom; School of Psychology and Psychiatry, Monash University, Melbourne, Australia; New Medicines, UCB Pharma, Brussels, Belgium.
Pradeep J
PJ
Nathan
D000328:Adult; D001921:Brain / Q000378:metabolism / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D004569:Electroencephalography; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D009483:Neuropsychological Tests; D011110:Polymorphism, Genetic / Q000235:genetics*; D013569:Synapses / Q000502:physiology*; D014633:Valine / Q000235:genetics; D055815:Young Adult
D019208:Brain-Derived Neurotrophic Factor; D008715:Methionine; D014633:Valine