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Quantitative PET/MR Imaging of Brain Derived Neurotrophic Factor (BDNF) / Tropomyosin Related Kinase B (TRKB) signaling in ALS – decoding a potential pathogenetic pathway

Principal Investigator:
  • Freimut Dankwart Eberhard Juengling, University of Alberta
Team Members:
  • Sanjay Kalra, University of Alberta
  • Ralf Schirrmacher, University of Alberta

Project Overview

Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB signaling can be triggered via activation of adenosine 2A receptors (A2aRs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been clinically successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. BDNF elicits rapid effects on synaptic transmission and membrane excitability, via activation of pathways in both the pre- and post-synaptic compartments. In the pre-synaptic compartment, BDNF causes release of glutamate and GABA, via the TrkB-ERK mediated pathway. Enhanced glutamate release at glutamatergic synapses is mediated by an increase in docked vesicles at presynaptic active zones. Hence, in the context of ALS, the increased neuronal activity observed is capable of increasing BDNF secretion, which in turn can increase release of glutamate to trigger excitotoxicity, leading to MN degeneration. Indeed, BDNF has been shown to enhance MN death by glutamate excitotoxicity, via activation of TrkB. Together, these findings highlight a possible role for BDNF in the death of MNs in ALS. While several studies documented the neuroprotective effects of BDNF on glutamate induced excitotoxicity in vitro, there is also evidence that therapeutic interventions aimed at enhancing BDNF/TrkB are unable to promote survival or prevent death of neurons in vivo, and it has to be considered that BDNF, in certain metabolic settings, may induce detrimental actions. Indeed, several studies report BDNF and TrkB to be key players in rendering MNs vulnerable to excitotoxic insult and thus also can exert negative effects on MN survival, making MNs more vulnerable to insults. Moreover, BDNF is potent at enhancing excitotoxic insult, by enhancing glutamatergic activity in neurons. 

To further elicit the differential role of BDNF/TrkB signaling in neurodegenerative disease such as ALS, we have developed and characterized preclinically the first available tropomyosin receptor kinase (TrkB/C) PET radiotracer, and have performed a first-in-human study. In a current study funded by a CIHR grant, we establish quantitative normal distribution and dosimetry, and for this grant application, we propose to apply quantitative [18F]TRACK PET/MRI in ALS patients, to quantify alterations in BDNF/TrkB signaling along with simultaneously acquired MR-spectroscopic metabolite markers and state-of-the-art diffusion tensor imaging (DTI). We plan to perform quantitative [18F]TRACK-PET/MRI imaging in 30 ALS patients at early, middle and late stages for a first-in-human mapping of BDNF/TrkB signaling in ALS, and to correlate those findings with MR spectroscopic metabolite and functional DTI findings, to establish a neuroanatomic pattern of metabolite and signaling alterations in ALS, which in turn might inform therapeutic considerations of possible, stage-specific pharmacological interventions. A broader understanding of the factors that regulate altered neuronal activity and BDNF could also help to identify new therapeutic targets in neurodegenerative diseases. Previous therapies that aimed to enhance endogenous BDNF could not be monitored for in-vivo effects on a cortical level and have yet failed to produce significant success in prevention or slowing of MN death in ALS. Our proposed approach will allow, for the first time in humans, to investigate both pro- and anti-trophic functions of BDNF/TrkB in ALS, which might be the base for novel therapeutic avenues to alleviate this devastating disease and other neurodegenerative conditions.