. [(18)F]FDG PET signal is driven by astroglial glutamate transport. Nat Neurosci. 2017 Jan 30; PubMed.

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  1. We thank Dr. Klunk for sparking an important discussion related to the role of astrocytes in AD by asking the question “If activated astrocytes drive the FDG PET signal, why would it go down in AD and not up?” As molecular imaging is based on pharmacokinetic compartments, inferences regarding cellular compartmentalization of PET signals should be carefully considered. Specifically regarding our results, one can link [18F]FDG uptake to the astrocytic compartment since GLT-1 is highly expressed in astrocytes (Dehnes et al., 2008). In pathological conditions, such as AD, one might predict regional coexistence between hypometabolism and astrocytosis, if the astrocyte is injured (expressing reduced or dysfunctional GLT-1). In fact, data from the human postmortem literature suggest abnormal GLT-1 expression in the brain of AD patients (Scott et al., 2011; Masliah et al., 2006). Animal model data shows that GLT-1 is a target of Aβ toxic effects (Scimemi et al., 2013). Indeed, an elegant study by Hefendehl and colleagues (recently covered in Alzforum) shows reduced GLT-1 levels in the vicinity of amyloid plaques (Hefendehl et al., 2016). These data suggest a link between astrocytic GLT-1 abnormalities and AD pathophysiology that might contribute with the reduced [18F]FDG uptake observed in AD brain. We believe that the molecular mechanism underling hypometabolism in AD is complex and involves the local deleterious actions of Aβ aggregates on astrocytes and neurons as well as depletions of remote cortical inputs. We hope that our results would contribute with the interpretation of FGD PET in normal and abnormal conditions. 

    References:

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    . Glutamate transporter variants reduce glutamate uptake in Alzheimer's disease. Neurobiol Aging. 2011 Mar;32(3):553.e1-11. PubMed.

    . Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease. Ann Neurol. 1996 Nov;40(5):759-66. PubMed.

    . Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing astrocytic GLT-1. J Neurosci. 2013 Mar 20;33(12):5312-8. PubMed.

    . Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nat Commun. 2016 Nov 11;7:13441. PubMed.

    View all comments by Pedro Rosa-Neto
  2. The authors demonstrate nicely that astrocytic glutamate transport affects glucose uptake and that this can be measured using [18F]FDG PET. This is a great example of the interaction between cell types and demonstrates that using imaging can help elucidate those interactions. The implications for PET studies in AD are also important given the fact that neuron/astrocyte communication is an important regulatory mechanism in a variety of brain functions.

    View all comments by Arthur Toga

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