Visualizing reactive astrocyte-neuron interaction in Alzheimer’s disease using 11C-acetate and 18F-FDG

Abstract

Reactive astrogliosis is a hallmark of Alzheimer’s disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-β is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients’ cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Tonic excitation by astrocytic GABA causes neuropathic pain by augmenting neuronal activity and glucose metabolism

“…3c, d). Furthermore, consistent with our previous findings in the brain 27 , we found that the increase in tonic GABA current was significantly reduced to a normal level by preincubation of acute spinal cord slices with MAOBi (100 nM; Fig. 3c, d).…”

“…Reactive astrocytes excessively release GABA in the dorsal horn Accumulating lines of evidence indicate that reactive astrocytes can excessively synthesize and release the inhibitory transmitter GABA in various brain regions 16,25,26 , which, in turn, can decrease neuronal activity and glucose metabolism 15,27 . Thus, we investigated whether reactive astrocytes in the spinal cord also synthesize excessive GABA in a neuropathic pain model.…”

11C-Acetate PET/CT for Reactive Astrogliosis Outperforms 11C-Methionine PET/CT in Glioma Classification and Survival Prediction

“…9,10 In contrast to tumor-directed amino acid radiotracers, 11 C-acetate (ACE) targets reactive astrogliosis in the tumor microenvironment (TME) and has been associated with reactive astrocytes under inflammatory conditions in the CNS. [13][14][15] Previous studies have confirmed that 11 C-ACE uptake is attributable to reactive astrocytes via monocarboxylate transporter 1 at the tumor boundary. 16 As an imaging tracer for reactive astrogliosis, high C-ACE uptake has been significantly associated with high-grade gliomas and poor prognosis.…”

In vivoassessment of astrocyte reactivity in patients with progressive supranuclear palsy

“…A recent PET study, which combined acetate- and FDG-PET, demonstrated that reactive astrogliosis is associated with decreased glucose utilization in AD. 25 With regard to brain energy metabolism related to astrocytes, lactate has emerged as a key molecule, given the reliance of astrocytes on glycolysis and their propensity to produce lactate. 24 We recently demonstrated increased lactate levels in the PCC and their association with increased myo-inositol levels by using an advanced MRS sequence in patients with AD.…”