Scientists have made a breakthrough in the search for a clinically validated neuroimaging probe to visualize reactive astrogliosis, a hallmark of Alzheimer’s disease (AD) that involves the activation of astrocytes in response to neuroinflammation. According to a recent study published in Brain, PET imaging with C-acetate and F-fluorodeoxyglucose (F-FDG) can functionally visualize reactive astrocyte-mediated neuronal hypometabolism in the brains of individuals with neuroinflammation and AD.
The study employed a multifaceted approach, including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology, to investigate alterations in acetate and glucose metabolism in diseased brains and their impact on AD pathology. Two AD rodent models, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used, along with a proof-of-concept human study that included C-acetate and F-FDG PET imaging analyses and neuropsychological assessments from eleven AD patients and ten healthy control subjects.
The study’s results indicate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. This excessive 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.
PET imaging with C-acetate and F-FDG was used to visualize reactive astrogliosis in AD patients. The study found that C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus, and temporo-parietal neocortex of AD patients compared to healthy controls, while F-FDG uptake was significantly reduced in the same regions. The PET signals of both C-acetate and F-FDG showed a strong correlation with the patient’s cognitive function.
These findings could have significant implications for the development of new therapies for AD. The acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD, highlighting the need to target this interaction in future therapeutic interventions. Additionally, PET imaging with C-acetate and F-FDG could be a valuable tool for visualizing reactive astrogliosis and the associated neuronal glucose hypometabolism in AD patients.
Previous research has largely focused on amyloid beta (Aβ) as the primary cause of Alzheimer’s disease (AD), with PET imaging targeting Aβ as a diagnostic tool and drugs aimed at removing it as a therapeutic target. However, these approaches have proven limited in diagnosing and treating AD. This study has opened up new possibilities by introducing C-acetate and F-FDG PET imaging as potential tool for early AD diagnosis. Moreover, the study’s identification of the role of acetate and MCT1 transporter in reactive astrogliosis suggests a promising new target for AD treatment.
The study’s findings demonstrate that PET imaging with C-acetate and F-FDG can potentially revolutionize our understanding of reactive astrogliosis in AD. By shedding light on the mechanisms underlying cognitive decline in AD, this research paves the way for future research on targeting the reactive astrocyte-neuron interaction as a therapeutic intervention.
