Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.
Min-Ho NamHae Young KoDongwoo KimSangwon LeeYongmin Mason ParkSeung Jae HyeonWoojin WonJee-In ChungSeon Yoo KimHan Hee JoKyeong Taek OhYoung-Eun HanGwan-Ho LeeYeon Ha JuHyowon LeeHyunjin KimJaejun HeoMridula BhallaKi Jung KimJea KwonThor D SteinMingyu KongHyunbeom LeeSeung Eun LeeSoo-Jin OhJoong-Hyun ChunMi-Ae ParkKi Duk ParkHoon RyuMijin YunJustin Daho LeePublished in: Brain : a journal of neurology (2023)
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.
Keyphrases
- pet imaging
- positron emission tomography
- end stage renal disease
- pet ct
- cognitive decline
- newly diagnosed
- prognostic factors
- computed tomography
- peritoneal dialysis
- chronic kidney disease
- skeletal muscle
- type diabetes
- mild cognitive impairment
- endothelial cells
- inflammatory response
- photodynamic therapy
- body mass index
- high resolution
- patient reported outcomes
- adipose tissue
- lipopolysaccharide induced
- blood pressure
- lps induced
- blood glucose
- traumatic brain injury
- weight gain
- functional connectivity
- living cells
- signaling pathway