An early appearance of reactive astrocytes is a hallmark of Alzheimer's disease (AD), providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-5 fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose 10 transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

Purpose Tumor mutational burden (TMB) is an approved biomarker for immunotherapy in metastatic cancer patients. While initially measured from tissue (tTMB), TMB derived from circulating tumor DNA (ctDNA) - also known as blood TMB (bTMB) - is increasingly being used in the clinic. Currently, real-world concordance between tTMB and bTMB is not well understood. Patients and methods From October 2020 to March 2021, cancer patients who had both tTMB and bTMB results were selected. Patients were classified according to clinical variables and tumor burden, and correlation analyses or tests of independence were performed to explore any associations. Results From a total of 38 patients included in our study, 20 patients (52.6%) had non-small cell lung carcinoma and 18 (47.4%) had other cancers. Median bTMB of 9.6 mut/MB was higher than median tTMB of 4.0 mut/Mb, and the distributions of bTMB and tTMB differed significantly (n=38, p < 0.001). bTMB was positively correlated with tTMB in the total study population (Spearman ρ=0.57, p < 0.001 ) and a tTMB of 10 mut/Mb correlated with a bTMB of 21.1 mut/Mb. Dividing patients by cancer type or site of tumor biopsy resulted in significantly differing strength and degree of correlation, but dividing patients by concordant and discordant bTMB:tTMB ratio did not reveal any significantly different distributions of clinical variables or tumor burden. Conclusion bTMB was positively correlated with tTMB, and median bTMB was higher than median tTMB. Cancer type and site of tissue biopsy may influence concordance between tTMB and bTMB. Future studies with more patients may help define the optimal bTMB threshold for receiving immunotherapy, which may be different from the tTMB threshold.

In response to phasic and tonic release, dopamine neurotransmission is regulated by its receptor subtypes, mainly dopamine receptor type 1 and 2 (DRD1 and DRD2). These dopamine receptors are known to form a heterodimer, however the receptor crosstalk between DRD1 and DRD2 was only suspected by measuring their downstream signaling products, due to the lack of methodology for selectively detecting individual activity of different dopamine receptors. Here, we develop red DRD1 sensor (R-DRD1) and green DRD2 sensor (G-DRD2) which can specifically monitor the real-time activity of DRD1 and DRD2, and apply these multicolor sensors to directly measure the receptor crosstalk in the DRD1-DRD2 heterodimer. Surprisingly, we discover that DRD1 activation in the heterodimer is inhibited only at micromolar phasic concentration of dopamine, while DRD2 activation is selectively inhibited at nanomolar tonic dopamine level. Differential receptor crosstalk in the DRD1-DRD2 heterodimer further modulates their downstream cAMP level. These data imply a novel function of the DRD1-DRD2 heterodimer at physiological dopamine levels of phasic and tonic release. Our approach utilizing multicolor receptor sensors will be useful to discover novel function of GPCR heterodimers.