Search

Background: The coronavirus disease 2019 (COVID-19) has been a major challenge to global health and a financial burden. Little is known regarding the possible causal effects of COVID-19 on the macro- and micro-structures of the human brain. Objective: To determine the causal links between susceptibility, hospitalization, and the severity of COVID-19 and brain imaging-derived phenotypes (IDPs). Methods: Mendelian randomization (MR) analyses were performed to investigate the causal effect of three COVID-19 exposures (SARS-CoV-2 infection, hospitalized COVID-19, and critical COVID-19) on brain structure employing summary datasets of genome-wide association studies. Results: In terms of cortical phenotypes, hospitalization due to COVID-19 was associated with a global decrease in the surface area (SA) of the cortex structure (β= –624.77, 95% CI: –1227.88 to –21.66, p = 0.042). At the regional level, SARS-CoV-2 infection was found to have a nominally causal effect on the thickness (TH) of the postcentral region (β= –0.004, 95% CI: –0.007 to –0.001, p = 0.01), as well as eight other IDPs. Hospitalized COVID-19 has a nominally causal relationship with TH of postcentral (β= –0.004, 95% CI: –0.007 to –0.001, p = 0.01) and other 6 IDPs. The nominally causal effects of critical COVID-19 on TH of medial orbitofrontal (β=0.004, 95% CI: 0.001to 0.007, p = 0.004) and other 7 IDPs were revealed. Conclusions: Our study provides compelling genetic evidence supporting causal relationships between three COVID-19 traits and brain IDPs. This discovery holds promise for enhancing predictions and interventions in brain imaging. [ABSTRACT FROM AUTHOR]

Objective: To investigate the characteristics of tau deposition and its impact on functional connectivity (FC) in Alzheimer's disease (AD). Methods: Hybrid PET/MRI scans with [18F]-THK5317 and neuropsychological assessments were undertaken in 26 participants with AD and 19 healthy controls (HC). The standardized uptake value ratio (SUVR) of [18F]-THK5317 PET imaging was compared between the AD and HC groups. Significant clusters that revealed higher tau deposition in the AD group compared to the HC group were selected as regions of interest (ROI) for FC analysis. We evaluated the difference in the FC between the two groups for each ROI pair. The clinical and radiological characteristics were compared between the AD patients with negative FC and AD patients with positive FC for exploratory analysis. Results: The bilateral inferior lateral temporal lobe, dorsal prefrontal cortex, precuneus, posterior cingulate cortex, hippocampus, and occipital lobe showed significantly higher [18F]-THK5317 accumulation in AD patients. Decreased FC in regions with higher SUVR was observed in AD patients, and the FC strength was negatively correlated with regional SUVR. Patients with a positive FC exhibited older ages, better cognitive performances, and a lower SUVR than patients with a negative FC. Conclusions: An impact of tau deposition was observed on FC at the individual level in AD patients. Our findings suggested that the combination of tau-PET and rs-fMRI might help predict AD progression. [ABSTRACT FROM AUTHOR]

Objective: To evaluate amyloid-β deposition with 18F-florbetaben (FBB) PET imaging against 11C-PIB PET in cognitive normal controls (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) patients. Methods: We recruited 45 subjects (15 in each group of NC, MCI, and mild/moderate AD) who had undergone dynamic 18F-FBB amyloid PET imaging. For comparison study, 17 participants, including six NC, five MCI, and six AD patients, also underwent 11C-PIB PET imaging on separate days. Standardized uptake value ratios (SUVR) were calculated using the cerebellar cortex as the reference region with regions of interest (ROI) manually defined on co-registered CT. Quantitative analysis of mean cortical uptake was calculated using global SUVR. Spearman correlation analysis between MMSE scores and SUVR of 18F-FBB and 11C-PIB images were calculated. Results: One (7%) of the 15 NC participants, nine (60%) of 15 MCI patients, and 12 (80%) of 15 AD patients had amyloid-positive lesions on 18F-FBB PET images. In AD patients, global SUVR was significantly higher than those of MCI patients (1.73 ± 0.62 vs. 1.55 ± 0.11, P < 0.001) and NC subjects (1.73 ± 0.62 vs. 1.13 ± 0.43, P < 0.001). In the comparison study, one NC participant, five MCI patients, and five AD patients had amyloid-positive lesions on 11C-PIB PET images. There was a significant linear correlation (r 2 = 0.81, P < 0.001) between 18F-FBB and PIB global SUVR values. MMSE scores had negative correlations with SUVR on 11C-PIB PET (r 1 = –0.650, P = 0.005) or SUVR on 18F-FBB PET (r 2 = –0.754, P < 0.0001). Conclusion: Our study suggests that 18F-FBB is a useful tracer for the evaluation of amyloid-β deposition in vivo and that global SUVR of 18F-FBB PET might be a reliable tool in the diagnosis of AD. [ABSTRACT FROM AUTHOR]

With the assistance of molecular docking and 3D-QSAR models established previously, structurally identical 18F- and 125I-labeled benzyloxybenzene derivatives were designed to achieve the early detection of Aβ plaques by PET/SPECT imaging. In competition binding assay, ligands 7a and 12a displayed high binding affinities to Aβ42 aggregates with Ki values of 19.5 nM and 23.9 nM, respectively. Specific plaque labeling was observed on the in vitro autoradiography of brain sections from AD patients and Tg mice. In biodistribution, [125I]7a, [18F]7a, [125I]12a and [18F]12a all exhibited high initial brain uptakes (>5% ID/g at 2 min). [125I]7a and [125I]12a cleared fast from the normal brain regions, while corresponding [18F]7a and [18F]12a showed slow washout rates. Dynamic microPET/CT and microSPECT/CT imaging data in normal ICR mice were in accordance with in vivo biodistribution results. In vivo metabolism results indicated that the different clearance profiles between the structurally identical 18F- and 125I-labeled tracers could be attributed to different biochemical characteristics of the radiometabolites. Radioiodinated benzyloxybenzene derivatives exhibited good in vivo biostability in brain. Ex vivo autoradiography further confirmed the strong in vivo Aβ labeling ability of [125I]7a. These new fluorinated and iodinated benzyloxybenzenes can develop into PET/SPECT dual imaging agents targeting Aβ plaques. [ABSTRACT FROM AUTHOR]

[Display omitted] We report the design, synthesis and evaluation of five o ‑aminopyridyl alkynyl derivatives as colony-stimulating factor 1 receptor (CSF-1R) ligands. Compounds 4 and 5 with the fluoroethoxy group at the meta - or para -position of the phenyl ring possessed nanomolar inhibitory potency against CSF-1R with IC 50 values of 7.6 nM and 2.3 nM, respectively. Radioligands [18F] 4 and [18F] 5 were obtained in radiochemical yields of 17.2 ± 5.3% (n = 5, decay-corrected) and 14.0 ± 4.3% (n = 4, decay-corrected), with radiochemical purity of > 99% and molar activity of 9–12 GBq/μmol (n = 5) and 6–8 GBq/μmol (n = 4), respectively. In biodistribution studies, radioligands [18F] 4 and [18F] 5 showed moderate brain uptake in male ICR mice with 1.52 ± 0.15 and 0.91 ± 0.07% ID/g, respectively, at 15 min. Metabolic stability studies in mouse brain revealed that [18F] 4 exhibited high stability while [18F] 5 suffered from low stability. Higher accumulation of [18F] 4 in the brain of lipopolysaccharide (LPS)-treated mice was observed, and further pretreatment of BLZ945 or CPPC led to remarkable reduction, indicating specific binding of [18F] 4 to CSF-1R. [ABSTRACT FROM AUTHOR]

A new class of optical isomers of 2-arylbenzofuran derivatives were synthesized and evaluated as potential β -amyloid plaques imaging agents. Both lipophilicity and signal-to-noise ratio were significantly improved by adding a chiral hydroxyl group to 1-fluoro-3-(oxidanyl)propan-2-ol side chain. These derivatives displayed moderate to high binding affinity towards A β 1-42 aggregates. Four tracers possessing potent binding affinity ( K i < 30 nM) were chosen for further investigation. In in vitro autoradiography studies, the four selected probes showed effective binding to A β plaques in Tg mouse and AD human brain tissue after labeled by 18 F. The purified enantiomers displayed apparent discrepancy in biodistribution experiments in normal mice, for ( S )-enantiomers provided rather faster clearance than ( R )-enantiomers. All in all, ( S )-[ 18 F] 17 ( K i = 14.6 nM) with excellent pharmacokinetics (brain 2 min = 8.60% ID/g, brain 2 min /brain 60 min = 14.1) deserves further evaluation. [ABSTRACT FROM AUTHOR]

Structural magnetic resonance imaging (sMRI) is an established technique for measuring brain atrophy, and dynamic positron emission tomography with 11 C-Pittsburgh compound B ( 11 C-PIB PET) has the potential to provide both perfusion and amyloid deposition information. It remains unclear, however, how to better combine perfusion, amyloid deposition and morphological information extracted from dynamic 11 C-PIB PET and sMRI with the goal of improving the diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). We adopted a linear sparse support vector machine to build classifiers for distinguishing AD and MCI subjects from cognitively normal (CN) subjects based on different combinations of regional measures extracted from imaging data, including perfusion and amyloid deposition information extracted from early and late frames of 11 C-PIB separately, and gray matter volumetric information extracted from sMRI data. The experimental results demonstrated that the classifier built upon the combination of imaging measures extracted from early and late frames of 11 C-PIB as well as sMRI achieved the highest classification accuracy in both classification studies of AD (100%) and MCI (85%), indicating that multimodality information could aid in the diagnosis of AD and MCI. [ABSTRACT FROM AUTHOR]

A novel series of fluorinated 2-phenylindole derivatives were synthesized and evaluated as β-amyloid imaging probes for PET. The in vitro inhibition assay demonstrated that their binding affinities for Aβ1–42 aggregates ranged from 28.4 to 1097.8nM. One ligand was labeled with 18F ([18F]1a) for its high affinity (K i =28.4nM), which was also confirmed by in vitro autoradiography experiments on brain sections of transgenic mouse (C57BL6, APPswe/PSEN1, 11months old, male). In vivo biodistribution experiments in normal mice showed that this radiotracer displayed high initial uptake (5.82±0.51% ID/g at 2min) into and moderate washout (2.77±0.31% ID/g at 60min) from the brain. [18F]1a could be developed as a promising new PET imaging probe for Aβ plaques although necessary modifications are still needed. [ABSTRACT FROM AUTHOR]

Abstract: In continuation of our study on the 2-phenylquinoxaline scaffold as potential β-amyloid imaging probes, two [18F]fluoro-pegylated 2-phenylquinoxaline derivatives, 2-(4-(2-[18F]fluoroethoxy)phenyl)-N-methylquinoxalin-6-amine ([18F]4a) and 2-(4-(2-(2-(2-[18F]fluoroethoxy)ethoxy)ethoxy)phenyl)-N-methylquinoxalin-6-amine ([18F]4b) were prepared. Both of them displayed high binding affinity to Aβ 1-42 aggregates (K i = 10.0 ± 1.4 nM for 4a, K i = 5.3 ± 3.2 nM for 4b). The specific and high binding of [18F]4a and [18F]4b to Aβ plaques was confirmed by in vitro autoradiography on brain sections of AD human and transgenic mice. In biodistribution in normal mice, [18F]4a displayed high initial brain uptake (8.17% ID/g at 2 min) and rapid washout from the brain. These preliminary results suggest [18F]4a may be a potential PET imaging agent for Aβ plaques in the living human brain. [Copyright &y& Elsevier]