New Iridoids and Acyclic Monoterpenoids from the Roots and Rhizomes of Valeriana officinalis var. latifolia.

Five new iridoids, valeralides A-E (1-5), two new acyclic monoterpenoids, valeralides F (6) and G (7), together with two known iridoids (8 and 9), were isolated from the roots and rhizomes of Valeriana officinalis var. latifolia. Their structures were elucidated based on 1D and 2D NMR, as well as HR-ESI-MS spectroscopic data. The absolute configuration of compounds 1-4 were elucidated based on electronic circular dichroism (ECD) calculation. In addition, all the isolates were evaluated for their inhibition on nitric oxide production, cytotoxicity and anti-influenza A virus activity.

Metabolic parameters of pretreatment 2-[18F]fluoro-D-glucose positron emission tomography for prognosis in patients with gallbladder adenocarcinoma: a cohort study.

Background: The incidence of gallbladder adenocarcinoma (GBA) is relatively low, yet it exhibits a high degree of malignancy and a significantly low 5-year survival rate. The aim of this study was to investigate the prognostic value of pretreatment 2-[18F]fluoro-D-glucose positron emission tomography {2-[18F]FDG PET} parameters in predicting outcomes for patients with GBA. Methods: In total, 67 patients with GBA who underwent 2-[18F]FDG PET/computed tomography (CT) before treatment were retrospectively analyzed at Chinese PLA General Hospital from January 2012 to June 2022. All patients were diagnosed by pathology, and their baseline characteristics and clinical data were collected. The metabolic PET parameters of the primary and metastatic lesions were measured, including the maximum and average standardized uptake values (SUVs), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The prognostic significance of metabolic parameters and other clinical variables was assessed using Cox proportional hazards regression models. Differences in progression-free survival (PFS) and overall survival (OS) in relation to metabolic parameters were examined using the Kaplan-Meier method. Results: During a median follow-up period of 14.2 months, 43 patients (64.2%) experienced tumor recurrence or progression, and 38 patients (56.7%) died of cancer. In the univariate Cox regression analysis, liver parenchymal invasion (P=0.001), lymph node metastasis (P=0.007), distant metastases (P=0.049), tumor differentiation (P=0.028), surgery (P=0.014), carcinoembryonic antigen (CEA) level (P=0.030), carbohydrate antigen 19-9 (CA19-9) level (P=0.003), TLG (P=0.005), MTV (P<0.001), sum of the TLGs of the primary and metastatic lesions (total TLG, tTLG) (P=0.001), and sum of the MTVs of the primary and metastatic lesions (total MTV, tMTV) (P<0.001) were significant predictors of PFS. In multivariate analysis, MTV was an independent predictor of PFS [hazard ratio (HR) =2.785; 95% confidence interval (CI): 1.204-6.441; P=0.017]. In the univariate Cox regression analysis, liver parenchymal invasion (P=0.001), lymph node metastasis (P=0.027), distant metastases (P=0.036), tumor differentiation (P=0.047), surgery (P=0.002), neutrophil-to-lymphocyte ratio (NLR) (P=0.011), CEA level (P=0.036), CA19-9 level (P<0.001), TLG (P=0.007), MTV (P<0.001), tTLG (P=0.003), and tMTV (P<0.001) were significant predictors of OS. In the multivariate analysis, higher CA19-9 levels >37 U/mL and a greater tMTV (HR =2.961; 95% CI: 1.092-8.024; P=0.033) were predictive of OS. Conclusions: Our study results suggest that pretreatment 2-[18F]FDG PET parameters can not only assist in the diagnosis of patients with GBA but may also serve as predictive factors for the prognosis of these patients and should thus be applied in their treatment.

Iridoids and other constituents from the leaves and stems of Valeriana officinalis var. latifolia.

Fifty-nine compounds, including nineteen previously undescribed iridoids (valeriananols A-S) and an undescribed alkaloid (5'-isovaleryl uridine), were isolated from the leaves and stems of Valeriana officinalis var. latifolia. Their structures were elucidated based on Mass spectrometry and NMR spectroscopy. The absolute configuration of valeriananols A-C, E-N, P, Q and S was determined by experimental and calculated electronic circular dichroism. Structurally, valeriananols A and B were two 1,3-seco-iridoids with a 3,6-epoxy moiety, valeriananols K and L were a pair of C-4 epimers, while valeriananol S was a 4'-deoxy iridoid glycoside. In addition, valeriananol P, stenopterin A and patriscabioin C exhibited significant inhibition on nitric oxide production with IC50 values of 10.31, 3.93 and 8.69 µM, respectively. Furthermore, stenopterin A and patriscabioin C showed anti-proliferation activity on the MCF-7 cell line with IC50 values of 17.28 and 13.89 µM, respectively.

Complexation and evolution of cis-prenyltransferase homologues in Cinnamomum kanehirae deduced from kinetic and functional characterizations.

Eukaryotic dehydrodolichyl diphosphate synthases (DHDDSs), cis-prenyltransferases (cis-PTs) synthesizing precursors of dolichols to mediate glycoprotein biosynthesis require partners, for eample Nus1 in yeast and NgBR in animals, which are cis-PTs homologues without activity but to boost the DHDDSs activity. Unlike animals, plants have multiple cis-PT homologues to pair or stand alone to produce various chain-length products with less known physiological roles. We chose Cinnamomum kanehirae, a tree that contains two DHDDS-like and three NgBR-like proteins from genome analysis, and found that one DHDDS-like protein acted as a homodimeric cis-PT to make a medium-chain C55 product, while the other formed heterodimeric complexes with either one of two NgBR homologues to produce longer-chain products. Both complexes were functional to complement the growth defect of the yeast rer2 deficient strain at a higher temperature. From the roles for the polyprenol and dolichol biosynthesis and sequence motifs, their homologues in various species were compared to reveal their possible evolutionary paths.

Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors.

A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC50 range of 0.001-0.026 µM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to discovery that the synthesized compounds also inhibited Spike's receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced bodyweight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2.

Circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis: a two-step bidirectional Mendelian randomization study.

Background: The relationship between gut microbiota and the occurrence of cholecystitis remains unclear. Existing research lacks a clear understanding of how circulating vitamin levels modulate this relationship. Therefore, our study aims to investigate whether circulating vitamin levels mediate the causal relationship between gut microbiota and cholecystitis using a two-step bidirectional Mendelian randomization approach. Methods: In this study, we initially employed Linkage Disequilibrium Score Regression (LDSC) analysis to assess the genetic correlation of five circulating vitamin level genome-wide association study (GWAS) summary datasets, thereby avoiding potential sample overlap. Subsequently, we conducted a two-step analysis to investigate the causal effects between gut microbiota and cholecystitis. In the second step, we explored the causal relationship between circulating vitamin levels and cholecystitis and identified the mediating role of vitamin D. The primary method used for causal analysis was the inverse variance-weighted approach. We performed additional sensitivity analyses to ensure result robustness, including the cML-MA method and reverse Mendelian randomization (MR) analysis. Results: An increment of one standard deviation in RuminococcaceaeUCG003 was associated with a 25% increased risk of cholecystitis (OR = 1.25, 95%CI = 1.01-1.54, p = 0.04), along with a 3% decrease in 25-hydroxyvitamin D levels (OR = 0.97, 95%CI = 0.944-0.998, p = 0.04). However, following the rigorous Bonferroni correction, every one standard deviation decrease in circulating vitamin D levels was associated with a 33% increased risk of cholecystitis (OR = 0.67, 95%CI = 0.49-0.90, p = 0.008, Padjust = 0.04). Thus, the potential link between gut microbiota and cholecystitis risk might be mediated by circulating vitamin D levels (proportion mediated = 5.5%). Sensitivity analyses provided no evidence of pleiotropy. Conclusion: Our study results suggest that an elevated abundance of specific gut microbiota is associated with an increased susceptibility to cholecystitis, with the causal relationship being mediated by circulating vitamin D levels. Further large-scale randomized controlled trials are necessary to validate the causal effects of gut microbiota on cholecystitis risk. This study provides novel insights into cholecystitis prevention through the regulation of gut microbiota.

Corrigendum: The role of 18F-FDG PET in predicting the pathological response and prognosis to unresectable HCC patients treated with lenvatinib and PD-1 inhibitors as a conversion therapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1151967.].

The role of 18F-FDG PET in predicting the pathological response and prognosis to unresectable HCC patients treated with lenvatinib and PD-1 inhibitors as a conversion therapy.

Purpose: To investigate the diagnostic value of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), as an imaging biomarker, for predicting pathological response and prognosis of unresectable hepatocellular carcinoma (HCC) patients treated with Lenvatinib and programmed cell death protein 1 (PD-1) inhibitors as a conversion therapy. Methods: A total of 28 unresectable HCC patients with BCLC stage B or C were treated with Lenvatinib and PD-1 inhibitors before surgery. The 18F-FDG PET/CT scans were acquired before pre- (scan-1) and post-conversion therapy (scan-2). The maximum standardized uptake value (SUVmax), TLR (tumor-to-normal liver standardized uptake value ratio), and the percentages of post-treatment changes in metabolic parameters (ΔSUVmax [%] and ΔTLR [%]) were calculated. Major pathological response (MPR) was identified based on the residual viable tumor in the resected primary tumor specimen (≤10%). Differences in the progression-free survival (PFS) and overall survival (OS) stratified by ΔTLR were examined by the Kaplan-Meier method. Results: 11 (11/28, 39.3%) patients were considered as MPR responders and 17 (17/28, 60.7%) patients as non-MPR responders after conversion therapy. ΔSUVmax (-70.0 [-78.8, -48.8] vs. -21.7 [-38.8, 5.7], respectively; P<0.001) and ΔTLR (-67.6 [-78.1, -56.8] vs. -18.6 [-27.9, 4.0], respectively; P<0.001) were reduced in the responder group than those in the non-responder group. According to the results of the receiver operating characteristic curve analysis, ΔTLR showed an excellent predictive value for the MPR of primary HCC lesions (area under curve=0.989, with the optimal diagnostic threshold of -46.15). When using ΔTLR of -21.36% as a threshold, patients with ΔTLR-based metabolic response had superior PFS (log-rank test, P=0.001) and OS (log-rank test, P=0.016) compared with those without ΔTLR-based metabolic response. Conclusion: 18F-FDG PET is a valuable tool for predicting pathological response and prognosis of unresectable HCC patients treated by Lenvatinib combined with PD-1 as a conversion therapy.

Can 18F-PSMA-7Q PET/CT replace prostate biopsy for the diagnosis of prostate cancer?-A single-center retrospective study.

Background: Of the currently available prostate-specific membrane antigen (PSMA) positron emission tomography (PET) tracers, although 68Ga-PSMA-11 and 18F-DCFPyL have been approved by the US Food and Drug Administration (FDA), both tracers are excreted rapidly through the urinary tract, resulting in strong accumulation in the bladder and blurring the prostate.18F-PSMA-7Q is a novel quinoline-containing PSMA PET tracer developed by our team, which is primarily excreted through the liver. It can reduce the incidence of urine-induced false-positives in the prostate. We aimed to explore the diagnostic efficacy of 18F-PSMA-7Q PET/computed tomography (CT), and when 18F-PSMA-7Q PET/CT can be used instead of prostate biopsy to diagnose prostate cancer. Methods: Patients who underwent 18F-PSMA-7Q PET/CT for prostate cancer staging or prostate biopsy guidance at our institution between July 2020 and December 2021 were retrospectively enrolled. Molecular imaging PSMA (miPSMA) scores were assigned for intra-prostatic lesions according to the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria, and the diagnostic efficacy of 18F-PSMA-7Q PET/CT for different miPSMA scores was evaluated using pathological diagnosis as the gold standard. Results: Of the 125 enrolled patients, 101 had prostate cancer, and 24 had prostatic hyperplasia or prostatitis. miPSMA ≥2 was the optimal diagnostic threshold, and area under curve (AUC) was 0.948, the sensitivity and specificity were 91.1% and 83.0%. The prostate cancer detection rates of 18F-PSMA-7Q PET/CT were 14.3% (3/21), 60.0% (6/10), 96.7% (58/60), and 100% (34/34) for patients with miPSMA scores of 0, 1, 2, and 3, respectively. There was no significant difference in the detection rate of prostate cancer between groups with miPSMA scores of 2 and 3, but there were significant differences between any other 2 groups. Conclusions: The prostate cancer detection rate of 18F-PSMA-7Q PET/CT was high for lesions with greater miPSMA scores of 2 and 3. For patients with a high miPSMA score, particularly those with a miPSMA score of 3, prostate biopsy can be omitted and prostate cancer-related treatment can be considered.

Iridoids and sesquiterpenoids from Valeriana officinalis and their bioactivities.

Twenty-six iridoids, including six undescribed ones (iridoidvols A-F) and an undescribed natural one, along with ten known sesquiterpenoids were isolated from the roots and rhizomes of Valeriana officinalis. Structurally, iridoidvol A is the first example of iridoid with sesquiterpenoid acid ester. In addition, all of the isolates were evaluated for anti-inflammatory and anti-influenza virus activities. Among them, isovaltrate isovaleroyloxyhydrin exhibited a significant inhibitory effect on NO production with an IC50 value of 19.00 µM.

18 F-DCFPyL positron emission tomography/magnetic resonance imaging-guided ultrasound fusion biopsy is an identical pathway in prostate cancer diagnosis.

BACKGROUND: Prostate biopsy is still unavoidable in patients with a rising prostate-specific antigen even though multiparametric magnetic resonance imaging (MRI) is widely used. 18 F-DCFPyL positron emission tomography (PET)/MRI was proved to be promising both in sensitivity and specificity. But its guiding fusion biopsy and the advantages in the diagnosis of prostate disease is seldom reported. This study aimed to verify the feasibility and advantage of 18 F-DCFPyL PET/MRI-guided fusion targeted biopsy (TB) over whole-mount histopathology (WMH) for prostate cancer diagnosis. METHODS: A prospective study of 94 biopsy-naïve patients were conducted using 18 F-DCFPyL PET/MRI scans and scored on a scale of 1-4. Systematic biopsy was performed for all patients. Patients with suspicious lesions also underwent PET/MRI/transrectal ultrasound-guided fusion biopsy. Patients with pathologically confirmed cancer underwent surgery and WMH sections. Systematic biopsy was compared with TB for the detection of index tumors (ITs). Significant cancer was defined as Grade group (GG) 2 or higher no matter the length of the cancer core. RESULTS: 18 F-DCFPyL PET/MRI detected 30/94 (32%) patients with a score of 4, all of whom were verified to have prostate cancer. While it detected 10 patients with a score of 1 (10.6%), they were shown to have no cancer. The sensitivity and specificity of 18 F-DCFPyL PET/MRI were 94.4% and 75%, respectively, if images with a score of 3 are defined as positive. Systematic biopsy detected 18% (203/1128) samples as prostate cancer; conversely, TB detected 113 samples out of 259 scores (43.6%). A statistically significant difference was seen between the PCa detection rates by TB and SB (p < 0.001). All targeted lesions were pathologically proven to be the IT on WMH. CONCLUSIONS: In biopsy-naïve patients, the ultrasound fusion biopsy targeted by 18 F-DCFPyL PET/MRI is an identical pathway for the detection of prostate cancer.

Medication overuse headache associated with decreased dopamine transporter availability in the medial but not in the lateral orbitofrontal cortex: a 11CFT PET/MR study.

BACKGROUNDS: Dysfunction of the mesocorticolimbic dopamine system in medication overuse headache (MOH) is unknown. This study aimed to determine dopamine transporter (DAT) availability, which is sensitive to dopamine levels, in the mesocorticolimbic dopamine system in MOH patients. METHODS: This case-control study investigated eligible MOH patients admitted to the International Headache Centre in the neurological department of Chinese PLA General Hospital between July 2018 and August 2019. All subjects underwent an integrated positron emission tomography (PET)/magnetic resonance (MR) brain scans with 11CFT, a radioligand that binds to DAT. Standardised uptake value ratio (SUVr) images were compared voxelwise between MOH patients and healthy controls (HCs). SUVr values from significantly changed regions were extracted, and partial correlation analyses with clinical measures were conducted. RESULTS: We examined 17 MOH patients and 16 HCs. MOH patients had lower SUVr levels in the medial rather than lateral orbitofrontal cortex (OFC) than HCs (T = -5.0317, PGRF < 0.01), which showed no correlation with clinical features. CONCLUSIONS: MOH is characterised by decreased DAT availability in the medial OFC, which might reflect compensatory downregulation due to low dopamine signalling within the mesocorticolimbic dopamine system and provide a new perspective to understand the pathogenesis of MOH.

Multiparameter diagnostic model based on 18F-FDG PET and clinical characteristics can differentiate thymic epithelial tumors from thymic lymphomas.

OBJECTIVE: To evaluate the diagnostic performance of combined multiparametric 18F-fluorodeoxyglucose positron emission tomography (18FDG PET) with clinical characteristics in differentiating thymic epithelial tumors (TETs) from thymic lymphomas. PATIENTS AND METHODS: A total of 173 patients with 80 TETs and 93 thymic lymphomas who underwent 18F-FDG PET/CT before treatment were enrolled in this retrospective study. All patients were confirmed by pathology, and baseline characteristics and clinical data were also collected. The semi-parameters of 18F-FDG PET/CT, including lesion size, SUVmax (maximum standard uptake value), SUVmean (mean standard uptake value), TLG (total lesion glycolysis), MTV (metabolic tumor volume) and SUVR (tumor-to-normal liver standard uptake value ratio) were evaluated. The differential diagnostic efficacy was evaluated using the receiver operating characteristic (ROC) curve. Integrated discriminatory improvement (IDI) and net reclassification improvement (NRI), and Delong test were used to evaluate the improvement in diagnostic efficacy. The clinical efficacy was evaluated by decision curve analysis (DCA). RESULTS: Age, clinical symptoms, and metabolic parameters differed significantly between patients with TETs and thymic lymphomas. The ROC curve analysis of SUVR showed the highest differentiating diagnostic value (sensitivity = 0.763; specificity = 0.888; area under the curve [AUC] = 0.881). The combined diagnostics model of age, clinical symptoms and SUVR resulted in the highest AUC of 0.964 (sensitivity = 0.882, specificity = 0.963). Compared with SUVR, the diagnostic efficiency of the model was improved significantly. The DCA also confirmed the clinical efficacy of the model. CONCLUSIONS: The multiparameter diagnosis model based on 18F-FDG PET and clinical characteristics had excellent value in the differential diagnosis of TETs and thymic lymphomas.

Correlation between apparent diffusion coefficient and tumor-stroma ratio in hybrid 18F-FDG PET/MRI: preliminary results of a rectal cancer cohort study.

Background: To explore possible correlations between the tumor-stroma ratio (TSR) and different imaging features of fluorine-18-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) in untreated rectal cancer patients. Methods: A patients with rectal cancer were included in this study. All participants were examined preoperatively with whole-body 18F-FDG PET/MRI. Two pathologists evaluated the TSR of tumors together. Apparent diffusion coefficient (ADC) values and PET-related parameters of the primary lesions were measured and compared between the stroma-high and stroma-low groups. Pearson's correlation or Spearman's rank correlation were used to evaluate the correlation between the ADC values, PET-related parameters, and pathological indices. Results: Our results showed that in the untreated rectal cancer patients, the ADC mean values correlated with the TSR (r=0.327; P=0.007), and stroma-high (low TSR) rectal cancer corresponded to relatively lower ADC mean values (813.54±88.68 vs. 879.92±133.18; P=0.018). The ADC mean and ADC minimum (ADCmin) values were found to be negatively correlated with the pathological T stages (r=-0.384, P=0.001; r=-0.416, P=0.001, respectively) as well as the largest tumor diameters (r=-0.340, P=0.005; r=-0.314, P=0.010, respectively) of rectal cancer. In addition, the pathological T stages correlated with all PET-related metabolic parameters, including mean standard uptake value (SUV), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) (r=0.338, P=0.006; r=0.350, P=0.004; r=0.326, P=0.007; and r=0.472, P<0.001, respectively). Our results also identified associations between the ADCmin values and SUVmean, SUVmax, and TLG (r=-0.335, P=0.006; r=-0.343, P=0.005; and r=-0.343, P=0.005, respectively). However, there were no statistical correlations between the PET/MRI parameters and the immunohistochemical (IHC) results. Conclusions: This study indicated that the intratumoral heterogeneity measured by PET/MRI may reflect characteristics of the tumor microenvironment. Hence, PET/MRI parameters might be helpful in predicting tumor aggressiveness and prognosis.

Prospective intraindividual comparison of 18F-PSMA-7Q and 18F-DCFPyL PET/CT in patients with newly diagnosed prostate cancer.

OBJECTIVE: Fluorine 18 (18F)-2-(3-{1-Carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL) is an early 18F-labeled prostate-specific membrane antigen (PSMA) targeted PET tracer that has shown promise in the diagnostic workup of prostate cancer and was recently approved by the US Food and Drug Administration. 18F-PSMA-7Q is a novel 18F-labeled PSMA-ligand PET tracer designed and synthesized by our team. This study compared the tracer-specific positron emission tomography/computed tomography (PET/CT) characteristics of 18F-PSMA-7Q with those of 18F-DCFPyL in patients with newly diagnosed prostate cancer. METHODS: Ten patients received similar doses of 18F-DCFPyL and 18F-PSMA-7Q 48 h apart and were imaged 1 h after injection on the same PET/CT scanner. Normal-organ biodistribution and tumor uptake were quantified using maximum and mean standardized uptake values (SUVmax and SUVmean), and all lesions were assigned a molecular imaging PSMA (miPSMA) score based on Prostate Cancer Molecular Imaging Standardized Evaluation criteria. RESULTS: Seventeen lesions were detected in the 10 patients by both 18F-DCFPyL and 18F-PSMA-7Q. No statistically significant difference was observed when comparing the SUVmax and SUVmean of 18F-DCFPyL and 18F-PSMA-7Q in the lesions and parotid gland. The κ value for the miPSMA scores of the lesions between the two tracers was 0.907, indicating excellent agreement. CONCLUSION: 18F-PSMA-7Q can be used in clinical research as reliably as 18F-DCFPyL. The limited urinary excretion of 18F-PSMA-7Q may represent a potential advantage over 18F-DCFPyL for detection of lesions in the pelvis, which need to be verified by further studies.

Sporadic adult-onset neuronal intranuclear inclusion disease without high-intensity signal on DWI and T2WI: a case report.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in cells in the central and peripheral nervous system. High-intensity signal in the corticomedullary junction on diffusion-weighted imaging (DWI) is supportive to the diagnosis of NIID. We describe a patient with sporadic adult-onset NIID but without any high-intensity signal on DWI and T2-weighted imaging (T2WI). CASE PRESENTATION: A 58-year-old woman without special family history developed mild persistent tremor in the right hand and deteriorated 2 years later. At 60 years of age, the patient began to conceive the bank, police and internet being deceptive, further presented apathy and confusion after two and a half years, as well as fabrication of non-existent things. Despite the treatment of antipsychotic drugs due to a diagnosis of mental disorder, the patient appeared weakness in the right limbs. Neurological examination revealed mutism, resting tremor, cogwheel-like rigidity in upper limbs, and weakness in all limbs. Brain magnetic resonance imaging displayed no cerebral atrophy initially but atrophy of frontal, temporal and parietal lobes 5 years later. No any high-intensity signal on DWI and T2WI was revealed. However, hypometabolism in the cortexes with atrophy and the right putamen nucleus were showed on 18F-fluoro-deoxy-glucose positron emission tomography/magnetic resonance. On the basis of 107 GGC repeats (normal number <40) in NOTCH2NLC gene and intranuclear inclusions with p62 immunoreactivity in the adipocyte of cutaneous sweat duct by skin biopsy, NIID was finally diagnosed. The symptomatic treatment was given but the patient had no evident improvement. CONCLUSIONS: Our case highlights that despite the lack of high-intensity signal on DWI and T2WI, NIID is still considered for patients with parkinsonism and mental impairment.

Diagnostic Value of 11C-PIB PET/MR in Cardiac Amyloidosis.

Background: The thioflavin T derivative, 11C-Pittsburgh-B (PIB), is used for Alzheimer's disease imaging because it specifically binds to ß-amyloid protein deposits in the brain. The aim of this study was to estimate the diagnostic value of combined 11C-PIB positron emission tomography/magnetic resonance (PET/MR) in cardiac amyloidosis (CA). Methods: We enrolled 23 heart failure patients with suspected CA based on echocardiographic and electrocardiograph findings. All patients underwent cardiac 11C-PIB PET/MR and non-cardiac biopsy within one week. We also enrolled eight healthy volunteers that underwent cardiac 11C-PIB PET/MR as a control group. The cardiac magnetic resonance (CMR) protocol included cine imaging, late gadolinium enhancement (LGE), and native and post-contrast T1 mapping. Extracellular volume (ECV) was measured using pre- and post-contrast T1 mapping images. LVEF, IVSD, LVPW, LVmass, LVESV, LVEDV, native T1 value, ECV, and maximum uptake of myocardial tissue-to-blood background ratio (TBR) values were obtained from PET/MR images in all patients and healthy subjects. Results: Thirteen out of twenty-three heart failure patients were clinically diagnosed with CA. The remaining 10 patients were CA-negative (non-CA patient group). Twelve of the thirteen CA patients showed diffuse transmural LGE patterns, whereas LGE was either absent or patchy in the non-CA patients. The diagnostic sensitivity and specificity of TBRmax were 92.3 and 100%, respectively, at a cut-off value of 1.09. Several CMR imaging parameters (LVEF, IVSD, LVmass, LVEDV, LVESV, LVPW, native T1 value and ECV) and TBR showed significant differences between CA patients, non-CA patients, and healthy controls (P < 0.05). Native T1 mapping values positively correlated with TBRmax values in CA and non-CA patients (r = 0.38, P = 0.0004). Conclusions: 11C-PIB PET/MRI is a valuable tool for the accurate and non-invasive diagnosis of CA because it distinguishes CA patients from non-CA patients and healthy subjects with high specificity and sensitivity. Moreover, native T1 mapping values positively correlated with TBRmax values in CA and non-CA patients. In the future, larger cohort studies are necessary to confirm our findings.

Glioblastoma Recurrence Versus Radiotherapy Injury: Combined Model of Diffusion Kurtosis Imaging and 11C-MET Using PET/MRI May Increase Accuracy of Differentiation.

PURPOSE: To evaluate the diagnostic potential of decision-tree model of diffusion kurtosis imaging (DKI) and 11C-methionine (11C-MET) PET, for the differentiation of radiotherapy (RT) injury from glioblastoma recurrence. METHODS: Eighty-six glioblastoma cases with suspected lesions after RT were retrospectively enrolled. Based on histopathology or follow-up, 48 patients were diagnosed with local glioblastoma recurrence, and 38 patients had RT injury between April 2014 and December 2019. All the patients underwent PET/MRI examinations. Multiple parameters were derived based on the ratio of tumor to normal control (TNR), including SUVmax and SUVmean, mean value of kurtosis and diffusivity (MK, MD) from DKI, and histogram parameters. The diagnostic models were established by decision trees. Receiver operating characteristic analysis was used for evaluating the diagnostic accuracy of each independent parameter and all the diagnostic models. RESULTS: The intercluster correlations of DKI, PET, and texture parameters were relatively weak, whereas the intracluster correlations were strong. Compared with models of DKI alone (sensitivity =1.00, specificity = 0.70, area under the curve [AUC] = 0.85) and PET alone (sensitivity = 0.83, specificity = 0.90, AUC = 0.89), the combined model demonstrated the best diagnostic accuracy (sensitivity = 1.00, specificity = 0.90, AUC = 0.95). CONCLUSIONS: Diffusion kurtosis imaging, 11C-MET PET, and histogram parameters provide complementary information about tissue. The decision-tree model combined with these parameters has the potential to further increase diagnostic accuracy for the discrimination between RT injury and glioblastoma recurrence over the standard Response Assessment in Neuro-Oncology criteria. 11C-MET PET/MRI may thus contribute to the management of glioblastoma patients with suspected lesions after RT.

Quantitative analysis of 68Ga-DOTA(0)-Tyr(3)-octreotate positron emission tomography/computed tomography imaging for the differential diagnosis of primary pheochromocytoma and paraganglioma.

Background: Pheochromocytomas/paragangliomas (PPGLs) predominantly express somatostatin receptors (SSTRs) 2 and 3. 68Ga-DOTA(0)-Tyr(3)-octreotate (68Ga-DOTA-TATE) is an imaging radiopharmaceutical that selectively targets SSTR 2 with high affinity. The purpose of this study was to evaluate the utility of 68Ga-DOTA-TATE in the differential diagnosis of suspected PPGLs, and determine the optimal threshold for differential diagnoses. Methods: This retrospective study reviewed consecutive patients referred to the Chinese PLA General Hospital, Beijing between April 2018 and December 2020 who underwent both biochemical testing for catecholamine and 68Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT) for suspected PPGLs, without prior history. Patients with pathologic confirmation were selected for analysis. The following values were obtained for a quantitative analysis of 68Ga-DOTA-TATE imaging: maximal standardized uptake value (SUVmax), the ratio between the SUVmax of the lesion and the mean SUV (SUVmean) of the liver (SUVR), and the Krenning score (KS) of the lesion. According to their location, tumors were grouped as adrenal or extra-adrenal. Receiver operating characteristic (ROC) curves of the SUVR and KS were determined, and their diagnostic performance was calculated using general and subgroup-specific optimal thresholds. Concordance between the SUVR and KS was analyzed using a McNemar test. Results: A total of 38 patients with PPGLs and 21 with non-PPGLs tumors were included in the final analysis. When a general optimal threshold for adrenal tumors was applied in pheochromocytoma (PCC) diagnosis, the sensitivity, specificity, and accuracy of the SUVR and KS were 86.4% (19/22) and 90.9% (20/22), 92.9% (13/14) and 78.6% (11/14), and 88.9% (32/36) and 86.1% (31/36), respectively. The SUVR and KS diagnostic results showed no differences in paraganglioma (PGL) diagnosis, with a sensitivity, specificity, and accuracy of 43.8% (7/16), 100.0% (7/7), and 60.9% (14/23), respectively. Using PPGL-specific optimal thresholds improved the diagnostic accuracy for extra-adrenal tumors. The diagnostic results of the SUVR and KS showed high concordance in both general and subgroup analyses. When PPGL-specific optimal thresholds were used, 68Ga-DOTA-TATE PET/CT correctly diagnosed 1 PCC with negative biochemical test results, and 5 PCCs and 1 PGL with borderline biochemical test results. Conclusions: Applying PPGL-specific thresholds of 68Ga-DOTA-TATE in diagnosing adrenal and extra-adrenal tumors is recommended for the differential diagnosis of PPGLs. When biochemical tests are negative or borderline, 68Ga-DOTA-TATE PET/CT should be included in the diagnostic procedure. The visual KS method has almost the same diagnostic efficiency as the quantitative SUVR method and has potential for recommendation in 68Ga-DOTA-TATE image analysis.

Diagnostic Utility of Integrated11C-Pittsburgh Compound B Positron Emission Tomography/Magnetic Resonance for Cerebral Amyloid Angiopathy: A Pilot Study.

Objective: We aimed to compare amyloid deposition at the lobar cerebral microbleed (CMB) sites of cerebral amyloid angiopathy (CAA), Alzheimer's disease (AD), and cognitively normal healthy controls (NC) and to propose a novel diagnostic method for differentiating CAA patients from AD patients with integrated 11C-Pittsburgh compound B (PIB) positron emission tomography (PET)/magnetic resonance (MR) and assess its diagnostic value. Methods: Nine CAA, 15 AD patients, and 15 NC subjects were enrolled in this study. Each subject underwent an 11C-PIB brain PET/MR examination. Susceptibility weighted imaging was assessed to detect CMB locations, and standardized uptake value ratios (SUVRs) were measured at these sites. Cortical PIB distributions were quantitatively evaluated. Patients with CAA, AD, and NC subjects were compared with global and regional cortical SUVRs at CMB cites. The diagnostic accuracy of MRI, PIB-PET, and PET/MR in differentiating CAA and AD was evaluated. Results: Lobar CMBs were detected in all the CAA patients, eight of the 15 AD patients (53.3%), and four of the 15 NC subjects (26.7%), respectively. The PIB deposition at CMB sites was significantly higher in CAA patients compared with AD patients and NC subjects in terms of SUVR (1.72 ± 0.10 vs. 1.42 ± 0.16 and 1.17 ± 0.08; p < 0.0001). The PIB deposition was associated with CMB locations and was greatest in the occipital and temporal regions of CAA patients. The global cortical PIB deposition was significantly higher in CAA than in NC subjects (1.66 ± 0.06 vs. 1.21 ± 0.06; p < 0.0001) and significantly lower than in AD patients (1.66 ± 0.06 vs. 1.86 ± 0.17; p < 0.0001). In contrast, the occipital/global PIB uptake ratio was significantly increased in CAA (occipital/global ratio, 1.05 ± 0.02) relative to AD patients (1.05 ± 0.02 vs. 0.99 ± 0.04; p < 0.001). PET/MR had a higher accuracy (sensitivity, 88.9%; specificity, 93.3%) than separate PET and MR. Conclusion: Our results indicate that the CMBs occur preferentially at loci with concentrated amyloid. By combining lobar CMBs with regional cortical amyloid deposition, the proposed workflow can further improve CAA diagnostic accuracy compared to each method alone. These findings improve our knowledge regarding the pathogenesis of CMBs and highlight the potential utility of PIB-PET/MR as a non-invasive tool for distinguishing CAA and AD patients.