Cerebrospinal Fluid Proteomics Identifies Potential Biomarkers for Early-Onset Alzheimer's Disease.

Background: Early-onset Alzheimer's disease (EOAD) exhibits a notable degree of heterogeneity as compared to late-onset Alzheimer's disease (LOAD). The proteins and pathways contributing to the pathophysiology of EOAD still need to be completed and elucidated. Objective: Using correlation network analysis and machine learning to analyze cerebrospinal fluid (CSF) proteomics data to identify potential biomarkers and pathways associated with EOAD. Methods: We employed mass spectrometry to conduct CSF proteomic analysis using the data-independent acquisition method in a Chinese cohort of 139 CSF samples, including 40 individuals with normal cognition (CN), 61 patients with EOAD, and 38 patients with LOAD. Correlation network analysis of differentially expressed proteins was performed to identify EOAD-associated pathways. Machine learning assisted in identifying crucial proteins differentiating EOAD. We validated the results in an Western cohort and examined the proteins expression by enzyme-linked immunosorbent assay (ELISA) in additional 9 EOAD, 9 LOAD, and 9 CN samples from our cohort. Results: We quantified 2,168 CSF proteins. Following adjustment for age and sex, EOAD exhibited a significantly greater number of differentially expressed proteins than LOAD compared to CN. Additionally, our data indicates that EOAD may exhibit more pronounced synaptic dysfunction than LOAD. Three potential biomarkers for EOAD were identified: SH3BGRL3, LRP8, and LY6 H, of which SH3BGRL3 also accurately classified EOAD in the Western cohort. LY6 H reduction was confirmed via ELISA, which was consistent with our proteomic results. Conclusions: This study provides a comprehensive profile of the CSF proteome in EOAD and identifies three potential EOAD biomarker proteins.

Automatic synthesis of 18F-AV-45 and its clinical application in Alzheimer's disease.

OBJECTIVE: To investigate the automatic synthesis of ß-amyloid (Aß) positron emission tomography (PET) imaging agent (E) -4- (2- (6- (2- (2-18F fluoroethoxy) ethoxy) ethoxy) pyridine-3-yl) vinyl) - N-methylaniline (18F-AV-45) for the diagnosis of Alzheimer's disease (AD) and its clinical application in AD patients. MATERIALS AND METHODS: Fluorine-18-AV-45 was synthesized with AV-105 as the precursor, and the factors affecting the synthesis efficiency, such as the amount of precursor, nucleophilic reaction temperature were studied. At the same time, 18F-AV-45 PET/computed tomography (CT) brain scanning was performed in 15 patients with dementia to determine whether AD was the cause of the dementia. RESULTS: After optimizing the parameters, it was discovered that the highest synthesis efficiency was achieved with a AV-105 dosage of 2mg, a reaction temperature of 130oC, and 1mL of DMSO. The radiochemical yield (RCP) was greater than 98, and the uncorrected synthesis efficiency was about 31.0%±2.8%. Ten of the 15 patients with dementia showed positive Aß protein deposition, and the main deposition site of the imaging agent was the gray matter area of the brain, which was consistent with AD diagnosis, while the other 5 patients showed negative Aß protein deposition, suggesting non-AD dementia. CONCLUSION: ß-amyloid protein 18F-AV-45 imaging agent can be easily and quickly prepared by the All in One radiochemical synthesis module. Our preliminary results offer hope that it can effectively detect ß-amyloid deposition in the brain of AD patients in order to determine the etiology of dementia.

Plasma Core Alzheimer's Disease Biomarkers Predict Amyloid Deposition Burden by Positron Emission Tomography in Chinese Individuals with Cognitive Decline.

Blood-based biomarkers have been considered as a promising method for the diagnosis of Alzheimer's disease (AD). The reliability and accuracy of plasma core AD biomarkers, including phosphorylated tau (P-tau181), total tau (T-tau), Aß42, and Aß40, have also been confirmed in diagnosing AD and predicting cerebral ß-amyloid (Aß) deposition in Western populations, while fewer research studies have ever been conducted in China's Han population. In this study, we investigated the capability of plasma core AD biomarkers in predicting cerebral Aß deposition burden among the China Aging and Neurodegenerative Disorder Initiative (CANDI) cohort consisting of cognitively normal (CN), mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Body fluid (plasma and CSF) AD core biomarkers were measured via single-molecule array (Simoa) immunoassay. The global standard uptake value ratio (SUVR) was then calculated by 18F-florbetapir PET, which was divided into positive (+) and negative (-). The most significant correlation between plasma and CSF was plasma P-tau181 (r = 0.526, P < 0.0001). Plasma P-tau181 and P-tau181/T-tau ratio were positively correlated with global SUVR (r = 0.257, P < 0.0001; r = 0.263, P < 0.0001, respectively), while Aß42 and Aß42/Aß40 ratio were negatively correlated with global SUVR (r = -0.346, P < 0.0001; r = -0.407, P < 0.0001, respectively). Interestingly, voxel-wise analysis showed that plasma P-tau181 and P-tau181/T-tau ratio were negatively related to 18F-florbetapir PET in the hippocampus and parahippocampal cortex. The optimal predictive capability in distinguishing all Aß+ participants from Aß- participants and MCI+ from MCI- subgroups was the plasma P-tau181/T-tau ratio (AUC = 0.825 and 0.834, respectively). Our study suggested that plasma P-tau181 and P-tau181/T-tau ratio possessed better diagnostic and predictive values than plasma Aß42 and Aß42/Aß40 in this cohort, a finding that may be useful in clinical practices and trials in China.

Design, synthesis, and preliminary evaluation of [18F]-aryl flurosulfates PET radiotracers via SuFEx methods for ß-amyloid plaques in Alzheimer's disease.

[18F]BAY-94-9172, [18F]AV-45, and [18F]GE-067 were FDA approved positron emission tomography (PET) imaging radiotracer of ß-amyloid plaques (Aß) in Alzheimer's disease (AD). However, the radiochemical synthesis requires multi-step reactions and complex procedure. Recently, a protocol for radiochemical synthesis of sulfur fluoride exchange (SuFEx) using ultrafast 19F/18F isotopic exchange had been reported. We developed three pairs of novel 18F-labeled radiotracers by the "SuFEx" method for PET imaging Aß plaques. The 18F labeling reaction can be completed quickly (30 s) at room temperature and purified using solid-phase extraction (SPE). The radiochemical purity (RCP) of the products was all greater than 95 %. In vitro fluorescent staining using Aß-transgenesis mice section preliminary verified the affinity of tracers with Aß. Competitive binding assay displayed high affinity of tracers for towards artificial Aß1-42 aggregates (Ki values ranging from 3.53 ± 0.39 to 42.0 ± 4.24 nM). In vivo biodistribution and Micro-PET imaging showed that [18F]-Sulfur Fluoride ß-Amyloid ([18F]SFA 1-6) could penetration the blood-brain barrier (BBB) in wild-type mice, and [18F]SFA 5-6 had a high initial brain uptake value (3.65 ± 0.9 % and 5.07 ± 0.1 % ID/g, respectively) and a fast washout (Brain uptake2 min/60 min = 4.15 and 4.61, respectively) from the brain. In vitro autoradiography demonstrated the affinity of the [18F]SFA 5-6 to Aß plaques in AD human brain tissues. Our results suggested that [18F]SFA maybe a potential PET radiotracers for detecting Aß in Alzheimer's disease.

Correlation between Cerebrospinal Fluid Core Alzheimer's Disease Biomarkers and ß-Amyloid PET in Chinese Dementia Population.

The current diagnoses of Alzheimer's disease (AD) mainly rely on such measures as amyloid-ß (Aß) and tau neuropathology biomarkers in vivo via cerebrospinal fluid (CSF) and positron emission tomography (PET) imaging, which had been systematically studied in Caucasian individuals, whereas diagnostic performances of these approaches in Chinese dementia population still remain unclear. This study investigated the associations between the levels of CSF core AD biomarkers, including phosphorylated tau (p-Tau181), total tau (t-Tau), Aß42, and Aß40 measured by the single-molecule array (Simoa) and cerebral Aß deposition status assessed by 18F-Florbetapir PET (Aß PET), and evaluated the predictive values of CSF core AD biomarkers in discriminating Aß PET status in a clinical dementia cohort of the Chinese population, which consisted of patients with mild cognitive impairment (MCI), AD dementia, and non-Alzheimer's dementia disease (Non-ADD). Global standard uptake value ratios (SUVRs) were calculated by Aß PET, which was divided into positive (Aß+) and negative (Aß-) through visual analysis. CSF p-Tau181 and p-Tau181/t-Tau ratio were positively correlated with the global SUVR, while CSF Aß42 and Aß42/Aß40 ratio were negatively correlated with the global SUVR. CSF Aß40 has the highest predictive value in discriminating the MCI group from the AD group, while CSF p-Tau181 was applied to discriminate the AD group from the non-ADD group. CSF Aß42/Aß40 ratio, as the optimal predictive factor, was combined with APOE ε4 status rather than age and education, which could improve the predictive ability in differentiating the Aß+ group from the Aß- group. The results reveal the universal applicability of CSF core AD biomarkers and Aß PET imaging in Chinese dementia population, which is helpful in clinical practice and drug trials in China.

Efficient and automatic synthesis of TSPO PET ligand [18F]-GE-180 and its application in rheumatoid arthritis model.

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic synovial inflammation, which ultimately leads to joint deformity and dysfunction. [18F]-GE-180 is a specific PET tracer of the 18 kDa translocator protein (TSPO), which is overexpressed on activated macrophages, and proposed as a biomarker of inflammation. Our study addresses the need to streamline the automatic synthesis of [18F]-GE-180 to make it more accessible for routine production and widespread clinical evaluation and application. The nucleophilic radiofluorination was performed on an AllinOne synthesis module by SPE purification method, and the formulated [18F]-GE-180 was obtained in non-decay corrected radiochemical yields of 69 ± 1.8% in 32 min. PET/CT imaging in animal model showed that [18F]-GE-180 highly concentrated in joints from RA rats. This methodology facilitates efficient synthesis of [18F]-GE-180 in a commercially available synthesis module and shows potential diagnosis performance in RA models.

[Value of 18F-FDG PET/CT Imaging in Secondary Extramedullary Infiltration of Multiple Myeloma].

OBJECTIVE: To investigate the characteristics of 18F-FDG PET/CT images of multiple myeloma secondary extramedullary infiltration in order to improve recognition. METHODS: Twenty-one patients with multiple myeloma secondary extramedullary infiltration confirmed by pathology or follow-up from January 2012 to October 2020 in the First Affiliated Hospital of University of Science and Technology of China were retrospectively analyzed. All the patients underwent 18F-FDG PET/CT imaging before treatment, and the PET/CT characteristics of extramedullary infiltration and bone marrow were analyzed. RESULTS: Twenty-one patients included 12 males and 9 females, aged from 41 to 77 years old, with an average of 58.3±10.0; 9 cases of extramedullary infiltration involving lymph nodes; lung, stomach, spleen, and kidney were involved respectively in 2 cases; retroperitoneal, right auricle, subcutaneous nodule, and spinal meninges involvement were reported in each one case respectively. The maximum SUVmax value of extra-medullary lesions was 21.2, the minimum value was 2.1, and mean was 7.7±5.3. The maximum SUVmax value of bone marrow was 33.5, the minimum was 2.4, and mean was 6.6±3.6. There was no statistically significant difference in SUVmax value between extra-medullary lesions and bone marrow (Z=-1.195, P=0.232). CONCLUSION: 18F-FDG PET/CT not only has a good diagnostic value for multiple myeloma, but also a good evaluation value for secondary extramedullary infiltration, which provides reference for clinical treatment and prognosis.

An automated radiosynthesis of (S)-[18F]28 for PET imaging of Alzheimer's disease.

18F-labeled 2-arylbenzoxazole derivative (S)-[18F]28 is potent and selective radiopharmaceutical Aß tracers for Alzheimer's disease positron-emission tomography (PET). Our study aimed to enable facile preparation of (S)-[18F]28 in commercially available PET tracer production facilities to promote the widespread application and clinical translation. Here, we successfully demonstrated an automated radiosynthesis of (S)-[18F]28 with high radiochemical yield and radiochemical purity by the AllinOne radiosynthesis module. The method developed here can facilitate extensive use of (S)-[18F]28 in large-scale clinical trials.

Association of MIF-173G/C and MBL2 codon 54 gene polymorphisms with rheumatoid arthritis: a meta-analysis.

The aim of this study was to evaluate the association between macrophage migration inhibitory factor (MIF) -173G/C (rs755622), mannose-binding lectin (MBL2) exon 1 codon 54 (rs1800450) gene polymorphisms and rheumatoid arthritis (RA) susceptibility in ethnically different populations. A meta-analysis was conducted (allelic contrast, the additive model, the dominant model and the recessive model) on the MIF-173G/C polymorphism across five studies (four European and one Asian studies), and the MBL2 codon 54 polymorphism with five studies (four Asian and one European studies), respectively. Meta-analysis indicated an association between the MIF-173G/C in all study subjects in allelic contrast (OR=1.19, 95%CI: 1.05-1.35, P=0.001), the additive model (OR=1.68, 95CI: 1.13-2.49, P=0.001), the dominant model (OR=1.17, 95CI: 1.01-1.35, P=0.003), the recessive model (OR=1.63, 95CI: 1.10-2.42, P=0.001). While stratified by ethnicity with European populations, an association was found in allelic contrast (OR=1.20, 95CI: 1.04-1.38, P=0.002), the additive model (OR=1.85, 95CI: 1.19-2.88, P=0.001), the dominant model (OR=1.20, 95CI: 1.02-1.41, P=0.003). With respect to MBL2 codon 54 polymorphism and RA, no association was found in all study subjects in all comparisons, but there was an association while stratified by ethnicity with Asian populations in the dominant model (OR=1.50, 95CI: 1.01-2.23, P=0.007). In conclusion, the present study suggests that the MIF-173G/C polymorphism is associated with RA susceptibility, but the MBL2 codon 54 polymorphism is not associated with RA.