Microglial Reactivity Correlates with Presynaptic Loss Independent of ß-Amyloid and Tau.

OBJECTIVE: Triggering receptor expressed on myeloid cells-2 (TREM2) and progranulin (PGRN) are critical regulators of microglia activation and can be detected in cerebrospinal fluid (CSF). However, whether microglial reactivity is detrimental or neuroprotective for Alzheimer disease (AD) is still debatable. METHODS: We identified 663 participants with baseline ß-amyloid (Aß) positron emission tomography (PET) and CSF biomarker data, including phosphorylated tau181 (p-Tau181), soluble TREM2 (sTREM2), PGRN, and growth-associated protein-43 (GAP-43). Among them, 254 participants had concurrent longitudinal CSF biomarkers. We used multivariate regression analysis to study the associations of CSF microglial biomarkers with Aß PET, CSF p-Tau181, and CSF GAP-43 cross-sectionally and longitudinally. A Chinese aging cohort's independent CSF samples (n = 65) were analyzed as a validation. RESULTS: Higher baseline levels of CSF microglial biomarkers were related to faster rates of CSF sTREM2 increase and CSF PGRN decrease. Elevated CSF p-Tau181 was associated with higher levels of CSF microglial biomarkers and faster rates of CSF sTREM2 increase and CSF PGRN decrease. In both cohorts, higher Aß burden was associated with attenuated CSF p-Tau181 effects on CSF microglial biomarker increases. Independent of Aß PET and CSF p-Tau181 pathologies, higher levels of CSF sTREM2 but not CSF PGRN were related to elevated CSF GAP-43 levels and faster rates of CSF GAP-43 increase. INTERPRETATION: These findings suggest that higher Aß burden may attenuate the p-Tau-associated microglial responses, and TREM2-related microglial reactivity may independently correlate with GAP-43-related presynaptic loss. This study highlights the two-edged role of microglial reactivity in AD and other neurodegenerative diseases. ANN NEUROL 2024;95:917-928.

Spatial and temporal patterns of cortical mean diffusivity in Alzheimer's disease and suspected non-Alzheimer's disease pathophysiology.

INTRODUCTION: The spatial and temporal patterns of cortical mean diffusivity (cMD), as well as its association with Alzheimer's disease (AD) and suspected non-Alzheimer's pathophysiology (SNAP), are not yet fully understood. METHODS: We compared baseline (n = 617) and longitudinal changes (n = 421) of cMD, cortical thickness, and gray matter volume and their relations to vascular risk factors, amyloid beta (Aß), and tau positron emission tomography (PET), and longitudinal cognitive decline in Aß PET negative and positive older adults. RESULTS: cMD increases were more sensitive to detecting brain structural alterations than cortical thinning and gray matter atrophy. Tau-related cMD increases partially mediated Aß-related cognitive decline in AD, whereas vascular disease-related increased cMD levels substantially mediated age-related cognitive decline in SNAP. DISCUSSION: These findings revealed the dynamic changes of microstructural and macrostructural indicators and their associations with AD and SNAP, providing novel insights into understanding upstream and downstream events of cMD in neurodegenerative disease. HIGHLIGHTS: Cortical mean diffusivity (cMD) was more sensitive to detecting structural changes than macrostructural factors. Tau-related cMD increases partially mediated amyloid beta-related cognitive decline in Alzheimer's disease (AD). White matter hyperintensity-related higher cMD mainly explained the age-related cognitive decline in suspected non-Alzheimer's pathophysiology (SNAP). cMD may assist in tracking earlier neurodegenerative signs in AD and SNAP.

Long-term Outcomes of Ultrasound-guided Thermal Ablation for the Treatment of Solitary Low-risk Papillary Thyroid Microcarcinoma: A Multicenter Retrospective Study.

OBJECTIVE: To report more than 5-year outcomes of ultrasound-guided thermal ablation (TA) for patients with solitary low-risk papillary thyroid microcarcinoma (PTMC) in a large multicenter cohort. BACKGROUND: TA, including radiofrequency ablation (RFA) and microwave ablation (MWA) have been used in patients with low-risk PTMC who refuse surgery or active surveillance. However, its clinical value remains controversial. MATERIALS AND METHODS: This retrospective multicenter study included 474 patients with solitary low-risk PTMC treated with TA (357 for RFA; 117 for MWA) from 4 centers and followed up for at least 5 years. Disease progression including lymph node metastasis and recurrent tumors, volume reduction rate (VRR), tumor disappearance rate, complications, and delayed surgery were assessed. RFA and MWA outcomes were compared using propensity score matching. RESULTS: During the median follow-up period of 77.2 months, disease progression incidence, lymph node metastasis, and recurrent tumors rates were 3.6%, 1.1%, and 2.5%, respectively. Age below 40 years old, male sex, Hashimoto thyroiditis, and tumor size were not independent factors associated with disease progression by Cox analysis. The median VRR was 100% and 471 tumors disappeared radiographically. Eight patients experienced transient voice change (1.7%) which recovered within 3 months. None of the patients underwent delayed surgery because of anxiety. After 1:1 matching, no significant differences were found in the disease progression, VRR, tumor disappearance rate, or complications between RFA and MWA subgroups. CONCLUSION: This multicenter study revealed that TA was an effective and safe treatment for patients with solitary low-risk PTMC, which could be offered as a treatment option for the management for low-risk PTMC.

Safety and efficacy of microwave ablation for the treatment of low-risk papillary thyroid microcarcinoma: a prospective multicenter study.

OBJECTIVES: To assess the safety and efficacy of ultrasound-guided thermal ablation for low-risk papillary thyroid microcarcinoma (PTMC) via a prospective multicenter study. METHODS: From January 2017 through June 2021, low-risk PTMC patients were screened. The management details of active surveillance (AS), surgery, and thermal ablation were discussed. Among patients who accepted thermal ablation, microwave ablation (MWA) was performed. The main outcome was disease-free survival (DFS). The secondary outcomes were tumor size and volume changes, local tumor progression (LTP), lymph node metastasis (LNM), and complication rate. RESULTS: A total of 1278 patients were included in the study. The operation time of ablation was 30.21 ± 5.14 min with local anesthesia. The mean follow-up time was 34.57 ± 28.98 months. Six patients exhibited LTP at 36 months, of whom 5 patients underwent a second ablation, and 1 patient received surgery. The central LNM rate was 0.39% at 6 months, 0.63% at 12 months, and 0.78% at 36 months. Of the 10 patients with central LNM at 36 months, 5 patients chose ablation, 3 patients chose surgery and the other 2 patients chose AS. The overall complication rate was 1.41%, and 1.10% of patients developed hoarseness of the voice. All of the patients recovered within 6 months. CONCLUSIONS: Thermal ablation of low-risk PTMC was observed to be safe and efficacious with few minor complications. This technique may help to bridge the gap between surgery and AS as treatment options for patients wishing to have their PTMC managed in a minimally invasive manner. CLINICAL RELEVANCE STATEMENT: This study proved that microwave ablation is a safe and effective treatment method for papillary thyroid microcarcinoma. KEY POINTS: Percutaneous US-guided microwave ablation of papillary thyroid microcarcinoma is a very minimally invasive treatment under local anesthesia during a short time period. The local tumor progression and complication rate of microwave ablation in the treatment of papillary thyroid microcarcinoma are very low.

Clinical outcomes of radiofrequency ablation for solitary T1aN0M0 versus T1bN0M0 papillary thyroid carcinoma: a propensity-matched cohort study.

OBJECTIVE: To conduct a cohort study comparing the treatment outcomes of radiofrequency ablation (RFA) therapy for solitary T1aN0M0 (T1a) versus T1bN0M0 (T1b) papillary thyroid carcinoma (PTC). METHODS: This retrospective analysis comprised 310 patients with low-risk PTC undergoing RFA classified into T1a (n = 272) and T1b (n = 38) groups according to the tumor size. A comparative analysis between the two groups was conducted for the volume reduction ratio (VRR), volume, local tumor progression (LTP), and recurrence-free survival (RFS) before and after 1:2 propensity score matching (PSM). Cox analysis was conducted to examine the influence of several variables, including T1b, on recurrence following RFA for PTC. RESULTS: The total VRR was 99.99 ± 0.11% throughout the median follow-up duration of 26 months, and the overall incidence of LTP was 2.58% (8/310). No irrecoverable complications occurred after RFA. The variations between the T1a and T1b groups following PSM were insignificant in terms of volume (p = 0.574), VRR (p = 0.574), complete disappearance rate (p = 0.210), LTP incidence (p = 1.000), and RFS rate (p = 0.610). The correlation between T1b and LTP continued to be insignificant (p = 0.686). No distant metastasis or delayed surgery occurred. CONCLUSIONS: The presence of T1b did not influence the patients' prognoses following RFA for T1N0M0 PTC. After appropriate patient selection and adequate preoperative assessment, RFA has the potential to serve as an effective therapy for individuals with T1a and T1b PTC.

Different effects of intravenous and local anesthesia in patients undergoing ultrasound-guided radiofrequency ablation of thyroid nodules: a prospective cohort study.

PURPOSE: To compare the efficacy and safety of intravenous anesthesia (IV) with local anesthesia (LA) in patients undergoing ultrasound (US)-guided radiofrequency ablation (RFA) of thyroid nodules. METHODS: 50 patients with American Society of Anesthesiologists classification grades I-II undergoing US-guided thyroid RFA were enrolled and randomly (1:1) divided into IV (conscious sedation with Ramsay Sedation Scale [RSS] scores of 2-3 with an anesthesiologist) and LA (subcutaneous anesthesia with lidocaine without an anesthesiologist) groups. Pre-, intra- and post-procedural blood pressure (BP) (SBP0/DBP0, SBP1/DBP1, and SBP2/DBP2), intra- and post-procedural pain (NRS1 and NRS2), ablated area volume, treatment time and adverse events were analyzed and compared. RESULTS: Age, sex, weight, number, nature, volume of nodules, and SBP0/DBP0 showed no difference between both groups. 11 and 0 patients' SBP1/DBP1 were elevated in the LA and IV groups. NRS1 differed between both groups. 6 patients in the LA group had moderate or severe pain, but none in the IV group. No between-group difference in SBP2/DBP2, NRS2, ablation completion rate and ablated volume was noted. The median procedure duration differed from 1109 (176) s in IV group and 723 (227) s in LA groups. There was no increased incidence of adverse events in IV group. CONCLUSIONS: IV with RSS scores of 2-3 maintained intra-procedural BP and relieved intra-procedural pain better, without affecting the ablation efficacy and increasing complications. Despite increased treatment time, IV is a potential option for patients undergoing US-guided RFA of thyroid nodules.

An unusual case of tertiary syphilis.

We report a rare case of tertiary syphilis in a middle aged man who presented with a 6-month history of ulceration of his left eye with extreme pain. Physical examination revealed fistulas, granuloma with ulcer, and corneal opacity with granulomatous conjunctivitis in the left eye. Based on the patient's clinical manifestations and auxiliary examination results, neurosyphilis was diagnosed.

circ_0004872 inhibits proliferation, invasion, and glycolysis of oral squamous cell carcinoma by sponged miR-424-5p.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is one of the most common oral malignant tumors. circ_0004872 can inhibit the progression of gastric cancer, but its effect on the growth and metastasis of OSCC is still unclear. METHODS: qRT-PCR was used to detect the expression levels of circ_0004872 and miR-424-5p in cancer tissues of OSCC patients and adjacent normal tissues, OSCC cell lines, and human normal oral keratinocytes (HOK). CCK-8, cell colony formation, flow cytometry, and transwell assay were used to detect cell proliferation rate, viability, apoptosis rate, and invasion ability. Use glucose/lactic acid kit to assay cell glycolysis ability. The dual-luciferase reporter gene experiment and RIP experiment verified the relationship between circ_0004872 and miR-424-5p. The protein levels were examined by Western blot. RESULTS: The expression of circ_0004872 was significantly downregulated in OSCC tissues and cells, and the overexpression of circ_0004872 inhibited the proliferation, vitality, invasion, and glycolysis of OSCC cells, and promoted apoptosis. The expression of miR-424-5p was greatly upregulated in OSCC tissues and OSCC cells. circ_0004872 can adsorb miR-424-5p in OSCC cells, and circ_0004872 can reverse the promoting effect of miR-424-5p overexpression on the process of OSCC cells. CONCLUSION: circ_0004872 suppresses the proliferation, invasion, and glycolysis of OSCC cells by sponged miR-424-5p, and promotes apoptosis, which can be used as a potential target for early diagnosis and targeted therapy of OSCC.

Efficacy and Safety of Thermal Ablation for Treatment of Solitary T1N0M0 Papillary Thyroid Carcinoma: A Multicenter Retrospective Study.

Background Microwave ablation (MWA) and radiofrequency ablation (RFA) have recently attracted interest as minimally invasive treatment modalities for papillary thyroid carcinoma (PTC). However, the ablation outcomes of T1N0M0 PTC are not well characterized. Purpose To evaluate the efficacy and safety of thermal ablation (MWA or RFA) of solitary T1N0M0 PTC in patients who were ineligible for (due to presence of comorbid cardiovascular disease, renal failure, other malignancy, etc) or who refused surgery. Materials and Methods This was a retrospective multicenter study of 847 patients (660 women) who underwent thermal ablation for PTC (673 T1a, 174 T1b) between March 2015 and March 2020; of these patients, 645 underwent MWA and 202 underwent RFA. The mean age of patients was 46 years ± 11 (standard deviation) (age range, 18-81 years); the mean follow-up time was 22 months ± 13 (range, 6-60 months). Changes in tumor size and volume and the rates of technical success, tumor disappearance, disease progression, and complications were assessed. Results The technical success rate was 100%. Relative to preablation measurements, the maximum diameter and volume of the ablation zone increased during the 1st month after ablation (P < .001), whereas there was no difference by the 3rd month; subsequently, the tumors showed reduction in size at 6, 9, and 12 months (all P < .001). Complete disappearance of tumors occurred in 68% of patients (577 of 847; 69% [466 of 673] in the T1a group vs 64% [111 of 174] in the T1b group; P < .001). The postablation disease progression rate was 1.1% (nine of 847 patients; 0.9% [six of 673 patients] in the T1a group vs 1.7% [three of 174 patients] in the T1b group; P = .54). The overall complication rate was 3.4% (29 of 847 patients; 2.7% [18 of 673 patients] in the T1a group vs 6.3% [11 of 174 patients] in the T1b group; P = .02). Conclusion This multicenter study provided evidence that thermal ablation is an effective and safe treatment option in selected -patients with solitary T1N0M0 papillary thyroid carcinoma. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Baek and Cho in this issue.

Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow in Parkinson's Disease Cognitive Decline.

BACKGROUND: Deposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function. OBJECTIVE: The objective of this current study was to determine if the decoupling of brain activity-CSF flow is linked to Parkinson's disease cognitive dysfunction. METHODS: Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting-state global blood-oxygen-level-dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. RESULTS: Global blood-oxygen-level-dependent signal-CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood-oxygen-level-dependent signal-CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood-oxygen-level-dependent signal-CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, -0.36; P = 0.012), an early structural change often seen in Alzheimer's disease. CONCLUSIONS: The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society.

Long-term follow-up results of PTMC treated by ultrasound-guided radiofrequency ablation: a retrospective study.

OBJECTIVES: To confirm the long-term efficacy and safety of radiofrequency ablation (RFA) for low-risk papillary thyroid microcarcinoma (PTMC). METHODS: We retrospectively reviewed data of 102 primary papillary thyroid carcinoma patients (82 women, 20 men; mean age: 43 [19] years) treated with radiofrequency ablation and thyroid-stimulating hormone (TSH) suppression therapy before December 2018. All patients were at high surgical risk or refused surgery. They were followed up at 1, 3, 6, 9, and 12 months and every 6-12 months thereafter using ultrasound and contrast-enhanced ultrasound. The volume and volume reduction ratio was calculated. Recurrence and lymph node or distant metastasis were evaluated. RESULTS: The mean initial tumor diameter was 0.50 (0.29) cm; the mean initial volume was 0.06 (0.09) mL. At 1, 3, 6, 9, 12, 24, 36, 48, and 60 months after RFA, complete resorption rates were 0, 0, 9.8 (10/102), 33.3 (34/102), 91.2 (93/102), 96.1 (98/102), 99 (101/102), 100, and 100%, respectively. Two patients had developed ipsilateral neck lymph node metastasis in regions IV and VI at 30- and 18-month follow-ups, respectively. After RFA, 3/102 patients (2.9%) developed hoarseness-the main side effect. No life-threatening or delayed complications occurred. The TSH value in the initial period was 0.06 (0.02) µIU/mL; the rate of reaching the TSH target was 85.7%. The TSH value at follow-up was 1.47 (0.91) µIU/mL; the compliance rate was 99.3%. CONCLUSIONS: Ultrasound-guided RFA for PTMC is highly effective and safe. RFA can serve as a minimally invasive treatment for PTMC patients who refuse surgery or active surveillance.

Ultrasound-guided thermal ablation for papillary thyroid microcarcinoma: a multicenter retrospective study.

PURPOSE: Ultrasound-guided thermal ablation (including microwave ablation [MWA] and radiofrequency ablation [RFA]) has emerged as a remarkable technology for the treatment of benign and malignant diseases. The objective of this multicenter study was to assess the efficacy and safety of thermal ablation in a large cohort of patients with papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS: Retrospective study of 725 patients who underwent MWA/RFA at 11 centers between March 2015 and March 2020. The mean age of patients was 46 ± 11 years (range, 22-81); the mean follow-up time was 21 ± 13 months (range, 6-60). Changes in size of tumor, the rates of tumor disappearance, disease progression, and complications were assessed. RESULTS: From 6 months post-ablation, the size of tumors was significantly reduced compared with those recorded pre-ablation (p < 0.001 for all). Five hundred and fifteen (71.0%) PTMCs had completely disappeared as assessed by ultrasound examination. Six (0.8%) patients developed disease progression post-ablation; of these, 5 (0.7%) patients developed new PTMCs, while one (0.1%) patient developed cervical lymph node metastasis. Nineteen (2.6%) patients developed complications post-ablation; of these 14 (1.9%) patients developed voice hoarseness, 4 (0.6%) developed hematoma, and one (0.1%) patient developed cough. CONCLUSIONS: Ultrasound-guided thermal ablation represents an effective and safe treatment for patients with PTMC besides active surveillance and surgery.

Mitochondrial-to-nuclear communications through multiple routes regulate cardiomyocyte proliferation.

The regenerative capacity of the adult mammalian heart remains a formidable challenge in biological research. Despite extensive investigations into the loss of regenerative potential during evolution and development, unlocking the mechanisms governing cardiomyocyte proliferation remains elusive. Two recent groundbreaking studies have provided fresh perspectives on mitochondrial-to-nuclear communication, shedding light on novel factors that regulate cardiomyocyte proliferation. The studies identified two mitochondrial processes, fatty acid oxidation and protein translation, as key players in restricting cardiomyocyte proliferation. Inhibition of these processes led to increased cell cycle activity in cardiomyocytes, mediated by reduction in H3k4me3 levels through accumulated α-ketoglutarate (αKG), and activation of the mitochondrial unfolded protein response (UPRmt), respectively. In this research highlight, we discuss the novel insights into mitochondrial-to-nuclear communication presented in these studies, the broad implications in cardiomyocyte biology and cardiovascular diseases, as well as the intriguing scientific questions inspired by the studies that may facilitate future investigations into the detailed molecular mechanisms of cardiomyocyte metabolism, proliferation, and mitochondrial-to-nuclear communications.

JAK activity regulates mesoderm cell fate by controlling MESP1 expression.

Cardiac development requires precise gene expression programs at each developmental stage guided by multiple signaling pathways and transcription factors (TFs). MESP1 is transiently expressed in mesoderm, and is essential for subsequent cardiac development, while the precise mechanism regulating its own transcription and mesoderm cell fate is not fully understood. Therefore, we developed a high content screen assay to identify regulators of MESP1 expression in mesodermal cells differentiated from human pluripotent stem cells (hPSCs). The screen identified CYT387, a JAK1/JAK2 kinase inhibitor, as a potent activator of MESP1 expression, which was also found to promote cardiomyocyte differentiation in vitro. Mechanistic studies found that JAK inhibition promotes MESP1 expression by reducing cytoplasmic calcium concentration and subsequently activating canonical WNT signaling. Our study identified a role of JAK signaling in early mesodermal cells, and sheds light on the connection between the JAK-STAT pathway and transcriptional regulation of MESP1, which expands our understanding of mesoderm and cardiac development.

Long-term comparison of image-guided thermal ablation vs. lobectomy for solitary papillary thyroid microcarcinoma: a multi-center retrospective cohort study.

BACKGROUND: Image-guided thermal ablation has been applied in patients with papillary thyroid microcarcinoma (PTMC) who refuse surgery or active surveillance. However, evidence to support ablation is limited by single-center designs and a lack of long-term data. The purpose of this study was to compare long-term outcomes between ablation and lobectomy for patients with solitary PTMC. MATERIALS AND METHODS: This multi-center retrospective study included 1021 consecutive patients with solitary PTMC who underwent ablation ( n =444) or lobectomy ( n =577) at the four university-affiliated hospitals. The primary outcomes were disease progression [lymph node metastasis (LNM), recurrent tumors, persistent tumors and distant metastasis] and disease-free survival (DFS). Secondary outcomes were complications, hospitalization, procedure time, estimated blood loss and cost. The two groups were compared using propensity score matching. RESULTS: After matching, no significant differences were observed in disease progression (4.7% vs. 3.4%, P =0.307), LNM (1.6% vs. 1.6%, P =1.000), recurrent tumors (2.9% vs. 1.8%, P =0.269), persistent tumors(0.2% vs. 0%, P =0.317) and DFS (95.5% vs. 97.1%, P =0.246) between the ablation and lobectomy groups during the median follow-up of 96.5 months. The ablation group had significantly lower complication rates (0.7% vs. 5.2%, P <0.001), shorter post-treatment hospitalization {median [interquartile range (IQR)], 0 vs. 4.0 [3.0] days, P <0.001}, shorter procedure time [8.5 (2.8) vs. 90.0 (43.8) min, P <0.001], reduced estimated blood loss [0 vs. 20.0 (10.0) ml, P <0.001], and lower cost [$1873.2 (254.0) vs. $2292.9 (797.8), P <0.001] than the lobectomy group. CONCLUSIONS: This study revealed comparable disease progression and survival outcomes between ablation and lobectomy for solitary PTMC. Imaged-guided thermal ablation could be effective and safe alternatives to lobectomy for properly selected patients with PTMC.

Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer's disease.

BACKGROUND: It is not fully established whether plasma ß-amyloid(Aß)42/Aß40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer's disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aß plaque deposition, tau tangle aggregation, and neurodegeneration. METHODS: We recruited 470 older adults and analyzed plasma Aß42/Aß40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aß and tau positron emission tomography imaging. The plasma Aß42/Aß40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aß-PET negative cognitively unimpaired individuals and Aß-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aß42/Aß40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aß plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates. RESULTS: Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aß plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aß42/Aß40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aß plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aß42/Aß40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aß42/Aß40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings. DISCUSSION: This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.

Pathophysiology characterization of Alzheimer's disease in South China's aging population: for the Greater-Bay-Area Healthy Aging Brain Study (GHABS).

INTRODUCTION: The Guangdong-Hong Kong-Macao Greater-Bay-Area of South China has an 86 million population and faces a significant challenge of Alzheimer's disease (AD). However, the characteristics and prevalence of AD in this area are still unclear due to the rarely available community-based neuroimaging AD cohort. METHODS: Following the standard protocols of the Alzheimer's Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in 2021. GHABS participants completed clinical assessments, plasma biomarkers, genotyping, magnetic resonance imaging (MRI), ß-amyloid (Aß) positron emission tomography (PET) imaging, and tau PET imaging. The GHABS cohort focuses on pathophysiology characterization and early AD detection in the Guangdong-Hong Kong-Macao Greater Bay Area. In this study, we analyzed plasma Aß42/Aß40 (A), p-Tau181 (T), neurofilament light, and GFAP by Simoa in 470 Chinese older adults, and 301, 195, and 70 had MRI, Aß PET, and tau PET, respectively. Plasma biomarkers, Aß PET, tau PET, hippocampal volume, and temporal-metaROI cortical thickness were compared between normal control (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia groups, controlling for age, sex, and APOE-ε4. The prevalence of plasma A/T profiles and Aß PET positivity were also determined in different diagnostic groups. RESULTS: The aims, study design, data collection, and potential applications of GHABS are summarized. SCD individuals had significantly higher plasma p-Tau181 and plasma GFAP than the NC individuals. MCI and dementia patients showed more abnormal changes in all the plasma and neuroimaging biomarkers than NC and SCD individuals. The frequencies of plasma A+/T+ (NC; 5.9%, SCD: 8.2%, MCI: 25.3%, dementia: 64.9%) and Aß PET positivity (NC: 25.6%, SCD: 22.5%, MCI: 47.7%, dementia: 89.3%) were reported. DISCUSSION: The GHABS cohort may provide helpful guidance toward designing standard AD community cohorts in South China. This study, for the first time, reported the pathophysiology characterization of plasma biomarkers, Aß PET, tau PET, hippocampal atrophy, and AD-signature cortical thinning, as well as the prevalence of Aß PET positivity in the Guangdong-Hong Kong-Macao Greater Bay Area of China. These findings provide novel insights into understanding the characteristics of abnormal AD pathological changes in South China's older population.

Bibliometric analysis of monoclonal antibodies for atherosclerosis.

Atherosclerosis (AS) is a prevalent cardiovascular disease that greatly increases mortality in the aging population and imposes a heavy burden on global healthcare systems. The purpose of this study is to examine the research structure and current trends of monoclonal antibodies (mAbs) against AS from a bibliometric perspective, since the development of these drugs is currently booming. This study collected articles and reviews on mAbs against AS from the Web of Science Core Collection, spanning from 2003 to 2022. Biblioshiny was utilized to analyze and visualize the characteristics of countries, regions, authors, institutions, and journals included in this collection. We used VOS viewer to illustrate the frequency of country co-occurrence, and CiteSpace to visualize co-cited reference, keywords co-occurrence, keywords citation bursts, keywords clustering and timeline plots. The study included 1325 publications, with the United States emerging as a leading contributor to the field. ATHEROSCLEROSIS, CIRCULATION and ARTERIOSCLEROSISTHROMBOSIS AND VASCULAR BIOLOGY are core journals that publish high-quality literature on the latest advances in the field. Noteworthy authors with numerous high-quality publications include Witztum JL and Tsimikas S. Currently, lipid metabolism and inflammation are the main research areas of interest in this field. The mAbs against AS is an evolving field, and ongoing research continues to advance our understanding. This paper provides a comprehensive overview of the current state of knowledge in this area, highlighting two primary research directions: inflammation and lipid metabolism. Additionally, the paper identifies emerging research hotspots, which will provide researchers with useful insights to guide future investigations and anticipate research directions.

Initial levels of ß-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimer's disease.

BACKGROUND: To better assist with the design of future clinical trials for Alzheimer's disease (AD) and aid in our understanding of the disease's symptomatology, it is essential to clarify what roles ß-amyloid (Aß) plaques and tau tangles play in longitudinal tau accumulation inside and outside the medial temporal lobe (MTL) as well as how age, sex, apolipoprotein E (APOE) ε4 (APOE-ε4), and Klotho-VS heterozygosity (KL-VShet) modulate these relationships. METHODS: We divided the 325 Aß PET-positive (A+) participants into two groups, A+/T- (N = 143) and A+/T+ (N = 182), based on the threshold (1.25) of the temporal meta-ROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We then compared the baseline and slopes of A+/T- and A+/T+ individuals' Aß plaques and temporal meta-ROI tau tangles with those of A-/T- cognitively unimpaired individuals (N = 162) without neurodegeneration. In addition, we looked into how baseline Aß and tau may predict longitudinal tau increases and how age, sex, APOE-ε4, and KL-VShet affect these associations. RESULTS: In entorhinal, amygdala, and parahippocampal (early tau-deposited regions of temporal meta-ROI), we found that baseline Aß and tau deposition were positively linked to more rapid tau increases in A+/T- participants. However, in A+/T+ individuals, the longitudinal tau accumulation in fusiform, inferior temporal, and middle temporal cortices (late tau-deposited regions of temporal meta-ROI) was primarily predicted by the level of tau tangles. Furthermore, compared to older participants (age ≥ 65), younger individuals (age < 65) exhibited faster Aß-dependent but slower tau-related tau accumulations. Additionally, compared to the KL-VShet- group, KL-VShet+ individuals showed a significantly lower rate of tau accumulation associated with baseline entorhinal tau in fusiform and inferior temporal regions. CONCLUSION: These findings offer novel perspectives to the design of AD clinical trials and aid in understanding the tau accumulation inside and outside MTL in AD. In particular, decreasing Aß plaques might be adequate for A+/T- persons but may not be sufficient for A+/T+ individuals in preventing tau propagation and subsequent downstream pathological changes associated with tau.

The association between parent-child relationship and problematic internet use among English- and Chinese-language studies: A meta-analysis.

As past studies of the association between parent-child relationship and problematic internet use show mixed results and are influenced by many factors, this meta-analysis of 75 primary Chinese and English language studies from 1990 to 2021 with 110,601 participants (aged 6-25 years) explored (a) the overall association between parent-child relationship and problematic internet use, and (b) whether the association is affected by their types, country, measures, objects of the parent-child relationship, gender, age, year and publication types. We used funnel plots, Classic fail-safe N and Egger's test to test for publication bias and for moderation with the homogeneity tests. The results showed a negative association between quality of parent-child relationship and problematic internet use (r = -0.18, 95% CI = [-0.20, -0.15]). The moderation analysis found that compared with internet addiction tendency, the association between social media addiction and parent-child relationship was stronger. Moreover, the association between the parent-child relationship and problematic internet use of emerging adults (18-25 years old) was stronger than that of adolescents (12-18 years old). Furthermore, the negative association between parent-child relationship and problematic internet use was weaker (a) in Italy than those in Turkey and China, (b) when using CPS (Closeness to Parents Scale), IPPA (Inventory of Parent and Peer Attachment), or PARQ (Parent-Child Relationship Questionnaire) measuring parent-child relationship than using PCCS (Parent-Child Communication Scale), (c) when using IAT measuring problematic internet use rather than using IGDS or APIUS. Hence, these results indicate a negative association between parent-child relationships and problematic internet use, and the association is moderated by types of problematic internet use, age, country, scales of both parent-child relationship and problematic internet use.