Innovative Multivariable Model Combining MRI Radiomics and Plasma Indexes Predicts Alzheimer's Disease Conversion: Evidence from a 2-Cohort Longitudinal Study.

To explore the complementary relationship between magnetic resonance imaging (MRI) radiomic and plasma biomarkers in the early diagnosis and conversion prediction of Alzheimer's disease (AD), our study aims to develop an innovative multivariable prediction model that integrates those two for predicting conversion results in AD. This longitudinal multicentric cohort study included 2 independent cohorts: the Sino Longitudinal Study on Cognitive Decline (SILCODE) project and the Alzheimer Disease Neuroimaging Initiative (ADNI). We collected comprehensive assessments, MRI, plasma samples, and amyloid positron emission tomography data. A multivariable logistic regression analysis was applied to combine plasma and MRI radiomics biomarkers and generate a new composite indicator. The optimal model's performance and generalizability were assessed across populations in 2 cross-racial cohorts. A total of 897 subjects were included, including 635 from the SILCODE cohort (mean [SD] age, 64.93 [6.78] years; 343 [63%] female) and 262 from the ADNI cohort (mean [SD] age, 73.96 [7.06] years; 140 [53%] female). The area under the receiver operating characteristic curve of the optimal model was 0.9414 and 0.8979 in the training and validation dataset, respectively. A calibration analysis displayed excellent consistency between the prognosis and actual observation. The findings of the present study provide a valuable diagnostic tool for identifying at-risk individuals for AD and highlight the pivotal role of the radiomic biomarker. Importantly, built upon data-driven analyses commonly seen in previous radiomics studies, our research delves into AD pathology to further elucidate the underlying reasons behind the robust predictive performance of the MRI radiomic predictor.

Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease.

The associations of synaptic loss with amyloid-ß (Aß) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aß plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aß42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aß and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aß deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aß deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aß42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aß plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aß plaques, and also can predict longitudinal synaptic loss.

Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment.

INTRODUCTION: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD). METHODS: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [18F]SynVesT-1 and [18F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability. The associations between mGluR5 availability and synaptic density were examined. A mediation analysis was performed to investigate the possible mediating effects of mGluR5 availability and synaptic loss on the relationship between amyloid deposition and cognition. RESULTS: CI patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and cognition. CONCLUSIONS: Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked. HIGHLIGHTS: Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition. With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in 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.

Association of ß-Amyloid, Microglial Activation, Cortical Thickness, and Metabolism in Older Adults Without Dementia.

BACKGROUND AND OBJECTIVES: Plasma ß-amyloid42 (Aß42)/Aß40 levels have shown promise in identifying Aß-PET positive individuals. This study explored the concordance and discordance of plasma Aß42/Aß40 positivity (Plasma±) with CSF Aß42/Aß40 positivity (CSF±) and Aß-PET positivity (PET±) in older adults without dementia. Associations of Aß deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated. METHODS: We selected participants without dementia who had concurrent plasma Aß42/Aß40 and Aß-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma±/PET± based on thresholds of composite 18F-florbetapir (FBP) standardized uptake value ratio (SUVR) ≥1.11 and plasma Aß42/Aß40 ≤0.1218. Aß-PET-negative individuals were further divided into Plasma±/CSF± (CSF Aß42/Aß40 ≤0.138), and the concordance and discordance of Aß42/Aß40 in the plasma and CSF were investigated. Baseline and slopes of regional FBP SUVR were compared among Plasma±/PET± groups, and associations of regional FBP SUVR, FDG SUVR, cortical thickness, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) levels were analyzed. RESULTS: One hundred eighty participants (mean age 72.7 years, 51.4% female, 96 cognitively unimpaired, and 84 with mild cognitive impairment) were included. We found that the proportion of Plasma+/PET- individuals was 6.14 times higher (odds ratio (OR) = 6.143, 95% confidence interval (CI) 2.740-16.185, p < 0.001) than that of Plasma-/PET+ individuals, and Plasma+/CSF- individuals showed 8.5 times larger percentage (OR = 8.5, 95% CI: 3.031-32.974, p < 0.001) than Plasma-/CSF+ individuals in Aß-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) Aß accumulation predominantly in bilateral banks of superior temporal sulcus (BANKSSTS) and supramarginal, and superior parietal cortices compared with Plasma-/PET- individuals, despite no difference in baseline FBP SUVRs. In Plasma+/PET+ individuals, higher CSF sTREM2 levels correlated with slower BANKSSTS Aß accumulation (standardized ß (ßstd) = -0.418, 95% CI -0.681 to -0.154, p = 0.002). Conversely, thicker cortical thickness and higher glucose metabolism in supramarginal and superior parietal cortices were associated with faster (p < 0.05) CSF sTREM2 increase in Plasma+/PET- individuals rather than in Plasma+/PET+ individuals. DISCUSSION: These findings suggest that plasma Aß42/Aß40 abnormalities may predate CSF Aß42/Aß40 and Aß-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate Aß accumulation primarily at relatively advanced stages.

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.

Sleep and APOE-ε4 have a synergistic effect on plasma biomarkers and longitudinal cognitive decline in older adults.

BACKGROUND: Sleep disorders are prevalent among patients with Alzheimer's disease (AD), and the APOE ε4 genotype is a key genetic risk factor for sporadic AD. However, the combined effect of the genotype and sleep disorders on cognitive decline remains uncertain. METHODS: A total of 972 participants were drawn from the SILCODE cohort, comprising 655 without the ε4 allele (APOE-) and 317 with ε4 allele (APOE+). Data were collected, including neuropsychological assessments, sleep measurements, plasma biomarkers, and PET imaging. A Sleep Composite Index (SCI) was created, categorizing participants into high risk (Sleep+) and low risk (Sleep-). RESULTS: Significant predictions of dementia risk associated with plasma p-tau181, neurofilament light chain (NfL), and SCI. Individuals with both Sleep+ and APOE+ had a higher risk of dementia compared to those with Sleep-. The Sleep+/APOE+ group had higher plasma NfL levels than the Sleep-/APOE- group. Similar trends emerged in plasma NfL levels among the Aß PET-positive subgroup. Plasma NfL levels explained 23% of the relationship between SCI and cognitive impairment. CONCLUSION: Our study highlights sleep disorder was associated with cognitive decline, with plasma NfL playing a partial mediating role. These findings explain how sleep disorders affect cognitive function and emphasize the importance of healthy sleep for older adults.

Relationship between topological efficiency of white matter structural connectome and plasma biomarkers across the Alzheimer's disease continuum.

Both plasma biomarkers and brain network topology have shown great potential in the early diagnosis of Alzheimer's disease (AD). However, the specific associations between plasma AD biomarkers, structural network topology, and cognition across the AD continuum have yet to be fully elucidated. This retrospective study evaluated participants from the Sino Longitudinal Study of Cognitive Decline cohort between September 2009 and October 2022 with available blood samples or 3.0-T MRI brain scans. Plasma biomarker levels were measured using the Single Molecule Array platform, including ß-amyloid (Aß), phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The topological structure of brain white matter was assessed using network efficiency. Trend analyses were carried out to evaluate the alterations of the plasma markers and network efficiency with AD progression. Correlation and mediation analyses were conducted to further explore the relationships among plasma markers, network efficiency, and cognitive performance across the AD continuum. Among the plasma markers, GFAP emerged as the most sensitive marker (linear trend: t = 11.164, p = 3.59 × 10-24 ; quadratic trend: t = 7.708, p = 2.25 × 10-13 ; adjusted R2 = 0.475), followed by NfL (linear trend: t = 6.542, p = 2.9 × 10-10 ; quadratic trend: t = 3.896, p = 1.22 × 10-4 ; adjusted R2 = 0.330), p-tau181 (linear trend: t = 8.452, p = 1.61 × 10-15 ; quadratic trend: t = 6.316, p = 1.05 × 10-9 ; adjusted R2 = 0.346) and Aß42/Aß40 (linear trend: t = -3.257, p = 1.27 × 10-3 ; quadratic trend: t = -1.662, p = 9.76 × 10-2 ; adjusted R2 = 0.101). Local efficiency decreased in brain regions across the frontal and temporal cortex and striatum. The principal component of local efficiency within these regions was correlated with GFAP (Pearson's R = -0.61, p = 6.3 × 10-7 ), NfL (R = -0.57, p = 6.4 × 10-6 ), and p-tau181 (R = -0.48, p = 2.0 × 10-4 ). Moreover, network efficiency mediated the relationship between general cognition and GFAP (ab = -0.224, 95% confidence interval [CI] = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA) or NfL (ab = -0.224, 95% CI = [-0.417 to -0.029], p = .0196 for MMSE; ab = -0.198, 95% CI = [-0.42 to -0.003], p = .0438 for MOCA). Our findings suggest that network efficiency mediates the association between plasma biomarkers, specifically GFAP and NfL, and cognitive performance in the context of AD progression, thus highlighting the potential utility of network-plasma approaches for early detection, monitoring, and intervention strategies in the management of AD.

Diversity and community composition of strictly anaerobic and culturable bacteria from the feces of Styrofoam-fed Tenebrio molitor larvae: a culturomics-based study.

Introduction: In recent years, researchers have been exploring the plastic-degrading abilities of bacteria residing in the guts of Styrofoam-eating Tenebrio molitor larvae. However, none of the reported strains have displayed highly efficient plastic degradation capabilities, and it's noteworthy that none of the existing studies have focused on strictly anaerobic microbes. Methods: In this study, we exclusively fed Styrofoam to T. molitor larvae and examined how this dietary change influence the gut's bacterial community composition, as observed through fecal bacteria using bacterial 16S rRNA gene amplicon sequencing and the small-scale culturomics method with 20 types of anaerobic media under four different conditions. Results: The results revealed a significant shift in the dominant phylogroup from Lactococcus (37.8%) to Escherichia-Shigella (54.7%) when comparing the feces of larvae fed with bran and Styrofoam, as analyzing through the bacterial 16S rRNA gene amplicon sequencing. For small-scale culturomics method, a total of 226 strains of anaerobic bacteria were isolated and purified using the rolling-tube/strictly anaerobic technique. Among them, 226 strains were classified into 3 phyla, 7 classes, 9 orders, 17 families, 29 genera, 42 known species and 34 potential novel species. Discussion: Interestingly, 24 genera in total, identified through the culturomics method, were not found in the results obtained from amplicon sequencing. Here, we present a collection of culturable anaerobic bacteria from the feces of T. molitor larvae, which might be a promising avenue for investigating the biodegradability of plastics by combining specific strains, either randomly or intentionally, while considering the abundance ratio of the microbial community composition.

Association of APOE-ε4 and GAP-43-related presynaptic loss with ß-amyloid, tau, neurodegeneration, and cognitive decline.

Apolipoprotein E-ε4 (APOE-ε4) carriers had elevated cerebrospinal fluid (CSF) presynaptic protein growth-associated protein-43 (GAP-43), but the underlying mechanism is not fully understood. We investigated how the APOE-ε4 genotype affects the baseline and longitudinal changes in CSF GAP-43 and their associations with ß-amyloid positron emission tomography (Aß PET), CSF phosphorylated tau 181 (p-Tau181), neurodegeneration, and cognitive decline. Compared to APOE-ε4 non-carriers, APOE-ε4 carriers had higher baseline levels and faster rates of increases in Aß PET, CSF p-Tau181, and CSF GAP-43. Both higher baseline levels and faster rates of increase in CSF GAP-43 were associated with greater baseline Aß PET and CSF p-Tau181, which fully mediated the APOE-ε4 effect on CSF GAP-43 elevations. Independent of Aß PET and CSF p-Tau181, APOE-ε4 carriage was associated with exacerbated GAP-43-related longitudinal hippocampal atrophy and cognitive decline, especially in Aß+ participants (GAP-43 × time × APOE-ε4). These findings suggest that the APOE-ε4 effect on GAP-43-related presynaptic dysfunction is mediated by primary Alzheimer's pathologies and independently correlates to hippocampal atrophy and cognitive decline in the future.

Body Mass Index Decrease Has a Distinct Association with Alzheimer's Disease Pathophysiology in APOE ɛ4 Carriers and Non-Carriers.

BACKGROUND: Body mass index (BMI) changes may be related to Alzheimer's disease (AD) alterations, but it is unclear how the apolipoprotein E ɛ4 (APOE ɛ4) allele affects their association. OBJECTIVE: To explore the association of BMI changes with AD pathologies in APOE ɛ4 carriers and non-carriers. METHODS: In 862 non-demented ADNI participants with≥2 BMI measurements, we investigated the relationships between BMI slopes and longitudinal changes in amyloid-ß (Aß) accumulation, neurodegeneration and cognition, and follow-up tau deposition in different Aß and APOE ɛ4 statuses. RESULTS: In Aß+ APOE ɛ4 non-carriers, faster BMI declines were associated with faster rates of Aß accumulation (standardized ß (ßstd) = -0.29, p = 0.001), AD meta regions of interest (metaROI) hypometabolism (ßstd = 0.23, p = 0.026), memory declines (ßstd = 0.17, p = 0.029), executive function declines (ßstd = 0.19, p = 0.011), and marginally faster Temporal-metaROI cortical thinning (ßstd = 0.15, p = 0.067) and higher follow-up Temporal-metaROI tau deposition (ßstd = -0.17, p = 0.059). Among Aß- individuals, faster BMI decreases were related to faster Aß accumulation (ßstd = -0.25, p = 0.023) in APOE ɛ4 carriers, whereas predicted faster declines in memory and executive function in both APOE ɛ4 carriers (ßstd = 0.25, p = 0.008; ßstd = 0.32, p = 0.001) and APOE ɛ4 non-carriers (ßstd = 0.11, p = 0.030; ßstd = 0.12, p = 0.026). CONCLUSIONS: This study highlights the significance of tracking BMI data in older adults by providing novel insights into how body weight fluctuations and APOE ɛ4 interact with AD pathology and cognitive decline.

Robust All-Waterborne Superhydrophobic Coating with Photothermal Deicing and Passive Anti-icing Properties.

The compelling integration of superhydrophobic coatings with light-to-heat conversion capabilities has garnered substantial interest due to their dual functionality encompassing passive anti-icing and deicing attributes. However, the insufficient mechanical stability and the environmental and human health concerns stemming from the extensive use of organic solvents limit their practical application. In this study, an all-waterborne superhydrophobic photothermal coating (PCPAS) was prepared through the synergy of composite micro-nanoparticles derived from carbon nanotubes (CNT), polydopamine (PDA), and Ag particles with fluorine-containing polyacrylic emulsion (PFA). The PDA provided active sites for Ag+ reduction reaction and enhanced the interfacial interaction between CNT and Ag particles. The interfacial enhancement enabled the coating to maintain stable superhydrophobicity after 260 times sandpaper abrasion and 240 times tape peeling. Simultaneously, the composite micro-nanoparticle's light-to-heat conversion ability gave the coating excellent anti-icing/deicing capabilities. Under the condition of -20 °C, the freezing time of 30 µL of water droplets was extended to 392 s, and 2 × 2 × 2 cm ice cubes placed on the surface of the coating could completely melt after only 1142 s under simulated sunlight irradiation with a 1 kW/m2 intensity. In addition, the coating also had suitable self-cleaning properties and substrate applicability. The comprehensive attributes of this all-waterborne photothermal superhydrophobic coating render it a promising contender for anti-icing and deicing applications in challenging outdoor environments.

Association of APOE-ε4, Osteoarthritis, ß-Amyloid, and Tau Accumulation in Primary Motor and Somatosensory Regions in Alzheimer Disease.

BACKGROUND AND OBJECTIVES: One of the most prevalent chronic diseases, osteoarthritis (OA), may work in conjunction with APOE-ε4 to accelerate Alzheimer disease (AD) alterations, particularly in the primary motor (precentral) and somatosensory (postcentral) cortices. To understand the reasoning behind this, we investigated how OA and APOE-ε4 influence the accumulation of ß-amyloid (Aß) and tau accumulation in primary motor and somatosensory regions in Aß-positive (Aß+) older individuals. METHODS: We selected Aß+ Alzheimer Disease Neuroimaging Initiative participants, defined by baseline 18F-florbetapir (FBP) Aß PET standardized uptake value ratio (SUVR) of AD summary cortical regions, who had longitudinal Aß PET, the records of OA medical history, and APOE-ε4 genotyping. We examined how OA and APOE-ε4 relate to baseline and longitudinal Aß accumulation and tau deposition measured at follow-up in precentral and postcentral cortical areas and how they modulate Aß-associated future higher tau levels, adjusting for age, sex, and diagnosis and using multiple comparison corrections. RESULTS: A total of 374 individuals (mean age 75 years, 49.2% female, 62.8% APOE-ε4 carriers) who underwent longitudinal FBP PET with a median follow-up of 3.3 years (interquartile range [IQR] 3.4, range 1.6-9.4) were analyzed, and 96 people had 18F-flortaucipir (FTP) tau PET measured at a median of 5.4 (IQR 1.9, range 4.0-9.3) years postbaseline FBP PET. Neither OA nor APOE-ε4 was related to baseline FBP SUVR in precentral and postcentral regions. At follow-up, OA rather than APOE-ε4 was associated with faster Aß accumulation in postcentral region (ß = 0.005, 95% CI 0.001-0.008) over time. In addition, OA but not the APOE-ε4 allele was strongly linked to higher follow-up FTP tau levels in precentral (ß = 0.098, 95% CI 0.034-0.162) and postcentral (ß = 0.105, 95% CI 0.040-0.169) cortices. OA and APOE-ε4 were also interactively associated with higher follow-up FTP tau deposition in precentral (ß = 0.128, 95% CI 0.030-0.226) and postcentral (ß = 0.124, 95% CI 0.027-0.223) regions. DISCUSSION: This study suggests that OA was associated with faster Aß accumulation and higher Aß-dependent future tau deposition in primary motor and somatosensory regions, providing novel insights into how OA increases the risk of AD.

Epidemiological characteristics and risk factors of multidrug-resistant tuberculosis in Luoyang, China.

Objective: We aimed to examine the prevalence of multidrug-resistant tuberculosis (MDR-TB) in Luoyang, China, identify related risk factors, inform clinical practices, and establish standardized anti-tubercular treatment regimens. Methods: We conducted a retrospective analysis of high-resolution melting curve (HRM) data from 17,773 cases (2,748 of which were positive) between June 2019 and May 2022 to assess the prevalence of MDR-TB and to identify its associated risk factors. Results: Between June 2019 and May 2022, out of the 17,773 HRM results, 2,748 were HRM-positive, and 312 were MDR-TB cases. The detection rates for HRM-positive and MDR-TB were 17.0 and 12.1% for males, and 12.4 and 8.2% for females, respectively. The MDR-TB detection rate was higher in the urban areas (14.6%) than in the rural areas (10.6%) and more common among individuals under 51 years of age (14.1%) than those over 50 years of age (9.3%). Notably, the rate of detecting MDR-TB was 18.3% higher in new male patients than in new female patients, which was at 10.6%, and this difference was statistically significant (p < 0.001). Moreover, the rate of MDR detection in females who had received anti-tuberculosis treatment (21.3%) was higher than that in males (16.9%). In the multivariate model that considered the results of the sputum smear and detection time, MDR-TB was positively correlated with a history of tuberculosis (TB) treatment, being male, being younger than 51 years, and living in urban areas. Conclusion: Local TB infections are complex and diverse; therefore, more comprehensive monitoring methods are needed to curb the spread of MDR-TB.

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.

Review on treatment and utilization of barium slag in China.

Barium slag (BS) is generated as a by-product waste during the production of barium salts from barite. A large amount of BS is discharged annually threating the ecological environment and restricting the development of the barium salts industry. In China, BS is classified as hazardous waste due to its corrosivity, and more importantly because of its extraction toxicity of barium. Soluble barium is toxic and can result in barium poisoning for environment and human beings. The current review presents a detailed summary on general characteristics, discharge and disposal status, harmless treatment pathways and comprehensive utilization of BS in China. BaO, SiO2, CaO, and SO3 occur as main chemical compositions in BS, especially BaO accounting approximately for 35-40%. The mineral compositions include unreacted barite, quartz, clay minerals, newly-formed phases from the side reactions such as BaCO3, BaSiO3 and BaSO3, and residual carbon. A special attention is given to the assessment of the harmless treatment methods for BS from hazardous waste to general waste, which will decrease its management costs. Precipitation and solidification of soluble barium is the common pathway for harmless treatment of BS, and the using of other industrial waste can realize cost-saving. Methods for comprehensive utilization of BS include recovery of barium and carbon, application in building materials, and using as adsorbents for wastewater treatment. In particular, we analyzed and discussed the advantages and disadvantages of these existing process routes, intending to promote potentials for comprehensive utilization of BS in the future.

Presynaptic membrane protein dysfunction occurs prior to neurodegeneration and predicts faster cognitive decline.

INTRODUCTION: Although presynaptic loss measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP-43) is significantly involved in Alzheimer's disease (AD), the sequential association between CSF GAP-43 and AD-typical neurodegeneration is poorly understood. METHODS: We compared baseline CSF GAP-43 levels (n = 730) and longitudinal CSF GAP-43 changes (n = 327) in various biological stages of AD, and investigated their relationships with cross-sectional and longitudinal measures of residual hippocampal volume, 18 F-fluorodeoxyglucose PET, regional gray matter volume and cortical thickness, and cognition. RESULTS: Elevated CSF GAP43 levels were significantly associated with faster rates of hippocampal atrophy, AD-signature hypometabolism and cortical thinning, and middle temporal gray matter atrophy-related and AD-signature hypometabolism-related cognitive decline. In contrast, baseline levels of all these neurodegeneration biomarkers did not predict longitudinal CSF GAP-43 increases. DISCUSSION: These findings suggest that presynaptic loss may occur prior to neurodegeneration, highlighting the importance of lowing tau aggregation and tau-related synaptic dysfunction in elderly adults and AD patients.

Fully synthetic phosphorylated Tau181, Tau217, and Tau231 calibrators for Alzheimer's disease diagnosis.

Background: The calibrator in immunoassay plays an essential role in diagnosing Alzheimer's disease (AD). Presently, the most well-studied biomarkers for AD diagnosis are three phosphorylated Tau (p-Tau): p-Tau231, p-Tau217, and p-Tau181. Glycogen synthase-3beta (GSK3ß)-phosphorated Tau-441 is the most commonly used calibrator for p-Tau immunoassays. However, the batch-to-batch inconsistency issue of the commonly used GSK3ß-phosphorylated Tau-441 limits its clinical application. Methods: We have successfully generated and characterized 61 Tau monoclonal antibodies (mAbs) with distinct epitopes by using the hybridoma technique and employed them as capture or detection antibodies for p-Tau immunoassays. Through chemical synthesis, we synthesized calibrators, which are three peptides including capture and detection antibody epitopes, for application in immunoassays that detect p-Tau231, p-Tau217, and p-Tau181. The novel calibrators were applied to Enzyme-linked immunosorbent assay (ELISA) and Single-molecule array (Simoa) platforms to validate their applicability and establish a range of p-Tau immunoassays. Results: By employing the hybridoma technique, 49 mAbs recognizing Tau (1-22), nine mAbs targeting p-Tau231, one mAb targeting p-Tau217, and two mAbs targeting p-Tau181 were developed. Peptides, including recognition epitopes of capture and detection antibodies, were synthesized. These peptides were used as calibrators to develop 60 immunoassays on the ELISA platform, of which six highly sensitive immunoassays were selected and applied to the ultra-sensitive Simoa platform. Remarkably, the LODs were 2.5, 2.4, 31.1, 32.9, 46.9, and 52.1 pg/ml, respectively. Conclusion: Three novel p-Tau calibrators were successfully generated and validated, which solved the batch-to-batch inconsistency issue of GSK3ß-phosphorylated Tau-441. The novel calibrators exhibit the potential to promote the standardization of clinical AD diagnostic calibrators. Furthermore, we established a series of highly sensitive and specific immunoassays on the Simoa platform based on novel calibrators, which moved a steady step forward in p-Tau immunoassay application for AD diagnosis.

Effects of Oxytetracycline/Lead Pollution Alone and in the Combined Form on Antibiotic Resistance Genes, Mobile Genetic Elements, and Microbial Communities in the Soil.

The application of livestock manure is the leading cause of antibiotic and heavy metal pollution in agricultural soil. However, the effects of oxytetracycline (OTC) and lead (Pb) pollution in the single or combined form on antibiotic resistance genes (ARGs) in the soil need to be further studied. This study was planned to investigate the effects of OTC and Pb application on ARGs, mobile genetic elements (MGEs), and bacterial abundance in the soil. The relative abundance of ARGs and MGEs increased by 0.31-fold and 0.03-fold after the addition of 80 mg kg-1 Pb to the soil, and by 0.49-fold and 0.03-fold after the addition of 160 mg kg-1 Pb. In addition, under the premise of the existence of OTC, the inhibitory effect of a low concentration of Pb on ARG is stronger than that of a high concentration of Pb, resulting in a lower abundance of ARGs. The abundance of ARGs and MGEs increased by 0.11-fold and 0.17-fold after the addition of OTC (30 mg kg-1) to the soil at a Pb concentration of 80 mg kg-1 and by 0.18-fold and 0.04-fold at a Pb concentration of 160 mg kg-1. The addition of OTC and Pb in the soil also decreased the many bacterial communities such as Bacteroidetes, Proteobacteria, Acidobacteria, and Firmicutes. Redundancy analysis (RDA) showed that organic matter content and pH were positively correlated with the abundance of ARGs and MGEs. At the same time, electrical conductivity (EC) had a negative correlation with the abundance of ARGs and MGEs in the soil. Intl1 was significantly associated with tetB, sul1, tetQ, sul2, and sul3. Network analysis illustrated that Actinobacteria, Bacteroidetes, and Proteobacteria were the main host bacteria causing changes in the abundance of ARGs and MGEs, and they were also predominant phylum in the culture environment. This conclusion can provide a reference for the related research of ARGs in soil.