Pulse oximeter bench tests under different simulated skin tones.

Pulse oximeters' (POs) varying performance based on skin tones has been highly publicised. Compared to arterial blood gas analysis, POs tend to overestimate oxygen saturation (SpO2) values for people with darker skin (occult hypoxemia). The objective is to develop a test bench for assessing commercial home and hospital-based POs in controlled laboratory conditions. A laboratory simulator was used to mimic different SpO2 values (~ 70 to 100%). Different neutral density and synthetic melanin filters were used to reproduce low signal and varying melanin attenuation levels. Six devices consisting of commercial home (Biolight, N = 13; ChoiceMMed, N = 18; MedLinket, N = 9) and hospital-based (Masimo Radical 7 with Neo L, N = 1; GE B450 Masimo SET with LNCS Neo L, N = 1; Nonin 9550 Onyx II™, N = 1) POs were reviewed and their response documented. Significant variations were observed in the recorded SpO2 values among different POs when exposed to identical simulated signals. Differences were greatest for lower SpO2 (< 80%) where empirical data is limited. All PO responses under low signal and melanin attenuation did not change across various simulated SpO2 values. The bench tests do not provide conclusive evidence that melanin does not affect in vivo SpO2 measurements. Research in the areas of instrument calibration, theory and design needs to be further developed.

Exosomal lncCRLA is predictive for the evolvement and development of lung adenocarcinoma.

Lung adenocarcinoma, the most common histological subtype of non-small cell lung cancer, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Our team uncovers that lncRNA related to chemotherapy resistance in lung adenocarcinoma (lncCRLA) is preferentially expressed in lung adenocarcinoma cells with the mesenchymal phenotype. lncCRLA can not enhance chemotherapy resistance in lung adenocarcinoma due to its binding to RIPK1 in exosomes, which is released into intercellular media and transferred by exosomes from mesenchymal-like to epithelial-like cells. However, plasmatic lncCRLA corresponding to tissue lncCRLA functions as a preferred biomarker to reflect the response to chemotherapy and disease progression of lung adenocarcinoma. Through single-cell sequencing, RNA-Mutect technique and spatial transcriptomics, a handful of hybrid EMT cells with elevated lncCRLA are characterized as the origin of lung adenocarcinoma, which are indiscriminated from hybrid EMT cells by the in-depth sequencing. Plasmatic lncCRLA is properly predictive for the preinvasive lesion of lung adenocarcinoma that would evolve to invasive lesion. That notion is confirmed by a brand-new transgenic mouse model in which EMT is tracked by Cre and Dre system. Dasatinib is potential to hinder the spontaneous progression from preinvasive to invasive lesion of lung adenocarcinoma. Together, plasmatic lncCRLA is defined as a brand-new circulating biomarker to predict the occurrence and evolvement of lung adenocarcinoma, a light for early detection of lung adenocarcinoma.

A novel selenite-tolerant rhizosphere bacterium Wautersiella enshiensis sp. nov., isolated from Chinese selenium hyperaccumulator, Cardamine hupingshanensis.

Selenium (Se) is a dietary essential trace element for humans with various physiological functions and it could also be accumulated by some plant species, like Astragalus bisulcatus, Stanleya pinnata, and Cardamine hupinshanensis. A novel Gram-stain-negative, facultatively anaerobic, selenite-tolerant bacterium, designated strain YLX-1T , was isolated from the rhizosphere of a Se hyperaccumulating plant, Cardamine hupingshanensis in Enshi, China. Phylogenetic analysis based on 16 S rRNA gene sequences indicated that strain YLX-1T is a potential new species in the genus Wautersiella. Strain YLX-1T could grow in the temperature range of 4-37°C (optimally at 28°C) and in the pH range of 5-9 (optimum pH 7), which also could tolerate Se up to 6000 mg Se/L via producing extracellular red nano-Se with 100-300 nm size. However, it could predominantly accumulate selenocystine (SeCys2 ) in the cell under lower Se stress (1.5 mg Se/L). These results would help broaden our knowledge about the Se accumulation and transformation mechanism involved in rhizosphere bacteria like strain YLX-1T in C. hupingshanensis. Based on polyphasic data, we propose the creation of the new species Wautersiella enshiensis sp. nov., strain YLX-1T ( = CCTCC M 2013671) which will be promising to produce nano-Se as fertilizer, food additives or medicine.

Silencing of long noncoding RNA X-inactive specific transcript alleviates Aß1-42-induced microglia-mediated neurotoxicity by shifting microglial M1/M2 polarization.

OBJECTIVES: This experimental study aims to investigate the role of long noncoding RNA X-inactive specific transcript (lncRNA XIST) in the microglial polarization and microglia-mediated neurotoxicity in Alzheimer's disease (AD). METHODS: The levels of XIST and microRNA-107 (miR-107) were detected by quantitative real-time polymerase chain reaction. The spatial learning and memory capability of APPswe/PS1dE9 (APP/PS1) mice were evaluated by the Morris water maze test. The morphology of mouse hippocampus cells was evaluated by hematoxylin and eosin staining. The Iba1-positive microglia were labeled by immunohistochemistry staining. The protein levels were determined by western blot and enzyme-linked immunosorbent assay. Neurotoxicity was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, caspase-3 activity, and Cell Counting Kit-8 assay. The XIST, miR-107, and AD targets were predicted by bioinformatics analysis. RESULTS: The level of XIST was increased in APP/PS1 mice, and XIST silencing ameliorated AD progression. XIST silencing suppressed microglia activation, microglial M1 polarization, and proinflammatory factor levels, but promoted microglial M2 polarization in APP/PS1 mice and Aß1-42-treated BV-2 cells. XIST knockdown reduced Aß1-42-induced microglia-mediated apoptosis and enhanced cell viability in HT22 cells. XIST silencing down-regulated miR-107 level and attenuated Aß1-42-caused suppression of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Those effects of XIST silencing were attenuated by miR-107 inhibitor or LY294002. CONCLUSION: Downregulation of XIST lessened Aß1-42-induced microglia-mediated neurotoxicity by modulating microglial M1/M2 polarization, which may be mediated by the miR-107/PI3K/Akt pathway.

Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

Unique regulation of TiO2 nanoporous topography on macrophage polarization via MSC-derived exosomes.

The comprehensive recognition of communications between bone marrow mesenchymal stem cells (bm-MSCs) and macrophages in the peri-implant microenvironment is crucial for implantation prognosis. Our previous studies have clarified the indirect influence of Ti surface topography in the osteogenic differentiation of bm-MSCs through modulating macrophage polarization. However, cell communication is commutative and multi-directional. As the immune regulatory properties of MSCs have become increasingly prominent, whether bm-MSCs could also play an immunomodulatory role on macrophages under the influence of Ti surface topography is unclear. To further illuminate the communications between bm-MSCs and macrophages, the bm-MSCs inoculated on Ti with nanoporous topography were indirectly co-cultured with macrophages, and by blocking exosome secretion or extracting the purified exosomes to induce independently, we bidirectionally confirmed that under the influence of TiO2 nanoporous topography with 80-100 nm tube diameters, bm-MSCs can exert immunomodulatory effects through exosome-mediated paracrine actions and induce M1 polarization of macrophages, adversely affecting the osteogenic microenvironment around the implant. This finding provides a reference for the optimal design of the implant surface topography for inducing better bone regeneration.

Correction: lncRNA PSMB8-AS1 promotes colorectal cancer progression through sponging miR-1299 to upregulate ADAMTS5.

This corrects the article DOI: 10.4149/neo_2022_220111N42.

Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-ß Levels in Alzheimer's Disease: The Chongqing Ageing & Dementia Study.

BACKGROUND: The kidney-brain crosstalk has been involved in Alzheimer's disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. OBJECTIVE: To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. METHODS: We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-ß (Aß)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aß, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. RESULTS: We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aß42, Aß40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aß42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aß42. CONCLUSION: Renal function impacts brain Aß metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

Smart thermally responsive perovskite materials: Thermo-chromic application and density function theory calculation.

With the continuous improvement of human's requirements for temperature control suitable for living, the energy consumption of electrical appliances such as air conditioners has become a major challenge in traditional architectural design. Generally, most of the solar energy passes through the glass to enter and exit the building, but the traditional glass can hardly control the light and heat energy, causing the indoor temperature to change dramatically with the environment. Therefore, it is more urgent to develop green and efficient smart windows. Perovskite is a temperature-adaptive material, which has the ability of phase transition and can adjust its band gap for thermochromic applications. In this work, we study the perovskite-based thermochromic smart window. As a new application of perovskite, a number of experiments have been carried out. However, there is still a lack of theoretical analysis on phase transition mechanisms and crystal structure prediction. Density functional theory (DFT) calculation is the most useful tool in optoelectronics, especially for perovskite crystal. Here, we extracted typical cases from published literature for analysis and comparison and summarized the crystal structure, electronic structure stability, interface engineering, and thermal characteristics employing DFT calculation We believe this work will pave the way for DFT application for the study of thermochromic perovskite.

Elevated Levels of Naturally-Occurring Autoantibodies Against the Extracellular Domain of p75NTR Aggravate the Pathology of Alzheimer's Disease.

The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aß neurotoxicity and promotes Aß clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.

A Non-Invasive Physiological Control System of a Rotary Blood Pump Based on Preload Sensitivity: Use of Frank-Starling-Like Mechanism.

Implanting rotary blood pumps (RBPs) has become the principal treatment for patients suffering from severe heart failure. There are still many challenges to address for RBP control systems. These problems include meeting the patient's physiological perfusion, eliminating postoperative complications, as well as debugging the patient's physiological control system (automatically and indiscriminately). This paper proposes a non-invasive adaptive control system based on the Frank-Starling-like mechanism (NAC-FSL) to solve these problems. This control system uses the motor speed of the rotary blood pump as the only input variable, and the pump flow was estimated by the motor speed for achieving non-invasive detection. Simultaneously, a cardiovascular reference model was developed to provide an appropriate real-time preload for heart failure patients. The Frank-Starling-like control baseline was tracked to obtain the desired reference average pump flow by using the preload. Avoiding suction was done by adopting the control baseline (CLn), which included a flat slope under a high preload. Moreover, the NAC-FSL system could potentially unload the left ventricle and provide a higher pump flow with a smaller error during the exercise state, as compared to the CSC system. Finally, the K value indicating the preload sensitivity in the NAC-FSL controller was optimized to meet the perfusion needs according to the hemodynamic parameters.

Association of rs2072446 in the NGFR gene with the risk of Alzheimer's disease and amyloid-ß deposition in the brain.

INTRODUCTION AND AIMS: Alzheimer's disease (AD) is the most common form of dementia with a complex genetic background. The cause of sporadic AD (sAD) remains largely unknown. Increasing evidence shows that genetic variations play a crucial role in sAD. P75 neurotrophin receptor (p75NTR, encoded by NGFR) plays a critical role in the pathogenesis of AD. Yet, the relationship between NGFR gene polymorphisms and AD was less studied. This study aims to analyze the relationship of NGFR gene polymorphism with the risk of AD in the Chinese Han population and amyloid-ß deposition in the ADNI cohort. METHODS: This case-control association study was conducted in a Chinese Han cohort consisting of 366 sporadic AD (sAD) patients and 390 age- and sex-matched controls. Twelve tag-SNPs were selected and genotyped with a multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The associations between tag-SNPs and the risk of AD were analyzed by logistic regression. Moreover, another cohort from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database was included to examine the association of one tag-SNP (rs2072446) with indicators of amyloid deposition. Kaplan-Meier survival analysis and Cox proportional hazards models were used to test the predictive abilities of rs2072446 genotypes for AD progression. The mediation effects of Aß deposition on this association were subsequently tested by mediation analyses. RESULTS: After multiple testing corrections, one tag-SNP, rs2072446, was associated with an increased risk of sAD (additive model, OR = 1.79, Padjustment  = 0.0144). Analyses of the ADNI cohort showed that the minor allele (T) of rs2072446 was significantly associated with the heavier Aß burden, which further contributed to an increased risk of AD progression in APOE ε4 non-carrier. CONCLUSION: Our study found that rs2072446 in NGFR is associated with both the risk of sAD in the Chinese Han population and the amyloid burden in the ADNI cohort, which reveals the role of p75NTR in AD from a genetic perspective.

Transfer RNAs-derived small RNAs and their application potential in multiple diseases.

The role of tRNAs is best known as adapter components of translational machinery. According to the central dogma of molecular biology, DNA is transcribed to RNA and in turn is translated into proteins, in which tRNA outstands by its role of the cellular courier. Recent studies have led to the revision of the canonical function of transfer RNAs (tRNAs), which indicates that tRNAs also serve as a source for short non-coding RNAs called tRNA-derived small RNAs (tsRNAs). tsRNAs play key roles in cellular processes by modulating complicated regulatory networks beyond translation and are widely involved in multiple diseases. Herein, the biogenesis and classification of tsRNAs were firstly clarified. tsRNAs are generated from pre-tRNAs or mature tRNAs and are classified into tRNA-derived fragments (tRFs) and tRNA halves (tiRNA). The tRFs include five types according to the incision loci: tRF-1, tRF-2, tRF-3, tRF-5 and i-tRF which contain 3' tiRNA and 5' tiRNA. The functions of tsRNAs and their regulation mechanisms involved in disease processes are systematically summarized as well. The mechanisms can elaborate on the specific regulation of tsRNAs. In conclusion, the current research suggests that tsRNAs are promising targets for modulating pathological processes, such as breast cancer, ischemic stroke, respiratory syncytial virus, osteoporosis and so on, and maintain vital clinical implications in diagnosis and therapeutics of various diseases.

lncRNA PSMB8-AS1 promotes colorectal cancer progression through sponging miR-1299 to upregulate ADAMTS5.

Long non-coding RNAs (lncRNAs) have been reported to be vital participants in tumor progression. Recently, lncRNA PSMB8-AS1 has been uncovered to facilitate pancreatic cancer progression by regulating miR-382-3p/STAT1/PD-L1 network. Nonetheless, the role of PSMB8-AS1 and its underlying mechanism have not been well-explored in colorectal cancer (CRC). The expression of RNAs or proteins was detected via qRT-PCR or western blot assays. Functional assays were involved in evaluating the effects of PSMB8-AS1/miR-1299/ADAMTS5 on the malignant behaviors of CRC cells. The molecular mechanism of PSMB8-AS1 was explored via mechanism analyses in CRC cells. Based on experimental results, PSMB8-AS1 expression was notably higher in CRC cell lines than in normal cells. The downregulation of PSMB8-AS1 repressed cell viability, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC while promoting cell apoptosis. It was also revealed that PSMB8-AS1 could sponge miR-1299 to upregulate ADAMTS5 in CRC cells. In rescue assays, we further discovered that miR-1299 inhibition or ADAMTS5 overexpression abrogated the suppressive influence of PSMB8-AS1 deficiency on CRC cell growth. In addition, PSMB8-AS1 was validated to induce M2 polarization. In conclusion, PSMB8-AS1 sponges miR-1299 to increase PSMB8-AS1 expression, thus promoting CRC cell growth.

Naturally-Occurring Antibodies Against Bim are Decreased in Alzheimer's Disease and Attenuate AD-type Pathology in a Mouse Model.

Increased neuronal apoptosis is an important pathological feature of Alzheimer's disease (AD). The Bcl-2-interacting mediator of cell death (Bim) mediates amyloid-beta (Aß)-induced neuronal apoptosis. Naturally-occurring antibodies against Bim (NAbs-Bim) exist in human blood, with their levels and functions unknown in AD. In this study, we found that circulating NAbs-Bim were decreased in AD patients. Plasma levels of NAbs-Bim were negatively associated with brain amyloid burden and positively associated with cognitive functions. Furthermore, NAbs-Bim purified from intravenous immunoglobulin rescued the behavioral deficits and ameliorated Aß deposition, tau hyperphosphorylation, microgliosis, and neuronal apoptosis in APP/PS1 mice. In vitro investigations demonstrated that NAbs-Bim were neuroprotective against AD through neutralizing Bim-directed neuronal apoptosis and the amyloidogenic processing of amyloid precursor protein. These findings indicate that the decrease of NAbs-Bim might contribute to the pathogenesis of AD and immunotherapies targeting Bim hold promise for the treatment of AD.

The Correlations of Plasma Liver-Type Fatty Acid-Binding Protein with Amyloid-ß and Tau Levels in Patients with Alzheimer's Disease.

BACKGROUND: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer's disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. OBJECTIVE: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-ß (Aß) and tau in the plasma and cerebrospinal fluid (CSF). METHODS: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The levels of FABP1 in plasma, and Aß and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aß levels. RESULTS: The level of plasma FABP1 was significantly elevated in the AD group (p = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aß42 (AUC = 0.6794, p = 0.0071) and FABP1/t-tau (AUC = 0.7168, p = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aß42, Aß40, and t-tau, both FABP1/Aß42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aß42 had the highest diagnostic value (AUC = 0.8075, p < 0.0001). CONCLUSION: These findings indicate that FABP1 may play a role in AD pathogenesis and be worthy of further investigation in the future.

Associations of plasma angiostatin and amyloid-ß and tau levels in Alzheimer's disease.

Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of Alzheimer's disease (AD). However, whether there are pathological changes in angiostatin levels in individuals with AD dementia is unclear, and whether plasma angiostatin has a relationship with major AD pathological processes and cognitive impairment remains unknown. To examine plasma angiostatin levels in patients with AD dementia and investigate the associations of angiostatin with blood and cerebrospinal fluid (CSF) AD biomarkers, we conducted a cross-sectional study including 35 cognitively normal control (CN) subjects and 59 PiB-PET-positive AD dementia patients. We found that plasma angiostatin levels were decreased in AD dementia patients compared to CN subjects. Plasma angiostatin levels were negatively correlated with plasma Aß42 and Aß40 levels in AD dementia patients and positively correlated with CSF total tau (t-tau) levels and t-tau/Aß42 in AD dementia patients with APOE-ε4. In addition, plasma angiostatin levels had the potential to distinguish AD from CN. These findings suggest a link between angiostatin and AD pathogenesis and imply that angiostatin might be a potential diagnostic biomarker for AD.

Application of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry for the Rapid Identification of Yeast Species From Polar Regions.

Protein profiling based on matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has proved to be a powerful tool for yeast identification. However, it is rarely used in the identification of yeast isolates from polar regions, which may be due to the limited data available for the differentiation of polar yeast species. The present study constructed a supplementary database of MALDI-TOF MS, including 33 yeast species from the Arctic and Antarctica. These yeast species were used to assess the accuracy and practicality of MALDI-TOF MS-based identification compared to the ribosomal DNA [internal transcribed spacer (ITS) and large subunit (LSU) gene regions] sequencing identification. Their dendrogram based on main spectra profiles (MSPs) in the supplementary database was somewhat consistent with their phylogenetic tree. The accuracy of MALDI-TOF MS identification was also compared by the ethanol-formic acid extraction method and the on-plate extraction method. In addition, peptide markers of some yeast species (e.g., Glaciozyma, Phenoliferia, Mrakia, and Vishniacozyma) were identified. It is concluded that the MALDI-TOF MS method can differentiate some closely related yeast species from polar regions, thus is suitable for the identification of polar yeasts.

Dynamic changes of CSF sPDGFRß during ageing and AD progression and associations with CSF ATN biomarkers.

BACKGROUND: Loss of brain capillary pericyte is involved in the pathologies and cognitive deficits in Alzheimer's disease (AD). The role of pericyte in early stage of AD pathogenesis remains unclear. METHODS: We investigated the dynamic changes of soluble platelet-derived growth factor receptor ß (sPDGFRß) in cerebrospinal fluid (CSF), a marker of brain pericyte injury, in transition from normal ageing to early AD in a cognitively unimpaired population aged 20 to 90 years. Association between sPDGFRß and ATN biomarkers were analyzed. RESULTS: In lifetime, CSF sPDGFRß continually increased since age of 20 years, followed by the increases of phosphorylated tau-181 (P-tau181) and total tau (T-tau) at the age of 22.2 years and 31.7 years, respectively; CSF Aß42 began to decline since the age of 39.6 years, indicating Aß deposition. The natural trajectories of biomarkers suggest that pericyte injury is an early event during transition from normal status to AD, even earlier than Aß deposition. In AD spectrum, CSF sPDGFRß was elevated in preclinical stage 2 and participants with suspected non-AD pathophysiologies. Additionally, CSF sPDGFRß was positively associated with P-tau181 and T-tau independently of Aß42, and significantly strengthened the effects of Aß42 on P-tau181, suggesting that pericyte injury accelerates Aß-mediated tau hyperphosphorylation. CONCLUSIONS: Our results suggest that pericyte injury contributes to AD progression in the early stage in an Aß-independent pathway. Recovery of pericyte function would be a target for prevention and early intervention of AD.