Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells.

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function.

BACKGROUND: Regulatory T cells (Tregs) are crucial in maintaining immune homeostasis and preventing autoimmunity and inflammation. A proportion of Treg cells can lose Foxp3 expression and become unstable under inflammation conditions. The precise mechanisms underlying this phenomenon remain unclear. METHODS: The PI16 gene knockout mice (PI16fl/flFoxp3Cre) in Treg were constructed, and the genotypes were identified. The proportion and phenotypic differences of immune cells in 8-week-old mice were detected by cell counter and flow cytometry. Two groups of mouse Naïve CD4+T cells were induced to differentiate into iTreg cells to observe the effect of PI16 on the differentiation and proliferation of iTreg cells, CD4+CD25+Treg and CD4+CD25- effector T cells (Teff) were selected and co-cultured with antigen presenting cells (APC) to observe the effect of PI16 on the inhibitory ability of Treg cells in vitro. The effects of directed knockout of PI16 in Treg cells on inflammatory symptoms, histopathological changes and immune cell expression in mice with enteritis and autoimmune arthritis were observed by constructing the model of antigen-induced arthritis (AIA) and colitis induced by dextran sulfate sodium salt (DSS). RESULTS: We identified peptidase inhibitor 16 (PI16) as a negative regulator of Treg cells. Our findings demonstrate that conditional knock-out of PI16 in Tregs significantly enhances their differentiation and suppressive functions. The conditional knockout of the PI16 gene resulted in a significantly higher abundance of Foxp3 expression (35.12 ± 5.71% vs. 20.00 ± 1.61%, p = 0.034) in iTreg cells induced in vitro compared to wild-type mice. Mice with Treg cell-specific PI16 ablation are protected from autoimmune arthritis (AIA) and dextran sulfate sodium (DSS)-induced colitis development. The AIA model of PI16CKO is characterized by the reduction of joint structure and the attenuation of synovial inflammation and in DSS-induced colitis model, conditional knockout of the PI16 reduce intestinal structural damage. Additionally, we found that the deletion of the PI16 gene in Treg can increase the proportion of Treg (1.46 ± 0.14% vs. 0.64 ± 0.07%, p < 0.0001) and decrease the proportion of Th17 (1.00 ± 0.12% vs. 3.84 ± 0.64%, p = 0.001). This change will enhance the shift of Th17/Treg toward Treg cells in AIA arthritis model (0.71 ± 0.06% vs. 8.07 ± 1.98%, p = 0.003). In DSS-induced colitis model of PI16CKO, the proportion of Treg in spleen was significantly increased (1.40 ± 0.15% vs. 0.50 ± 0.11%, p = 0.003), Th17 (2.18 ± 0.55% vs. 6.42 ± 1.47%, p = 0.017), Th1 (3.42 ± 0.19% vs. 6.59 ± 1.28%, p = 0.028) and Th2 (1.52 ± 0.27% vs. 2.76 ± 0.38%, p = 0.018) in spleen was significantly decreased and the Th17/Treg balance swift toward Treg cells (1.44 ± 0.50% vs. 24.09 ± 7.18%, p = 0.012). CONCLUSION: PI16 plays an essential role in inhibiting Treg cell differentiation and function. Conditional knock out PI16 gene in Treg can promote the Treg/Th17 balance towards Treg dominance, thereby alleviating the condition. Targeting PI16 may facilitate Treg cell-based therapies for preventing autoimmune diseases and inflammatory diseases. The research provides us with novel insights and future research avenues for the treatment of autoimmune diseases, particularly arthritis and colitis.

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis.

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene-related peptide (CGRP+). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP+ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP+ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Gums make IL-23, no professionals needed.

IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.

Prognostic significance of systemic inflammatory parameters in high-grade glial tumor patients: Two center experience.

We aimed to determine the prognostic values of the neutrophil-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, body mass index, and prognostic nutritional index scores in patients with high-grade glioma. This was a retrospective observational case series. Between 2015 and 2020, 79 patients with high-grade gliomas 2 oncology centers were included in our study. All patients (n = 79) had high-grade glial tumors and were treated with RT. Sixty-nine (87.3%) patients died, and the median 2 years overall survival was 12.7 months. Recurrence was observed in 25 (31.6%) patients at the end of the treatment. The median recurrence free survival was 24.4 months. There was no significant correlation between systemic inflammation indicators and survival parameters for OS and RFS. Only a marginally significant association between the neutrophil-lymphocyte ratio and RFS was found. Systemic inflammatory parameters and outcomes were not significantly correlated in patients with high-grade gliomas.

Btbd8 deficiency reduces susceptibility to colitis by enhancing intestinal barrier function and suppressing inflammation.

Introduction: BTBD8 has been identified as a susceptible gene for inflammatory bowel diseases (IBD). However, the function of BTBD8 in normal development and IBD pathogenesis remains unknown. Methods: We administered drinking water with 3% dextran sodium sulfate (DSS) to wild-type (WT) and Btbd8 knockout (KO) mice for seven consecutive days to induce IBD. Subsequently, we further examined whether Btbd8 KO affects intestinal barrier and inflammation. Results: We demonstrated that Btbd8 deficiency partially protects mice from DSS-induced IBD, even though no obvious phenotypes were observed in Btbd8 KO mice. Btbd8 deletion leads to strengthened tight junctions between intestinal epithelial cells, elevated intestinal stem cell activity, and enhanced mucus layer. All these three mechanisms work together to improve the intestinal barrier integrity in Btbd8 KO mice. In addition, Btbd8 deficiency mitigates inflammation by reducing the expression of IL-1ß and IL-6 by macrophages. Discussion: Our studies validate the crucial role of Btbd8 in IBD pathogenesis, and reveal that Btbd8 deficiency may ameliorate DSS-induced IBD through improving the intestinal barrier integrity, as well as suppressing inflammatory response mediated by macrophages. These findings suggest that Btbd8 could be a promising therapeutic target for the treatment of IBD.

Immune Homeostasis Maintenance Through Advanced Immune Therapeutics to Target Atherosclerosis.

Atherosclerosis remains the leading cause of coronary heart disease (CHD) with enormous health and societal tolls. Traditional drug development approaches have been focused on small molecule-based compounds that aim to lower plasma lipids and reduce systemic inflammation, two primary causes of atherosclerosis. However, despite the widely available lipid-lowering and anti-inflammatory small compounds and biologic agents, CHD prevalence still remains high. Based on recent advances revealing disrupted immune homeostasis during atherosclerosis pathogenesis, novel strategies aimed at rejuvenating immune homeostasis with engineered immune leukocytes are being developed. This chapter aims to assess basic and translational efforts on these emerging strategies for the effective development of atherosclerosis treatment, as well as key challenges in this important translational field.

Scutellarein Ameliorated Chondrocyte Inflammation and Osteoarthritis in Rats.

OBJECTIVE: Osteoarthritis (OA) is a degenerative joint disorder characterized by the gradual degradation of joint cartilage and local inflammation. This study aimed to investigate the anti-OA effect of scutellarein (SCU), a single-unit flavonoid compound obtained from Scutellaria barbata D. Don, in rats. METHODS: The extracted rat chondrocytes were treated with SCU and IL-1ß. The chondrocytes were divided into control group, IL-1ß group, IL-1ß+SCU 50 µmol/L group, and IL-1ß+SCU 100 µmol/L group. Morphology of rat chondrocytes was observed by toluidine blue and safranin O staining. CCK-8 method was used to detect the cytotoxicity of SCU. ELISA, qRT-PCR, Western blotting, immunofluorescence, SAß-gal staining, flow cytometry, and bioinformatics analysis were applied to evaluate the effect of SCU on rat chondrocytes under IL-1ß intervention. Additionally, anterior cruciate ligament transection (ACL-T) was used to establish a rat OA model. Histological changes were detected by safranin O/fast green, hematoxylin-eosin (HE) staining, and immunohistochemistry. RESULTS: SCU protected cartilage and exhibited anti-inflammatory effects via multiple mechanisms. Specifically, it could enhance the synthesis of extracellular matrix in cartilage cells and inhibit its degradation. In addition, SCU partially inhibited the nuclear factor kappa-B/mitogen-activated protein kinase (NF-κB/MAPK) pathway, thereby reducing inflammatory cytokine production in the joint cartilage. Furthermore, SCU significantly reduced IL-1ß-induced apoptosis and senescence in rat chondrocytes, further highlighting its potential role in OA treatment. In vivo experiments revealed that SCU (at a dose of 50 mg/kg) administered for 2 months could significantly delay the progression of cartilage damage, which was reflected in a lower Osteoarthritis Research Society International (OARSI) score, and reduced expression of matrix metalloproteinase 13 (MMP13) in cartilage. CONCLUSION: SCU is effective in the therapeutic management of OA and could serve as a potential candidate for future clinical drug therapy for OA.

Neutrophil extracellular traps as a unique target in the treatment of inflammatory pain.

Pain is a widespread motivation for seeking healthcare and stands as a substantial global public health concern. Despite comprehensive investigations into the mechanisms of pain sensitization induced by inflammation, efficacious treatments options remain scarce. Neutrophil extracellular traps (NETs) have been associated with the progression and tissue damage of diverse inflammatory diseases. This study aims to explore the impact of NETs on the progression of inflammatory pain and explore potential therapeutic approaches. Initially, we observed neutrophil infiltration and the formation of NETs in the left hind paw of mice with inflammatory pain induced by complete Freund's adjuvant (CFA). Furthermore, we employed the peptidyl arginine deiminase 4 (PAD4) inhibitor Cl-amidine (diluted at 50 mg/kg in saline, administered via tail vein injection once daily for three days) to impede NETs formation and administered DNase1 (diluted at 10 mg/kg in saline, once daily for three days) to break down NETs. We investigated the pathological importance of peripheral NETs formation in inflammatory pain and its influence on the activation of spinal dorsal horn microglia. The findings indicate that neutrophils infiltrating locally generate NETs, leading to an increased release of inflammatory mediators that worsen peripheral inflammatory reactions. Consequently, this results in the transmission of more harmful peripheral stimuli to the spinal cord, triggering microglial activation and NF-κB phosphorylation, thereby escalating neuroinflammation and fostering pain sensitization. Suppression of peripheral NETs can mitigate peripheral inflammation in mice with inflammatory pain, reverse mechanical and thermal hypersensitivity by suppressing microglial activation in the spinal cord, ultimately diminishing inflammatory pain. In conclusion, these discoveries propose that obstructing or intervening with NETs introduces a novel therapeutic avenue for addressing inflammatory pain.

Kidney damage associated with COVID-19: from the acute to the chronic phase.

Severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) infection is well established as a systemic disease including kidney damage. The entry point into the renal cell remains the angiotensin-converting enzyme 2 (ACE-2) receptor and the spectrum of renal lesions is broad, with a clear predominance of structural and functional tubular lesions. The most common form of glomerular injury is collapsing glomerulopathy (CG), which is strongly associated with apolipoprotein L1(APOL-1) risk variants. These acute lesions, which are secondary to the direct or indirect effects of SARS-CoV-2, can progress to chronicity and are specific to long COVID-19 in the absence of any other cause. Residual inflammation associated with SARS-CoV-2 infection, in addition to acute kidney injury (AKI) as a transitional state with or without severe histological lesions, may be responsible for greater kidney function decline in mild-to-moderate COVID-19. This review discusses the evidence for renal histological markers of chronicity in COVID-19 patients and triggers of low-grade inflammation that may explain the decline in kidney function in the post-COVID-19 period.

Prognostic significance of inflammation scores in malignant mesothelioma.

OBJECTIVE: The relationship between inflammatory markers and survival in many cancers has been investigated previously. Inflammatory markers may also offer the possibility of predicting surveillance in patients with malignant mesothelioma. Our study seeks to enhance comprehension of how variables such as the nutritional status and inflammation indices of malignant mesothelioma patients impact the disease's progression and prognosis. PATIENTS AND METHODS: This study included patients who were treated at the Erciyes University Medical Oncology Clinic between 2010 and 2022 and diagnosed with malignant mesothelioma. This is a retrospective single-center cohort study. Receiver Operating Characteristic (ROC) analysis was applied to determine the inflammation markers' optimal cut-off values with high sensitivity and specificity. Patients were categorized based on these values. The differences in overall survival (OS) and progression-free survival (PFS) between categorized groups were assessed using Log-rank curves and Kaplan-Meier tests. Multivariate analysis was performed using Cox regression analysis on statistically significant data. The relationship between inflammation markers and malignant mesothelioma survival was evaluated. RESULTS: There are 115 patients in this study. Pre-treatment high neutrophil to lymphocyte ratio (NLR) (HR: 1.34, 95% CI: 1.12-2.83, p=0.04), high pan-immune inflammation value (PIIV) (HR: 2.01, 95% CI: 1.32-4.79, p=0.03), and high systemic inflammation response index (SIRI) (HR: 1.34, 95% CI: 1.2-2.78, p=0.04) were associated with poor OS. Conversely, high advanced lung cancer inflammation index (ALI) (HR: 0.73, 95% CI: 0.53-0.84, p=0.03) and high hemoglobin-albumin-lymphocyte and platelet (HALP) (HR: 0.67, 95% CI: 0.23-0.78, p=0.02) were associated with favorable survival. CONCLUSIONS: Our study investigated the prognostic value of various inflammation markers in malignant mesothelioma patients and suggests that composite formulas like NLR, PIIV, SIRI, ALI, and HALP that incorporate CBC cells and nutritional parameters like albumin, height, and weight could more consistently and accurately predict malignant mesothelioma prognosis.

The neuroprotective effect of human primary astrocytes in multiple sclerosis: In vitro model.

Recent studies highlighted the role of astrocytes in neuroinflammatory diseases, particularly multiple sclerosis, interacting closely with other CNS components but also with the immune cells. However, due to the difficulty in obtaining human astrocytes, their role in these pathologies is still unclear. In this study we develop an astrocyte in vitro model to evaluate their role in multiple sclerosis after being treated with CSF isolated from both healthy and MS diagnosed patients. Gene expression and ELISA assays reveal that several pro-inflammatory markers IL-1ß, TNF-α and IL-6, were significantly downregulated in astrocytes treated with MS-CSF. In contrast, neurotrophic survival, and growth factors, and GFAP, BDNF, GDNF and VEGF, were markedly elevated upon the same treatment. In summary, this study supports the notion of the astrocyte involvement in MS. The results reveal the neuroprotective role of astrocyte in MS pathogenicity by suppressing excessive inflammation and increasing the expression of tropic factors.

Prognostic and clinicopathological value of systemic inflammation response index (SIRI) in patients with breast cancer: a meta-analysis.

BACKGROUND: Many studies have explored the value of the systemic inflammation response index (SIRI) in predicting the prognosis of patients with breast cancer (BC); however, their findings remain controversial. Consequently, we performed the present meta-analysis to accurately identify the role of SIRI in predicting BC prognosis. METHODS: PubMed, Embase, Cochrane Library, and Web of Science databases were comprehensively searched between their inception and February 10, 2024. The significance of SIRI in predicting overall survival (OS) and disease-free survival (DFS) in BC patients was analyzed by calculating pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). RESULTS: Eight articles involving 2,997 patients with BC were enrolled in the present study. According to our combined analysis, a higher SIRI was markedly associated with dismal OS (HR = 2.43, 95%CI = 1.42-4.15, p < 0.001) but not poor DFS (HR = 2.59, 95%CI = 0.81-8.24, p = 0.107) in patients with BC. Moreover, based on the pooled results, a high SIRI was significantly related to T3-T4 stage (OR = 1.73, 95%CI = 1.40-2.14, p < 0.001), N1-N3 stage (OR = 1.61, 95%CI = 1.37-1.91, p < 0.001), TNM stage III (OR = 1.63, 95%CI = 1.34-1.98, p < 0.001), and poor differentiation (OR = 1.25, 95%CI = 1.02-1.52, p = 0.028). CONCLUSION: According to our results, a high SIRI significantly predicted poor OS in patients with BC. Furthermore, elevated SIRI was also remarkably related to increased tumor size and later BC tumor stage. The SIRI can serve as a novel prognostic biomarker for patients with BC.

Based on our knowledge, this study is the first meta-analysis to explore value of SIRI in predicting BC prognosis.According to our results, a high SIRI significantly predicted the dismal OS in BC patients.SIRI can serve as the novel prognostic biomarker for BC patients.

Genetically engineered macrophages derived from iPSCs for self-regulating delivery of anti-inflammatory biologic drugs.

In rheumatoid arthritis, dysregulated cytokine signaling has been implicated as a primary factor in chronic inflammation. Many antirheumatic and biological therapies are used to suppress joint inflammation, but despite these advances, effectiveness is not universal, and delivery is often at high doses, which can predispose patients to significant off-target effects. During chronic inflammation, the inappropriate regulation of signaling factors by macrophages accelerates progression of disease by driving an imbalance of inflammatory cytokines, making macrophages an ideal cellular target. To develop a macrophage-based therapy to treat chronic inflammation, we engineered a novel induced pluripotent stem cell (iPSC)-derived macrophage capable of delivering soluble TNF receptor 1 (TNFR1), an anti-inflammatory biologic inhibitor of tumor necrosis factor alpha (TNF-α), in an auto-regulated manner in response to TNF-α. Murine iPSCs were differentiated into macrophages (iMACs) over a 17-day optimized protocol with continued successful differentiation confirmed at key timepoints. Varying inflammatory and immunomodulatory stimuli demonstrated traditional macrophage function and phenotypes. In response to TNF-α, therapeutic iMACs produced high levels of sTNFR1 in an autoregulated manner, which inhibited inflammatory signaling. This self-regulating iMAC system demonstrated the potential for macrophage-based drug delivery as a novel therapeutic approach for a variety of chronic inflammatory diseases.

Clinical Evaluation of the Adult with Eosinophilic Esophagitis.

Adult patients with eosinophilic esophagitis (EoE) typically present with a history of dysphagia for solids, sometimes with additional reflux-like pain and a history of prior food impactions. In contrast to these alarming symptoms, the general appearance and physical examination of adult patients with EoE is in line with apparently healthy individuals. Therefore, the diagnosis is based on a history of solid-food dysphagia and eosinophilic tissue infiltration. Importantly, the increasing prevalence of EoE variants, that is, typical EoE symptoms in the absence of a relevant eosinophilia, and several studies with eosinophil-targeting drugs, call the pathogenic role of eosinophils into question.

Developmental self-reactivity determines pathogenic Tc17 differentiation potential of naive CD8+ T cells in murine models of inflammation.

The differentiation of naive CD8+ T cells into effector cells is important for establishing immunity. However, the effect of heterogeneous naive CD8+ T cell populations is not fully understood. Here, we demonstrate that steady-state naive CD8+ T cells are composed of functionally heterogeneous subpopulations that differ in their ability to differentiate into type 17 cytotoxic effector cells (Tc17) in a context of murine inflammatory disease models, such as inflammatory bowel disease and graft-versus-host disease. The differential ability of Tc17 differentiation is not related to T-cell receptor (TCR) diversity and antigen specificity but is inversely correlated with self-reactivity acquired during development. Mechanistically, this phenomenon is linked to differential levels of intrinsic TCR sensitivity and basal Suppressor of Mothers Against Decapentaplegic 3 (SMAD3) expression, generating a wide spectrum of Tc17 differentiation potential within naive CD8+ T cell populations. These findings suggest that developmental self-reactivity can determine the fate of naive CD8+ T cells to generate functionally distinct effector populations and achieve immense diversity and complexity in antigen-specific T-cell immune responses.

Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury.

Biliary atresia is a neonatal disease characterized by damage, inflammation, and fibrosis of the liver and bile ducts and by abnormal bile metabolism. It likely results from a prenatal environmental exposure that spares the mother and affects the fetus. Our aim was to develop a model of fetal injury by exposing pregnant mice to low-dose biliatresone, a plant toxin implicated in biliary atresia in livestock, and then to determine whether there was a hepatobiliary phenotype in their pups. Pregnant mice were treated orally with 15 mg/kg/d biliatresone for 2 days. Histology of the liver and bile ducts, serum bile acids, and liver immune cells of pups from treated mothers were analyzed at P5 and P21. Pups had no evidence of histological liver or bile duct injury or fibrosis at either timepoint. In addition, growth was normal. However, serum levels of glycocholic acid were elevated at P5, suggesting altered bile metabolism, and the serum bile acid profile became increasingly abnormal through P21, with enhanced glycine conjugation of bile acids. There was also immune cell activation observed in the liver at P21. These results suggest that prenatal exposure to low doses of an environmental toxin can cause subclinical disease including liver inflammation and aberrant bile metabolism even in the absence of histological changes. This finding suggests a wide potential spectrum of disease after fetal biliary injury.

Vascular dysfunction in sporadic bvFTD: white matter hyperintensity and peripheral vascular biomarkers.

BACKGROUND: Vascular dysfunction was recently reported to be involved in the pathophysiological process of neurodegenerative diseases, but its role in sporadic behavioral variant frontotemporal dementia (bvFTD) remains unclear. The aim of this study was to systematically explore vascular dysfunction, including changes in white matter hyperintensities (WMHs) and peripheral vascular markers in bvFTD. METHODS: Thirty-two patients with bvFTD who with no vascular risk factors were enrolled in this cross-sectional study and assessed using positron emission tomography/magnetic resonance (PET/MRI) imaging, peripheral plasma vascular/inflammation markers, and neuropsychological examinations. Group differences were tested using Student's t-tests and Mann-Whitney U tests. A partial correlation analysis was implemented to explore the association between peripheral vascular markers, neuroimaging, and clinical measures. RESULTS: WMH was mainly distributed in anterior brain regions. All peripheral vascular factors including matrix metalloproteinases-1 (MMP-1), MMP-3, osteopontin, and pentraxin-3 were increased in the bvFTD group. WMH was associated with the peripheral vascular factor pentraxin-3. The plasma level of MMP-1 was negatively correlated with the gray matter metabolism of the frontal, temporal, insula, and basal ganglia brain regions. The WMHs in the frontal and limbic lobes were associated with plasma inflammation markers, disease severity, executive function, and behavior abnormality. Peripheral vascular markers were associated with the plasma inflammation markers. CONCLUSIONS: WMHs and abnormalities in peripheral vascular markers were found in patients with bvFTD. These were found to be associated with the disease-specific pattern of neurodegeneration, indicating that vascular dysfunction may be involved in the pathogenesis of bvFTD. This warrants further confirmation by postmortem autopsy. Targeting the vascular pathway might be a promising approach for potential therapy.

Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats.

Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer's disease (AD). While it is known that vascular fibrillar amyloid ß (Aß) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-ß1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-ß1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.