Pathological Changes Research Articles

Use of biomarkers in the early detection of Alzheimer’s disease

In 1906, Alois Alzheimer described the disease bearing his name, a progressive neurodegenerative pathology with high prevalence. This condition is characterized by progressive cognitive impairment, particularly memory loss, resulting from the degeneration and death of neurons in cortical and subcortical regions. Late diagnosis remains one of the main factors negatively impacting the prognosis of patients with Alzheimer’s disease (AD). Evidence from studies using positron emission tomography (PET) and cerebrospinal fluid (CSF) analysis indicates that neuropathological changes associated with AD begin up to 20 years before the onset of clinical symptoms. This study aims to present the growing role of biomarkers in the early detection of Alzheimer’s disease, emphasizing their importance in identifying early pathological changes before the appearance of clinical symptoms. This review seeks to investigate the use of biomarkers in the early detection of Alzheimer’s disease, focusing on articles from the last five years, both national and international. The methodology will be conducted systematically and structurally. The development of biomarkers for Alzheimer’s disease has advanced considerably, providing essential tools for the prevention, diagnosis, and monitoring of disease progression. Among the most studied biomarkers are Beta-Amyloid and phosphorylated Tau protein, which serve as biological indicators of the underlying pathological processes of the disease. These biomarkers can be measured objectively; however, obtaining this information often requires invasive methods, such as the collection of cerebrospinal fluid (CSF) to quantify protein levels. Phosphorylated Tau protein (p-tau), for instance, has proven particularly useful when combined with other biomarkers, offering a more accurate evaluation of the pathology. The integration of protein, genetic, and lipid biomarkers, together with new measurement platforms, will likely be essential in transforming the clinical approach to AD, providing a more comprehensive understanding of the disease from its early stages to its more advanced phases.

Cognitive variation reflects amyloid, tau, and neurodegenerative biomarkers in Alzheimer's disease.

In Alzheimer's disease (AD), the accumulation of neuropathological markers such as amyloid-β plaques, neurofibrillary tangles, and cortical neurodegeneration occurs over many years before overt manifestation of cognitive impairment. There is thus a need for neuropsychological markers that are indicative of pathological changes in the early stages of the disease. Intra-individual cognitive variability (IICV), defined as the variation of an individual's performance across cognitive domains, is a promising neuropsychological marker measuring heterogeneous changes in cognition that may reflect these early pathological changes. In this study, we comprehensively evaluated the global and regional associations of IICV with positron emission tomography (PET) and magnetic resonance imaging (MRI) measures of AD biomarkers in cognitively normal (CN) and mild cognitive impairment (MCI) participants. We found that higher IICV was robustly associated with increased Aβ, increased tau, decreased brain glucose metabolism, and reduced cortical thickness. Higher IICV was also associated with tau (OR = 2.53, P < .001) and fluorodeoxyglucose (OR = 1.34, P < .001) positivity but not Aβ positivity (OR = 1.15, P = .107). In regional analyses, IICV showed widespread associations with AD biomarkers, with the strongest Aβ and tau effects in the frontal and temporal regions, respectively. The strongest regional cortical thickness effects were found in the entorhinal and parahippocampal cortices. Our findings suggest that IICV may be a useful neuropsychological marker for increased Aβ, and especially increased tau and neurodegeneration that are reflective of emerging AD pathology in individuals without dementia.

Epstein-Barr Virus-Induced 3 Attributes to TLR7-Mediated Splenomegaly.

Epstein-Barr virus-induced 3 (EBI3) functions as a component of the heterodimer cytokine IL-27, which regulates innate and acquired immune responses. The expression of EBI3 gene is induced by Toll-like receptors (TLRs). Repeated treatment with imiquimod (IMQ), a TLR7 agonist, induces splenomegaly and cytopaenia due to increased splenic function. Although immune cell activation is speculated to play a role in chronic infection-mediated splenomegaly, the detailed mechanisms remain unknown. This study shows that IMQ treatment induces marked splenomegaly and severe bicytopaenia (anaemia and thrombocytopaenia) in wild-type mice. In IMQ-treated mice, myeloid cell populations in the spleen increased, and extramedullary haematopoiesis was observed. RNA-seq analysis revealed the upregulation of type I interferon (IFN)-related genes in the spleens of IMQ-treated mice. IMQ-induced pathological changes were partially mitigated by EBI3 deficiency. To investigate the mechanism of the improved phenotypes in the Ebi3 KO mice, we examined the involvement of IL-27, a heterodimer of EBI3 and IL-27p28. The expression of Il27a, which encodes IL-27p28, was increased in the spleen and peripheral blood by IMQ treatment. Furthermore, IL-27 stimulation upregulated type I IFN-related genes in bone marrow-derived macrophage cultures without type I IFN. These findings suggest that EBI3 deficiency mitigated IMQ-mediated pathological changes, presumably via a lack of IL-27 formation. Our study thus provides insights into the molecular mechanisms underlying chronic infection-mediated splenomegaly.

Regenerating Locus Coeruleus-Norepinephrine (LC-NE) Function: A Novel Approach for Neurodegenerative Diseases.

Pathological changes in the locus coeruleus-norepinephrine (LC-NE) neurons, the major source of norepinephrine (NE, also known as noradrenaline) in the brain, are evident during the early stages of neurodegenerative diseases (ND). Research on both human and animal models have highlighted the therapeutic potential of targeting the LC-NE system to mitigate the progression of ND and alleviate associated psychiatric symptoms. However, the early and widespread degeneration of the LC-NE system presents a significant challenge for direct intervention in ND. Recent advances in regenerative cell therapy offer promising new strategies for ND treatment. The regeneration of LC-NE from pluripotent stem cells (PSCs) could significantly broaden the scope of LC-NE-based therapies for ND. In this review, we delve into the fundamental background and physiological functions of LC-NE. Additionally, we systematically examine the evidence and role of the LC-NE system in the neuropathology of ND and psychiatric diseases over recent years. Notably, we focus on the significance of PSCs-derived LC-NE and its potential impact on ND therapy. A deeper understanding and further investigation into the regeneration of LC-NE function could pave the way for practical and effective treatments for ND.

Expression profiles of NOD1 and NOD2 and pathological changes in gills during Flavobacterium columnare infection in yellow catfish, Tachysurus fulvidraco.

NOD-like receptors are significant contributors to the immune response of fish against different types of pathogen invasion. NOD1 and NOD2 genes of yellow catfish (Tachysurus fulvidraco) were identified and characterized in this study. Yellow catfish NOD1 and NOD2 have open reading frames (ORFs) of 2841 and 2949 bp, encoding 946 and 982 amino acids, respectively. Both NOD1 and NOD2 are intracellular proteins lacking transmembrane regions and signal peptides. Sequence homology analysis revealed that the protein sequences of NOD1 and NOD2 of yellow catfish are highly similar to those of channel catfish. Both NOD1 and NOD2 showed high expression in the head kidney, and spleen. Following challenge with Flavobacterium columnare, NOD1 expression obviously increased in the liver, spleen, midgut, and hindgut, whereas NOD2 clearly increased in head kidney, and gut. Microscopic observation of gill tissues revealed evident epithelial hyperplasia in the secondary gill filaments at 3 and 6 hpi, with a notable decrease in the aspect ratio in comparison with the control group, followed by a return to baseline levels. These findings indicate a potential involvement of NOD1 and NOD2 genes in defense against F. columnare invasion. The findings of this study contribute valuable insights into NOD1 and NOD2's functions in the innate immune response of yellow catfish and other fish species to bacterial infection.

Highly specific amyloid and tau PET ligands for ATN classification in suspected Alzheimer's disease patients.

This study aims to accurately classify ATN profiles using highly specific amyloid and tau PET ligands and MRI in patients with cognitive impairment and suspected Alzheimer's disease (AD). It also aims to explore the relationship between quantified amyloid and tau deposition and cognitive function. Twenty-seven patients (15 women and 12 men; age range: 64-81years) were included in this study. Amyloid and tau PET scans were performed using 18F-NAV4694 and 18F-MK6240, respectively. For each patient, amyloid and tau PET images were visually assessed and classified as either amyloid-positive or amyloid-negative, and as 18F-MK6240 Braak stage 0 (tau-negative) or Braak stages I-VI (tau-positive). Voxel-based morphometry of three-dimensional T1-weighted MRI was used to evaluate neurodegeneration. Amyloid and tau depositions were quantified using the Centiloid scale and standardized uptake value ratio (SUVR), respectively. Global cognitive function was assessed with the Mini-Mental State Examination (MMSE). Patients were categorized into seven ATN profiles. Six patients (22%) exhibited a normal AD biomarker profile, 15 patients (56%) fell within the Alzheimer's continuum, and 14 patients (52%) were diagnosed with AD. Additionally, six patients (22%) displayed non-AD pathological changes. Positive and negative findings of amyloid and tau PET were concordant in 24 patients (89%). Among the 14 patients diagnosed with AD, the Centiloid scale for amyloid deposition did not show a significant negative correlation with MMSE scores (r = 0.269, p = 0.451). In contrast, the SUVR for tau deposition in the neocortex exhibited a significant negative correlation (r = -0.689, p = 0.014), while tau deposition in the mesial temporal region did not show a significant correlation (r = 0.158, p = 0.763). Highly specific amyloid and tau PET scans, along with MRI, can be utilized to accurately classify ATN profiles in patients with cognitive impairment and suspected AD. The discordance in amyloid and tau PET findings in three patients allowed for a more precise AD diagnosis. Furthermore, tau PET imaging provided insight into the propagation of tau deposition in the neocortex beyond the mesial temporal region, which is associated with cognitive decline.

Sempervirine inhibits proliferation, invasion and metastasis of ovarian cancer cells and induces ultrastructural changes in vivo

Ovarian cancer is one of the deadliest gynecological malignancies due to its late diagnosis and easy recurrence. Therefore, it is urgent to develop novel therapeutics for ovarian cancer treatment. In this study, we evaluated the anti-ovarian cancer effects of sempervirine in vitro and in vivo. CCK8 assays showed that sempervirine dose-dependently inhibited the proliferation of SKOV3 ovarian cancer cells. Transwell assays demonstrated that sempervirine significantly suppressed the invasion and metastasis of SKOV3 cells. Furthermore, in an orthotopic ovarian cancer mouse model, sempervirine dramatically inhibited tumor growth and induced pathological changes in tumor tissues, including poor development of tumor mucosa, collagen deposition, endoplasmic reticulum damage, mitochondrial swelling and vacuolar degeneration, which were similar to the positive control 5-Fu. Mechanistic studies revealed that sempervirine decreased the expression of proteins related to apelin signaling pathway. In conclusion, our results demonstrate the potent anti-ovarian cancer effects of sempervirine both in vitro and in vivo. Sempervirine may repress ovarian cancer by down-regulating apelin signaling pathway. Our study suggests that sempervirine is a promising therapeutic agent against ovarian cancer.

Isoliquiritigenin Protects Against Diabetic Nephropathy in db/db Mice by Inhibiting Advanced Glycation End Product-Receptor for Advanced Glycation End Product Axis.

Diabetes nephropathy (DN) is a severe diabetic chronic microvascular complication and the major cause of end-stage renal disease (ESRD). Our study aimed to investigate the effects of isoliquiritigenin (ISL) a natural flavonoid compound on DN and to explore the underlying mechanisms. The db/db mice were received intragastric treatments of ISL (5, 10, or 20 mg/kg), vehicle or positive drug metformin (300 mg/kg) once a day for 12 weeks, and the db/m mice treated with vehicle were used as controls. ISL significantly ameliorated pathological changes and functional injury in the kidneys of db/db mice in a dose-dependent manner. The administration of 20 mg/kg ISL reduced the levels of serum creatinine (Scr; 49.0 ± 1.7 vs. 56.9 ± 2.9 μmol/L; p < 0.01), blood urine nitrogen (BUN; 9.6 ± 1.3 vs. 12.0 ± 1.1 mmol/L; p < 0.05), albumin to creatinine ratio (ACR; 1925.8 ± 798.1 vs. 4269.4 ± 925.6 μg/mg; p < 0.01) and urinary albumin (276.2 ± 39.9 vs. 576.9 ± 108.9 μg; p < 0.05). Further study identified advanced glycation end product (AGE)-receptor for AGE (RAGE) axis as a target of ISL. ISL (20 mg/kg) lowered renal AGE level (2.5 ± 0.5 vs. 3.8 ± 0.6 μg/mg; p < 0.01) and RAGE expression, leading to improvements in renal fibrosis, oxidative stress, and inflammation. To sum up, our study demonstrated that ISL displayed preventive effects on the experimental model of DN through suppressing AGE-RAGE pathway, and provided some insights into the application of ISL in DN treatment.

Effectiveness of gua sha with Masanggoubang oil in rats with chronic soft tissue injury.

Chronic soft tissue injury is characterized by sterile inflammation and pain. Gua sha with Masanggoubang oil (GSMO) treatment has been found to possess anti-inflammatory and analgesic effects. To explore the mechanism of GSMO in chronic soft tissue injuries. Fifty male rats were randomly divided into 5 groups (n = 10): 1) control group; 2) chronic soft tissue injury model group; 3) GSMO group; 4) inunction with Masanggoubang oil (IMO) group; and 5) ua sha with tea oil (GSTO) group. The control group and model group received no treatment, while the GSTO group and GSMO group received gua sha therapy with tea oil or Masanggoubang oil on the injured sites. The rats in the IMO group were treated with Masanggoubang oil inunction on the injured sites once every other day, 4 times in total. All animals were sacrificed 48 h after the last treatment. Muscle tissue sections from the injured sites of the rats were stained with hematoxylin & eosin (H&E) staining to observe pathological changes. The protein levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), and β-endorphin (β-EP) in the rats' skin, serum, and muscle were determined using enzyme-linked immunosorbent assay (ELISA). Gua sha with Masanggoubang oil treatment alleviated necrosis and the denaturation of muscle fibers at the injured sites, reduced connective tissue proliferation and scar tissue generation, downregulated the levels of TNF-α, IL-6 and iNOS in the skin and TNF-α, IL-1β, IL-6, and iNOS in the muscle and serum, and upregulated β-EP levels in the muscle. Gua sha with Masanggoubang oil treatment significantly improved the inflammatory response in rats with chronic soft tissue injury, which may be associated with a reduction of M1 macrophage polarization in the peripheral blood and local tissues. Additionally, the combination of gua sha therapy and Masanggoubang oil may have a synergistic effect in treating chronic soft tissue injuries.

Endplate Remodeling: a key indicator of cigarette smoke exposure-induced intervertebral disc degeneration in a male rat model

Abstract Recent clinical studies have established a strong association between cigarette smoking and degenerative disc disease. Both in vitro and in vivo research indicated that cigarette smoke disrupts cellular homeostasis in the intervertebral disc (IVD), leading to spatiotemporal remodeling of the extracellular matrix, with a notable reduction in solute diffusivity within the cartilage endplate (CEP). As the CEP serves as a critical mechanical barrier and solute diffusion pathway for the IVD, both roles can be compromised by pathological changes in the tissue. This underscores the need for a more comprehensive examination of endplate remodeling during IVD degeneration, particularly in the context of cigarette smoking and cessation. The objective of this study was to perform a quantitative analysis of the structure-material property relationship changes in the endplate at tissue and cellular levels to determine how endplate mineralization progresses during IVD degeneration in the context of cigarette smoke exposure and cessation, using our previously developed Sprague–Dawley rat model. Our results indicates that cigarette smoke exposure induced endplate remodeling is characterized by a higher CEP histological grade, increased aberrant CEP calcification level, and elevated bony endplate surface flatness score, all of which correlated with an accelerated chondrocyte cell life cycle. Smoke cessation alone was insufficient to reverse the mineralization progression in the endplate. Principal component analysis further identified alterations in endplate morphometry at the tissue level and disruptions in the chondrocyte life cycle at cellular level as key markers of degenerative remodeling. These findings establish endplate remodeling as a key indicator of smoke exposure induced IVD degeneration and inform the development of novel therapeutic strategies aimed at preserving or improving disc health.

Impact of variations in airborne microbiota on pneumonia infection: An exploratory study.

Previous studies showed airborne bacteria affect pneumonia incidence, but specific impacts of bacterial communities on Klebsiella pneumoniae infection were unknown. Five different ratios of bacterial community structures were randomly generated. Mice were divided into control, artificial bacterial community exposure, and corresponding Klebsiella pneumoniae challenge groups. Changes in body weight, blood parameters, pulmonary pathology, inflammatory factors, metabolomics, and fecal microbiota were analyzed. Different bacterial community exposures had varying degrees of influence on body weight, complete blood count, inflammatory factors, alveolar lavage fluid and plasma metabolome, as well as intestinal microbiota at baseline and after infection. Metabolomic analysis showed that microbial exposure affected both bronchoalveolar lavage fluid and plasma metabolomes, suggesting systemic effects of microbial exposure on the organism. Differences in the structure of artificial microbiota had inconsistent effects on both the baseline state and the post-infection state, hinting at crosstalk between microbial exposure and Klebsiella pneumoniae infection. KEGG pathway analysis unveiled possible molecular mechanisms underlying the overall impact of microbial exposure on the lungs and the body as a whole. In the intestinal microbiota, differences were found in composition at the phylum and genus levels. Spearman correlation analysis established potential correlations between intestinal microbiota and differential metabolites, suggesting a potential link within the lung-gut axis. This study demonstrated the significant and systemic impact of air microbiota structure differences on health. Future research should explore the underlying mechanisms to enhance our understanding of the air-environment-health relationship and identify interventions for improving public health strategies.

Advances in neural stem cells in aging and age-related neurodegenerative diseases

With aging, neural stem cells (NSCs) undergo age-related changes, including metabolic abnormalities, disrupted protein homeostasis, mitochondrial dysfunction, reduced genetic stability, and more notably, a diminished capacity for proliferation and differentiation. These changes may contribute to the development of age-related neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In these conditions, disease-specific pathological changes may interact with age-related alterations of NSCs, resulting in impairment of neurogenesis, which further leads to cognitive, mood, and motor decline. Based on these changes, potential therapeutics targeting neurogenesis and stem cell-based therapies may restore the functions of NSCs and replace the degenerated neurons, aiming to ameliorate functional decline in these neurodegenerative diseases. While stem cell-based therapies, including stem cell transplantation and stem cell secretome therapy, show great potential in the treatment of neurodegenerative diseases, challenges in tumorigenesis, immune rejection, and extraction or storage of the stem cell secretome need to be further addressed. A better understanding of age- and disease-related changes in NSCs, the underlying mechanism driving these changes, and the benefits and drawbacks of the therapeutic approaches may provide insights for novel disease-modifying interventions for the future treatment of these diseases.

A preliminary exvivo diffusion tensor imaging study of distinct aortic morphologies.

Changes in the microstructure of the aortic wall precede the progression of various aortic pathologies, including aneurysms and dissection. Current clinical decisions with regards to surgical planning and/or radiological intervention are guided by geometric features, such as aortic diameter, since clinical imaging lacks tissue microstructural information. The aim of this proof-of-concept work is to investigate a non-invasive imaging method, diffusion tensor imaging (DTI), in exvivo aortic tissue to gain insights into the microstructure. This study examines healthy, aneurysm and a type B chronic dissection aortae, via DTI. DTI-derived metrics, such as the fractional anisotropy, mean diffusivity, helical angle and tractography, were examined in each morphology. The results from this work highlighted distinct differences in fractional anisotropy (healthy, 0.24 ± 0.008; aneurysmal, 0.19 ± 0.002; dissected, 0.13 ± 0.006) and a larger variation in the helical angle in the dissected aorta compared to healthy (39.28 ± 11.93° vs. 26.12 ± 4.60°, respectively). These differences were validated by histological characterisation. This study demonstrates the sensitivity of DTI to pathological changes in aortic tissue, highlighting the potential of this methodology to provide improved clinical insight.

Pharmacological modulation of Sigma-1 receptor ameliorates pathological neuroinflammation in rats with diabetic neuropathic pain via the AKT/GSK-3β/NF-κB pathway.

Diabetic neuropathic pain (DNP) is a common complication of diabetes mellitus (DM) and is characterized by spontaneous pain and neuroinflammation. The Sigma-1 receptor (Sig-1R) has been proposed as a target for analgesic development. It is an important receptor with anti-inflammatory properties and has been found to regulate DNP. However, it is not known whether Sig-1R can ameliorate pathological neuroinflammation in DNP. The present study used a rat model of DNP and a highly selective agonist of Sig-1R to assess the effects of the protein on neuropathic pain in rats with type 2 diabetes mellitus. The rats were divided into Control, Model, Sig-1R agonist PRE-084 (0.3, 0.6, 1mg/kg), and metformin (Met, 20mg/kg) groups, with seven rats per group, and their body weight, fasting blood glucose, mechanical withdrawal threshold and thermal withdrawal latency were tested weekly for two weeks. After treatment with PRE-084, the pain thresholds in the DNP rats were significantly improved, together with pathological changes in the dorsal root ganglion, reductions in the serum levels of TNF-α, IL-1β, IL-6, MOD, and prostaglandin E2 (PGE2), and the activity of superoxide dismutase was increased. The mRNA levels of TNF-α, IL-1β, and cyclooxygenase 2 (COX-2) were reduced. Pharmacological inhibition of Sig-1R with BD1047 (10μM) abolished Sig-1R-mediated activation of lipopolysaccharide-treated BV-2 microglial cells. It was also found that PRE-084 increased phosphorylation of serine/threonine protein kinase B (AKT) and glycogen synthase kinase 3β (GSK-3β) at Ser9, inhibiting nuclear factor kappa B (NF-κB)-mediated neuroinflammation in the dorsal root ganglion, thus reducing DNP. The findings suggest that the effect of Sig-1R agonist PRE-084 on DNP may reduce the level of inflammation through the up-regulation of AKT/GSK-3β and down-regulation of the NF-κB signaling, thereby contributing to the treatment of the disease.

Adolescent mice exposed to TBI developed PD-like pathology in middle age

Traumatic brain injury (TBI) is identified as a risk factor for Parkinson’s disease (PD), which is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN). However, the precise mechanism by which chronic TBI initiates PD pathogenesis is not yet fully understood. In our present study, we assessed the chronic progression and pathogenesis of PD-like behavior at different intervals in TBI mice. More than half of the mice exhibited PD-like behavior at 6 months post injury. PD-like behavioral dysfunction and pathological changes were aggravated with the injured time extension in chronic phase of TBI. The loss of tyrosine hydroxylase positive (TH+) neurons in the SN were partly associated with the accumulation of misfolded a-Synuclein and the cytoplasmic translocation of TDP-43 from nuclear. Moreover, the present of chronic inflammation was observed in SN of TBI mice, as evidenced by the enhancement of proinflammatory cytokines and reactive astrocytes and microgliosis post lesion. The enhanced phagocytosis of reactive microglia accounted for the reduction of dendrite spines. Our results revealed that chronic inflammation associated with the damage of TH+ neurons and the development of progressive PD-like pathology after chronic TBI in mice. Our study shed new light on the TBI-triggered molecular events on PD-like pathology. Additional research is required to have a deeper understanding of the molecular factors underlying the impairment of dopaminergic neurons following TBI.

Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy.

CSF1R-related leukoencephalopathy (CSF1R-L) and AARS2-related leukoencephalopathy (AARS2-L) were two disease entities sharing similar phenotype and even pathological changes. Although clinically, radiologically, and pathologically similar, they were caused by mutation of two different genes. As the rarity of the two diseases, the differential diagnosis of them was difficult. 23 CSF1R-L and 6 AARS2-L patients were enrolled from the Leukoencephalopathy Clinic, Peking Union Medical College Hospital in China. Detailed clinical information, neuroimaging manifestations, and genetic data were collected and analyzed. Demographically, female patients were more in AARS2-L than CSF1R-L. Clinically, cognitive impairment and emotion/personality change were common in both groups. Bulbar palsy, extrapyramidal symptoms, and hemiplegia/pyramidal impairment were more common in CSF1R-L, while ataxia was significantly more common in AARS2-L. Abnormal menstruation including infertility was significantly more in AARS2-L. Radiologically, similar features were found, including lateral ventricle-centered white matter lesions, involving corpus callosum, avoiding U fibers. The lesions showed persistent hyperintensity on DWI image and were not contrasted after gadolinium enhancement. In CSF1R-L, the lesions could be widespread confluent or patchy and spotted, extending to centrum semiovale and subcortical white matter occasionally, which was significantly different from AARS2-L. Besides, brain stem lesion caused by pyramidal degeneration, spotted or linear calcification and obviously brain atrophy were common in CSF1R-L. In AARS2-L, periventricular white matter rarefaction was significantly common. No genotype and phenotype association was found in these two diseases. Although similar, there were several clinical and radiological features helping differentiating the two distinct diseases.

Non-Invasive Retinal Biomarkers for Early Diagnosis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain associated with ageing and is the most prevalent form of dementia, affecting an estimated 55 million people worldwide, with projections suggesting this number will exceed 150 million by 2050. With its increasing prevalence, AD represents a significant global health challenge with potentially serious social and economic consequences. Diagnosing AD is particularly challenging as it requires timely recognition. Currently, there is no effective therapy for AD; however, certain medications may help slow its progression. Existing diagnostic methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and biomarker analysis in cerebrospinal fluid tend to be expensive and invasive, making them impractical for widespread use. Consequently, research into non-invasive biomarkers that enable early detection and screening for AD is a crucial area of contemporary clinical investigation. One promising approach for the early diagnosis of AD may be retinal imaging. As an extension of the central nervous system, the retina offers a distinctive opportunity for non-invasive brain structure and function assessment. Considering their shared embryological origins and the vascular and immunological similarities between the eye and brain, alterations in the retina may indicate pathological changes in the brain, including those specifically related to AD. Studies suggest that structural and vascular changes in the retina, particularly within the neuronal network and blood vessels, may act as markers of cerebral changes caused by AD. These retinal alterations have the potential to act as biomarkers for early diagnosis. Since AD is typically diagnosed only after a significant neuronal loss has occurred, identifying early diagnostic markers could enable timely intervention and help prevent disease progression. Non-invasive retinal imaging techniques, such as optical coherence tomography (OCT) and OCT angiography, provide accessible methods for the early detection of changes linked to AD. This review article focuses on the potential of retinal imaging as a non-invasive biomarker for early diagnosis of AD. Investigating the ageing of the retina and its connections to neurodegenerative processes could significantly enhance the diagnosis, monitoring, and treatment of AD, paving the way for new diagnostic and therapeutic approaches.

Realistic total-body J-PET geometry optimization: Monte Carlo study.

Total-body (TB) Positron Emission Tomography (PET) is one of the most promising medical diagnostics modalities, opening new perspectives for personalized medicine, low-dose imaging, multi-organ dynamic imaging or kinetic modeling. The high sensitivity provided by total-body technology can be advantageous for novel tomography methods like positronium imaging, demanding the registration of triple coincidences. Currently, state-of-the-art PET scanners use inorganic scintillators. However, the high acquisition cost reduces the accessibility of TB PET technology. Several efforts are ongoing to mitigate this problem. Among the alternatives, the Jagiellonian PET (J-PET) technology, based on axially arranged plastic scintillator strips, offers a low-cost alternative solution for TBPET. The work aimed to compare five total-body J-PET geometries with plastic scintillators suitable for multi-organ and positronium tomography as a possible next-generation J-PET scannerdesign. We present comparative studies of performance characteristics of the cost-effective total-body PET scanners using J-PET technology. We investigated in silico five TB scanner geometries, varying the number of rings, scanner radii, and other parameters. Monte Carlo simulations of the anthropomorphic XCAT phantom, the extended 2-m sensitivity line source and positronium sensitivity phantoms were used to assess the performance of the geometries. Two hot spheres were placed in the lungs and in the liver of the XCAT phantom to mimic the pathological changes. We compared the sensitivity profiles and performed quantitative analysis of the reconstructed images by using quality metrics such as contrast recovery coefficient, background variability and root mean squared error. The studies are complemented by the determination of sensitivity for the positronium lifetime tomography and the relative cost analysis of the studiedsetups. The analysis of the reconstructed XCAT images reveals the superiority of the seven-ring scanners over the three-ring setups. However, the three-ring scanners would be approximately 2-3 times cheaper. The peak sensitivity values for two-gamma vary from 20 to 34cps/kBq and are dominated by the differences in geometrical acceptance of the scanners. The sensitivity curves for the positronium tomography have a similar shape to the two-gamma sensitivity profiles. The peak values are lower compared to the two-gamma cases, from about 20-28 times, with a maximum value of 1.66 cps/kBq. This can be contrasted with the 50-cm one-layer J-PET modular scanner used to perform the first in-vivo positronium imaging with a sensitivity of 0.06 cps/kBq. The results show the feasibility of multi-organ imaging of all the systems to be considered for the next generation of TB J-PET designs. Among the scanner parameters, the most important ones are related to the axial field-of-view coverage. The two-gamma sensitivity and XCAT image reconstruction analyzes show the advantage of seven-ring scanners. However, the cost of the scintillator materials and SiPMs is more than two times higher for the longer modalities compared to the three-ring solutions. Nevertheless, the relative cost for all the scanners is about 10-4 times lower compared to the cost of the uExplorer. These properties coupled together with J-PET cost-effectiveness and triggerless acquisition mode enabling three-gamma positronium imaging, make the J-PET technology an attractive solution for broad application inclinics.

Three-Plane Calcaneal Osteotomy With Joint Preservation vs Subtalar Arthrodesis to Treat Painful Calcaneal Fracture Malunions.

Calcaneal fracture malunion (CFM) commonly occurs with multiple pathologic changes and progressive pain and difficulty walking. The purpose of this study was to propose a modified 3-plane joint-preserving osteotomy for the treatment of CFM with subtalar joint incongruence, and to compare its efficacy to subtalar arthrodesis. A retrospective comparative analysis of the data of 56 patients with CFM admitted from January 2017 to December 2022 was performed. Twenty-six patients were in the osteotomy group and 30 in the arthrodesis group. Computed tomographic (CT) scans were used for measurement of the intraarticular steps. Radiologic parameters, visual analog scale (VAS) score for pain, 12-Item Short Form Health Survey (SF-12) mental component summary (MCS) and physical component summary (PCS) scores were compared between the 2 groups of patients to assess the outcome preoperatively and at last follow-up, which averaged 22.6 ± 3.6 months and 27.6 ± 3.6 months for the osteotomy and arthrodesis groups, respectively. Improvements in pain, function, and overall quality of life were obtained in both groups compared with the preoperative values at last follow-up. The VAS and SF-12 scores were similar between the groups at the last follow-up. In the osteotomy group, the average CT scan-measured intraarticular step-offs were significantly reduced from 3.7 ± 1.2 mm to 0.9 ± 0.3 mm. The osteotomy group showed improvement in pronation and supination range of motion (ROM) of the feet (P < .01). The correction of the ankle height and Meary angle were slightly better in the osteotomy group. In this short-term follow-up study, good results were achieved in both joint-preserving osteotomy and subtalar arthrodesis groups for the treatment of CFM with subtalar joint incongruence. The osteotomy group preserved the subtalar joint and achieved improvements in pronation and supination ROM.

Adipose Tissue-Derived Mesenchymal Stem Cells Regulate Th17/Treg in a Rat Model of Allergic Rhinitis by Activating IL-2/JAK3/STAT5 Signaling Pathway.

To investigate how adipose-derived mesenchymal stem cells (ADSCs) regulate the balance between regulatory T cells (Treg) and Th17 cells through the IL-2/JAK3/STAT5 signaling pathway in a rat model of allergic rhinitis (AR). Adipose-derived stem cells (ADSCs) were used to treat an ovalbumin (OVA)-induced AR rat model. The pathological changes and nasal symptoms were observed by HE staining and scanning electron microscopy. The concentrations of OVA-sIgE, IL-10, and IL-17 in serum were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of JAK-3, STAT-5, forkhead box P3 (Foxp3), and retinoic acid-associated orphan receptor γt (RORγt) in nasal mucosa were detected by reverse transcription-polymerase chain reaction (RT-PCR). The expression of IL-2, JAK-3, and STAT-5 proteins in nasal mucosa was detected by Western blotting, and the expression patterns of these proteins were analyzed. ADSCs significantly reduced nasal symptoms and histological abnormalities by significantly reducing the levels of OVA-sIgE and IL-10. The expressions of IL-2, JAK-3, STAT-5, IL-2, JAK-3, STAT-5, Foxp3 mRNA, and RORγ t mRNA in the nasal mucosa of AR rats were significantly increased. ADSC can control the development of Treg/Th17 cells by the IL-2/JAK-3/STAT-5 signaling pathway and reduce OVA-induced allergic inflammation.