Novel Potential Diagnostic Serum Biomarkers of Metabolomics in Osteoarticular Tuberculosis Patients: A Preliminary Study.

Osteoarticular tuberculosis is one of the extrapulmonary tuberculosis, which is mainly caused by direct infection of Mycobacterium tuberculosis or secondary infection of tuberculosis in other parts. Due to the low specificity of the current detection method, it is leading to a high misdiagnosis rate and subsequently affecting the follow-up treatment and prognosis. Metabolomics is mainly used to study the changes of the body's metabolites in different states, so it can serve as an important means in the discovery of disease-related metabolic biomarkers and the corresponding mechanism research. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to detect and analyze metabolites in the serum with osteoarticular tuberculosis patients, disease controls, and healthy controls to find novel metabolic biomarkers that could be used in the diagnosis of osteoarticular tuberculosis. Our results showed that 68 differential metabolites (p<0.05, fold change>1.0) were obtained in osteoarticular tuberculosis serum after statistical analysis. Then, through the evaluation of diagnostic efficacy, PC[o-16:1(9Z)/18:0], PC[20:4(8Z,11Z,14Z,17Z)/18:0], PC[18:0/22:5(4Z,7Z,10Z,13Z,16Z)], SM(d18:1/20:0), and SM[d18:1/18:1(11Z)] were found as potential biomarkers with high diagnostic efficacy. Using bioinformatics analysis, we further found that these metabolites share many lipid metabolic signaling pathways, such as choline metabolism, sphingolipid signaling, retrograde endocannabinoid signaling, and sphingolipid and glycerophospholipid metabolism; these results suggest that lipid metabolism plays an important role in the pathological process of tuberculosis. This study can provide certain reference value for the study of metabolic biomarkers of osteoarticular tuberculosis and the mechanism of lipid metabolism in osteoarticular tuberculosis and even other tuberculosis diseases.

Emerging Roles of Extracellular Vesicle-Delivered Circular RNAs in Atherosclerosis.

Atherosclerosis (AS) is universally defined as chronic vascular inflammation induced by dyslipidaemia, obesity, hypertension, diabetes and other risk factors. Extracellular vesicles as information transmitters regulate intracellular interactions and their important cargo circular RNAs are involved in the pathological process of AS. In this review, we summarize the current data to elucidate the emerging roles of extracellular vesicle-derived circular RNAs (EV-circRNAs) in AS and the mechanism by which EV-circRNAs affect the development of AS. Additionally, we discuss their vital role in the progression from risk factors to AS and highlight their great potential for use as diagnostic biomarkers of and novel therapeutic strategies for AS.

Development of an immune-related prognostic biomarker for triple-negative breast cancer.

Purpose: Oncology studies employing digital dissection methodologies have provided some insight on the biological features of tumor microenvironment of Triple-negative breast cancer (TNBC), but molecular diagnostics rarely have therapeutic impact. We aimed to identify a novel prognostic biomarker to investigate immune characteristics of TNBC using transcriptomic features.Patients and Methods: We extracted whole transcriptome from breast cancer tissue of 30 TNBC patients and then used bioinformatics approaches to characterize the different immune cell contents in tumor tissue and para-cancerous tissue. We extract 2 indicators to describe the major differences in immune infiltration in the microenvironment between tumor tissue and para-cancerous tissue. We then combined the 2 indicators that represent the levels of increased and decreased infiltration in each sample to obtain the Immune Infiltration Score (IIS). Then we compared the tumor-infiltrating immune cell contents and immune infiltrating status in TNBC samples with CIBERSORT and ESTIMATE score to validate the IIS. Finally, 132 TNBC patients from the Cancer Genome Atlas program (TCGA) dataset was used to validate the predictive power of IIS.Results: 4 types of upregulated and 4 types of downregulated immune cells were identified in the tumor tissue samples of the TNBC patients. Then we developed a novel biomarker, IIS. Results showed that IIS score can clearly separate cancer and para-cancerous tissue. Using the same cutoff value of 0 in the TNBC-TCGA cohort, we show that those patients with a higher IIS had significantly higher PD-L1 expression and shorter progression-free survival time than those with a lower IIS value, indicating IIS score can be generalized to other TNBC datasets.Conclusion: we explored the immune infiltration landscape in 30 TNBC patients and provided IIS as a novel and reliable biomarker to evaluate the progression-free survival and prognosis of the TNBC patients.

Immune ULBP1 is Elevated in Colon Adenocarcinoma and Predicts Prognosis.

Background: Colon adenocarcinoma (COAD) is still the main cause of cancer deaths worldwide. Although immunotherapy has made progress in recent years, there is still a need to improve diagnosis, prognosis, and treatment tools. UL-16 binding protein 1 (ULBP1) is a ligand that activates the receptor natural killer cell group 2 receptor D (NKG2D) and plays an important immunomodulatory role. We aimed to investigate the clinical significance of ULBP1 in COAD. Methods: We obtained the relevant data from The Cancer Genome Atlas (TCGA). A total of 438 patients with COAD were included in this study, with a mean age of 67.1 ± 13.03 years old, of which 234 (53.42%) were male. The diagnostic value of COAD tumor tissues and adjacent tissues was analyzed by ROC curve. Univariate and multivariate survival analysis investigated the prognostic value of ULBP1 gene, and Gene Set Enrichment Analysis (GSEA) curve was performed to analyze the biological process and enriched enrichment pathway of ULBP1 in COAD. Combination survival analysis investigated the combined prognostic effect of prognostic genes. Results: ULBP1 gene had a high diagnostic value in COAD [AUC (TCGA) = 0.959; AUC (Guangxi) = 0.898]. Up-regulated ULBP1 gene of patients with COAD predicted a worse prognosis compared to those patients with down-regulated ULBP1 gene (Adjusted HR = 1.544, 95% CI = 1.020-2.337, p = 0.040). The GSEA showed that ULBP1 was involved in the apoptotic pathway and biological process of T cell mediated cytotoxicity, regulation of natural killer cell activation, and T cell mediated immunity of COAD. The combination survival analysis showed that the combination of high expression of ULBP1, AARS1, and DDIT3 would increase the 2.2-fold death risk of COAD when compared with those of low expression genes. Conclusion: The immune-related ULBP1 gene had diagnostic and prognostic value in COAD. The combination of ULBP1, AARS1, and DDIT3 genes could improve the prognostic prediction performance in COAD.

Biomarkers in Cardiorenal Syndrome and Potential Insights Into Novel Therapeutics.

Heart and kidney failure often co-exist and confer high morbidity and mortality. The complex bi-directional nature of heart and kidney dysfunction is referred to as cardiorenal syndrome, and can be induced by acute or chronic dysfunction of either organ or secondary to systemic diseases. The five clinical subtypes of cardiorenal syndrome are categorized by the perceived primary precipitant of organ injury but lack precision. Traditional biomarkers such as serum creatinine are also limited in their ability to provide an early and accurate diagnosis of cardiorenal syndrome. Novel biomarkers have the potential to assist in the diagnosis of cardiorenal syndrome and guide treatment by evaluating the relative roles of implicated pathophysiological pathways such as hemodynamic dysfunction, neurohormonal activation, endothelial dysfunction, inflammation and oxidative stress, and fibrosis. In this review, we assess the utility of biomarkers that correlate with kidney and cardiac (dys)function, inflammation/oxidative stress, fibrosis, and cell cycle arrest, as well as emerging novel biomarkers (thrombospondin-1/CD47, glycocalyx and interleukin-1ß) that may provide prediction and prognostication of cardiorenal syndrome, and guide potential development of targeted therapeutics.

Do Relapses Follow ANCA Rises? A Systematic Review and Meta-Analysis on the Value of Serial ANCA Level Evaluation.

Objectives: ANCA-vasculitis (AAV) patients frequently suffer from relapses and risk subsequent organ damage. There is much debate on the value of serial ANCA level evaluation to monitor disease activity. We aimed to evaluate the association between ANCA rises and disease relapses at (I) moment of the rise, (II) within 6 months or (III) within a year from the rise. Methods: 3 databases (MEDLINE, EMBASE, COCHRANE) were searched from 1993 through September 2021. We included studies that reported relapse incidence within 12 months after an ANCA rise measured by antigen-specific immunoassays in peripheral blood of AAV patients in remission. Quality assessment was performed using QUADAS-2. Finally, a meta-analysis was carried out to estimate average OR using a random effects model. Results: Twenty unique studies were included. The methodological quality was limited due to risk of selection bias. An ANCA rise often preceded a disease relapse within 6 months (OR 3.65, 95% CI 1.66-8.03) and less often within 12 months (OR 2.88, 95% CI 1.21-6.88), while it was not indicative of a concurrent relapse (OR 0.13, 95% CI 0.03-0.53). Once a relapse is diagnosed, ANCA is significantly more often present than not (OR 10.80, 95% CI 3.82-30.55). As expected based on clinical, technical and methodological variability between studies, there was substantial heterogeneity across studies in all analyses (I2 = 70-87%). Conclusion: In previously ANCA-positive patients, the ANCA test is often positive upon clinical suspicion of a disease relapse. Patients with a rise in ANCA are at risk of encountering disease relapses in the upcoming 6 or 12 months.

Hemorrhagic Stroke Induces a Time-Dependent Upregulation of miR-150-5p and miR-181b-5p in the Bloodstream.

To date, the only effective pharmacological treatment for ischemic stroke is limited to the clinical use of recombinant tissue plasminogen activator (rtPA), although endovascular therapy has also emerged as an effective treatment for acute ischemic stroke. Unfortunately, the benefit of this treatment is limited to a 4.5-h time window. Most importantly, the use of rtPA is contraindicated in the case of hemorrhagic stroke. Therefore, the identification of a reliable biomarker to distinguish hemorrhagic from ischemic stroke could provide several advantages, including an earlier diagnosis, a better treatment, and a faster decision on ruling out hemorrhage so that tPA may be administered earlier. microRNAs (miRNAs) are stable non-coding RNAs crucially involved in the downregulation of gene expression via mRNA cleavage or translational repression. In the present paper, taking advantage of three preclinical animal models of stroke, we compared the miRNA blood levels of animals subjected to permanent or transient middle cerebral artery occlusion (MCAO) or to collagenase-induced hemorrhagic stroke. Preliminarily, we examined the rat miRNome in the brain tissue of ischemic and sham-operated rats; then, we selected those miRNAs whose expression was significantly modulated after stroke to create a list of miRNAs potentially involved in stroke damage. These selected miRNAs were then evaluated at different time intervals in the blood of rats subjected to permanent or transient focal ischemia or to hemorrhagic stroke. We found that four miRNAs-miR-16-5p, miR-101a-3p, miR-218-5p, and miR-27b-3p-were significantly upregulated in the plasma of rats 3 h after permanent MCAO, whereas four other different miRNAs-miR-150-5p, let-7b-5p, let-7c-5p, and miR-181b-5p-were selectively upregulated by collagenase-induced hemorrhagic stroke. Collectively, our study identified some selective miRNAs expressed in the plasma of hemorrhagic rats and pointed out the importance of a precise time point measurement to render more reliable the use of miRNAs as stroke biomarkers.

Machine Learning Profiling of Alzheimer's Disease Patients Based on Current Cerebrospinal Fluid Markers and Iron Content in Biofluids.

Alzheimer's disease (AD) is the most common form of dementia, characterized by a complex etiology that makes therapeutic strategies still not effective. A true understanding of key pathological mechanisms and new biomarkers are needed, to identify alternative disease-modifying therapies counteracting the disease progression. Iron is an essential element for brain metabolism and its imbalance is implicated in neurodegeneration, due to its potential neurotoxic effect. However, the role of iron in different stages of dementia is not clearly established. This study aimed to investigate the potential impact of iron both in cerebrospinal fluid (CSF) and in serum to improve early diagnosis and the related therapeutic possibility. In addition to standard clinical method to detect iron in serum, a precise quantification of total iron in CSF was performed using graphite-furnace atomic absorption spectrometry in patients affected by AD, mild cognitive impairment, frontotemporal dementia, and non-demented neurological controls. The application of machine learning techniques, such as clustering analysis and multiclassification algorithms, showed a new potential stratification of patients exploiting iron-related data. The results support the involvement of iron dysregulation and its potential interaction with biomarkers (Tau protein and Amyloid-beta) in the pathophysiology and progression of dementia.

Understanding Fatigue in Sjögren's Syndrome: Outcome Measures, Biomarkers and Possible Interventions.

Sjögren's syndrome (SS) is an autoimmune disease affecting the salivary and lacrimal glands. Symptoms range from dryness to severe extra-glandular disease involving manifestations in the skin, lungs, nervous system, and kidney. Fatigue occurs in 70% of patients, characterizing primary SS (pSS) and significantly impacting the patient's quality of life. There are some generic and specific instruments used to measure fatigue in SS. The mechanisms involved with fatigue in SS are still poorly understood, but it appears fatigue signaling pathways are more associated with cell protection and defense than with pro-inflammatory pathways. There are no established pharmacological treatment options for fatigue in pSS. So far, exercise and neuromodulation techniques have shown positive effects on fatigue in pSS. This study briefly reviews fatigue in pSS, with special attention to outcome measures, biomarkers, and possible treatment options.

Neurofilament Light Chain Protein Is a Predictive Biomarker for Stroke After Surgical Repair for Acute Type A Aortic Dissection.

Background: Although great progress has been made in surgery and perioperative care, stroke is still a fatal complication of acute type A aortic dissection (ATAAD). Serum biomarkers may help assess brain damage and predict patient's prognosis. Methods: From March, 2019 to January, 2020, a total of 88 patients underwent surgical treatment at the Department of Cardiovascular Surgery of Beijing Anzhen Hospital, China, and were enrolled in this study. Patients were divided into two groups according to whether they had suffered a stroke after the operation. Blood samples were collected at 8 time points within 3 days after surgery to determine the level of S100ß, neuron-specific enolase (NSE) and neurofilament light chain protein (NFL). Receiver operating characteristic curves (ROC) were established to explore the biomarker predictive value in stroke. The area under the curve (AUC) was used to quantify the ROC curve. Results: The patient average age was 48.1 ± 11.0 years old and 70 (79.6%) patients were male. Fifteen (17.0%) patients suffered stroke after surgery. The NFL levels of patients in the stroke group at 12 and 24 h after surgery were significantly higher than those in the non-stroke group (all P < 0.001). However, the NSE and S100ß levels did not differ significantly at any time point between the two groups. The predictive value of NFL was the highest at 12 and 24 h after surgery, and the AUC was 0.834 (95% CI, 0.723-0.951, P < 0.001) and 0.748 (95% CI, 0.603-0.894, P = 0.004), respectively. Its sensitivity and specificity at 12 h were 86.7 and 71.6%, respectively. The NFL cutoff value for the diagnosis of stroke at 12 h after surgery was 16.042 ng/ml. Conclusions: This study suggests that NFL is an early and sensitive serum marker for predicting post-operative neurological prognosis of ATAAD patients. Further studies, including large-scale prospective clinical trials, are necessary to test whether the NFL can be used as a biomarker for clinical decision-making.

PD-1 Inhibitors Plus Capecitabine as Maintenance Therapy for Advanced Intrahepatic Cholangiocarcinoma: A Case Report and Review of Literature.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer with a poor prognosis. Recently, an immunotherapy strategy represented by programmed cell death 1 (PD-1) inhibitors has been applied to the systemic treatment of advanced iCCA. However, immunotherapy combined with chemotherapy as first-line maintenance therapy was rarely reported. Our report presented an advanced iCCA patient who had a dramatic response to the PD-1 inhibitor sintilimab combined with gemcitabine plus cisplatin as the first-line therapy and sintilimab combined with capecitabine as maintenance therapy, yielding an ongoing progression-free survival of 16 months.

Advances in miR-132-Based Biomarker and Therapeutic Potential in the Cardiovascular System.

Atherosclerotic cardiovascular disease and subsequent heart failure threaten global health and impose a huge economic burden on society. MicroRNA-132 (miR-132), a regulatory RNA ubiquitously expressed in the cardiovascular system, is up-or down-regulated in the plasma under various cardiac conditions and may serve as a potential diagnostic or prognostic biomarker. More importantly, miR-132 in the myocardium has been demonstrated to be a master regulator in many pathological processes of ischemic or nonischemic heart failure in the past decade, such as myocardial hypertrophy, fibrosis, apoptosis, angiogenesis, calcium handling, neuroendocrine activation, and oxidative stress, through downregulating target mRNA expression. Preclinical and clinical phase 1b studies have suggested antisense oligonucleotide targeting miR-132 may be a potential therapeutic approach for ischemic or nonischemic heart failure in the future. This review aims to summarize recent advances in the physiological and pathological functions of miR-132 and its possible diagnostic and therapeutic potential in cardiovascular disease.

Colonic Leucine-Rich Repeat Kinase 2 Expression Is Increased and Associated With Disease Severity in Patients With Parkinson's Disease.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise a common genetic risk factor for Parkinson's disease (PD) and inflammatory bowel disease (IBD). We investigated the expression of LRRK2 in colonic biopsies obtained from a cohort of PD patients and healthy controls. METHODS: A cohort of 51 PD patients and 40 age- and gender-matched controls who have colonic biopsied samples were recruited. Among these participants, 26 individuals (12 PD patients and 14 controls) had a series of colon biopsies. For the patients with PD, the first biopsies were taken before the PD diagnosis. The colonic expression of LRRK2 was assayed by immunohistochemical staining. RESULTS: The fraction of LRRK2-positive cells among the total cell count in biopsied colonic tissues was significantly higher in PD patients than controls (0.81% ± 0.53% vs. 0.45% ± 0.39%; P = 0.02). Colonic LRRK2 immunoreactivity was higher in those with LRRK2 genetic variants compared to those with wild type LRRK2 (2.44% ± 1.15% vs. 0.21 ± 0.13%, P < 0.01). Age had no effect on LRRK2 expression (P = 0.96). LRRK2 expression correlated with disease severity in regards to motor symptoms measured by the UPDRS part III scores (r = 6335, P < 0.001) and cognitive dysfunction measured by the mini-mental status examination scores (r = -0.5774, P < 0.001). PD patients in the prodromal phase had a steeper increase in colonic LRRK2 expression compared to controls during the serial colon biopsy assessment (P < 0.01). CONCLUSION: Colonic LRRK2 expression was increased in PD patients compared to controls, and the expression level correlated with disease severity.

Circulating Tumor Cells: A Promising Biomarker in the Management of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignancy that arises from the mucosal epithelium of the nasopharynx, and its prognosis is relatively favorable. The 5-year overall survival rate in patients with locally advanced NPC currently exceeds 80%, but the development of individualized diagnosis and treatment at the molecular level is relatively lacking. Circulating tumor cells (CTCs) is the generic term for tumor cells that are present in the peripheral blood circulation. As a new biomarker with good clinical application prospects, the detection of CTCs has the advantages of being non-invasive, simple, and repeatable. By capturing and detecting CTCs in peripheral blood and monitoring the dynamic variation of its type and quantity, we can assess the biological characteristics of tumor in a timely manner and evaluate the therapeutic effect and prognosis of patients in advance, which will help to develop individualized treatments of tumors. The primary purposes of this review were the clinical application of CTCs in tumor stage determination, treatment efficacy evaluation, and prognosis prediction of NPC. In addition, we estimated the correlation between Epstein-Barr virus infection and CTCs and analyzed the difference in karyotypes and specific markers expressed on CTCs. We believe that our study will provide new insights and biomarkers for the individualized treatment of patients with NPC.

A 3-Biomarker 2-Point-Based Risk Stratification Strategy in Acute Heart Failure.

Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge. Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715-0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF). Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747-0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers. Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality.

Dynamic R2' Imaging can Be a Biomarker for Diagnosing and Staging Early Acute Kidney Injury in Animals.

Background: Early diagnosis of acute kidney injury (AKI) is essential in clinical settings. None of the current biomarkers are widely applied. The combination of pulse-shifting multi-echo asymmetric spin-echo sequence (psMASE) and a modified hemodynamic response imaging (HRI) technique is promising. The purpose of this study was to evaluate the feasibility of psMASE combined with HRI in detecting early ischemic AKI in animal models of different severities. Methods: Twenty rabbits were divided into four groups (mild, moderate, and severe AKI and control groups). Transarterial embolization with different doses of microspheres was performed to establish AKI animal models of different severities. The 3T psMASE and HRI scans of kidneys were conducted. The R2*, R2, and R2' during room air and gas stimulation were acquired and the difference of R2' (dR2') was evaluated in different AKI groups. Results: The values were not different in R2* and R2 during room air and in R2* and R2, and R2' during gas stimulation. The value of R2' was significantly different during room air (P = 0.014), but the difference was only found between control and moderate/severe AKI groups (P = 0.032 and 0.022). The values of dR2' were different among groups (P < 0.0001) and differences between every two groups except comparison of moderate and severe AKI groups were significant (P < 0.01). Conclusion: The dR2' imaging acquired by a combination of renal psMASE and HRI technique can serve as a potential quantitative biomarker for early detection and staging of AKI.

Oxidized Albumin and Cartilage Acidic Protein-1 as Blood Biomarkers to Predict Ischemic Stroke Outcomes.

Background: There is high demand for blood biomarkers that reflect the therapeutic response or predict the outcomes of patients with acute ischemic stroke (AIS); however, few biomarkers have been evidentially verified to date. This study evaluated two proteins, oxidized albumin (OxHSA) and cartilage acidic protein-1 (CRTAC1), as potential prognostic markers of AIS. Methods: The ratio of OxHSA to normal albumin (%OxHSA) and the level of CRTAC1 in the sera of 74 AIS patients were analyzed on admission (day 0), and at 1 and 7 days after admission. AIS patients were divided into two groups according to their modified Rankin Scale (mRS) at 3 months after discharge: the low-mRS (mRS < 2) group included 48 patients and the high-mRS (mRS ≥ 2) group included 26 patients. The differences in %OxHSA and CRTAC1 between the two groups on days 0, 1, and 7 were evaluated. Results: The mean %OxHSA values of the high-mRS group on days 0, 1, and 7 were significantly higher than those of the low-mRS group (p < 0.05). The CRTAC1 levels continuously increased from day 0 to day 7, and those of the high-mRS group were significantly higher than those of the low-mRS group on day 7 (p < 0.05). Conclusions: These results suggest that higher %OxHSA and CRTAC1 are associated with poor outcomes in AIS patients. An index that combines %OxHSA and CRTAC1 can accurately predict the outcomes of AIS patients.

Sex-Specific Retinal Anomalies Induced by Chronic Social Defeat Stress in Mice.

Major depressive disorder (MDD) is one of the most common consequences of chronic stress. Still, there is currently no reliable biomarker to detect individuals at risk to develop the disease. Recently, the retina emerged as an effective way to investigate psychiatric disorders using the electroretinogram (ERG). In this study, cone and rod ERGs were performed in male and female C57BL/6 mice before and after chronic social defeat stress (CSDS). Mice were then divided as susceptible or resilient to stress. Our results suggest that CSDS reduces the amplitude of both oscillatory potentials and a-waves in the rods of resilient but not susceptible males. Similar effects were revealed following the analysis of the cone b-waves, which were faster after CSDS in resilient mice specifically. In females, rod ERGs revealed age-related changes with no change in cone ERGs. Finally, our analysis suggests that baseline ERG can predict with an efficacy up to 71% the expression of susceptibility and resilience before stress exposition in males and females. Overall, our findings suggest that retinal activity is a valid biomarker of stress response that could potentially serve as a tool to predict whether males and females will become susceptible or resilient when facing CSDS.

Pathophysiological Underpinnings of Extra-Motor Neurodegeneration in Amyotrophic Lateral Sclerosis: New Insights From Biomarker Studies.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) lie at opposing ends of a clinical, genetic, and neuropathological continuum. In the last decade, it has become clear that cognitive and behavioral changes in patients with ALS are more frequent than previously recognized. Significantly, these non-motor features can impact the diagnosis, prognosis, and management of ALS. Partially overlapping neuropathological staging systems have been proposed to describe the distribution of TAR DNA-binding protein 43 (TDP-43) aggregates outside the corticospinal tract. However, the relationship between TDP-43 inclusions and neurodegeneration is not absolute and other pathophysiological processes, such as neuroinflammation (with a prominent role of microglia), cortical hyperexcitability, and synaptic dysfunction also play a central role in ALS pathophysiology. In the last decade, imaging and biofluid biomarker studies have revealed important insights into the pathophysiological underpinnings of extra-motor neurodegeneration in the ALS-FTLD continuum. In this review, we first summarize the clinical and pathophysiological correlates of extra-motor neurodegeneration in ALS. Next, we discuss the diagnostic and prognostic value of biomarkers in ALS and their potential to characterize extra-motor neurodegeneration. Finally, we debate about how biomarkers could improve the diagnosis and classification of ALS. Emerging imaging biomarkers of extra-motor neurodegeneration that enable the monitoring of disease progression are particularly promising. In addition, a growing arsenal of biofluid biomarkers linked to neurodegeneration and neuroinflammation are improving the diagnostic accuracy and identification of patients with a faster progression rate. The development and validation of biomarkers that detect the pathological aggregates of TDP-43 in vivo are notably expected to further elucidate the pathophysiological underpinnings of extra-motor neurodegeneration in ALS. Novel biomarkers tracking the different aspects of ALS pathophysiology are paving the way to precision medicine approaches in the ALS-FTLD continuum. These are essential steps to improve the diagnosis and staging of ALS and the design of clinical trials testing novel disease-modifying treatments.

The Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis: Signals From the CNS and Beyond.

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative condition, most widely characterized by the selective vulnerability of motor neurons and the poor life expectancy of afflicted patients. Limited disease-modifying therapies currently exist, which only further attests to the substantial heterogeneity associated with this disease. In addition to established prognostic factors like genetic background, site of onset, and age at onset, wide consensus on the role of neuroinflammation as a disease exacerbator and driver has been established. In lieu of this, the emerging literature on chitinases in ALS is particularly intriguing. Individual groups have reported substantially elevated chitotriosidase (CHIT1), chitinase-3-like-1 (CHI3L1), and chitinase-3-like-2 (CHI3L2) levels in the cerebrospinal, motor cortex, and spinal cord of ALS patients with multiple-and often conflicting-lines of evidence hinting at possible links to disease severity and progression. This mini-review, while not exhaustive, will aim to discuss current evidence on the involvement of key chitinases in ALS within the wider framework of other neurodegenerative conditions. Implications for understanding disease etiology, developing immunomodulatory therapies and biomarkers, and other translational opportunities will be considered.