Systemic Inflammation Index Values Are Associated With Worsened Disease Severity and Poor Response to Autoimmune Encephalitis Treatment

Both specific and innate immune responses play important roles in autoimmune encephalitis (AE). We aimed to explore the predictive value of the systemic inflammation index (SII) at admission as a peripheral biomarker of treatment response of AE. A total of 146 patients diagnosed with AE in the First Affiliated Hospital of Zhengzhou University from January 1, 2018 to September 22, 2020 were retrospectively and consecutively analyzed as per the inclusion criteria and divided into two groups according to their response to immunotherapy after 30 days. The predictive value of the SII as a peripheral biomarker for AE treatment response was calculated using the receiver operating characteristic curve analysis, which showed that the best SII cut-off value for predicting poor response to AE treatment was 863.3; the area under the curve was 0.75, with 83.0% sensitivity and 72.0% specificity. The risk factors for poor response to AE treatment were analyzed; univariable analysis showed that the rate of decreased level of consciousness, rate of cognitive or mental behavior abnormality, cerebrospinal fluid pressure, blood neutrophils, platelets, time until treatment initiation, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and SII were significantly higher in patients with poor response to AE immunotherapy after 30 days than in patients with good response. Meanwhile, the blood lymphocyte counts and Glasgow Coma Scale (GCS) scores in patients with poor response were significantly lower than those in patients with good response (all p < 0.05), and multivariable binary logistic regression with backward stepwise method showed that decreased levels of consciousness, time until treatment initiation and SII were associated with poor response to immunotherapy. Moreover, the SII ≤ 863.3 group had lower rates of decreased consciousness levels, admission to the intensive care unit, and mechanical ventilation; lower cerebrospinal fluid pressure, blood neutrophil count, and platelet count; and higher blood lymphocyte count and GCS scores. The SII was associated with worsened disease severity and poor response to treatment after 30 days of the initially diagnosed AE, and patients with an SII > 863.3 were more likely to have poor response to immunotherapy.

Novel exosome biomarker candidates for Alzheimer´s disease unraveled through Mass Spectrometry analysis

Exosomes are small extracellular vesicles (EVs) present in human biofluids that can transport specific disease-associated molecules. Consequently blood-derived exosomes have emerged as important peripheral biomarker sources for a wide range of diseases, among them Alzheimer’s disease (AD). Although there is no effective cure for AD, an accurate diagnosis, relying on easily accessible peripheral biofluids, is still necessary to discriminate this disease from other dementias, test potential therapies and even monitor rate of disease progression. The ultimate goal is to produce a cost-effective and widely available alternative, which can also be employed as a first clinical screen. In this study, EVs with exosome-like characteristics were isolated from serum of Controls and AD cases through precipitation- and column-based methods, followed by mass spectrometry analysis. The resulting proteomes were characterized by Gene Ontology (GO) functional enrichment and multivariate analyses. Although GO terms were similar for exosomes proteomes of Controls and ADs, using both methodologies, a clear segregation of disease cases was obtained when using the precipitation-based method. Nine significantly different abundant proteins were identified between Controls and AD cases, representing putative biomarker candidate targets. Among them AACT and C4BPα, two Aβ-binding proteins, whose exosome levels were further validated in individuals from independent cohorts using antibody-based approaches. The findings discussed represent an important contribution to the identification of novel exosomal biomarker candidates useful as potential blood-based tools for AD diagnosis.

The Role of the Second Extracellular Loop of Norepinephrine Transporter, Neurotrophin-3 and Tropomyosin Receptor Kinase C in T Cells: A Peripheral Biomarker in the Etiology of Schizophrenia

The neurobiology of schizophrenia is multifactorial, comprising the dysregulation of several biochemical pathways and molecules. This research proposes a peripheral biomarker for schizophrenia that involves the second extracellular loop of norepinephrine transporter (NEText), the tropomyosin receptor kinase C (TrkC), and the neurotrophin-3 (NT-3) in T cells. The study of NEText, NT-3, and TrkC was performed in T cells and plasma extracted from peripheral blood of 54 patients with schizophrenia and 54 healthy controls. Levels of NT-3, TrkC, and NET were significantly lower in plasma and T cells of patients compared to healthy controls. Co-immunoprecipitation (co-IPs) showed protein interactions with Co-IP NEText–NT-3 and Co-IP NEText–TrkC. Computational modelling of protein–peptide docking by CABS-dock provided a medium–high accuracy model for NT-3–NEText (4.6935 Å) and TrkC–NEText (2.1365 Å). In summary, immunocomplexes reached statistical relevance in the T cells of the control group contrary to the results obtained with schizophrenia. The reduced expression of NT-3, TrkC, and NET, and the lack of molecular complexes in T cells of patients with schizophrenia may lead to a peripheral dysregulation of intracellular signaling pathways and an abnormal reuptake of norepinephrine (NE) by NET. This peripheral molecular biomarker underlying schizophrenia reinforces the role of neurotrophins, and noradrenergic and immune systems in the pathophysiology of schizophrenia.

Advances with Long Non-Coding RNAs in Alzheimer’s Disease as Peripheral Biomarker

One of the most compelling needs in the study of Alzheimer’s disease (AD) is the characterization of cognitive decline peripheral biomarkers. In this context, the theme of altered RNA processing has emerged as a contributing factor to AD. In particular, the significant role of long non-coding RNAs (lncRNAs) associated to AD is opening new perspectives in AD research. This class of RNAs may offer numerous starting points for new investigations about pathogenic mechanisms and, in particular, about peripheral biomarkers. Indeed, altered lncRNA signatures are emerging as potential diagnostic biomarkers. In this review, we have collected and fully explored all the presented data about lncRNAs and AD in the peripheral system to offer an overview about this class of non-coding RNAs and their possible role in AD.

Pregnancy Specific Adaptations in Leptin and Melanocortin Neuropeptides in Early Human Gestation

Introduction Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and CSF leptin and AgRP as well as CSF POMC as surrogates for brain melanocortin activity. Methods Plasma leptin, Ob-Re, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women prior to cerclage placement (16.6±1.1wks; N=24), scheduled cesarean section (39.2±0.2wks; N=24), and from non-pregnant controls (N=24), matched for age and BMI. Results Plasma leptin was 1.5 times higher in pregnancy vs. controls (P=0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs. controls (0.8±0.1 vs. 1.7±0.2; P<0.0001) and remained unchanged at term (0.9 ±0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs. controls (95.0±7.8 vs. 67.5±5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P=0.006). In contrast, at term, CSF AgRP was 42% higher vs. controls (P=0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs. controls, reflecting a decrease in melanocortin tone favoring appetitive drive. Conclusions Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.

VGF Expression by Monocytes in Patients with Alzheimer’s Disease and Vascular Dementia

Because its secretion is changed in cerebrospinal fluid and peripheral blood, the neuronal polypeptide VGF (nonacronymic) has been discussed as a biomarker for neuropsychiatric disorders. We have shown an enhanced VGF expression by T-cells from Alzheimer’s disease (AD) patients. In this study, we investigated the VGF expression by peripheral monocytes in 38 AD patients, 5 patients with vascular dementia (VD), and 20 neuropsychiatrically healthy individuals using flow cytometry. We determined an enhanced number of VGF-expressing monocytes in VD patients compared to AD patients. VGF+CD14+ monocytes were not correlated with age, body mass index, Mini-Mental State Examination (MMSE), or Q albumin. These preliminary data support findings indicating that VGF might play a role as a peripheral biomarker in VD.