Biomarker Of Neuroinflammation Research Articles

Inflammatory biomarkers are associated with changes in cerebral large artery thickness and lumen diameter in older adults

AbstractBackgroundAge‐associated remodeling of cerebral large arteries contributes to worse systemic and brain health in older adults. Vessel wall imaging (VWI) is a neuroimaging technique that offers the critical ability to quantify thickness and lumen diameter across arterial segments of the circle of Willis (CoW). Inflammation, a well‐known feature of aging, cerebrovascular disease, and Alzheimer’s disease, may be a central driver of age‐related changes in CoW morphology. We investigate if fluid biomarkers of inflammation predict key features of intracranial arterial aging, including CoW thickening and dilatation over time.MethodsVanderbilt Memory and Aging Project participants were studied (n=96, 73±7 years, 80% male, mean follow‐up=3.0 years). Baseline systemic inflammatory biomarkers (TNF‐α, IL‐6) were quantified from blood plasma samples. Baseline neuroinflammatory biomarkers (sTREM2, YKL‐40, MMP‐2, MMP‐3, MMP‐9) were quantified from cerebrospinal fluid samples. Intracranial artery lumen diameter and thickness were manually measured across the basilar artery (BA) and bilateral segments of the internal carotid artery (ICA), anterior cerebral artery (ACA), and middle cerebral artery (MCA) using serial VWI MRI. Linear mixed effects regressions related time x inflammatory biomarker (one predictor per model) to longitudinal VWI lumen diameter and thickness outcomes, adjusting for baseline age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive status, apolipoprotein ε4 status, T1‐weighted intracranial volume, and time.ResultsHigher CSF sTREM2 levels related to faster luminal narrowing (right ACA, p‐value=0.001). Higher CSF YKL‐40 levels related to faster luminal narrowing (right ACA, p‐value=0.07). Lower CSF MMP‐2 levels related to faster wall thickening (left MCA, p‐value<0.05). Lower CSF MMP‐3 levels related to luminal narrowing, while higher CSF MMP‐3 levels related to luminal widening (left ICA, p‐value=0.05). TNF‐α, IL‐6, and MMP‐9 were unrelated to any VWI changes (p‐values>0.14).ConclusionResults suggest neuroinflammatory biomarkers are largely related to longitudinal intracranial artery narrowing and thickening. However, additional associations between MMPs and luminal widening may reflect the mixed nature of MMP activity on cerebrovascular remodeling. Immune responses mediated by astroglial and microglial activity as well as MMPs may be key pathophysiological mechanisms underlying age‐related cerebral arterial remodeling.

Effect of Neuroinflammation on white matter structure and memory performance in the spectrum from aging to AD

AbstractBackgroundNeuroinflammation is a hallmark of Alzheimer ́s disease (AD) and other neurodegenerative disorders and is likely to be triggered throughout different stages of the disease. Microglia and Astrocytes are the main resident glia that mediate neuroinflammation through production of cytokines, chemokines and other neuroinflammatory biomarkers. Inflammatory processes have been implicated in the pathogenesis of cerebrovascular disease and white matter (WM) injury. However, imaging studies on the contribution of inflammation on WM structure in the aging and AD are rare.MethodHere, we aim to examine the relationship between inflammatory markers and WM hyperintensities (WMH) in the spectrum from normal aging towards AD. To do that, we used baseline data from the DZNE DELCODE study that is enriched in subjects at risk for development of AD and examined a panel of 16 inflammatory biomarkers from CSF of 249 subjects who also underwent FLAIR imaging. Participants included cognitively unimpaired (CU) individuals (healthy controls, AD relatives, and SCD) and cognitively impaired patients (CI) with MCI or AD dementia. WMH lesion volumes were automatically segmented from FLAIR images. Principal component analysis on the CSF markers generated one main composite factor (CP1) that included mainly TREM2, YKL40, AXL, Tyro3 and C1q (see Figure). Age, sex, vascular risk factors, Abeta ratio and ptau181 were used as covariates.ResultLinear regression models showed that higher values of this inflammatory composite factor was related to lower global WMH (p<0.01) and better memory performance (p<0.01) in the whole sample. These effects were also significant when including whole brain GM volume as additional covariate. Mediation model showed that global WMH partially mediated the effect of neuroinflammation on memory performance.ConclusionThese results suggest that some neuroinflammatory markers (e.g. sTyro3 and sAXL) might have a protective effect on WM structure, thus being beneficial for memory function as suggested by a recent study (Brosseron, Maass, Kleineidam et al, 2022), in which sTyro3 and sAXL were related to higher GM volume. Follow‐up analyses will aim to distinguish the effect of neuroinflammation in different clinical groups. Longitudinal studies are ultimately needed to determine whether the observed effect is “protective” or related to “brain reserve”.

IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by stunted growth, cognitive impairment, and increased risk of diverse neurological conditions. Although signs of lifelong neurodegeneration are well documented in DS, the mechanisms underlying this phenotype await elucidation. Here we report a multi-omics analysis of neurodegeneration and neuroinflammation biomarkers, plasma proteomics, and immune profiling in a diverse cohort of more than 400 research participants. We identified depletion of insulin growth factor 1 (IGF1), a master regulator of growth and brain development, as the top biosignature associated with neurodegeneration in DS. Individuals with T21 display chronic IGF1 deficiency downstream of growth hormone production, associated with a specific inflammatory profile involving elevated tumor necrosis factor alpha (TNF-α). Shorter children with DS show stronger IGF1 deficiency, elevated biomarkers of neurodegeneration, and increased prevalence of autism and other conditions. These results point to disruption of IGF1 signaling as a potential contributor to stunted growth and neurodegeneration in DS.

Deconvolving Cerebrospinal Fluid Soluble TREM2 Signal and Longitudinal Associations with Cognition

AbstractBackgroundCerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer’s disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. We previously found a novel association between high Aβ40 (but not Aβ42) and high sTREM2 levels at baseline and replicated additional associations between a fluid biomarker of blood‐brain barrier (BBB) integrity and CSF biomarkers of neurodegeneration. Therefore, we sought to determine the relative contributions of these biological correlates to CSF sTREM2 levels during the prodromal stages of AD. Additionally we investigated whether the residual variance in sTREM2 level correlated with each biomarker predicted future cognitive performance.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6, male=67%, mild cognitive impairment=47%), previously established associations between baseline CSF sTREM2 concentrations and CSF AD biomarkers (Aβx‐40, total tau, phosphorylated tau, and neurofilament light) and BBB integrity (CSF/plasma albumin ratio) were examined via hierarchical linear regression using sTREM2 as an outcome variable. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status. Baseline CSF sTREM2 levels and corresponding residual components when adjusting for other biomarker levels in independent models were used in longitudinal mixed effects models predicting an episodic memory composite calculated as a z‐score from independent tests. Participants had up to five visits (mean±sd=2.63±1.30 visits).ResultHigh baseline CSF sTREM2 levels predicted slower longitudinal memory decline in VMAP (β=1.442e‐05, p=0.035). Additionally, the component of sTREM2 signal correlated with Aβx‐40 best predicted future memory performance (β=2.217e‐05, p=0.007). Together, Aβx‐40, phosphorylated tau, and the CSF/plasma albumin ratio jointly explained 36% of variance in sTREM2 levels. Aβx‐40 levels and the CSF/plasma albumin ratio explained sTREM2 signal above and beyond established associations with tau (R2=0.21; R2=0.21; and R2=0.17, respectively).ConclusionWe highlight potential contributions of Aβ homeostasis and BBB integrity to elevations in CSF sTREM2, underscoring novel biomarker associations relevant to disease progression. Results suggest that the tight correlation between baseline CSF sTREM2 and Aβx‐40 levels may have notable importance to cognitive trajectory in an aged cohort enriched for mild cognitive impairment.

Hibiscus sabdariffa (Roselle) calyx: a systematic and meta-analytic review of memory-enhancing, anti-neuroinflammatory and antioxidative activities.

In this study, we summarized the preclinical investigations of the neuroprotective activities of Hibiscus sabdariffa (HSD) extract via its effect on memory function, neuroinflammation and oxidative damage in the central nervous system, which may help to guide future studies. Preclinical studies that investigated the effect of HSD extract on memory impairment, neuroinflammation and oxidative stress-induced neuronal damage were searched systematically in PubMed, EBSCOhost (including MEDLINE, CINAHL, APA PsycInfo, etc.), Web of Science (WoS) and Scopus. Parameters and indexes included Morris water maze, passive avoidance test, acetylcholinesterase activity, interleukin 1 (IL-1), tumour necrosis factor-alpha (TNF-α), MAPK, malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS) and mitochondria membrane potential (MMP). A total of 285 documents were identified; however, only ten articles were included and used for meta-analysis. The meta-analytic outcome revealed that HSD did not show any significant effect on memory function, neuroinflammatory biomarkers (IL-1, MAPK) and oxidative stress (GSH, MDA, ROS and MMP) in neuronal cells and tissues. Individual study revealed that HSD showed improved memory function, attenuated neuroinflammation and prevented oxidative damage to neurons. However, a conflicting result was observed from the meta-analytic outcomes which showed that HSD has no significant effect on cognitive impairment, neuroinflammation and oxidative stress-induced neuronal damage. However the contradiction in this finding may be associated with small number of studies included. Hence, more studies on the memory-enhacing effects and anti-neuroinflammatory activity of HSD in preclinical and clinical model are required to validate its neuroprotective effect.

Quantifying Dilated Perivascular Spaces in Children with Sickle Cell Disease

Introduction: The neurological complications of sickle cell disease (SCD) are particularly devastating and range from "overt stroke" to cerebral small vessel disease (CSVD), including silent cerebral infarction (SCI) and cognitive deficits despite the absence of magnetic resonance imaging (MR)-detectable evidence of cerebral injury. This suggests the possibility of additional, possibly covert, mechanisms of injury. Perivascular (Virchow-Robin) spaces (PVS) are fluid filled spaces that surround cerebral vessels penetrating or leaving the brain parenchyma and become visible when enlarged (dilated), due to inflammation or hypertension. The presence of dilated PVS (dPVS) in the basal ganglia (BG) and centrum semiovale (CO) are rare in children and have been associated with multiple neurodegenerative and neuroinflammatory disorders in aging populations. dPVS in the BG specifically are associated with CSVD, while those in the CO are associated with neuroinflammation. However, until now, the presence of dPVS has not been studied in either adults or children with SCD. Our overall objectives were to use MR images from children who were screened and/or participated in the Silent Cerebral Infarct Treatment in SCD (SIT) trial to 1) determine the burden of dPVS in children with SCD, specifically within the basal ganglia and centrum semiovale, and 2) correlate these findings with other markers of CSVD, specifically silent cerebral infarctions. Methods: The SIT trial was a multicenter, randomized clinical trial that evaluated the effect of monthly chronic transfusions to prevent the development of new SCI in children with SCD. As part of the enrollment process, all children underwent an initial MRI. We used both the Wardlaw (currently used as part of the international consensus criteria for evaluating CSVD) and Rotterdam criteria to quantify dPVS burden on T2-weighted screening MR images for 340 participants from the SIT trial. Briefly, both rating scales evaluate dPVS in the BG, CO, and midbrain (MB); the Rotterdam criteria also includes the hippocampus. The Wardlaw criteria categorize dPVS on an ordinal scale from 0 (none) to 4 (> 40) in the BG and CO and 0 or 1 point (absent or present) for the MB, with a total score of 9 as the maximum dPVS burden from all 3 brain regions. The Rotterdam criteria uses a semi-continuous scale and specifies counting dPVS to a total of 20 for each region for a maximum combined dPVD burden score of 80. Additional variables in our analysis were participant's age, hemoglobin, total white blood cell (WBC) count, and presence of SCI at baseline. We categorized dPVS burden score from the Wardlaw rating scale into low (0-2), medium (3-4), and high ( 5) and performed an ordinal multivariate logistic regression with age, sex, presence of SCI, hemoglobin, and total WBC count as independent variables. Results: We completed the two dPVS rating scales on 340 initial (screening) MR images from 340 children screened for the SIT trial, with a median age of 8.3 years (range 5 - 15 years). Eighty-eight (26%) had evidence of at least one SCI. The mean hemoglobin was 8 ± 1.1 g/dL and total WBC count was 12,000 ± 4200 cells/ml. The mean dPVS burden score from the Wardlaw criteria was 3.7 ± 1.7, while for the Rotterdam criteria, the mean was 32 ± 14 (Table). Global and regional dPVS scores from the two rating scales were well correlated (p < 0.001, r = 0.72 - 0.8). dPVS score in the BG and CSO was moderately correlated (p < 0.001, r = 0.45). There was no significant sex difference in dPVS burden (mean Wardlaw rating: males = 3.9 versus females = 3.6, p = 0.08). Multivariate analysis show that increasing age was associated with dPVS burden (p = 0.005), as was increasing hemoglobin, which showed a trend towards association (p = 0.06), potentially due to increased pressure within microvasculature, resulting in extravasation of fluid into the surrounding space. Surprisingly, presence or size of SCI were not associated with dPVS burden. Conclusions: Children with SCD have evidence of more than expected dilated perivascular spaces compared to not only healthy children but also adults, which increase with age. Although likely involved in neurological injury, dilated PVS in children with SCD do not appear to be associated with the presence of CSVD phenotypes such as SCI. We reasoned that in SCD, dPVS may be sequelae of underlying neuroinflammation. Future studies are needed to examine correlation of dPVS with biomarkers of neuroinflammation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Astrocytes in the Neuropathology of Bipolar Disorder: Review of Current Evidence.

(1) Background: Approximately one-third of patients with bipolar disorder (BD) do not experience sustained remission with current treatments. Presently, astrocytes, i.e., glial cells that act as key regulators of neuroinflammation, have been a target for therapeutic development. Research regarding their role in the neuropathology of BD is limited. We conducted a scoping review on evidence linking astrocytes to the pathology of BD. (2) Methods: The search was conducted in MEDLINE for studies published from inception to August 2022. Studies of interest were data-extracted and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols. (3) Results: Overall, 650 publications were identified, of which 122 full texts were evaluated and 12 included. Four were in vitro, seven were ex vivo, and one study was both in vitro and in vivo. In vitro investigations focused on plasma levels of neuroinflammatory biomarkers S100B and glial fibrillary acidic protein (GFAP). Ex vivo investigations were post-mortem brain studies assessing astrocytes in regions of interest (i.e., anterior cingulate cortex, dorsolateral prefrontal cortex) using phosphorylated GFAP and ASCT-1. The in vivo and in vitro study evaluated morphological and chemical variations of YKL-40 between cohorts. (4) Conclusions: Reports indicate an association between astrocyte dysfunction and BD although larger studies are required to validate this association.

Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study.

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The 'nootropic-like' activity could be related to diminished AChE and neuroinflammatory mediator levels.

TLR4-Pathway-Associated Biomarkers in Subarachnoid Hemorrhage (SAH): Potential Targets for Future Anti-Inflammatory Therapies.

Subarachnoid hemorrhage is associated with severe neurological deficits for survivors. Among survivors of the initial bleeding, secondary brain injury leads to additional brain damage. Apart from cerebral vasospasm, secondary brain injury mainly results from cerebral inflammation taking place in the brain parenchyma after bleeding. The brain’s innate immune system is activated, which leads to disturbances in brain homeostasis, cleavage of inflammatory cytokines and, subsequently, neuronal cell death. The toll-like receptor (TLR)4 signaling pathway has been found to play an essential role in the pathophysiology of acute brain injuries such as subarachnoid hemorrhage (SAH). TLR4 is expressed on the cell surface of microglia, which are key players in the cellular immune responses of the brain. The participants in the signaling pathway, such as TLR4-pathway-like ligands, the receptor itself, and inflammatory cytokines, can act as biomarkers, serving as clues regarding the inflammatory status after SAH. Moreover, protein complexes such as the NLRP3 inflammasome or receptors such as TREM1 frame the TLR4 pathway and are indicative of inflammation. In this review, we focus on the activity of the TLR4 pathway and its contributors, which can act as biomarkers of neuroinflammation or even offer potential new treatment targets for secondary neuronal cell death after SAH.

World Trade Center Site Exposure Duration Is Associated with Hippocampal and Cerebral White Matter Neuroinflammation

Responders to the World Trade Center (WTC) attacks on 9/11/2001 inhaled toxic dust and experienced severe trauma for a prolonged period. Studies report that WTC site exposure duration is associated with peripheral inflammation and risk for developing early-onset dementia (EOD). Free Water Fraction (FWF) can serve as a biomarker for neuroinflammation by measuring in vivo movement of free water across neurons. The present case-controlled study aimed to examine associations between WTC site exposure duration as well as EOD status with increased hippocampal and cerebral neuroinflammation. Ninety-nine WTC responders (mean age of 56) were recruited between 2017 and 2019 (N = 48 with EOD and 51 cognitively unimpaired). Participants were matched on age, sex, occupation, race, education, and post-traumatic stress disorder (PTSD) status. Participants underwent neuroimaging using diffusion tensor imaging protocols for FWF extraction. Region of interest (ROI) analysis and correlational tractography explored topographical distributions of FWF associations. Apolipoprotein-e4 allele (APOEε4) status was available for most responders (N = 91). Hippocampal FWF was significantly associated with WTC site exposure duration (r = 0.30, p = 0.003), as was cerebral white matter FWF (r = 0.20, p = 0.044). ROI analysis and correlational tractography identified regions within the limbic, frontal, and temporal lobes. Hippocampal FWF and its association with WTC exposure duration were highest when the APOEε4 allele was present (r = 0.48, p = 0.039). Our findings demonstrate that prolonged WTC site exposure is associated with increased hippocampal and cerebral white matter neuroinflammation in WTC responders, possibly exacerbated by possession of the APOEε4 allele.

CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis

Several biomarkers from multiple sclerosis (MS) patients’ biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

Serum concentrations of NLRP3 in relation to functional outcome and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BackgroundNucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) participates in neuroinflammation. We endeavored to determine the role of serum NLRP3 as a biomarker of neuroinflammation, severity, delayed cerebral ischemia (DCI) and functional outcome following aneurysmal subarachnoid hemorrhage (aSAH). MethodsIn this prospective and observational study, a total of 118 aSAH patients and 118 healthy volunteers were enrolled. Serum NLRP3 concentrations, blood glucose concentrations, serum C-reactive protein concentrations, and blood leucocyte counts were quantified. A poor outcome was defined as extended Glasgow outcome scale scores of 1–4 at post-injury 90 days. ResultsAs compared to controls, significantly increased serum NLRP3 concentrations after aSAH were intimately correlated with the Glasgow coma scale scores, World Federation of Neurological Surgeons scale scores, Hunt-Hess scores, modified Fisher scores, extended Glasgow outcome scale scores, blood glucose concentrations, serum C-reactive protein concentrations and blood leucocyte counts. Serum NLRP3 emerged as an independent predictor for DCI and poor 90-day outcome. Using receiver operating characteristic curve, serum NLRP3 concentrations were significantly predictive of DCI and poor 90-day outcome. Its prognostic predictive ability was comparable to those of the Glasgow coma scale scores, World Federation of Neurological Surgeons scale scores, Hunt-Hess scores and modified Fisher scores. ConclusionsSerum NLRP3 may represent an inflammatory biomarker in relation to the severity, DCI and poor functional outcome after aSAH.

MODULATORY ACTIVITY OF RESVERATROL AND ENVIRONMENTAL ENRICHMENT ON BEHAVIOURAL AND NEUROINFLAMMATORY RESPONSES OF MICE TREATED WITH ALUMINIUM CHLORIDE

The study investigated the modulatory activity of resveratrol and environmental enrichment (EE) on behavioural and neuroinflammatory responses of male mice treated with aluminium chloride (AlCl3). Sixty-three Swiss albino mice were divided into nine groups of seven animals each as follows; 0.2 mL normal saline/kg (control), 0.2 mL Carboxymethyl cellulose (CMC)/kg,Resveratrol (200 mg/kg), CMC 0.2 mL/kg + EE, AlCl3 (50 mg/kg), Resveratrol (200 mg/kg) + EE, AlCl3 (50 mg/kg) + Resveratrol (200 mg/kg), AlCl3 (50 mg/kg) + EE, and AlCl3 (50 mg/kg) + Resveratrol (200 mg/kg) + EE, respectively. All treatments were given oral and lasted for 8 weeks. Assessments of behaviour were carried out at 0, 4 and 8 weeks after treatments, followedby biochemical analyses. AlCl3 significantly (p &lt; 0.05) induced motor endurance deficits at the fourth week which was improved by Resveratrol and EE. The concentration of NF-Kβ significantly decreased in AlCl3 when compared to AlCl3 + EE + resveratrol treated group. Furthermore, the concentration of TNF-α was significantly decreased in Resveratrol, and AlCl3 + EE treated groups, when compared to AlCl3 + EE + Resveratrol treatment group. AlCl3 induced motor function deficits, which was improved by Resveratrol and EE. Resveratrol treatment alone and EE + AlCl3 decreased biomarkers of neuro-inflammation.

Chitotriosidase 1 in the cerebrospinal fluid as a putative biomarker for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) progression

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an inflammatory neurodegenerative disease that affects motor, urinary, intestinal, and sensory functions. Typically, HAM/TSP is slowly progressive, but it may vary from limited motor disability after decades (very slow progression) to loss of motor function in a few years from disease onset (rapid). In this study, we aimed to identify prognostic biomarkers for HAM/TSP to support patient management. Thus, proteomic analysis of the cerebrospinal fluid (CSF) was performed with samples from HTLV-1 asymptomatic carriers (AC) (n=13) and HAM/TSP patients (n=21) with rapid, typical, and very slow progression using quantitative label-free liquid chromatography/tandem mass spectrometry. Enrichment analyses were also carried out to identify key biological processes associated with distinct neurological conditions in HTLV-1 infection. Candidate biomarkers were validated by ELISA in paired CSF and serum samples, and samples from HTLV-1-seronegative individuals (n=9) were used as controls. CSF analysis identified 602 proteins. Leukocyte/cell activation, immune response processes and neurodegeneration pathways were enriched in rapid progressors. Conversely, HTLV-1 AC and HAM/TSP patients with typical and very slow progression had enriched processes for nervous system development. Differential expression analysis showed that soluble vascular cell adhesion molecule 1 (sVCAM-1), chitotriosidase 1 (CHIT1), and cathepsin C (CTSC) were upregulated in HAM/TSP. However, only CHIT1 was significantly elevated after validation, particularly in HAM/TSP rapid progressors. In contrast, none of these biomarkers were altered in serum. Additionally, CSF CHIT1 levels in HAM/TSP patients positively correlated with the speed of HAM/TSP progression, defined as points in the IPEC-2 HAM/TSP disability scale per year of disease, and with CSF levels of phosphorylated neurofilament heavy chain, neopterin, CXCL5, CXCL10, and CXCL11. In conclusion, higher CSF levels of CHIT1 were associated with HAM/TSP rapid progression and correlated with other biomarkers of neuroinflammation and neurodegeneration. Therefore, we propose CHIT1 as an additional or alternative CSF biomarker to identify HAM/TSP patients with a worse prognosis.

Cerebrospinal Fluid and Blood Biomarkers of Neuroinflammation and Blood-Brain Barrier in Psychotic Disorders and Individually Matched Healthy Controls.

Neuroinflammation and blood-brain barrier (BBB) dysfunction have been observed in patients with psychotic disorders. However, previous studies have mainly focused on selected patients and broad screenings of cerebrospinal fluid (CSF) of patients with recent onset psychosis compared to healthy controls are lacking. We included 104 patients with recent onset psychotic disorder and 104 individually matched healthy controls. CSF and blood were analyzed for readily available markers assessing neuroinflammation and BBB dysfunction. Primary outcomes were CSF white blood cell count (WBC), total protein, IgG Index, and CSF/serum albumin ratio. Secondary outcomes included additional markers of inflammation and BBB, and analyses of association with clinical variables. CSF/serum albumin ratio (Relative Mean Difference (MD): 1.11; 95%CI: 1.00-1.23; P = .044) and CSF/serum IgG ratio (MD: 1.17; 95%CI: 1.01-1.36; P = .036) was increased in patients compared to controls. A higher number of patients than controls had CSF WBC >3 cells/µl (seven vs. one, OR: 7.73, 95%CI: 1.33-146.49, P = .020), while WBC>5 cells/µl was found in two patients (1.9%) and no controls. Inpatients had higher serum WBC and neutrophil/lymphocyte ratio (all p-values for effect heterogeneity < .011). Mean CSF WBC (MD: 1.10; 95%CI: 0.97-1.26), protein (MD: 1.06; 95%CI: 0.98-1.15) and IgG index (MD: 1.05; 95%CI: 0.96-1.15) were not significantly elevated. When comparing a broad group of patients with psychotic disorders with healthy controls, patients had increased BBB permeability, more patients had high CSF WBC levels, and inpatients had increased peripheral inflammation, consistent with the hypothesis of a subgroup of patients with increased activation of the immune system.

Inflammatory plasma biomarkers in subjects with preclinical Alzheimer’s disease

BackgroundThis study investigated plasma biomarkers for neuroinflammation associated with Alzheimer’s disease (AD) in subjects with preclinical AD compared to healthy elderly. How these biomarkers behave in patients with AD, compared to healthy elderly is well known, but determining these in subjects with preclinical AD is not and will add information related to the onset of AD. When found to be different in preclinical AD, these inflammatory biomarkers may be used to select preclinical AD subjects who are most likely to develop AD, to participate in clinical trials with new disease-modifying drugs.MethodsHealthy elderly (n= 50; age 71.9; MMSE >24) and subjects with preclinical AD (n=50; age 73.4; MMSE >24) defined by CSF Aβ1-42 levels < 1000 pg/mL were included. Four neuroinflammatory biomarkers were determined in plasma, GFAP, YKL-40, MCP-1, and eotaxin-1. Differences in biomarker outcomes were compared using ANCOVA. Subject characteristics age, gender, and APOE ε4 status were reported per group and were covariates in the ANCOVA. Least square means were calculated for all 4 inflammatory biomarkers using both the Aβ+/Aβ− cutoff and Ptau/Aβ1-42 ratio.ResultsThe mean (standard deviation, SD) age of the subjects (n=100) was 72.6 (4.6) years old with 62 male and 38 female subjects. Mean (SD) overall MMSE score was 28.7 (0.49) and 32 subjects were APOE ε4 carriers. The number of subjects in the different APOE ε4 status categories differed significantly between the Aβ+ and Aβ− groups. Plasma GFAP concentration was significantly higher in the Aβ+ group compared to the Aβ− group with significant covariates age and sex, variables that also correlated significantly with GFAP.ConclusionGFAP was significantly higher in subjects with preclinical AD compared to healthy elderly which agrees with previous studies. When defining preclinical AD based on the Ptau181/Aβ1-42 ratio, YKL-40 was also significantly different between groups. This could indicate that GFAP and YKL-40 are more sensitive markers of the inflammatory process in response to the Aβ misfolding and aggregation that is ongoing as indicated by the lowered Aβ1-42 levels in the CSF. Characterizing subjects with preclinical AD using neuroinflammatory biomarkers is important for subject selection in new disease-modifying clinical trials.Trial registrationISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).

Modelos experimentales en el estudio de la epileptogénesis

Epilepsy is a chronic neurological disease characterized by spontaneous recurrently occurring epileptic seizures as a consequence of abnormal, excessive and synchronous neuronal activity in the brain. Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy in adults, being characterized by hippocampal sclerosis, reactive gliosis, neurodegeneration, and synaptic reorganization. Animal models of TLE based on the administration of convulsive agents trigger a status epilepticus (SE) that progresses towards the occurrence of spontaneous recurrent seizures. Among these models are those induced by the systemic administration of pilocarpine or by intrahippocampal injection of kainic acid, both being characterized by 3 clearly defined phases: (i) acute SE seizures; (ii) latent period and (iii) occurrence of recurrent spontaneous seizures. These models not only reproduce most of the neuropathological TLE features but also allow for the identification of biomarkers of epileptogenesis and potential pharmacological targets. The use of neuroimaging techniques such as positron emission tomography (PET) with the radiotracer 18F-Fluorodeoxyglucose (18F-FDG) identifies brain hypometabolism in the latent period that not only localizes the epileptic focus but is also an biomarker of early diagnosis. Other neuroimaging techniques allow for detecting, among others, biomarkers of neuroinflammation, alterations in the permeability of the blood-brain barrier and astrocytic activation, all of them associated with epileptogenesis. Finally, the use of chemogenetics through DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) technology in murine models leads to targeted modulation of astrocytic activity, being a novel tool that considers the contribution of the astrocytes role in brain metabolic alterations in epileptogenesis.

Sarcococca saligna ameliorated D-galactose induced neurodegeneration through repression of neurodegenerative and oxidative stress biomarkers.

Sarcococca saligna is a valuable source of bioactive secondary metabolites exhibiting antioxidant, anti-inflammatory and acetylcholinesterase inhibitory activities. The study was intended to explore the therapeutic pursuits of S. saligna in amelioration of cognitive and motor dysfunctions induced by D-galactose and linked mechanistic pathways. Alzheimer's disease model was prepared by administration of D-galactose subcutaneous injection100 mg/kg and it was treated with rivastigmine (100mg/kg, orally) and plant extract for 42days. Cognitive and motor functions were evaluated by behavioral tasks and oxidative stress biomarkers. Level of acetylcholinesterase, reduced level of glutathione, protein and nitrite level, and brain neurotransmitters were analyzed in brain homogenate. The level of apoptosis regulator Bcl-2, Caspases 3 and heat shock protein HSP-70 in brain homogenates were analyzed by ELISA and colorimetric method, respectively. AChE, IL-1β, TNF-α, IL-1α and β secretase expressions were analyzed by RT-PCR. S. saligna dose dependently suppressed the neurodegenerative effects of D-galactose induced behavioral and biochemical impairments through modulation of antioxidant enzymes and acetylcholinesterase inhibition. S. saligna markedly (P < 0.05) ameliorated the level of brain neurotransmitters, Bcl-2, HSP-70 and Caspases-3 level. S. saligna at 500-1000mg/kg considerably recovered the mRNA expression of neurodegenerative and neuro-inflammatory biomarkers, also evident from histopathological analysis. These findings suggest that S. saligna could be applicable in cure of Alzheimer's disease.

YKL-40 changes are not detected in post-mortem brain of patients with Alzheimer’s disease and frontotemporal lobar degeneration

BackgroundYKL-40 (Chitinase 3-like I) is increased in CSF of Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) patients and is therefore considered a potential neuroinflammatory biomarker. Whether changed YKL-40 levels in the CSF reflect dysregulation of YKL-40 in the brain is not completely understood yet. We aimed to extensively analyze YKL-40 levels in the brain of AD and different FTLD pathological subtypes. The direct relationship between YKL-40 levels in post-mortem brain and ante-mortem CSF was examined in a small set of paired brain-CSF samples.MethodYKL-40 was analyzed in post-mortem temporal and frontal cortex of non-demented controls and patients with AD and FTLD (including FTLD-Tau and FTLD-TDP) pathology by immunohistochemistry (temporal cortex: 51 controls and 56 AD and frontal cortex: 7 controls and 24 FTLD patients), western blot (frontal cortex: 14 controls, 5 AD and 67 FTLD patients), or ELISA (temporal cortex: 11 controls and 7 AD and frontal cortex: 14 controls, 5 AD and 67 FTLD patients). YKL-40 levels were also measured in paired post-mortem brain and ante-mortem CSF samples from dementia patients (n = 9, time-interval collection: 1.4 years) by ELISA.ResultsWe observed that YKL-40 post-mortem brain levels were similar between AD, FTLD, and controls as shown by immunohistochemistry, western blot, and ELISA. Interestingly, strong YKL-40 immunoreactivity was observed in AD cases with cerebral amyloid angiopathy (CAA; n = 6). In paired CSF-brain samples, YKL-40 concentration was 8-times higher in CSF compared to brain.ConclusionOur data suggest that CSF YKL-40 changes may not reflect YKL-40 changes within AD and FTLD pathological brain areas. The YKL-40 reactivity associated with classical CAA hallmarks indicates a possible relationship between YKL-40, neuroinflammation, and vascular pathology.

Biochemical and clinical biomarkers in adult SMA 3-4 patients treated with nusinersen for 22 months.

ObjectiveTo investigate biomarkers of disease progression in cerebrospinal fluid (CSF) and serum in adult patients with spinal muscular atrophy (SMA). Furthermore, we assess the clinical response to nusinersen treatment in adults with SMA over a longer follow‐up period than the previously reported 6–14 months.MethodsWe included 16 adults with SMA type 3–4 for nusinersen treatment over 22 months in this prospective study. We evaluated chitotriosidase‐1 (CHIT1) and chitinase‐3‐like protein 1 (YKL‐40) as neuroinflammatory biomarkers in CSF, and neurofilament light chain (NfL) and heavy chain (pNfH) as neurodegenerative markers in CSF and serum at baseline, month 6, 14 and 22, together with a wide range of clinical outcome measures.ResultsLevels of CHIT1 increased significantly (p = 0.048) throughout the 22‐month treatment period and pNfH decreased significantly (p = 0.022) in CSF, but both did not correlate with clinical outcome measures. YKL‐40 correlated strongly with neurofilaments in CSF (rho = 0.76) and decreased significantly (p = 0.037) in patients with improvements in the revised upper limb module (RULM). Finally, patients showed significant improvements in hand grip strength, hand motor function, medical research council (MRC) sum score, and peak expiratory flow (PEF) after 22 months of treatment.InterpretationYKL‐40 in CSF correlated with clinical improvements during nusinersen treatment. In contrast, CHIT1 and pNfH in CSF changed significantly during treatment but did not correlate with clinical outcomes. Finally, we demonstrated a sustained clinical effect of nusinersen treatment in adults after 22 months.