Molecular Signatures of Normal Pressure Hydrocephalus: A Largescale Proteomic Analysis of Cerebrospinal Fluid.

Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimer's disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction. Moreover, downregulation of multiple proteins associated with congenital hydrocephalus (e.g., L1CAM, PCDH9, ISLR2, ADAMTSL2, and B4GAT1) points to a possible shared molecular foundation between congenital hydrocephalus and iNPH. Through orthogonal partial least squares discriminant analysis (OPLS-DA), a panel comprising 13 proteins has been identified as potential diagnostic biomarkers of iNPH, pending external validation. These findings offer novel insights into the pathophysiology of iNPH, with implications for improved diagnosis.

Exploratory Assessment of Proteomic Network Changes in Cerebrospinal Fluid of Mild Cognitive Impairment Patients: A Pilot Study.

(1) Background: Despite the existence of well-established, CSF-based biomarkers such as amyloid-ß and phosphorylated-tau, the pathways involved in the pathophysiology of Alzheimer's disease (AD) remain an active area of research. (2) Methods: We measured 3072 proteins in CSF samples of AD-biomarker positive mild cognitive impairment (MCI) participants (n = 38) and controls (n = 48), using the Explore panel of the Olink proximity extension assay (PEA). We performed group comparisons, association studies with diagnosis, age, and APOE ε4 status, overrepresentation analysis (ORA), and gene set enrichment analysis (GSEA) to determine differentially expressed proteins and dysregulated pathways. (3) Results: GSEA results demonstrated an enrichment of granulocyte-related and chemotactic pathways (core enrichment proteins: ITGB2, ITGAM, ICAM1, SELL, SELP, C5, IL1A). Moreover, some of the well-replicated, differentially expressed proteins in CSF included: ITGAM, ITGB2, C1QA, TREM2, GFAP, NEFL, MMP-10, and a novel tau-related marker, SCRN1. (4) Conclusion: Our results highlight the upregulation of neuroinflammatory pathways, especially chemotactic and granulocyte recruitment in CSF of early AD patients.

Metal concentrations in cerebrospinal fluid, blood, serum, plasma, hair, and nails in amyotrophic lateral sclerosis: A systematic review and meta-analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive muscle wasting, paralysis, and respiratory failure. Whereas approximately 10-15 % of ALS cases are familial, the etiology of the remaining, sporadic ALS cases remains largely unknown. Environmental exposures have been suggested as causative factors for decades, and previous studies have found elevated concentrations of metals in ALS patients. PURPOSE: This meta-analysis aims to assess metal concentrations in body fluids and tissues of ALS patients. METHODS: We searched the MEDLINE and EMBASE databases on December 7th, 2022 for cross-sectional, case-control, and cohort studies which measure metal concentrations in whole blood, blood plasma, blood serum, cerebrospinal fluid (CSF), urine, erythrocytes, nail, and hair samples of ALS patients. Meta-analysis was then performed when three or more articles existed for a comparison. FINDINGS: Twenty-nine studies measuring 23 metals were included and 13 meta-analyses were performed from 4234 screened entries. The meta-analysis results showed elevated concentrations of lead and selenium. Lead, measured in whole blood in 6 studies, was significantly elevated by 2.88 µg/L (95 % CI: 0.83-4.93, p = 0.006) and lead, measured in CSF in 4 studies, was significantly elevated by 0.21 µg/L (95 % CI: 0.01 - 0.41, p = 0.04) in ALS patients when compared to controls. Selenium, measured in serum/plasma in 4 studies, was significantly elevated by 4.26 µg/L (95% CI: 0.73 - 7.79, p = 0.02) when compared to controls.Analyses of other metal concentrations showed no statistically significant difference between the groups. CONCLUSION: Lead has been discussed as a possible causative agent in ALS since 1850. Lead has been found in the spinal cord of ALS patients, and occupational exposure to lead is more common in ALS patients than in controls. Selenium in the form of neurotoxic selenite has been shown to geochemically correlate to ALS occurrence in Italy. Although no causal relationship can be established from the results of this meta-analysis, the findings suggest an involvement of lead and selenium in the pathophysiology of ALS. After a thorough meta-analysis of published studies on metal concentrations in ALS it can only be concluded that lead and selenium are elevated in ALS.

Convergent regional brain abnormalities in behavioral variant frontotemporal dementia: A neuroimaging meta-analysis of 73 studies.

Introduction: Numerous studies have reported brain alterations in behavioral variant frontotemporal dementia (bvFTD). However, they pointed to inconsistent findings. Methods: We used a meta-analytic approach to identify the convergent structural and functional brain abnormalities in bvFTD. Following current best-practice neuroimaging meta-analysis guidelines, we searched PubMed and Embase databases and performed reference tracking. Then, the coordinates of group comparisons between bvFTD and controls from 73 studies were extracted and tested for convergence using activation likelihood estimation. Results: We identified convergent abnormalities in the anterior cingulate cortices, anterior insula, amygdala, paracingulate, striatum, and hippocampus. Task-based and resting-state functional connectivity pointed to the networks that are connected to the obtained consistent regions. Functional decoding analyses suggested associated dysfunction of emotional processing, interoception, reward processing, higher-order cognitive functions, and olfactory and gustatory perceptions in bvFTD. Discussion: Our findings highlighted the key role of the salience network and subcortical regions in the pathophysiology of bvFTD.

A national and sub-national metaregression of the trend of insufficient physical activity among Iranian adults between 2001 and 2016.

Insufficient physical activity (IPA) caused approximately 5% of mortalities in 2017 in Iran, almost double its global average. Despite the relatively considerable burden, a knowledge gap exists regarding the trend of IPA in recent years. We described the trend of IPA prevalence utilizing the data from six rounds of STEPwise approach to risk factor Surveillance (STEPS) in Iran. We estimated the physical activity status of Iranian adults from 2006 to 2016 after adjusting for years of schooling, urbanization percentage, and wealth index. We used the spatiotemporal model to interpolate and extrapolate the IPA prevalence for the years in-between the series and from 2001 to 2006, respectively. We used the data of 177,910 participants from six STEPS surveys and found that the national prevalence of IPA had steadily increased over the course of 16 years and had almost doubled in this time period (23.1% in 2001 to 55.4% in 2016). The increase was persistent across all age and gender strata and in every province. Moreover, IPA was more prevalent among women than their male peers regardless of their age category or province of residence. The prevalence of IPA in Khuzestan (highest prevalence) was almost double compared to that in Lorestan (lowest prevalence) in 2016. The IPA prevalence increased considerably and almost doubled in 16 years among Iranian adults, particularly women. Policies need to target IPA as a high priority contributing to the burden of Non-communicable diseases.

Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways.

Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, ß-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.

Evaluation of the pharmacological involvement of ATP-sensitive potassium (KATP) channels in the antidepressant-like effects of topiramate on mice.

Acute doses of topiramate (TPM) have been shown to reduce immobility time in the mice forced swimming test (FST) through inhibition of the nitric oxide (NO) pathway. Adenosine triphosphate-sensitive potassium (KATP) channels are known to have an active role in depression. This study investigates the potential participation of KATP channels in the antidepressant-like effect of TPM through the stimulatory effects of NO. FST and tail suspension tests (TST) were applied to adult male mice for assessment of the antidepressant-like activity of TPM. Different doses of glibenclamide and cromakalim were also applied in order to investigate the involvement of KATP channels. Fluoxetine was used as a positive control for evaluation of antidepressant-like effects. In addition, each animal's locomotor activity was evaluated by the open-field test (OFT). TPM (30 mg/kg intraperitoneal (i.p.)) had a significant reductive effect on the immobility behavior similar to fluoxetine (20 mg/kg). Co-administration of sub-effective doses of glibenclamide (1 mg/kg i.p.) and TPM (10 mg/kg i.p.) led to significant synergistic effects in FST and TST. Additionally, the results showed that administration of the sub-effective dose of cromakalim (0.1 and 0.3 mg/kg i.p.) blocked the antidepressant-like effects of TPM (30 mg/kg i.p.) in both tests. These interventions had no impact on the locomotor movement of mice in OFT. This study shows that the antidepressant-like activity of TPM may potentially be mediated by the blocking of the KATP channels.

Longitudinal Alterations of Alpha-Synuclein, Amyloid Beta, Total, and Phosphorylated Tau in Cerebrospinal Fluid and Correlations Between Their Changes in Parkinson's Disease.

Background: Parkinson's disease (PD) is characterized by proteinopathies and these proteinopathies seem to interact synergistically and lead to protein aggregations and changes in protein cerebrospinal fluid (CSF) levels. In this study, we aimed to explore the longitudinal changes of CSF a lpha-synuclein (α-syn), total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (Aß1-42) and their relationships with each other and with baseline clinical entities like REM sleep behavior disorder (RBD), cognitive impairment, motor symptoms, and olfaction dysfunction. Method: One hundred and twelve non-demented PD patients and 110 controls were recruited from Parkinson's Progression Markers Initiative (PPMI).We used a linear mixed model within groups to assess longitudinal protein changes over 6 and 12 months and a random regression coefficient within the linear mixed model to investigate the correlation between proteins and their baseline clinical characteristics. Results: P-tau was lower in PDs only at baseline, but during a year, p-tau increased more rapidly in PDs than controls. Aß1-42 was not significantly different between groups at any separate timepoint; however, when assessed longitudinally, Aß1-42 showed significant changes in both groups. Conversely, t-tau and α-syn differed significantly between groups, but their longitudinal changes were not significant in either of the groups. Moreover, all proteins' baseline levels, except p-tau, could determine estimated longitudinal tau changes. Baseline RBDSQ scores but not UPDRS III, MoCA, or UPSIT scores were predictive of longitudinal increase in α-syn levels. Conclusion: Longitudinal changes in levels of CSF proteins are related to each other and could help researchers further understand PD pathology. In addition, RBD seems to be a potential prognostic factor for PD progression. However, in order to reach a consensus, longer follow-up times are required.

A statistical approach in human brain connectome of Parkinson Disease in elderly people using Network Based Statistics.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder assumed to involve different areas of CNS and PNS. Thus, Diffusion Tensor Imaging (DTI) is used to examine the areas engaged in PD neurodegeneration. In the present study, we computed average tract length and fiber volume as a measure of white matter integrity and adopted Network Based Statistics (NBS) to conduct group analyses between age- and gender-matched PD patients and healthy control connectivity matrices. NBS is a powerful statistical tool that utilizes the presence of every link in connectivity matrices and controls family wise error rates (in weak sense). The major regions with significantly reduced interconnecting fiber volume or average tract length were cingulum, temporal lobe, frontal lobe, parahippocampus, hippocampus, olfactory lobe, and occipital lobe.