Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to ...cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder.
To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB.
This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205).
The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition.
Among this cohort of 987 patients (512 men 51.9%; mean SD age, 70.0 8.8 years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, -3.61 pg/mL; 95% CI, -5.43 to -1.79 pg/mL; P = .049; difference in the groups in p-tau231, -2.51 pg/mL; 95% CI, -3.63 to -1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, -0.092 MMSE points; 95% CI, -0.12 to -0.06 MMSE points; P = .001; for p-tau231, -0.16 MMSE points; 95% CI, -0.21 to -0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of -0.094 MMSE points per year (95% CI, -0.144 to -0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of -0.130 MMSE points (95% CI, -0.201 to -0.071 MMSE points; P = .02), after adjusting for sex and age.
This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.
Cholesterol is responsible for the plasticity of plasma membranes and is involved in physiological and pathophysiological responses. Cholesterol homeostasis is regulated by oxysterols, such as ...25-hydroxycholesterol. The presence of 25-hydroxycholesterol at the membrane level has been shown to interfere with several viruses' entry into their target cells. We used atomic force microscopy to assess the effect of 25-hydroxycholesterol on different properties of supported lipid bilayers with controlled lipid compositions. In particular, we showed that 25-hydroxycholesterol inhibits the lipid-condensing effects of cholesterol, rendering the bilayers less rigid. This study indicates that the inclusion of 25-hydroxycholesterol in plasma membranes or the conversion of part of their cholesterol content into 25-hydroxycholesterol leads to morphological alterations of the sphingomyelin (SM)-enriched domains and promotes lipid packing inhomogeneities. These changes culminate in membrane stiffness variations.
Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes ...to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.
Decompensated heart failure patients are characterised by functional dependence and low exercise tolerance. Aerobic exercise can improve symptoms, functional capacity and an increase in exercise ...tolerance. However, the benefits of early rehabilitation have not yet been validated.
To evaluate the safety and feasibility of an aerobic exercise training programme in functional capacity of decompensated heart failure patients.
A single centre, parallel, randomised controlled, open label trial, with 100 patients. The training group (TG,
=50) performed the training protocol and the control group (CG,
=50) performed the usual rehabilitation procedures. The London chest activity of daily living (LCADL) scale, the Barthel index (BI) and the 6 minute walking test (6MWT) at discharge were used to evaluate the efficacy of the protocol. Safety was measured by the existence of adverse events.
The mean age of the patients was 70 years, 20% were New York Heart Association (NYHA) class IV and 80% NYHA class III at admission. The major heart failure aetiology was ischaemic (35 patients) and valvular disease (25 patients). There were no significant differences between groups at baseline in terms of sociodemographic or pathophysiological characteristics. There was a statistically significant difference of 54.2 meters for the training group (
=0.026) in the 6MWT and at LCADL 12 versus 16 (
=0.003), but the BI did not: 96 versus 92 (
=0.072). No major adverse events occurred.
The training protocol demonstrated safety and efficacy, promoting functional capacity. This study elucidated about the benefits of a systematised implementation of physical exercise during the patient's clinical stabilisation phase, which had not yet been demonstrated.Trial registration: Clinicaltrials.gov NCT03838003, URL: https://clinicaltrials.gov/ct2/show/NCT03838003.
Recently, it was demonstrated that 25-hydroxycholesterol (25HC), an oxidized cholesterol derivative, inhibits human immunodeficiency virus type 1 (HIV) entry into its target cells. However, the ...mechanisms involved in this action have not yet been established. The aim of this work was to study the effects of 25HC in biomembrane model systems and at the level of HIV fusion peptide (HIV-FP). Integration of different biophysical approaches was made in the context of HIV fusion process, to clarify the changes at membrane level due to the presence of 25HC that result in the suppressing of viral infection.
Lipid vesicles mimicking mammalian and HIV membranes were used on spectroscopy assays and lipid monolayers in surface pressure studies. Peptide-induced lipid mixing assays were performed by Förster resonance energy transfer to calculate fusion efficiency. Liposome fusion is reduced by 50% in the presence of 25HC, comparatively to cholesterol. HIV-FP conformation was assessed by infrared assays and it relies on sterol nature. Anisotropy, surface pressure and dipole potential assays indicate that the conversion of cholesterol in 25HC leads to a loss of the cholesterol modulating effect on the membrane.
With different biophysical techniques, we show that 25HC affects the membrane fusion process through the modification of lipid membrane properties, and by direct alterations on HIV-FP structure. The present data support a broad antiviral activity for 25HC.
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•The conversion of cholesterol to 25HC can directly block the membrane fusion promoted by HIV fusion peptide.•HIV fusion peptide secondary structure varies according to the sterol content.•The replacement of cholesterol by 25HC promotes a loss of the cholesterol modulating effect on membrane properties.
Objective
To analyze (1) the effect of an aerobic training program on functional exercise tolerance in decompensated heart failure (DHF) patients; (2) to assess the effects of an aerobic training ...program on functional independence; and (3) dyspnea during activities of daily living.
Design
A randomized controlled clinical trial with follow-up at discharge.
Settings
Eight hospitals. Recruitment took place between 9/ 2017 and 3/2019.
Group Assignments
Patients with DHF who were admitted to the hospital, were randomly assigned to usual rehabilitation care guideline recommended (control group) or aerobic training program (exercise group).
Main outcome
Functional exercise tolerance was measured with a 6-min walking test at discharge.
Results
In total 257 patients with DHF were included, with a mean age of 67 ± 11 years, 84% (n = 205) had a reduced ejection fraction and the hospital stay was 16 ± 10 days. At discharge, patients in the intervention group walked further compared to the control group (278 ± 117m vs 219 ± 115m, p < 0.01) and this difference stayed significant after correcting for confounders (p < 0.01). A significant difference was found favoring the exercise group in functional independence (96 ± 7 vs 93 ± 12, p = 0.02) and dyspnea associated to ADL (13 ± 5 vs 17 ± 7, p < 0.01) and these differences persisted after correcting for baseline values and confounders (functional independence p < 0.01; dyspnea associated with ADL p = 0.02).
Conclusion
The ERIC-HF program is safe, feasible, and effective in increasing functional exercise tolerance and functional independence in hospitalized patients admitted due to DHF.
Infectious diseases are one of the main causes of human morbidity and mortality. In the last few decades, pathogenic microorganisms' resistance to conventional drugs has been increasing, and it is ...now pinpointed as a major worldwide health concern. The need to search for new therapeutic options, as well as improved treatment outcomes, has therefore increased significantly, with biologically active peptides representing a new alternative. A substantial research effort is being dedicated towards their development, especially due to improved biocompatibility and target selectivity. However, the inherent limitations of peptide drugs are restricting their application. In this review, we summarize the current status of peptide drug development, focusing on antiviral and antimicrobial peptide activities, highlighting the design improvements needed, and those already being used, to overcome the drawbacks of the therapeutic application of biologically active peptides.
•Conventional drug-resistant infections are a major health concern.•Small active peptides are considered possible therapeutic alternatives.•Application limitations led to downsides in peptide drug therapeutics.•Different strategies are essential to improve peptide therapeutic activity.•Peptides are promising strategies against bacterial and viral infections.
Neurodegenerative dementias are progressive diseases that cause neuronal network breakdown in different brain regions often because of accumulation of misfolded proteins in the brain extracellular ...matrix, such as amyloids or inside neurons or other cell types of the brain. Several diagnostic protein biomarkers in body fluids are being used and implemented, such as for Alzheimer’s disease. However, there is still a lack of biomarkers for co-pathologies and other causes of dementia. Such biofluid-based biomarkers enable precision medicine approaches for diagnosis and treatment, allow to learn more about underlying disease processes, and facilitate the development of patient inclusion and evaluation tools in clinical trials. When designing studies to discover novel biofluid-based biomarkers, choice of technology is an important starting point. But there are so many technologies to choose among. To address this, we here review the technologies that are currently available in research settings and, in some cases, in clinical laboratory practice. This presents a form of lexicon on each technology addressing its use in research and clinics, its strengths and limitations, and a future perspective.
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•Biomarkers in body fluids have clinical value in neurodegenerative dementias.•There are several technologies for discovery and implementation of biomarkers.•We review these technologies for their value in research and clinics.
We review technologies used for body fluid protein biomarker discovery and translation to clinical practice. We address their main characteristics, their use in research and clinics, strengths and limitations, and a future perspective.
SARS-CoV-2 is the causative agent of COVID-19 and is responsible for the current global pandemic. The viral genome contains 5 major open reading frames of which the largest ORF1ab codes for two ...polyproteins, pp1ab and pp1a, which are subsequently cleaved into 16 nonstructural proteins (nsp) by two viral cysteine proteases encoded within the polyproteins. The main protease (Mpro, nsp5) cleaves the majority of the nsp’s, making it essential for viral replication and has been successfully targeted for the development of antivirals. The first oral Mpro inhibitor, nirmatrelvir, was approved for treatment of COVID-19 in late December 2021 in combination with ritonavir as Paxlovid. Increasing the arsenal of antivirals and development of protease inhibitors and other antivirals with a varied mode of action remains a priority to reduce the likelihood for resistance emerging. Here, we report results from an artificial intelligence-driven approach followed by in vitro validation, allowing the identification of five fragment-like Mpro inhibitors with IC50 values ranging from 1.5 to 241 μM. The three most potent molecules (compounds 818, 737, and 183) were tested against SARS-CoV-2 by in vitro replication in Vero E6 and Calu-3 cells. Compound 818 was active in both cell models with an EC50 value comparable to its measured IC50 value. On the other hand, compounds 737 and 183 were only active in Calu-3, a preclinical model of respiratory cells, showing selective indexes twice as high as those for compound 818. We also show that our in silico methodology was successful in identifying both reversible and covalent inhibitors. For instance, compound 818 is a reversible chloromethylamide analogue of 8-methyl-γ-carboline, while compound 737 is an N-pyridyl-isatin that covalently inhibits Mpro. Given the small molecular weights of these fragments, their high binding efficiency in vitro and efficacy in blocking viral replication, these compounds represent good starting points for the development of potent lead molecules targeting the Mpro of SARS-CoV-2.
Secernin-1 (SCRN1) is a neuronal protein that co-localizes with neurofibrillary tangles in Alzheimer's disease (AD), but not with tau inclusions in corticobasal degeneration (CBD), progressive ...supranuclear palsy (PSP), or Pick's disease.
We measured SCRN1 concentration in cerebrospinal fluid (CSF) using a novel mass spectrometric parallel reaction monitoring method in three clinical cohorts comprising patients with neurochemically characterized AD (n = 25) and controls (n = 28), clinically diagnosed Parkinson's disease (PD; n = 38), multiple system atrophy (MSA; n = 31), PSP (n = 20), CBD (n = 8), healthy controls (n = 37), and neuropathology-confirmed AD (n = 47).
CSF SCRN1 was significantly increased in AD (P < 0.01, fold change = 1.4) compared to controls (receiver operating characteristic area under the curve = 0.78) but not in CBD, PSP, PD, or MSA. CSF SCRN1 positively correlated with CSF total tau (R = 0.78, P = 1.1 × 10
), phosphorylated tau
(R = 0.64, P = 3.2 × 10
), and Braak stage and negatively correlated with Mini-Mental State Examination score.
CSF SCRN1 is a candidate biomarker of AD, reflecting tau pathology.
We developed a parallel reaction monitoring assay to measure secernin-1 (SCRN1) in cerebrospinal fluid (CSF). CSF SCRN1 was increased in Alzheimer's disease compared to healthy controls. CSF SCRN1 remained unchanged in Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration compared to controls. CSF SCRN1 correlated strongly with CSF phosphorylated tau and total tau. CSF SCRN1 increased across Braak stages and negatively correlated with Mini-Mental State Examination score.
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