Explore the vast range of titles available.

Parkinson’s disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.

Inflammation-induced sickness is associated with a large set of behavioral alterations; however, its motivational aspects remain poorly explored in humans. The present study assessed the effect of lipopolysaccharide (LPS) administration at a dose of 2 ng/kg of body weight on motivation in 21 healthy human subjects in a double-blinded, placebo (saline)-controlled, cross-over design. Incentive motivation and reward sensitivity were measured using the Effort Expenditure for Rewards Task (EEfRT), in which motivation for high-effort/high-reward trials vs low-effort/low-reward trials are manipulated by variations in reward magnitude and probability to win. Because of the strong interactions between sleepiness and motivation, the role of sleepiness was also determined. As expected, the probability to win predicted the choice to engage in high-effort/high-reward trials; however, this occurred at a greater extent after LPS than after saline administration. This effect was related to the level of sleepiness. Sleepiness increased motivation to choose the high-effort/high-reward mode of response, but only when the probability to win was the highest. LPS had no effect on reward sensitivity either directly or via sleepiness. These results indicate that systemic inflammation induced by LPS administration causes motivational changes in young healthy subjects, which are associated with sleepiness. Thus, despite its association with energy-saving behaviors, sickness allows increased incentive motivation when the effort is deemed worthwhile.

Although social withdrawal is a prominent symptom of sickness, the mechanisms associated with this behavioral change remain unclear. In animals, the amygdala is a key neural region involved in sickness-induced social withdrawal. Consistent with this, in humans, heightened amygdala activity to negative social cues is associated with social avoidance tendencies. Based on these findings, we investigated whether an experimental inflammatory challenge selectively increased amygdala activity to socially threatening images as well as whether this activity related to feelings of social disconnection. Thirty-nine participants were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammatory activity. Pro-inflammatory cytokines were assessed at 7 hourly time points via blood draws; self-reported feelings of social disconnection and physical sickness symptoms were assessed hourly as well. Two hours post-injection, participants underwent an fMRI procedure to assess amygdala reactivity during the presentation of socially threatening images (fear faces) as well as non-socially threatening images (guns), socially non-threatening images (happy faces), and non-social, non-threatening images (household objects). Endotoxin led to greater amygdala activity in response to socially threatening vs. all other types of images. No such differences were found for placebo participants. Additionally, increased amygdala activity in endotoxin participants during the viewing of socially vs. non-socially threatening images was associated with increased feelings of social disconnection. These findings highlight the amygdala as a neural region that may be important for sickness-induced social withdrawal. The implications of amygdalar involvement in sickness-induced social withdrawal are discussed. ► We investigated neural responses to social stimuli after an inflammatory challenge. ► Inflammation led to greater amygdala to socially threatening vs. other images. ► Amygdala activity was positively correlated with feelings of social disconnection. ► Amygdala activity may be important for sickness-induced social withdrawal.

Acute respiratory effects of low-level ozone exposure are not well defined in older adults. MOSES (The Multicenter Ozone Study in Older Subjects), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults. We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.9 ± 4.5 yr old; 60% female) to 0, 70, and 120 ppb ozone for 3 hours with intermittent exercise. Outcome measures included spirometry, sputum markers of airway inflammation, and plasma club cell protein-16 (CC16), a marker of airway epithelial injury. The effects of ozone exposure on these outcomes were evaluated with mixed-effect linear models. A P value less than 0.01 was chosen a priori to define statistical significance. The mean (95% confidence interval) FEV and FVC increased from preexposure values by 2.7% (2.0-3.4) and 2.1% (1.3-2.9), respectively, 15 minutes after exposure to filtered air (0 ppb). Exposure to ozone reduced these increases in a concentration-dependent manner. After 120-ppb exposure, FEV and FVC decreased by 1.7% (1.1-2.3) and 0.8% (0.3-1.3), respectively. A similar concentration-dependent pattern was still discernible 22 hours after exposure. At 4 hours after exposure, plasma CC16 increased from preexposure levels in an ozone concentration-dependent manner. Sputum neutrophils obtained 22 hours after exposure showed a marginally significant increase in a concentration-dependent manner (P = 0.012), but proinflammatory cytokines (IL-6, IL-8, and tumor necrosis factor-α) were not significantly affected. Exposure to ozone at near ambient levels induced lung function effects, airway injury, and airway inflammation in older healthy adults. Clinical trial registered with www.clinicaltrials.gov (NCT01487005).

•Higher sympathetic and lower parasympathetic activity 2 h after LPS-injection.•2 h Post-baseline difference in HEP amplitude lower in placebo compared to LPS group.•Reduced HEP amplitudes after 2 h in placebo group compared to LPS group.•ANS activity (HRV variables) correlated with HEP amplitudes under LPS. Interoception, or the perception of internal somatic states, is crucial for signaling the individual to take care of the body when needed. It enables behavioral adaptations to sickness states, which further impact autonomic nervous system (ANS) activity. Whether acute inflammation affects interoceptive processing and how this relates to sickness behavior remains unknown. Therefore, we investigated interoceptive processing in participants undergoing experimental endotoxemia. In neuroimaging research, heartbeat-evoked potentials (HEP) - defined as event-related potentials time-locked to electrocardiogram (ECG) R-waves during electroencephalogram (EEG) recordings - have emerged as a promising metric for cardiac interoceptive processing. We analyzed the effects of intravenous administration of lipopolysaccharide (LPS; 0.4 ng/kg) or placebo, on HEP amplitudes and ANS functioning in healthy, female participants (n = 52) during 8 min resting-state EEG and ECG recordings before and 2 h after injections. Our results showed increased cortisol and cytokine levels in the LPS group, along with increased sympathetic and decreased parasympathetic activity 2 h after injections compared to the placebo group. Placebo-injected participants exhibited lower post injection-baseline differences in HEP amplitudes in an early timeframe (255–455 ms), indicating lower HEPs 2 h after administrations. Moreover, post-injection HEP amplitudes differed between groups, suggesting that while participants in the placebo group showed altered HEP amplitudes after injection, HEPs remained unresponsive to LPS administration. These findings are discussed in the context of predictive processing, expectation violation and attention direction to external and interoceptive cues. Future research should further investigate the role of LPS dose and explore behavioral measures of interoception under experimental inflammation. [Display omitted]

Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18–50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P’s < 0.001). Inflammation-induced depressed mood is predicted by peripheral transcriptome profiles related to immune activation, sympathetic activation, and glucocorticoid insensitivity. With further replication, these stress-related molecular profiles could be used for a novel genomic approach for identifying individuals at high-risk for the inflammatory subtype of depression.

The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55-70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion (ppb) (filtered air), 70 ppb, and 120 ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. The definition of statistical significance was p<0.01. There were no effects of ozone on the three primary markers of systemic inflammation and a prothrombotic state: C-reactive protein, monocyte-platelet conjugates, and microparticle-associated tissue factor activity. However, among the secondary endpoints, endothelin-1, a potent vasoconstrictor, increased from pre- to post-exposure with ozone concentration (120 vs 0 ppb: 0.07 pg/mL, 95% confidence interval [CI] 0.01, 0.14; 70 vs 0 ppb: -0.03 pg/mL, CI -0.09, 0.04; p = 0.008). Nitrotyrosine, a marker of oxidative and nitrosative stress, decreased with increasing ozone concentrations, with marginal significance (120 vs 0 ppb: -41.5, CI -70.1, -12.8; 70 vs 0 ppb: -14.2, CI -42.7, 14.2; p = 0.017). GSTM1 status did not modify the effect of ozone exposure on any of the outcomes. These findings from healthy older adults fail to identify any mechanistic basis for the epidemiologically described cardiovascular effects of exposure to ozone. The findings, however, may not be applicable to adults with cardiovascular disease.

Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors, sitagliptin and vildagliptin, known to have different efficacy on mean amplitude of glycemic excursions (MAGE), on oxidative stress, and on systemic inflammatory markers in patients with type 2 diabetes. A prospective, randomized, open-label PROBE design (parallel group with a blinded end point) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin. The study assigned 45 patients to receive sitagliptin (100 mg once daily; sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice daily; vildagliptin group) for 12 weeks. MAGE, evaluated during 48 h of continuous subcutaneous glucose monitoring, allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients. Assessment of oxidative stress (nitrotyrosine) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients. HbA(1c), fasting and postprandial glucose, MAGE, and inflammatory and oxidative stress markers were similar between the groups at baseline. After 12 weeks, MAGE (P < 0.01) was lower in the vildagliptin group than in the sitagliptin group. After treatment, HbA(1c) and postprandial glucose evidenced similar changes between the groups (P = NS). Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine (P < 0.01), IL-6 (P < 0.05), and IL-18 (P < 0.05) than sitagliptin treatment. Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA(1c). MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients. These effects were greater in the vildagliptin group than in the sitagliptin group.

Disturbances in mitochondrial function are implicated in several chronic and acute diseases. Systemic inflammation has been described to affect mitochondrial respiration. Yet, in vivo measurement of mitochondrial respiration is notoriously difficult. We measured mitochondrial oxygen tension (mitoPO 2 ) and mitochondrial oxygen consumption (mitoVO 2 ) using the bedside COMET (Cellular Oxygen METabolism) system during systemic inflammation elicited by intravenous administration of 2 ng/kg lipopolysaccharide (LPS) in 42 healthy male volunteers. Four male subjects who did not receive LPS served as uninflamed controls. MitoPO 2 and mitoVO 2 were measured immediately prior to LPS administration, and at 1.45 h, 4 h, and 7 h, as well as at the corresponding timepoints in the control group. Compared to the control group, MitoPO 2 significantly decreased over time in the LPS group ( p  = 0.002), with the nadir observed at 1.45 h post-LPS administration (45.8 ± 1.8 vs. 75.2 ± 2.6 mmHg); while mitoVO 2 did not change. Concluding, the COMET monitor detects changes in mitochondrial parameters in a relatively mild model of systemic inflammation. This study paves the way for bedside monitoring of alterations in mitochondrial oxygenation and respiration, which may represent a vital next step in early diagnosis of mitochondrial dysfunction and stratification of patients in the intensive care unit. Trial registration : ClinicalTrials.gov NCT03240497. (12/04/2016) toetsingonline.nl NL56686.091.16 (11/04/2016) and NL65767.078.18 (01/05/2018).

Although beta-amyloid (Aβ) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer’s disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS) = 3] and an extension with an additional 12-month follow-up. During the first 12 months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240 mg orally (study group, n  = 50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n  = 50). After the first 12 months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240 mg tablet per day orally. All participants will be monitored for an additional 12 months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers ( https://www.olink.com/products/inflammation/ ) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1 years, and the mean time between symptom onset and MCI diagnosis was 2.9 years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI. Trial registration: Registro Español de estudios clínicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355.