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Depressive symptoms may increase the risk of progressing from mild cognitive impairment (MCI) to dementia. Consumption of n-3 PUFA may alleviate both cognitive decline and depression. The aim of the present study was to investigate the benefits of supplementing a diet with n-3 PUFA, DHA and EPA, for depressive symptoms, quality of life (QOL) and cognition in elderly people with MCI. We conducted a 6-month double-blind, randomised controlled trial. A total of fifty people aged >65 years with MCI were allocated to receive a supplement rich in EPA (1·67 g EPA+0·16 g DHA/d; n 17), DHA (1·55 g DHA+0·40 g EPA/d; n 18) or the n-6 PUFA linoleic acid (LA; 2·2 g/d; n 15). Treatment allocation was by minimisation based on age, sex and depressive symptoms (Geriatric Depression Scale, GDS). Physiological and cognitive assessments, questionnaires and fatty acid composition of erythrocytes were obtained at baseline and 6 months (completers: n 40; EPA n 13, DHA n 16, LA n 11). Compared with the LA group, GDS scores improved in the EPA (P = 0·04) and DHA (P = 0·01) groups and verbal fluency (Initial Letter Fluency) in the DHA group (P = 0·04). Improved GDS scores were correlated with increased DHA plus EPA (r 0·39, P = 0·02). Improved self-reported physical health was associated with increased DHA. There were no treatment effects on other cognitive or QOL parameters. Increased intakes of DHA and EPA benefited mental health in older people with MCI. Increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia. This needs to be investigated in larger, depressed samples with MCI.

Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography–MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.

Objective This study was performed to investigate the role of probiotics (Clostridium butyricum combined with Bifidobacterium infantis) in the treatment of minimal hepatic encephalopathy (MHE) in patients with hepatitis B virus (HBV)-induced liver cirrhosis. Methods Sixty-seven consecutive patients with HBV-induced cirrhosis without overt hepatic encephalopathy were screened using the number connection test and digit symbol test. The patients were randomized to receive probiotics (n = 30) or no probiotics (n = 37) for 3 months. At the end of the trial, changes in cognition, intestinal microbiota, venous ammonia, and intestinal mucosal barriers were analyzed using recommended systems biology techniques. Results The patients’ cognition was significantly improved after probiotic treatment. The predominant bacteria (Clostridium cluster I and Bifidobacterium) were significantly enriched in the probiotics-treated group, while Enterococcus and Enterobacteriaceae were significantly decreased. Probiotic treatment was also associated with an obvious reduction in venous ammonia. Additionally, the parameters of the intestinal mucosal barrier were obviously improved after probiotic treatment, which might have contributed to the improved cognition and the decreased ammonia levels. Conclusion Treatment with probiotics containing C. butyricum and B. infantis represents a new adjuvant therapy for the management of MHE in patients with HBV-induced cirrhosis.

(1) Background: Chlorogenic acids (CGAs) have been attracting interest of late, owing to their health benefits. Here, we performed a randomized, double-blind, placebo-controlled trial to investigate whether CGAs improved cognitive function in humans. (2) Methods: Thirty-eight healthy participants were assigned to either the CGA group, which was given CGA-added beverage daily for 16 weeks, or the placebo group. Cognitive functions were assessed using the Japanese version of the CNS Vital Signs (Cognitrax). (3) Results: The CGA group showed significant increase in the Cognitrax domain scores for motor speed, psychomotor speed, and executive function compared with the placebo group, as well as an improvement in the shifting attention test scores. In blood analysis, the CGA group showed increased levels of apolipoprotein A1 and transthyretin, both of which are putative biomarkers for early-stage cognitive decline. (4) Conclusions: These results suggest that CGAs may improve some cognitive functions, which would help in the efficient performance of complex tasks.

Abstract Context The effects of physiological improvements on cognitive function among persons with type 2 diabetes mellitus (T2DM) are not fully understood. Objective To determine whether improvements in physiological markers (body weight, blood sugar control, and physical activity) during intensive lifestyle intervention (ILI) are associated with enhancements in cognitive function in older adults with T2DM. Design Multisite randomized controlled trial. Setting Academic research centers. Patients or Other Participants Participants were aged 45–76 years, with T2DM. Intervention The Action for Health in Diabetes (Look AHEAD) study, a randomized, controlled clinical trial of ILI. Main Outcome Measure Two to 3 cognitive assessments were collected from 1089 participants, the first and last occurring a mean (standard deviation) of 8.6 (1.0) and 11.5 (0.7) years after enrollment. Results Greater improvement in blood sugar control was associated with better cognitive scores (fasting glucose and Rey Auditory Verbal Learning Test [AVLT]: P = 0.0148; fasting glucose and Digit Symbol Coding (DSC): P = 0.0360; HbA1C and DSC: P = 0.0477); but weight loss had mixed associations with cognitive scores (greater body mass index [BMI] reduction and worse AVLT overall: P = 0.0053; and greater BMI reduction and better DSC scores among those overweight but not obese at baseline: P = 0.010). Associations were strongest among those who were overweight (not obese) at baseline, and among those with a history of cardiovascular disease (CVD) at baseline. Conclusions Improvements in glycemic control, but not necessarily weight status, during ILI may be associated with better subsequent cognitive performance. These associations may differ by adiposity and CVD history.

Background Inflammatory processes have been implicated in the etiology of schizophrenia and related psychoses, in which cognitive deficits represent core symptoms. The aim of the present study was to investigate possible associations between the level of the inflammation marker C-reactive protein (CRP) and cognitive performance in patients through the acute phase of psychosis. Methods A total of 124 patients were assessed at admittance to hospital and 62 patients were retested at discharge or after 6 weeks at the latest, with measurements of the CRP levels and alternative forms of the Repeatable Battery for the Assessment of Neuropsychological Status. Results There was an inverse relationship between overall cognitive performance and CRP level at admittance. The association increased in sub-analyses including only patients with schizophrenia. In cognitive subdomain analyses statistically significant inverse associations were found between the CRP level and Delayed memory and Attention, respectively. No associations were found between CRP level and other measures of psychopathology including psychosis symptoms, depression, or functioning. At follow-up the association between CRP level and cognition was no longer present. There was a significant increase in cognitive performance between baseline and follow-up. There was a stronger increase in overall cognition scores in patients with higher baseline CRP levels. Conclusions The findings indicate that signs of inflammation may serve as a state-dependent marker of cognitive dysfunctions in acute psychosis. Trial registration ClinicalTrials.gov ID; NCT00932529 , registration date: 02.07.2009

The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. Plasma levels were obtained 2.5 h post administration. In non-smokers, levels were similar to those reached transiently with 75-150 mg DMXB-A immediate-release formulations twice daily, which were earlier shown to be effective doses. However, the extended-release formulation produced no cognitive or clinical effect either in non-smokers or smokers. The 10-fold lower DMXB-A plasma levels in smokers suggest that chronic smoking enhances DMXB-A metabolism. Pro-cognitive effects of DMXB-A may result from transient increases in cell signaling that are limited by receptor tachyphylaxis. Future efforts to improve cognition in schizophrenia by enhancing alpha7 nAChR function may require consideration of these pharmacokinetic limitations.

Carotenoids may help to prevent the ageing of the brain. Previous findings regarding β-carotene alone are not consistent. In the present study, we evaluated the cross-time association between a carotenoid-rich dietary pattern (CDP) and subsequent cognitive performance using a sample of 2983 middle-aged adults participating in the SU.VI.MAX (Supplémentation en Vitamines et Minéraux Antioxydants) study. Cognitive performance was assessed in 2007–9 using six neuropsychological tests, and a composite cognitive score was computed. The cognitive data were related to dietary data obtained by repeated 24 h dietary records (1994–6) and to measurements of baseline plasma concentrations of carotenoids (lutein, zeaxanthin, β-cryptoxanthin, lycopene, α-carotene, trans-β-carotene and cis-β-carotene). DP were extracted using the reduced rank regression method for 381 participants and then extrapolated to the whole sample using plasma carotenoid concentrations as response variables. Associations between a CDP and cognitive function measured 13 years later were estimated with ANCOVA providing mean difference values and 95 % CI across the tertiles of CDP. A correlation between CDP and consumption of orange- and green-coloured fruits and vegetables, vegetable oils and soup was observed. CDP was found to be associated with a higher composite cognitive score (mean difference 1·04, 95 % CI 0·20, 1·87, P for trend 0·02), after adjustment for sociodemographic, lifestyle and health factors. Similar findings were obtained for scores obtained in the cued recall task, backward digit span task, trail making test and semantic fluency task (all P for trend < 0·05). Further studies ought to confirm whether a diet providing sufficient quantity and variety of coloured fruits and vegetables may contribute to the preservation of cognitive function during ageing.

Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines. Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy. Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration. The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. clinicaltrials.gov NCT01205503.

Background Symptomatic benefits have been reported for 5-HT 6 receptor antagonists in Alzheimer’s disease (AD) trials. SAM-760 is a potent and selective 5-HT 6 receptor antagonist that has demonstrated central 5-HT 6 receptor saturation in humans at a dose of 30 mg. Methods This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10–24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score ≥ 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. Results At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points ( P = 0.43) for ADAS-cog13 and 2.19 points ( P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). Conclusions SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT 6 receptor antagonists. Trial registration Clinicaltrials.gov, NCT01712074 . Registered 19 October 2012.