Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.

Glucose administration and cognitive function: differential effects of age and effort during a dual task paradigm in younger and older adults

RATIONALE: Current research suggests that glucose facilitates performance on cognitive tasks which possess an episodic memory component and a relatively high level of cognitive demand. However, the extent to which this glucose facilitation effect is uniform across the lifespan is uncertain. METHODS: This study was a repeated measures, randomised, placebo-controlled, cross-over trial designed to assess the cognitive effects of glucose in younger and older adults under single and dual task conditions. Participants were 24 healthy younger (average age 20.6 years) and 24 healthy older adults (average age 72.5 years). They completed a recognition memory task after consuming drinks containing 25 g glucose and a placebo drink, both in the presence and absence of a secondary tracking task. RESULTS AND CONCLUSIONS: Glucose enhanced recognition memory response time and tracking precision during the secondary task, in older adults only. These findings do not support preferential targeting of hippocampal function by glucose, rather they suggest that glucose administration differentially increases the availability of attentional resources in older individuals.

Glucose enhancement of recognition memory: differential effects on effortful processing but not aspects of 'remember-know' responses

The administration of a glucose drink has been shown to enhance cognitive performance with effect sizes comparable with those from pharmaceutical interventions in human trials. In the memory domain, it is currently debated whether glucose facilitation of performance is due to differential targeting of hippocampal memory or whether task effort is a more important determinant. Using a placebo-controlled, double-blind, crossover 2(Drink: glucose/placebo) × 2(Effort: ± secondary task) design, 20 healthy young adults' recognition memory performance was measured using the 'remember-know' procedure. Two high effort conditions (one for each drink) included secondary hand movements during word presentation. A 25 g glucose or 30 mg saccharine (placebo) drink was consumed 10 min prior to the task. The presence of a secondary task resulted in a global impairment of memory function. There were significant Drink × Effort interactions for overall memory accuracy but no differential effects for 'remember' or 'know' responses. These data suggest that, in some circumstances, task effort may be a more important determinant of the glucose facilitation of memory effect than hippocampal mediation. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: a randomised, placebo-controlled trial

OBJECTIVE: Nutritional and vitamin status may be related to cognitive function and decline in older adults. The aim of this study was to investigate the effects of nutritional supplementation on cognition in older men. METHOD: The current study was an 8-week, placebo-controlled, double-blind investigation into the effects of a multivitamin, mineral and herbal supplement (Swisse Men's Ultivite®, Swisse Vitamins Pty Ltd, Melbourne, Australia) on cognitive performance in older men. Participants were 51 male individuals aged between 50 and 74 years, with a sedentary lifestyle. Cognitive performance was assessed at baseline and post-treatment using a computerised battery of cognitive tasks, enabling the measurement of a range of attentional and memory processes. Blood measures of vitamin B(12) , folate and homocysteine were collected prior to and after supplementation. RESULTS: The results of this study revealed that contextual recognition memory performance was significantly improved following multivitamin supplementation (p < 0.05). Performance on other cognitive tasks did not change. Levels of vitamin B(12) and folate were significantly increased with a concomitant decrease in homocysteine, indicating that relatively short-term supplementation with a multivitamin can benefit these risk factors for cognitive decline. CONCLUSION: Findings from this study indicate that daily multivitamin supplementation may improve episodic memory in older men at risk of cognitive decline.

Memory improvements in elderly women following 16 weeks treatment with a combined multivitamin, mineral and herbal supplement: a randomized controlled trial.

RATIONALE: There is potential for multivitamin supplementation to improve cognition in the elderly. This randomized, double-blind, placebo-controlled trial was conducted to investigate the effects of 16 weeks multivitamin supplementation (Swisse Women's 50+ Ultivite ®) on cognition in elderly women. METHODS: Participants in this study were 56 community dwelling, elderly women, with subjective complaints of memory loss. Cognition was assessed using a computerized battery of memory and attention tasks designed to be sensitive to age-related declines to fluid intelligence, and a measure of verbal recall. Biochemical measures of selected nutrients, homocysteine, markers of inflammation, oxidative stress, and blood safety parameters were also collected. All cognitive and haematological parameters were assessed at baseline and 16 weeks post-treatment. RESULTS: The multivitamin improved speed of response on a measure of spatial working memory, however benefits to other cognitive processes were not observed. Multivitamin supplementation decreased levels of homocysteine and increased levels of vitamin B(6) and B(12), with a trend for vitamin E to increase. There were no hepatotoxic effects of the multivitamin formula indicating this supplement was safe for everyday usage in the elderly. CONCLUSION: Sixteen weeks ssupplementation with a combined multivitamin, mineral and herbal formula may benefit working memory in elderly women at risk of cognitive decline.

The effects of multivitamins on cognitive performance: a systematic review and meta-analysis

Complementary medicine use is becoming increasingly popular with multivitamins being the most commonly used vitamin supplement. Although adequate vitamin and nutrient concentrations are necessary for optimal health and cognitive functioning, there is no scientific consensus as to whether multivitamin use prevents cognitive decline or improves mental functioning. The aim of the present study was to determine if multivitamins can be used efficaciously to improve cognitive abilities. A systematic review of randomized controlled trials was performed. Meta-analysis was performed on those cognitive tests used across the largest number of studies. Multiple electronic databases were searched until July 2011 by two authors. Randomized, placebo-controlled trials were considered appropriate if they reported on the chronic effects (≥1 month) of oral multivitamin supplementation on any valid cognitive outcomes. Ten trials were included in review (n = 3,200). Meta-analysis indicated that multivitamins were effective in improving immediate free recall memory (SMD = 0.32; 95% CI: 0.09-0.56, p < 0.01) but not delayed free recall memory (SMD = -0.14; 95% CI: -0.43-0.14, p = 0.33) or verbal fluency (SMD = 0.06; 95% CI: -0.05-0.18, p = 0.26). There was no evidence of publication bias or heterogeneity. Other cognitive abilities sensitive to AD pathology, such as executive and visuospatial functions, were found to be under researched. In conclusion, multivitamins were found to enhance immediate free recall memory but no other cognitive domains.

Effect of resistance exercise contraction mode and protein supplementation on members of the STARS signalling pathway

The striated muscle activator of Rho signalling (STARS) pathway is suggested to provide a link between external stress responses and transcriptional regulation in muscle. However, the sensitivity of STARS signalling to different mechanical stresses has not been investigated. In a comparative study, we examined the regulation of the STARS signalling pathway in response to unilateral resistance exercise performed as either eccentric (ECC) or concentric (CONC) contractions as well as prolonged training; with and without whey protein supplementation. Skeletal muscle STARS, myocardian-related transcription factor-A (MRTF-A) and serum response factor (SRF) mRNA and protein, as well as muscle cross-sectional area and maximal voluntary contraction, were measured. A single-bout of exercise produced increases in STARS and SRF mRNA and decreases in MRTF-A mRNA with both ECC and CONC exercise, but with an enhanced response occurring following ECC exercise. A 31% increase in STARS protein was observed exclusively after CONC exercise (P < 0.001), while pSRF protein levels increased similarly by 48% with both CONC and ECC exercise (P < 0.001). Prolonged ECC and CONC training equally stimulated muscle hypertrophy and produced increases in MRTF-A protein of 125% and 99%, respectively (P < 0.001). No changes occurred for total SRF protein. There was no effect of whey protein supplementation. These results show that resistance exercise provides an acute stimulation of the STARS pathway that is contraction mode dependent. The responses to acute exercise were more pronounced than responses to accumulated training, suggesting that STARS signalling is primarily involved in the initial phase of exercise-induced muscle adaptations.

Effects of persisting emotional impact from child abuse and norepinephrine transporter genetic variation on antidepressant efficacy in major depression: a pilot study

OBJECTIVE: Previous studies suggest child abuse and serotonergic polymorphism influence depression susceptibility and antidepressant efficacy. Polymorphisms of the norepinephrine transporter (NET) may also be involved. Research in the area is possibly clouded by under reporting of abuse in researcher trials. METHODS: Adults (n=51) with major depressive disorder has 8 weeks treatment with escitalopram or venlafaxine. Abuse history was obtained, the ongoing emotional impact of which was measured with the 15-item impact of event scale (IES-15). The 17-item Hamilton Depression Rating Scale (HDRS) was applied serially. Two NET polymorphisms (rs2242446 and rs5569) were assayed, blinded to HDRS ratings and abuse history. RESULTS: No subjects reporting abuse with high impact in adulthood (IES-15 ≥26, n=12) remitted; whereas 77% reporting low impact (IES-15 <26; n=26) remitted (p<0.001). Subjects reporting high impact abuse (n=12) had a 50-fold (95% confidence interval=4.85-514.6) greater odds of carrying rs2242446-TT genotype, but the small sample size leaves this finding vulnerable to type I error. CONCLUSIONS: The level of persisting impact of child abuse appears relevant to antidepressant efficacy, with susceptibility to such possibly being influence by NET rs2242446 polymorphism. Larger studies may be merited to expand on this pilot level finding given potential for biomarker utility.

Online mindfulness-based intervention for late-stage bipolar disorder: pilot evidence for feasibility and effectiveness

OBJECTIVES: People in the late stage of bipolar disorder (BD) experience elevated relapse rates and poorer quality of life (QoL) compared with those in the early stages. Existing psychological interventions also appear less effective in this group. To address this need, we developed a new online mindfulness-based intervention targeting quality of life (QoL) in late stage BD. Here, we report on an open pilot trial of ORBIT (online, recovery-focused, bipolar individual therapy). METHODS: Inclusion criteria were: self-reported primary diagnosis of BD, six or more episodes of BD, under the care of a medical practitioner, access to the internet, proficient in English, 18-65 years of age. Primary outcome was change (baseline - post-treatment) on the Brief QoL.BD (Michalak and Murray, 2010). Secondary outcomes were depression, anxiety, and stress measured on the DASS scales (Lovibond and Lovibond, 1993). RESULTS: Twenty-six people consented to participate (Age M=46.6 years, SD=12.9, and 75% female). Ten participants were lost to follow-up (38.5% attrition). Statistically significant improvement in QoL was found for the completers, t(15)=2.88, 95% CI:.89-5.98, p=.011, (Cohen׳s dz=.72, partial η(2)=.36), and the intent-to-treat sample t(25)=2.65, 95% CI:.47-3.76, (Cohen׳s dz=.52; partial η(2)=.22). A non-significant trend towards improvement was found on the DASS anxiety scale (p=.06) in both completer and intent-to-treat samples, but change on depression and stress did not approach significance. LIMITATIONS: This was an open trial with no comparison group, so measured improvements may not be due to specific elements of the intervention. Structured diagnostic assessments were not conducted, and interpretation of effectiveness was limited by substantial attrition. CONCLUSION: Online delivery of mindfulness-based psychological therapy for late stage BD appears feasible and effective, and ORBIT warrants full development. Modifications suggested by the pilot study include increasing the 3 weeks duration of the intervention, adding cautions about the impact of extended meditations, and addition of coaching support/monitoring to optimise engagement.

The relationships between common measurements of taste function

BACKGROUND: There are five common, independent measures used to characterize taste function in humans: detection and recognition thresholds (DT and RT), suprathreshold intensity ratings of prototypical tastants, propylthiouracil (PROP) bitterness intensity, and fungiform papillae (FP) number. METHODS: We employed all five methods to assess taste function of 65 women (21.5 ± 4 years, BMI 22.3 ± 2.8 kg/m(2)). Pearson correlation coefficients were calculated between the different measures. RESULTS: The DT and RT were positively correlated for sweet, bitter, sour, and umami (p < 0.05), but not for salt. The DT or RT did not correlate with suprathreshold intensity ratings, except for umami (suprathreshold intensity and RT: r = -0.32, p = 0.009). FP number did not correlate with any measurement of taste function. PROP bitterness intensity ratings did not correlate with any measurement of taste function, except for suprathreshold ratings for saltiness (r = 0.26, p = 0.033). CONCLUSION: As most of the individual measures of taste function did not correlate with each other, with exception of the two threshold measures, we conclude that there are multiple perceptual phases of taste, with no single measure able to represent the sense of taste globally.

Synchronization by low-amplitude light-dark cycles of 24-hour pineal and plasma melatonin rhythms of hatchling European starlings (Sturnus vulgaris)

In young European starlings, as in other avian species, high-amplitude 24-hr rhythms in plasma and pineal melatonin are already present around the time of hatching. In chickens this rhythmicity results at least partly from the light sensitivity of the melatonin-producing and -secreting system. In contrast to the chicken, the starling is a hole-nesting bird, and it seemed questionable whether the low light intensities in the nest are sufficient to synchronize perinatal melatonin rhythms. We therefore exposed starling eggs to light cycles roughly simulating those measured in nest-boxes, i.e., an 11-hr phase of complete darkness and a 13-hr phase consisting of 15 min of dim light (10 lux) alternating with 30 min of darkness. For one group the photophase lasted from 0600 to 1900 hr; for the other group the photophase lasted from 1800 to 0700 hr. In approximately 10-hr-old hatchlings of both groups, plasma and pineal melatonin concentrations were high during the dark phase and low during the light phase. We conclude that perinatal low-amplitude light intensity changes of the kind experienced by hatching starlings in the field are sufficient for synchronizing the melatonin-producing and -secreting system in the pineal and possibly other organs.

Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.