Stress is now recognized as a universal premorbid factor associated with many risk factors of various chronic diseases. Acute stress may induce an individual’s adaptive response to environmental demands. However, chronic, excessive stress causes cumulative negative impacts on health outcomes through “allostatic load”. Thus, monitoring the quantified levels of long-term stress mediators would provide a timely opportunity for prevention or earlier intervention of stressrelated chronic illnesses. Although either acute or chronic stress could be quantified through measurement of changes in physiological parameters such as heart rate, blood pressure, and levels of various metabolic hormones, it is still elusive to interpret whether the changes in circulating levels of stress mediators such as cortisol can reflect the acute, chronic, or diurnal variations. Both serum and salivary cortisol levels reveal acute changes at a single point in time, but the overall long-term systemic cortisol exposure is difficult to evaluate due to circadian variations and its protein-binding capacity. Scalp hair has a fairy predictable growth rate of approximately 1 cm/month, and the most 1 cm segment approximates the last month’s cortisol production as the mean value. The analysis of cortisol in hair is a highly promising technique for the retrospective assessment of chronic stress. [BMB Reports 2015; 48(4): 209-216]

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterised by TDP-43 pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here, we have created a novel TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed leading to a gain of TDP-43 function, and altered splicing of Mapt, another pivotal dementia gene. Furthermore, a novel approach to stratify transcriptomic data by phenotype in differentially affected mutant mice reveals 471 changes linked with improved behaviour. These changes include downregulation of two known modifiers of neurodegeneration, Atxn2 and Arid4a, and upregulation of myelination and translation genes. With one base change in murine Tardbp, this study identifies TDP-43 misregulation as a pathogenic mechanism that may underpin ALS-FTD, and exploits phenotypic heterogeneity to yield candidate suppressors of neurodegenerative disease.

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Background: Although atrial fibrillation (AF) has a risk of cognitive dysfunction, it is not clear whether AF catheter ablation improves or worsens cognitive function. This prospective case-control study sought to assess the 1-year serial changes in the cognitive function with or without AF catheter ablation. Methods: We evaluated the Montreal Cognitive Assessment score in 308 patients (71.4% male, 60.6±9.1 years of age, 34.1% persistent AF) who underwent AF ablation (ablation group) and 50 AF patients on medical therapy who met the same indication for AF ablation (control group), at baseline and 3 and 12 months after enrollment. Cognitive impairment was defined as a published cutoff score of <23 points. To exclude any learning effects, we used the practice-adjusted reliable change index for assessing the cognitive changes. Results: Preablation cognitive impairment was detected in 18.5% (57/308). The Montreal Cognitive Assessment score significantly improved 1 year after radiofrequency catheter ablation in both overall ablation group (24.9±2.9–26.4±2.5; P <0.001) and the propensity-matched ablation group (25.4±2.4–26.5±2.3; P <0.001), but not in the control group (25.4±2.5–24.8±2.5; P =0.012). Preablation cognitive impairment (odds ratio, 13.70; 95% CI, 4.83–38.87; P <0.001) was independently associated with an improvement in the 1-year post-ablation cognitive function. In the reliable change index analyses, 94.7% of propensity-matched ablation group showed an improved/stable cognitive function at the 1-year follow-up. Conclusions: Catheter ablation of AF, at least, does not deteriorate the cognitive function, but rather improves the performance on 1-year follow-up neurocognitive tests, especially in patients with a preablation cognitive impairment.

Background HIV-associated neurocognitive disorder (HAND) is an independent predictor of early mortality and is associated with many difficulties in activities of daily living. We sought to determine the prevalence of and risk factors for HAND in HIV-infected Koreans. In addition, we investigated the performance of screening tools and components of neuropsychological (NP) tests for diagnosing HAND. Methods HIV-infected patients were enrolled consecutively from two different urban teaching hospitals in Seoul, South Korea between March 2012 and September 2012. Participants completed a detailed NP assessment of six cognitive domains commonly affected by HIV. The Frascati criteria were used for diagnosing HAND. Four key questions, international HIV dementia scale (IHDS) and MoCA-K were also assessed as potential tools for screening for HAND. Results Among the 194 participants, the prevalence of HAND was 26.3%. Asymptomatic neurocognitive impairment, minor neurocognitive disorder accounted for 52.9% and 47.1% of the patients with HAND, respectively. In multivariate analysis, hemoglobin levels ≤13g/dL (p=0.046) and the current use of protease inhibitor-based regimen (p=0.031) were independent risk factors for HAND. The sensitivity and specificity of IHDS were 72.6% and 60.8%, and MoCA-K were 52.9% and 73.4%, respectively. IHDS (p<0.001) and MoCA-K (p<0.001) were both useful for screening for HAND. Among NP tests, the sensitivity and specificity of the Grooved Pegboard Test were 90.2% and 72.0%, and the Wisconsin Card Sorting Test were 61.2% and 84.4%, respectively. Conclusions HAND is a prevalent comorbidity in HIV-infected Koreans. Active screening and diagnosis with useful tools, like IHDS, MoCA-K and Grooved Pegboard Test, could be used to identify this important complication.

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The risk of Alzheimer's disease (AD) is higher in patients with type 2 diabetes mellitus (T2DM). Previous studies in high-fat diet-induced AD animal models have shown that brain insulin resistance in these animals leads to the accumulation of amyloid beta (Aβ) and the reduction in GSK-3β phosphorylation, which promotes tau phosphorylation to cause AD. No therapeutic treatments that target AD in T2DM patients have yet been discovered. Agmatine, a primary amine derived from l-arginine, has exhibited anti-diabetic effects in diabetic animals. The aim of this study was to investigate the ability of agmatine to treat AD induced by brain insulin resistance. ICR mice were fed a 60% high-fat diet for 12 weeks and received one injection of streptozotocin (100 mg/kg/ip) 4 weeks into the diet. After the 12-week diet, the mice were treated with agmatine (100 mg/kg/ip) for 2 weeks. Behaviour tests were conducted prior to sacrifice. Brain expression levels of the insulin signal molecules p-IRS-1, p-Akt, and p-GSK-3β and the accumulation of Aβ and p-tau were evaluated. Agmatine administration rescued the reduction in insulin signalling, which in turn reduced the accumulation of Aβ and p-tau in the brain. Furthermore, agmatine treatment also reduced cognitive decline. Agmatine attenuated the occurrence of AD in T2DM mice via the activation of the blunted insulin signal.

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