The purpose of this study was to demonstrate the potential alterations in structural network properties related to physical activity (PA) in healthy elderly. We recruited 76 elderly individuals with normal cognition from Samsung Medical Center in Seoul, Korea. All participants underwent the Cambridge Neuropsychological Test Automated Battery and 3.0T brain magnetic resonance imaging (MRI). Participants were subdivided into quartiles according to the International Physical Activity Questionnaire scores, which represents the amount of PA. Through graph theory based analyses, we compared global and local network topologies according to PA quartile. The higher PA group demonstrated better performance in speed processing compared to the lower PA group. Regional nodal strength also significantly increased in the higher PA group, which involved the bilateral middle frontal, bilateral inferior parietal, right medial orbitofrontal, right superior, and middle temporal gyri. These results were further replicated when the highest and the lowest quartile groups were compared in terms of regional nodal strengths and local efficiency. Our findings that the regional nodal strengths associated with the attentional network were increased in the higher PA group suggest the preventive effects of PA on age-related cognitive decline, especially in attention.

The amygdala has been known to play a pivotal role in mediating fear-related responses including panic attacks. Given the functionally distinct role of the amygdalar subregions, morphometric measurements of the amygdala may point to the pathophysiological mechanisms underlying panic disorder. The current study aimed to determine the global and local morphometric alterations of the amygdala related to panic disorder.

Repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) may induce functional modulation of motor performance and sensory perception. To address the underlying neurophysiological modulation following 10 Hz rTMS applied over M1, we examined cortical activation using 3T functional magnetic resonance imaging (fMRI), as well as the associated motor and sensory behavioral changes. The motor performance measure involved a sequential finger motor task that was also used as an activation task during fMRI. For sensory assessment, current perception threshold was measured before and after rTMS outside the MR scanner, and noxious mechanical stimulation was used as an activation task during fMRI. We found that significant activation in the bilateral basal ganglia, left superior frontal gyrus, bilateral pre-SMA, right medial temporal lobe, right inferior parietal lobe, and right cerebellar hemisphere correlated with enhanced motor performance in subjects that received real rTMS compared with sham-stimulated controls. Conversely, significant deactivation in the right superior and middle frontal gyri, bilateral postcentral and bilateral cingulate gyri, left SMA, right insula, right basal ganglia, and right cerebellar hemisphere were associated with an increase in the sensory threshold. Our findings reveal that rTMS induced rapid changes in the sensorimotor networks associated with sensory perception and motor performance and demonstrate the complexity of such intervention.

Background: In neuromyelitis optica spectrum disorder (NMOSD), brain involvement is common and cognitive dysfunction is frequently found. The study investigated alterations of white matter (WM) connectivity using graph theory and correlations with cognitive dysfunction in patients with NMOSD. Methods: We prospectively enrolled patients with NMOSD (N = 14) and age- and sex-matched healthy controls (N = 21). Structural connections between any pair of the 90 cortical and subcortical regions were established using diffusion tensor imaging and graph theory. Network-based statistics was employed to assess differences in WM connectivity between the NMOSD and healthy control groups. We further investigated the relationship between the topological network characteristics and cognitive test performances. Results: WM network analysis showed decreased total strength of brain networks and two disrupted sub-networks in patients with NMOSD. The first featured six hub nodes in the rectus, hippocampus, calcarine, cuneus, and precuneus with the left-sided predominance. The second had six hub nodes in the orbitomiddle frontal, post-central, superior parietal, superior, and middle temporal, and caudate with the right-sided predominance. Compared to healthy controls, NMOSD patients showed poor performance on tests for attention/working memory and processing speed, visuospatial processing, and executive function, which were associated with significant decreases in nodal clustering coefficient, local efficiency, and regional efficiency in the disrupted sub-networks (all p < 0.05). Conclusions: The data show the overall WM disruption and the relationship between poor cognitive function and sub-network alterations identified by the network analysis in NMOSD patients. We suggest that cognitive dysfunction is related to dysconnectivity of WM network including default mode network in NMOSD.

The protective effect of education has been well established in Alzheimer's disease, whereas its role in patients with isolated cerebrovascular diseases remains unclear. We examined the correlation of education with cortical thickness and cerebral small vessel disease markers in patients with pure subcortical vascular mild cognitive impairment (svMCI) and patients with pure subcortical vascular dementia (SVaD).

To investigate the whole-brain resting-state functional connectivity in patients with chronic migraine (CM) using a data-driven method.

Cognitive dysfunction has long been recognized as a frequently observed symptom in individuals with repetitive mild traumatic brain injury (rmTBI) such as professional boxers. The exact neurobiological mechanisms underlying this cognitive deficit have not yet been identified, but it is agreed upon that the prefrontal cortex (PFC) is one of the most commonly affected brain regions in professional boxers. Noting the pivotal role of the two major brain metabolites in human cognitive functions, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), we hypothesized that alterations in levels of GABA and Glx in the PFC would be prominent and may correlate with cognitive deficits in professional boxers. Twenty male professional boxers (Boxers) and 14 age-matched healthy males who had never experienced any TBI (CON) were recruited. Using a 3T magnetic resonance imaging (MRI) scanner, single-voxel proton magnetic resonance spectroscopy with Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence was performed to evaluate the levels of GABA and Glx in the PFC. Cognitive function was assessed using the memory and attention domains from the Cambridge Neuropsychological Test Automated Battery. The Boxers showed lower GABA level in the PFC compared to the CON, while also showing lower performance in the attention and memory domains. There were no significant between-group differences in Glx levels. Furthermore, the GABA level correlated with memory performance in the Boxers, but not in attention performance. The current findings may suggest that alterations in GABA levels in the PFC may be a potential neurochemical correlate underlying memory dysfunction related to rmTBI.

The aim of this study was to develop a coenzyme Q10 (CoQ10) microemulsion system with improved solubility, penetration, and wound healing efficacy. Based on the pseudo-ternary diagram, microemulsions containing isopropyl myristate (IPM), Cremophor EL®, and Transcutol® HP were selected and confirmed to be nanosized (<20 nm) and thermodynamically stable based on the dilution and thermodynamic stability tests. The CoQ10-loaded microemulsion with a surfactant/co-surfactant (S/CoS) ratio of 2:1 (w/w %) demonstrated a higher permeation efficacy compared to microemulsions with S/CoS ratio of 3:1 or 4:1 (w/w %). Additionally, the CoQ10-loaded microemulsion with an S/CoS ratio of 2:1 demonstrated a relatively rapid wound healing effect in keratinocytes and fibroblasts. Overall, these data suggest that a microemulsion based on IPM, Cremophor EL®, and Transcutol® HP could be an effective vehicle for the topical administration of CoQ10 and could be utilized for the application of other therapeutic agents that have difficulty in penetrating the skin.

Among mild cognitive impairment (MCI) patients, those with memory impairment (amnestic MCI, aMCI) are at a high risk of dementia. However, the precise cognitive domain, beside memory, that predicts dementia conversion is unclear. Therefore, we investigated the cognitive domain that predicts dementia conversion in a longitudinal aMCI cohort. We collected data of 482 aMCI patients who underwent neuropsychological tests and magnetic resonance imaging at baseline and were followed for at least 1 year. The patients were categorized according to number (1-4) and type of impaired cognitive domains (memory, language, visuospatial, and frontal-executive function). We evaluated dementia conversion risk in each group when compared to single-domain aMCI after controlling for age, education, diabetes and dyslipidemia. Baseline cortical thickness of each group was compared to that of 410 cognitively normal controls (NCs) after controlling for age, intracranial volume, diabetes and dyslipidemia. Compared to single-domain aMCI, aMCI patients with frontal-executive dysfunction at baseline had a higher risk of dementia conversion than aMCI patients with visuospatial or language dysfunction. Compared to NCs, aMCI patients with frontal-executive dysfunction had overall cortical thinning including frontal areas. Our findings suggest that aMCI patients with frontal-executive dysfunction have poor prognosis and,thus, should be considered for intervention therapy with a higher priority among aMCI patients.

We investigated the effect of education on the edge efficiency in resting state functional networks (RSFNs) in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD). We collected the data of 57 early aMCI, 141 late aMCI, 173 mild ADD, and 39 moderate-to-severe ADD patients. We used years of education as a proxy for cognitive reserve. We measured edge efficiency for each edge in RSFNs, and performed simple slope analyses to discover their associations with education level among the four groups. In the late aMCI, a sub-network that had hub nodes in the right middle frontal gyrus and the right posterior cingulate gyrus, showed a positive association between RSFN edge efficiency and education (threshold = 2.5, p = 0.0478). There was no negative effect of education on the RSFN edge efficiency. In the early aMCI, mild ADD, and moderate-to-severe ADD, there were no sub-networks showing positive or negative correlation between education and RSFN edge efficiency. There was a positive effect of higher education on RSFN edge efficiency in the late aMCI, but not in the early aMCI or ADD. This indicates that in late aMCI, those who have higher education level have greater ability to resist collapsed functional network.

Triple intrinsic brain networks including the salience network (SN), default mode network (DMN), and central executive network (CEN), are known to be important in human cognition. Therefore, investigating those intrinsic brain networks in transient global amnesia (TGA) may offer novel insight useful for the pathophysiology of TGA. Fifty TGA patients underwent the resting state functional magnetic resonance imaging (rsfMRI) within 24 h, at 72 h, and 3 months after TGA onset. Twenty-five age, gender matched controls also underwent rsfMRI. Within 24 h of TGA onset, TGA patients showed greater functional connectivity in the SN and lower functional connectivity in the DMN, while relatively preserved functional connectivity was observed in the CEN. Interestingly, TGA patients continued to show decreased connectivity in the DMN, while no alterations were shown in the SN 72 h after illness onset. Three months after TGA onset, alterations of functional connectivity in the SN or the DMN were normalized. Our findings suggest that TGA is associated with transient greater functional connectivity in the SN and lower connectivity in the DMN.

Biodegradable nanoparticles (NPs) are preferred as drug carriers because of their effectiveness in encapsulating drugs, ability to control drug release, and low cytotoxicity. Although poly(lactide co-glycolide) (PLGA)-based NPs have been used for controlled release strategies, they have some disadvantages. This study describes an approach using biodegradable polyhydroxyalkanoate (PHA) to overcome these challenges. By varying the amount of PHA, NPs were successfully fabricated by a solvent evaporation method. The size range of the NPS ranged from 137.60 to 186.93 nm, and showed zero-order release kinetics of paclitaxel (PTX) for 7 h, and more sustained release profiles compared with NPs composed of PLGA alone. Increasing the amount of PHA improved the PTX loading efficiency of NPs. Overall, these findings suggest that PHA can be used for designing polymeric nanocarriers, which offer a potential strategy for the development of improved drug delivery systems for sustained and controlled release.

Patients with probable Alzheimer's disease (AD) and the amnesic form of mild cognitive impairment (aMCI) often demonstrate several types of neuropsychological deficits. These deficits are often related to cortical atrophy, induced by neuronal degradation. The purpose of this study is to investigate whether different anatomic patterns of cortical atrophy are associated with specific neuropsychological deficits. The participants were 170 patients with AD and 99 patients with aMCI. All participants underwent the Seoul Neuropsychological Screening Battery (SNSB), which includes tests that assess attention, language, visuospatial functions, verbal and visual memory, and frontal/executive functions. Cortical atrophy (thinning) was quantified by measuring the thickness of the cortical mantle across the entire brain using automated, three-dimensional magnetic resonance imaging. The relationship between cortical thickness and neuropsychological performance was analysed using stepwise multiple linear regression analyses. These analyses (corrected P<.001) showed that several specific brain regions with cortical thinning were associated with cognitive dysfunction including: digit span backward, verbal and picture recall, naming and fluency, drawing-copying, response inhibition and selective attention. Some of the other functions, however, were not associated with specific foci of cortical atrophy (digit span forward, the word reading portion of the Stroop test, word and picture recognition). Our study, involving a large sample of participants with aMCI and AD, provides support for the postulate that cortical thinning-atrophy in specific anatomic loci are pathological markers for specific forms of cognitive dysfunction.

Subcortical vascular dementia (SVaD), one of common causes of dementia, has concomitant Alzheimer's disease (AD) pathology in over 30%, termed "mixed dementia". Identifying mixed dementia from SVaD is important because potential amyloid-targeted therapies may be effective for treatment in mixed dementia. The purpose of this study was to discriminate mixed dementia from pure SVaD using magnetic resonance imaging (MRI). We measured brain amyloid deposition using the 11C-Pittsburgh compound B positron emission tomography (PiB-PET) in 68 patients with SVaD. A PiB retention ratio greater than 1.5 was considered PiB(+). Hippocampal and amygdalar shape were used in the incremental learning method to discriminate mixed dementia from pure SVaD because these structures are known to be prominently involved by AD pathologies. Among 68 patients, 23 (33.8%) patients were positive for PiB binding. With use of hippocampal shape analysis alone, PiB(+) SVaD could be discriminated from PiB(-) SVaD with 77.9% accuracy (95.7% sensitivity and 68.9% specificity). With use of amygdalar shape, the discrimination accuracy was 75.0% (87.0% sensitivity and 68.9% specificity). When hippocampal and amygdalar shape were analyzed together, accuracy increased to 82.4% (95.7% sensitivity and 75.6% specificity). An incremental learning method using hippocampal and amygdalar shape distinguishes mixed dementia from pure SVaD. Furthermore, our results suggest that amyloid pathology and vascular pathology have different effects on the shape of the hippocampus and amygdala.

The purpose of this study was to investigate if multi-domain cognitive training, especially robot-assisted training, alters cortical thickness in the brains of elderly participants. A controlled trial was conducted with 85 volunteers without cognitive impairment who were 60 years old or older. Participants were first randomized into two groups. One group consisted of 48 participants who would receive cognitive training and 37 who would not receive training. The cognitive training group was randomly divided into two groups, 24 who received traditional cognitive training and 24 who received robot-assisted cognitive training. The training for both groups consisted of daily 90-min-session, five days a week for a total of 12 weeks. The primary outcome was the changes in cortical thickness. When compared to the control group, both groups who underwent cognitive training demonstrated attenuation of age related cortical thinning in the frontotemporal association cortices. When the robot and the traditional interventions were directly compared, the robot group showed less cortical thinning in the anterior cingulate cortices. Our results suggest that cognitive training can mitigate age-associated structural brain changes in the elderly.

Transcranial direct current stimulation (tDCS) has been increasingly used to investigate human brain functions. Especially, tDCS on the dorsolateral prefrontal cortex (DLPFC) enhances cognitive functions in both healthy subjects and patients with neuropsychiatric disorders. In spite of its effects on behavioral improvement, neural correlates of tDCS on the DLPFC have not been fully described. In this study, we acquired resting state functional magnetic resonance imaging data before and after real or sham stimulation on the left DLPFC. Resting state functional connectivity of the stimulated brain region was compared between the two groups. Compared to the sham stimulation group, the tDCS group showed increased DLPFC connectivity to the right hemisphere and decreased DLPFC connectivity to the brain regions around the stimulation site in the left hemisphere. Application of tDCS on the DLPFC may induce increased interhemispheric connectivity even at rest, possibly associated with the behavioral effects of tDCS.

Background: Serum lactate is a useful biomarker for prediction of mortality in critically ill patients. The purpose of this study was to identify if serum lactate could be used as a biomarker for predicting mortality in patients with subarachnoid hemorrhage (SAH) in the emergency department. Methods: This retrospective study enrolled 189 patients. Baseline demographic data and clinical characteristics of patients were obtained from medical record review. Multiple logistic regression analysis was performed to determine predictor variables significantly associated with mortality. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of variables for mortality prediction in SAH. Results: Using multivariate logistic regression analysis, age [OR 1.05; 95% confidence interval (CI) 1.00-1.10; p = 0.037], Hunt and Hess scale score (OR 3.29; 95% CI 1.62-6.70; p = 0.001), serum lactate level (OR 1.33; 95% CI 1.03-1.74; p = 0.032), and serum glucose level (OR 1.01; 95% CI 1.00-1.02; p = 0.049) predicted overall mortality in SAH. The area under the ROC curve (AUC) value for the use of serum lactate level to predict mortality in SAH was 0.815 (95% CI 0.753-0.868) (p < 0.001). Conclusion: Serum lactate may be a useful biomarker for the early prediction of mortality in SAH patients in the emergency department.

Abnormal adipogenesis regulation is accompanied by a variety of metabolic dysfunctions and disorders. Caveolae play an important role in the regulation of fat production, modulated by caveolae-associated proteins (Cavin-1 to 4). Here, we investigated the role of Cavin-3 in lipogenesis and adipocyte differentiation, as the regulatory functions and roles of Cavin-3 in adipocytes are unknown. A Cavin-3 knockdown/overexpression stable cell line was established, and adipogenesis-related gene and protein expression changes were investigated by real-time quantitative PCR and Western blot analysis, respectively. Additionally, confocal immune-fluorescence microscopy was used to verify the intracellular position of the relevant factors. The results showed that Cavin-3 mRNA and protein expression were elevated, along with physiological factors such as lipid droplet formation, during adipogenesis. Cavin-3 silencing resulted in retarded adipocyte differentiation, and its overexpression accelerated this process. Furthermore, Cavin-3 knockdown resulted in decreased expression of adipogenesis-related genes, such as PPAR-γ, FAS, aP2, and Adipoq, whereas preadipocyte factor-1 (Pref-1) was markedly increased during adipocyte maturation. Overall, Cavin-3 influences caveolar stability and modulates the tumor necrosis factor-alpha-converting enzyme (TACE)-mediated Pref-1 shedding process in both mouse and human adipocytes. The Cavin-3-dependent shedding mechanism appears to be an important process in adipocyte maturation, providing a potential therapeutic target for obesity-related disorders.

Although fatigue is a major symptom in patients with neuromyelitis optica spectrum disorder (NMOSD), the underlying mechanism remains unclear. We explored the relationship between subcortical structures and fatigue severity to identify neural substrates of fatigue in NMOSD. Clinical characteristics with brain magnetic resonance imaging were evaluated in forty patients with NMOSD. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) questionnaire (a higher score indicates less fatigue). We assessed the correlation between subcortical structures and fatigue severity using surface-based shape analysis. Most of the enrolled patients showed fatigue (72.5%; mean FACIT-fatigue score, 34.8 ± 10.8). The FACIT-fatigue score was negatively correlated with Expanded Disability Status Scale and Beck Depression Inventory scores (r = - 0.382, p = 0.016; r = - 0.578, p < 0.001). We observed that the right thalamus was the only extracted region for various threshold experiments. Further, patients with lower FACIT-fatigue scores (more fatigue) had decreased local shape volume in the right thalamus. Fatigue is common in patients with NMOSD, and atrophy in the right thalamus is strongly correlated with fatigue severity. The local shape volume of the right thalamus might serve as a biomarker of fatigue in NMOSD.

Despite therapeutic advances, the prognosis for glioblastoma (GBM) remains poor. In particular, leptomeningeal dissemination (LMD) has a dismal prognosis. The aim of this study was to identify tumor molecular phenotype, which has a great propensity to develop LMD. Between May 2004 and December 2012, a total of 145 GBM tumor samples were obtained from data registry. A total of 20 of the 145 patients with GBM were found to develop LMD. A specialized radiologist confirmed the diagnosis of LMD on magnetic resonance imaging. To clarify the genomic signatures in GBM with LMD, we performed integrative analysis of whole transcriptome sequencing and copy number alteration in the radiological features indicating LMD phenotypes in GBM. Eleven newly diagnosed patients with GBM with LMD had worse prognosis than those without LMD (median 5.55 vs. 12.94 months, P < 0.0001). Integrating analysis using gene expression based on the change of copy number revealed that SPOCK1, EHD2, SLC2A3, and ANXA11 were highly expressed with the gain of copy number, compared with the gene expression in the non-LMD group. In addition, it was demonstrated that NME2, TMEM100, and SIVA1 were downregulated with the loss of copy number. We also found that mesenchymal subtype accounted for 50% in LMD group, whereas mesenchymal subtype consisted of 29% in non-LMD group, even though there was no statistical significance (P = 0.06). Through this radiogenomic analysis, we suggested the possibility of finding candidate genes associated with LMD and highlighted the significance of integrating approach to clarify the molecular characteristics in LMD.