Personalized virtual reality exposure for panic disorder and agoraphobia: A preliminary neurophysiological study.

BACKGROUND: Personalization is considered an important principle in virtual reality (VR) exposure therapy. We aimed to identify whether personalized VR exposure could provoke increased anxiety in patients with panic disorder and agoraphobia as it is considered the first step in successful treatment for anxiety. METHODS: We performed a double-arm, one-day preliminary study among 28 patients with panic disorder and agoraphobia. Three sessions of VR exposure, including a theater, train, and elevator scenario, were conducted in two groups. In the personalized group (n = 14), the brightness and crowd density were customized based on a pre-assessment. In the control group (n = 14), these conditions were fully randomized. Self-reported anxiety, heart rate, skin conductance, and electroencephalography were measured before, during, and after the VR sessions. RESULTS: In the later VR sessions, higher self-reported anxiety levels measured by the Visual Analogue Scale were observed in the personalized exposure group. Increased heart rates during and after the VR sessions were observed in the personalized group. The changes in skin conductance peaks were not significantly different between the groups, but the increase in skin conductance was associated with the participants' perception of presence. The electroencephalogram showed widespread increases in alpha waves in the frontal and temporal areas of the brain in the personalized group than in the control group. CONCLUSION: Personalized VR exposure elicits stronger anxiogenic effects in patients with panic disorder and agoraphobia as suggested by self-report and neurophysiological data. Personalization of VR exposure has the potential for effective behavioral therapy.

Ultrasound and CT findings of subcutaneous metastases in trunk and pelvis: a comprehensive analysis.

OBJECTIVE: This study aimed to describe the ultrasound, CT findings, and clinical manifestations of pathologically confirmed metastases involving the subcutaneous fat layer of the trunk and pelvis. MATERIALS AND METHODS: We included 30 patients with subcutaneous metastases in the trunk and pelvis, verified by ultrasound-guided biopsy. We comprehensively reviewed ultrasound findings of all 30 patients and contrast-enhanced CT findings of 25 patients obtained before biopsy. Medical records were reviewed, including primary malignancy type, presence of coexisting distant metastasis, and detection method leading to biopsy referral. RESULTS: Most subcutaneous metastases were heterogeneously hypoechoic (86.7%) with well-defined margins (80.0%), lobulated (46.7%) or round-to-oval (40.0%) shape, and vascularity (96.7%). Metastases frequently exhibited no contact (53.3%) or focal contact with deep peripheral fascia, resulting in acute contact angle formation (30.0%). Common CT manifestations included central low attenuation with peripheral rim-like enhancement (60.0%) or well-circumscribed lesion with heterogeneous enhancement (32.0%). Lung cancer (46.7%) was the prevalent primary malignancy. CT was the predominant detection method (56.7%). Coexisting subcutaneous metastases were present in 50.0% of cases, and distant metastases (less subcutaneous metastases) were observed in 90.0% of patients. CONCLUSION: This study describes typical imaging findings of subcutaneous metastases involving the trunk and pelvis. CT may play a crucial role in their early detection, and our results may assist radiologists in their diagnosis.

Genome-wide analyses of early-onset acute myocardial infarction identify 29 novel loci by whole genome sequencing.

Early-onset acute myocardial infarction (AMI) may have a higher genetic predisposition than late-onset AMI. The present study aimed to identify and characterize germline variants that affect early-onset AMI using whole-genome sequencing (WGS). We performed a genome-wide association study based on the WGS of 1239 Koreans, including 596 early-onset AMI patients and 643 healthy individuals. Patients with AMI who underwent percutaneous coronary intervention (PCI) caused by atherothrombotic occlusive lesions were included in the study. A total of 29 novel loci were found to be associated with early-onset AMI. These loci are involved in thrombosis, fibrinolysis, inflammation, and lipid metabolism. One of the associated single nucleotide variants (SNVs), rs1614576, located upstream of PRKCB, is known to be associated with thrombus formation. Additionally, the results revealed a novel locus, rs78631167, located upstream of PLAUR which plays a critical role in regulating plasminogen activation and is related to fibrinolysis. The association between early-onset AMI and rs9357455, which is located upstream of PHACTR1 and regulates inflammation in AMI, was found. Moreover, we identified a lipid metabolism related genetic risk locus, rs5072, in the APOA1-AS gene. This study provides new evidence supporting the genetic association between early-onset AMI and thrombosis and fibrinolysis, as well as inflammation and lipid metabolism, by analyzing the whole-genome of 596 patients with early-onset AMI who have been treated with PCI. Our findings highlight potential genetic markers for the prediction and management of AMI, as well as for understanding the etiology of AMI.

Predicting Role of Prestroke Glycemic Variability Estimated by Glycated Albumin for Reperfusion and Prognosis after Endovascular Treatment.

INTRODUCTION: Glycated hemoglobin is widely used for the diagnosis of diabetes, but it is not accurately correlated with blood glucose fluctuations. We evaluated the impact of prestroke glycemic variability, measured by glycated albumin (GA) on reperfusion rate and stroke outcomes after endovascular treatment (EVT). METHODS: We consecutively collected 310 EVT-treated patients for 60 months using a multicenter registry database. Primary outcome was unsuccessful reperfusion defined by modified Thrombolysis in Cerebral Infarction grade 0 to 2a. Secondary outcomes were occurrence of early neurologic deterioration (END), symptomatic hemorrhagic transformation (SHT) and a 3-month poor outcome (modified Rankin Scale >2). GA was measured in the morning after hospital admission with overnight fasting and determined to reflect high prestroke glycemic variability (GA ≥16.0%). RESULTS: Over the median follow-up of 60 months of 310 patients, there were 64 (20.6%) events of unsuccessful reperfusion, 66 (21.3%) of END, 21 (6.8%) of SHT, and 180 (58.1%) of 3-month poor outcome. In the higher GA group (130, 41.9%), proportion of unsuccessful reperfusion, END, SHT, and poor outcome were higher than lower GA group. The multivariate analysis showed that higher GA was associated with unsuccessful reperfusion after EVT (adjusted odds ratio 4.13; 95% confidence interval [CI], 1.93-8.85). The area under the receiver operating characteristic of GA (0.644; 95% CI: 0.634-0.740) for predicting poor outcome was better than that of glycated hemoglobin (0.586; 95% CI: 0.529-0.642, p for DeLong's pairwise comparison = 0.005). CONCLUSION: GA, reflecting prestroke glycemic variability, could be a reliable parameter for predicting reperfusion rate and acute ischemic stroke outcome in this study.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

Restoration of Cathepsin D Level via L-Serine Attenuates PPA-Induced Lysosomal Dysfunction in Neuronal Cells.

L-serine is a non-essential amino acid endogenously produced by astrocytes and is abundant in human diets. Beneficial roles of the metabolic products from L-serine in various conditions in the brain including neuronal development have been reported. Through several preclinical studies, L-serine treatment was also shown to offer beneficial therapeutic effects for brain damage such as ischemic stroke, amyotrophic lateral sclerosis, and Parkinson's disease. Despite evidence for the value of L-serine in the clinic, however, its beneficial effects on the propionic acid (PPA)-induced neuronal toxicity and underlying mechanisms of L-serine-mediated neuroprotection are unknown. In this study, we observed that PPA-induced acidic stress induces abnormal lipid accumulation and functional defects in lysosomes of hippocampal neurons. L-serine treatment was able to rescue the structure and function of lysosomes in PPA-treated hippocampal neuronal cells. We further identified that L-serine suppressed the formation of lipid droplets and abnormal lipid membrane accumulations inside the lysosomes in PPA-treated hippocampal neuronal cells. Taken together, these findings indicate that L-serine can be utilized as a neuroprotective agent for the functionality of lysosomes through restoration of cathepsin D in disease conditions.

Pre-Stroke Glycemic Variability Estimated by Glycated Albumin Is Associated with Early Neurological Deterioration and Poor Functional Outcome in Prediabetic Patients with Acute Ischemic Stroke.

INTRODUCTION: Whether glycemic variability prior to stroke increases the risk of stroke outcomes in prediabetic patients presenting with acute ischemic stroke is still unclear. We evaluated whether pre-stroke glycemic variability, estimated by glycated albumin (GA), increased early neurological deterioration (END) and functional outcomes in prediabetic patients with acute ischemic stroke. METHODS: A total of 215 acute ischemic stroke patients with prediabetes were evaluated. The primary outcome was END, defined as an incremental increase in the National Institutes of Health Stroke Scale score by ≥1 point in motor power or ≥2 points in the total score within the 7 days after admission. The secondary outcome was poor functional status defined by a modified Rankin Scale at 3 months. Higher GA (≥16.0%) was determined to reflect glycemic fluctuation prior to ischemic stroke. RESULTS: Of the 215 prediabetic patients, 77 (35.8%) were in the higher GA group. In prediabetic patients, END occurrence and poor functional status were higher in the higher GA group than in the lower GA group. The multivariate analysis showed that a higher GA was associated with an increased risk of END occurrence and poor functional outcomes at 3 months (adjusted odds ratio [95% confidence interval], 4.58 [1.64-12.81], p = 0.004 and 2.50 [1.19-5.25], p = 0.02, respectively). CONCLUSION: Pre-stroke glycemic variability estimated by GA was associated with END occurrence and poor functional outcome after ischemic stroke in patients with prediabetes.

Structural basis for stereospecificity to d-amino acid of glycine oxidase from Bacillus cereus ATCC 14579.

Glycine oxidase (GO) is an enzyme that catalyzes the oxidation of the primary and secondary amines of various chemicals, including glycine, and the enzyme has been applied in a variety of fields, such as biosensor and genetically modified glyphosate resistance plants. Here, we report that the gene product of BC0747 from Bacillus cereus (BcGO) shows oxidase activity for glycine and small d-amino acids, such as d-proline and d-alanine. We also determined the crystal structure of BcGO complexed with the FAD cofactor at a 2.36 Å resolution and revealed how the cofactor binds to the deep pocket of the enzyme. We performed the molecular docking calculation of the glycine substrate to the BcGO structure and identified how the carboxyl- and amine-groups of the d-amino acid are stabilized at the substrate binding site. Structural analysis of BcGO also provided information on the structural basis for the stereospecificity of the enzyme to d-amino acids. In addition, we placed the glyphosate molecule, a plant herbicide, at the substrate binding site, and explained how the mutation of Gly51 to arginine enhances enzyme activity.

Automatic, Qualitative Scoring of the Interlocking Pentagon Drawing Test (PDT) based on U-Net and Mobile Sensor Data.

We implemented a mobile phone application of the pentagon drawing test (PDT), called mPDT, with a novel, automatic, and qualitative scoring method for the application based on U-Net (a convolutional network for biomedical image segmentation) coupled with mobile sensor data obtained with the mPDT. For the scoring protocol, the U-Net was trained with 199 PDT hand-drawn images of 512ⅹ512 resolution obtained via the mPDT in order to generate a trained model, Deep5, for segmenting a drawn right or left pentagon. The U-Net was also trained with 199 images of 512ⅹ512 resolution to attain the trained model, DeepLock, for segmenting an interlocking figure. Here, the epochs were iterated until the accuracy was greater than 98% and saturated. The mobile senor data primarily consisted of x and y coordinates, timestamps, and touch-events of all the samples with a 20 ms sampling period. The velocities were then calculated using the primary sensor data. With Deep5, DeepLock, and the sensor data, four parameters were extracted. These included the number of angles (0-4 points), distance/intersection between the two drawn figures (0-4 points), closure/opening of the drawn figure contours (0-2 points), and tremors detected (0-1 points). The parameters gave a scaling of 11 points in total. The performance evaluation for the mPDT included 230 images from subjects and their associated sensor data. The results of the performance test indicated, respectively, a sensitivity, specificity, accuracy, and precision of 97.53%, 92.62%, 94.35%, and 87.78% for the number of angles parameter; 93.10%, 97.90%, 96.09%, and 96.43% for the distance/intersection parameter; 94.03%, 90.63%, 92.61%, and 93.33% for the closure/opening parameter; and 100.00%, 100.00%, 100.00%, and 100.00% for the detected tremor parameter. These results suggest that the mPDT is very robust in differentiating dementia disease subtypes and is able to contribute to clinical practice and field studies.

Association between Osteoporosis and Cognitive Impairment during the Acute and Recovery Phases of Ischemic Stroke.

Background and objectives: Little is known about the effect of osteoporosis on cognitive function in the acute and recovery phases of stroke. Early bone mineral density assessments during acute stroke may be a useful marker of cognitive function. We evaluated the effect of osteoporosis on cognitive function at the early and recovery phase of ischemic stroke in patients aged >50 years. Materials and Methods: We retrospectively examined consecutive patients with acute stroke hospitalized between 2016 and 2018. Osteoporosis was defined as a T-score <-2.5 for the femoral neck or lumbar spine bone mineral density. The primary outcome was cognitive impairment measured by the Korean Mini-Mental State Examination in the acute phase and recovery phase of ischemic stroke. Results: Of the 260 included subjects (107 men and 153 women), 70 (26.9%) had osteoporosis. Cognitive impairment was more severe in the osteoporosis group than in the non-osteoporosis group (30.5% versus 47.1%, p = 0.001). After the recovery phase of stroke, the proportion of patients with cognitive impairment remained higher in the osteoporosis group. The multivariate analysis revealed a correlation between a low femoral neck bone mineral density and severe cognitive impairment in the acute and recovery phases of stroke (adjusted odds ratio (OR) 4.09, 95% confidence interval (CI) 1.11-15.14 in the acute phase, and adjusted OR 11.17, 95% CI 1.12-110.98 in the recovery phase). Conclusions: Low bone mineral density is associated with poor cognitive function in the acute and recovery phases of stroke.

A molecular mechanism of nickel (II): reduction of nucleotide excision repair activity by structural and functional disruption of p53.

Nickel is a major carcinogen that is implicated in tumor development through occupational and environmental exposure. Although the exact molecular mechanisms of carcinogenesis by low-level nickel remain unclear, inhibition of DNA repair is frequently considered to be a critical mechanism of carcinogenesis. Here, we investigated whether low concentrations of nickel would affect p53-mediated DNA repair, especially nucleotide excision repair. Our results showed that nickel inhibited the promoter binding activity of p53 on the downstream gene GADD45A, as a result of the disturbance of p53 oligomerization by nickel. In addition, we demonstrated that nickel exposure trigger the reduction of GADD45A-mediated DNA repair by impairing the physical interactions between GADD45A and proliferating cell nuclear antigen or xeroderma pigmentosum G. Notably, in the GADD45A-knockdown system, the levels of unrepaired DNA photoproducts were higher than wild-type cells, elucidating the importance of GADD45A in the nickel-associated inhibition of DNA repair. These results imply that inhibition of p53-mediated DNA repair can be considered a potential carcinogenic mechanism of nickel at low concentrations.

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PD patients has not been systematically studied. METHODS: Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. RESULTS: In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PD patients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). CONCLUSION: Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD. © 2017 International Parkinson and Movement Disorder Society.

Relative impact of amyloid-ß, lacunes, and downstream imaging markers on cognitive trajectories.

SEE COHEN DOI101093/AWW183 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Amyloid-ß and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-ß and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-ß and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized ß = -0.79, P < 0.001; visual memory test, unstandardized ß = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized ß = -0.05, P = 0.002; Stroop colour test, unstandardized ß = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized ß = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized ß = 0.21, P = 0.010) and time-varying nodal efficiency (standardized ß = 0.17, P = 0.024). Time-varying lacune number (standardized ß = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized ß = 0.17, P = 0.021). Finally, time-varying lacune number (ß = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized ß = 0.19, P = 0.026). Our multimodal imaging analyses suggest that cognitive trajectories related to amyloid-ß and lacunes have distinct paths, and that amyloid-ß or lacunes have greatest impact on cognitive decline. Our results provide rationale for the targeting of amyloid-ß and lacunes in therapeutic strategies aimed at ameliorating cognitive decline.

Prediction of post-stroke dementia using NINDS-CSN 5-minute neuropsychology protocol in acute stroke.

BACKGROUND: The National Institute of Neurological Disease and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute neuropsychology protocol consists of only verbal tasks, and is proposed as a brief screening method for vascular cognitive impairment. We evaluated its feasibility within two weeks after stroke and ability to predict the development of post-stroke dementia (PSD) at 3 months after stroke. METHOD: We prospectively enrolled subjects with ischemic stroke within seven days of symptom onset who were consecutively admitted to 12 university hospitals. Neuropsychological assessments using the NINDS-CSN 5-minute and 60-minute neuropsychology protocols were administered within two weeks and at 3 months after stroke onset, respectively. PSD was diagnosed with reference to the American Heart Association/American Stroke Association statement, requiring deficits in at least two cognitive domains. RESULTS: Of 620 patients, 512 (82.6%) were feasible for the NINDS-CSN 5-minute protocol within two weeks after stroke. The incidence of PSD was 16.2% in 308 subjects who had completed follow-up at 3 months after stroke onset. The total score of the NINDS-CSN 5-minute protocol differed significantly between those with and without PSD (4.0 ± 2.7, 7.4 ± 2.7, respectively; p < 0.01). A cut-off value of 6/7 showed reasonable discriminative power (sensitivity 0.82, specificity 0.67, AUC 0.74). The NINDS-CSN 5-minute protocol score was a significant predictor for PSD (adjusted odds ratio 6.32, 95% CI 2.65-15.05). DISCUSSION: The NINDS-CSN 5-minute protocol is feasible to evaluate cognitive functions in patients with acute ischemic stroke. It might be a useful screening method for early identification of high-risk groups for PSD.

Decreased hemoglobin levels, cerebral small-vessel disease, and cortical atrophy: among cognitively normal elderly women and men.

BACKGROUND: Decreased hemoglobin levels increase the risk of developing dementia among the elderly. However, the underlying mechanisms that link decreased hemoglobin levels to incident dementia still remain unclear, possibly due to the fact that few studies have reported on the relationship between low hemoglobin levels and neuroimaging markers. We, therefore, investigated the relationships between decreased hemoglobin levels, cerebral small-vessel disease (CSVD), and cortical atrophy in cognitively healthy women and men. METHODS: Cognitively normal women (n = 1,022) and men (n = 1,018) who underwent medical check-ups and magnetic resonance imaging (MRI) were enrolled at a health promotion center. We measured hemoglobin levels, white matter hyperintensities (WMH) scales, lacunes, and microbleeds. Cortical thickness was automatically measured using surface based methods. Multivariate regression analyses were performed after controlling for possible confounders. RESULTS: Decreased hemoglobin levels were not associated with the presence of WMH, lacunes, or microbleeds in women and men. Among women, decreased hemoglobin levels were associated with decreased cortical thickness in the frontal (Estimates, 95% confidence interval, -0.007, (-0.013, -0.001)), temporal (-0.010, (-0.018, -0.002)), parietal (-0.009, (-0.015, -0.003)), and occipital regions (-0.011, (-0.019, -0.003)). Among men, however, no associations were observed between hemoglobin levels and cortical thickness. CONCLUSION: Our findings suggested that decreased hemoglobin levels affected cortical atrophy, but not increased CSVD, among women, although the association is modest. Given the paucity of modifiable risk factors for age-related cognitive decline, our results have important public health implications.

Association of Body Fat Percentage and Waist-hip Ratio With Brain Cortical Thickness: A Study Among 1777 Cognitively Normal Subjects.

BACKGROUND: Increasing evidence has emerged that there is a link between body weight and the risk of developing dementia. However, the relationship between adiposity and brain structure has not yet been fully elucidated. We aimed to evaluate the association of body fat composition with cortical thickness in cognitively normal subjects. METHODS: In total, 1777 (887 men and 890 women) cognitively normal subjects, aged 45 years or older, were recruited from the Health Promotion Center in South Korea. Medical records including 3-dimensional magnetic resonance imaging, body fat percentage, waist-hip ratio (WHR), and other factors were reviewed. RESULTS: In men, the percentage of fat was positively associated with cortical thickness and the highest WHR group showed significantly decreased cortical thickness compared with the reference group. WHR showed an inverted U-shaped association with total cortical thickness and frontal lobe thickness in men. Among women, there was no significant association. CONCLUSIONS: Our findings suggest that in men, body fat is positively associated with cortical thickness, whereas abdominal fat is negatively associated with cortical thickness.

Postmorbid learning of saxophone playing in a patient with frontotemporal dementia.

Some patients with frontotemporal dementia (FTD) show an artistic enhancement of musical abilities. However, no patients with FTD, to date, have been reported to be able to learn how to play a musical instrument after disease onset. Herein we describe a patient (J. K.) who had never played any musical instruments premorbidly, but who learned to play the saxophone after being diagnosed with a behavioral variant of FTD. He mastered a repertoire that consisted of 10 pieces of Korean folk songs over a period of three years. Furthermore, his saxophone skills were high enough to outperform other students in his class.

Higher education affects accelerated cortical thinning in Alzheimer's disease: a 5-year preliminary longitudinal study.

BACKGROUND: Epidemiological studies have reported that higher education (HE) is associated with a reduced risk of incident Alzheimer's disease (AD). However, after the clinical onset of AD, patients with HE levels show more rapid cognitive decline than patients with lower education (LE) levels. Although education level and cognition have been linked, there have been few longitudinal studies investigating the relationship between education level and cortical decline in patients with AD. The aim of this study was to compare the topography of cortical atrophy longitudinally between AD patients with HE (HE-AD) and AD patients with LE (LE-AD). METHODS: We prospectively recruited 36 patients with early-stage AD and 14 normal controls. The patients were classified into two groups according to educational level, 23 HE-AD (>9 years) and 13 LE-AD (≤9 years). RESULTS: As AD progressed over the 5-year longitudinal follow-ups, the HE-AD showed a significant group-by-time interaction in the right dorsolateral frontal and precuneus, and the left parahippocampal regions compared to the LE-AD. CONCLUSION: Our study reveals that the preliminary longitudinal effect of HE accelerates cortical atrophy in AD patients over time, which underlines the importance of education level for predicting prognosis.

Structural insights into the novel ARM-repeat protein CTNNBL1 and its association with the hPrp19-CDC5L complex.

The hPrp19-CDC5L complex plays a crucial role during human pre-mRNA splicing by catalytic activation of the spliceosome. In order to elucidate the molecular architecture of the hPrp19-CDC5L complex, the crystal structure of CTNNBL1, one of the major components of this complex, was determined. Unlike canonical ARM-repeat proteins such as ß-catenin and importin-α, CTNNBL1 was found to contain a twisted and extended ARM-repeat structure at the C-terminal domain and, more importantly, the protein formed a stable dimer. A highly negatively charged patch formed in the N-terminal ARM-repeat domain of CTNNBL1 provides a binding site for CDC5L, a binding partner of the protein in the hPrp19-CDC5L complex, and these two proteins form a complex with a stoichiometry of 2:2. These findings not only present the crystal structure of a novel ARM-repeat protein, CTNNBL1, but also provide insights into the detailed molecular architecture of the hPrp19-CDC5L complex.

Structural insights into substrate specificity of crotonase from the n-butanol producing bacterium Clostridium acetobutylicum.

Crotonase from Clostridium acetobutylicum (CaCRT) is an enzyme that catalyzes the dehydration of 3-hydroxybutyryl-CoA to crotonyl-CoA in the n-butanol biosynthetic pathway. To investigate the molecular mechanism underlying n-butanol biosynthesis, we determined the crystal structures of the CaCRT protein in apo- and acetoacetyl-CoA bound forms. Similar to other canonical crotonase enzymes, CaCRT forms a hexamer by the dimerization of two trimers. A crystal structure of CaCRT in complex with acetoacetyl-CoA revealed that Ser69 and Ala24 to be signature residues of CaCRT, which results in a distinct ADP binding mode wherein the ADP moiety is bound at a different position compared with other crotonases. We also revealed that the substrate specificity of crotonase enzymes is determined by both the structural feature of the α3 helix region and the residues contributing the enoyl-CoA binding pocket. A tight formed α3 helix and two phenylalanine residues, Phe143 and Phe233, aid CaCRT to accommodate crotonyl-CoA as the substrate. The key residues involved in substrate binding, enzyme catalysis and substrate specificity were confirmed by site-directed mutagenesis.