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We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed 18F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

We aimed to evaluate the feasibility of multidomain intervention (MI) tailored to the Korean context. In an outcome assessor-blinded, randomized controlled trial, participants without dementia and with one or more modifiable dementia risk factors, aged 60-79 years, were randomly assigned to the facility-based MI (FMI; n=51), the home-based MI (HMI; n=51), or the control group receiving general health advice (n=50). The 24-week intervention comprised vascular risk management, cognitive training, social activity, physical exercise, nutrition guidance, and motivational enhancement. The FMI participants performed all intervention programs at a facility three times a week. The HMI participants performed some programs at a facility once every 1-2 weeks and performed others at home. The primary outcome was feasibility measured through retention, adherence, and at least no differences from the control group in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In the FMI and HMI groups, the retention rates were 88.2% and 96.1%, and adherence to the intervention was 94.5% and 96.8%, respectively. The RBANS total scale index score improved significantly in the FMI (5.46 ± 7.50, P = 0.004) and HMI (5.50 ± 8.14, P = 0.004) groups compared to the control group (-0.74 ± 11.51). The FMI and HMI are feasible and there are indicators of efficacy.

Cerebrospinal fluid (CSF) biomarkers based on the core pathological proteins associated with Alzheimer’s disease (AD), i.e., amyloid-β (Aβ) and tau protein, are widely regarded as useful diagnostic biomarkers. However, a lack of biomarkers for monitoring the treatment response and indexing clinical severity has proven to be problematic in drug trials targeting Aβ. Therefore, new biomarkers are needed to track non-Aβ and non-tau pathology. Many proteins involved in the pathophysiological progression of AD have shown promise as new biomarkers. Neurodegeneration- and synapse-related biomarkers in CSF (e.g., neurofilament light polypeptide [NFL], neurogranin, and visinin-like protein 1) and blood (e.g., NFL) aid prediction of AD progress, as well as early diagnosis. Neuroinflammation, lipid dysmetabolism, and impaired protein clearance are considered important components of AD pathophysiology. Inflammation-related proteins in the CSF, such as progranulin, intercellular adhesion molecule 1, and chitinase-3-like protein 1 (YKL-40), are useful for the early detection of AD and can represent clinical severity. Several lipid metabolism-associated biomarkers and protein clearance-linked markers have also been suggested as candidate AD biomarkers. Combinations of subsets of new biomarkers enhance their utility in terms of broadly characterizing AD-associated pathological changes, thereby facilitating precise selection of susceptible patients and comprehensive monitoring of the treatment response. This approach could facilitate the development of effective treatments for AD., Alzheimer’s disease: New ways to track disease progression Finding new biomarkers for Alzheimer’s disease (AD) may help in tracking disease progression and identifying optimal patient-specific treatments. Although useful markers are available for diagnosis of AD, they are unreliable for tracking disease progression. Looking for better ways to track disease progression, Sun Ah Park at the Ajou University School of Medicine, Suwon, South Korea, and coworkers have reviewed alternative AD markers. They report that several markers for axonal degeneration, synaptic loss, brain inflammation and lipid metabolism show promise for tracking AD. Some of these markers can be obtained from blood samples, which are minimally invasive to collect. Use of combinations of markers is especially promising for estimating a patient’s disease stage. These results will contribute to developing tailored treatments for this common cause of dementia.

Background and Purpose: Cerebral small vessel disease is characterized by progressive cerebral white matter changes (WMCs). This study aimed to compare the effects of cilostazol and aspirin on changes in WMC volume in patients with cerebral small vessel disease. Methods: In a multicenter, double-blind, randomized controlled trial, participants with moderate or severe WMCs and at least one lacunar infarction detected on brain magnetic resonance imaging were randomly assigned to the cilostazol and aspirin groups in a 1:1 ratio. Cilostazol slow release (200 mg) or aspirin (100 mg) capsules were administered once daily for 2 years. The primary outcome was the change in WMC volume on magnetic resonance images from baseline to 2 years. Secondary imaging outcomes include changes in the number of lacunes or cerebral microbleeds, fractional anisotropy, and mean diffusivity on diffusion tensor images, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all ischemic vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. Results: Between July 2013 and August 2016, 256 participants were randomly assigned to the cilostazol (n=127) and aspirin (n=129) groups. Over 2 years, the percentage of WMC volume to total WM volume and the percentage of WMC volume to intracranial volume increased in both groups, but neither analysis showed significant differences between the groups. The peak height of the mean diffusivity histogram in normal-appearing WMs was significantly reduced in the aspirin group compared with the cilostazol group. Cilostazol significantly reduced the risk of ischemic vascular event compared with aspirin (0.5 versus 4.5 cases per 100 person-years; hazard ratio, 0.11 [95% CI, 0.02–0.89]). Conclusions: There was no significant difference between the effects of cilostazol and aspirin on WMC progression in patients with cerebral small vessel disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01932203.

OBJECTIVE Treatment of super-refractory status epilepticus (SRSE) is associated with various complications of anaesthetic coma therapy. This study aimed to describe the factors affecting the prognosis, especially in-hospital mortality, of patients receiving pentobarbital coma therapy for the treatment of SRSE. METHODS This was a retrospective cohort study conducted in a single tertiary referral centre with patients who received pentobarbital coma therapy for the treatment of SRSE from 2006 to 2018. Exploratory analyses were performed for clinical, laboratory, electrographic, and radiological factors for the entire cohort and were compared between the mortality and survivor groups. RESULTS In total, 19 patients were enrolled, and five (26.3%) patients died in the hospital. The maximal pentobarbital infusion dose was higher in the mortality group than in the survivor group (4.4±1.0 mg/kg/h vs. 2.9±1.4 mg/kg/h, respectively; p=0.025). The high-dose pentobarbital infusion group (>3.75 mg/kg/h) underwent longer mechanical ventilation (24 [20-36.75] vs. 41 [28-70], p=0.025) and blood culture results were more frequently positive, suggestive of septicaemia (8.3% vs. 57.1%, p=0.038). SIGNIFICANCE The group of SRSE patients treated with pentobarbital coma therapy who died in the hospital received a higher pentobarbital infusion dose compared to survivors; a complication of high-dose pentobarbital infusion was septicaemia. Considering the high rate of septicaemia observed, systematic treatment strategies focusing on infectious complications should be established and implemented. The association between maximal pentobarbital infusion dose and in-hospital mortality needs to be further validated.

Objective Focused ultrasound has been applied in brain therapeutics. Although focusing ultrasonic beams on multiple arbitrary regions under the guidance of magnetic resonance imaging(MRI) is needed for precise treatments, current therapeutic transducers with large pitch sizes have been optimized to focus on deep brain regions. While annular arrays can adjust the beam foci from cortical to deep regions, their circular shape may generate eddy current-induced magnetic flux during MRI. In this study, a quadrisected annular array is proposed to address these limitations. Methods Conventional and quadrisected annular arrays with three elements were implemented by loading the electrode patterns onto an 850kHz 1-3 composite PZT disc, with a diameter of 31mm, including three rings. MR compatibilities were demonstrated by imaging an MRI phantom with pulse sequences for B0 and B1 mapping and spin-echo imaging. Acoustic beam profiles, with and without a macaque monkey skull, were measured. A quadrisected transducer was also used to open the blood-brain barrier(BBB). Results The flip angle distortion improved by 20% in spin-echo MR imaging. The acoustic beam distortions shifting the focal point from 36 to 41mm and elongating the focal zone from 10 to 15 mm could be recovered to nearly the original values. BBB openings in the hippocampus and basal region were also demonstrated. Conclusion The MR compatibility was improved by the increased resistance of the electrodes in the quadrisected array maintaining dynamic focusing capabilities. Significance The quadrisected annular design can be a fundamental structure for a larger MR-compatible segmented array transducer generating multiple acoustic foci.

Background: Status epilepticus (SE), characterized by prolonged, self-sustained seizures, is a medical emergency associated with high mortality, requiring immediate diagnosis and treatment. This study aimed to evaluate the sensitivity and prognostic value of arterial spin labelling (ASL) in a large group of SE patients and compare them with those of other magnetic resonance (MR) sequences, including dynamic susceptibility contrast (DSC) perfusion imaging. Methods: We retrospectively collected data of patients with SE in a tertiary center between September 2016 and March 2020. For comparison, patients with self-limiting seizures were included. MR images were visually assessed, and the sensitivity for the detection of SE and prognostication was compared among multi-delay ASL, DSC, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). Findings: We included 51 SE patients and 46 patients with self-limiting seizures. Relevant changes in ASL signals were observed in 90·2% (46/51) of SE patients, a percentage higher than those for DSC, FLAIR, and DWI. ASL was the most sensitive and accurate method for initial differentiation between SE and self-limiting seizures. The sensitivity of ASL for detecting refractory SE (89·5%) or estimating poor outcomes (100%) was higher than those of other MR protocols or electroencephalography and comparable to those of clinical prognostic scores. Interpretation: In a large patient population, ASL showed considerable capability to detect SE and a better prognostic value than other MR sequences. ASL may be valuable for the initial evaluation of SE patients. Funding: This work was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT; Ministry of Science and ICT) (NRF-2018M3A9E8023853, NRF-2018R1C1B6006145, NRF-2019R1A5A2026045, and NRF-2019R1I1A1A01064291). Declaration of Interest: None to declare. Ethical Approval: This retrospective study was approved by the Institutional Review Board of Ajou University Hospital (IRB no. AJIRB-MED-MDB- 20-114), and the requirement to obtain informed consent was waived.

Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.

This work suggests 2020 potential candidates in rice for the functional annotation of unannotated genes using meta-analysis of anatomical samples derived from microarray and RNA-seq technologies and this information will be useful to identify novel morphological agronomic traits. Although the genome of rice (Oryza sativa) has been sequenced, 14,365 genes are considered unannotated because they lack putative annotation information. According to the Rice Genome Annotation Project Database ( http://rice.plantbiology.msu.edu/ ), the proportion of functionally characterized unannotated genes (0.35%) is quite limited when compared with the approximately 3.9% of annotated genes with assigned putative functions. Researchers require additional information to help them investigate the molecular mechanisms associated with those unannotated genes. To determine which of them might regulate morphological or physiological traits in the rice genome, we conducted a meta-analysis of expression data that covered a wide range of tissue/organ samples. Overall, 2020 genes showed cultivar-, tissue-, or organ-preferential patterns of expression. Representative candidates from featured groups were validated by RT-PCR, and the GUS reporter system was used to validate the expression of genes that were clustered according to their leaf or root preference. Taking a molecular and genetics approach, we examined meta-expression data and found that 127 genes were differentially expressed between japonica and indica rice cultivars. This is potentially significant for future agronomic applications. We also used a T-DNA insertional mutant and performed a co-expression network analysis of Sword shape dwarf1 (SSD1), a gene that regulates cell division. This network was refined via RT-PCR analysis. Our results suggested that SSD1 represses the expression of four genes related to the processes of DNA replication or cell division and provides insight into possible molecular mechanisms. Together, these strategies present a valuable tool for in-depth characterization of currently unannotated genes.

Methanol poisoning results in neurological complications including visual disturbances, bilateral putaminal hemorrhagic necrosis, parkinsonism, cerebral edema, coma, or seizures. Almost all reported cases of methanol poisoning are caused by oral ingestion of methanol. However, recently there was an outbreak of methanol poisoning via non-oral exposure that resulted in severe neurological complications to a few workers at industrial sites in Korea. We present 3 patients who had severe neurological complications resulting from non-oral occupational methanol poisoning. Even though initial metabolic acidosis and mental changes were improved with hemodialysis, all of the 3 patients presented optic atrophy and ataxia or parkinsonism as neurological complications resulting from methanol poisoning. In order to manage it adequately, as well as to prevent it, physicians should recognize that methanol poisoning by non-oral exposure can cause neurologic complications., Graphical Abstract

Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P

Cerebrospinal fluid (CSF) Aβ42 and tau protein levels are established diagnostic biomarkers of Alzheimer’s disease (AD). However, their inadequacy to represent clinical efficacy in drug trials indicates the need for new biomarkers. Sequential window acquisition of all theoretical fragment ion spectra (SWATH)-based mass spectrometry (MS) is an advanced proteomic tool for large-scale, high-quality quantification. In this study, SWATH-MS showed that VGF, chromogranin-A, secretogranin-1, and opioid-binding protein/cell adhesion molecule were significantly decreased in 42 AD patients compared to 39 controls, whereas 14-3-3ζ was increased (FDR < 0.05). In addition, 16 other proteins showed substantial changes (FDR < 0.2). The expressions of the top 21 analytes were closely interconnected, but were poorly correlated with CSF Aβ42, tTau, and pTau181 levels. Logistic regression analysis and data mining were used to establish the best algorithm for AD, which created novel biomarker panels with high diagnostic value (AUC = 0.889 and 0.924) and a strong correlation with clinical severity (all p < 0.001). Targeted proteomics was used to validate their usefulness in a different cohort (n = 36) that included patients with other brain disorders (all p < 0.05). This study provides a list of proteins (and combinations thereof) that could serve as new AD biomarkers.

In this study, we report a first 226leucine (Leu) mutation to phenylalanine (Phe) in (PSEN1, CTC>TTC, L226F) in Asia from a Korean early-onset Alzheimer's disease (EOAD) patient. Polymerase chain reaction (PCR)-single strand conformation polymorphism, sequencing, and in silico predictions were performed. Previously, L226F was reported in EOAD patients by Zekanowski et al and Gomez-Tortosa et al. Disease phenotypes appeared in their thirties, and family history was positive in both cases. In our patient, age of onset was similar (37 years of age), but the mutation seemed to be de novo, since no affected family member was found. This leucine to phenylalanine substitution may cause additional stresses inside the transmembrane region due to large aromatic side chain and increased hydrophobic interactions with hydrocarbon chains in the membrane and its binding partners. Clinical phenotype of the mutation was aggressive progression into neurodegeneration, resulting in rapid cognitive decline. One of the patients was initially diagnosed with frontotemporal dementia, but the diagnosis was revised to AD upon postmortem studies in which Aβ plaques were seen. A second mutation, L226R, was found for the L226 residue. Similar to L226F, the patient with L226R also developed the first symptoms in his 30s, but EOAD was diagnosed in his 40s. These findings suggested that L226 might be an important residue in PSEN1, since mutations could result in neurodegenerative disease phenotypes at relatively young ages. There are mutations, such as L226F, which may not present clear clinical symptoms for the definitive diagnosis between frontotemporal dementia and AD. In addition, the similarities in the phenotypes could also be possible between AD and frontotemporal dementia, suggesting difficulties in differential diagnosis of various neurodegenerative diseases.

BACKGROUND & OBJECTIVE Depression frequently combines with dementia, including early-onset Alzheimer's disease (EOAD). We investigated differences in prevalence and characteristics of depressive symptoms according to dementia severity in EOAD patients. METHODS The 15-item Korean version of the Geriatric Depression Scale (GDS-15) was administered to 412 EOAD patients. Factor analysis was used to assess GDS-15 factor structure. We subdivided participants into three groups by disease severity, then compared the frequencies and scores of individual GDS-15 items and performed logistic regression analysis to assess associations between depressive symptoms and EOAD stage. RESULTS Factor analysis yielded three factor categories: 1) "hopelessness and ominousness" (symptoms no. 6, 8, 12, 14, 15); 2) "unhappiness and dissatisfaction" (no. 1, 3, 5, 7, 11); and 3) "monotony and lack of energy" (no. 2, 4, 9, 10, 13). Factor 2 depressive symptoms (no. 1, 5, 11) were less common in moderate EOAD. The risk of Factor 1 symptoms: no. 12 (OR, 2.04; 95% CI, 1.19-3.50; p = 0.010) and 14 (OR, 1.84; 95% CI, 1.07-3.16; p = 0.028) was higher in mild than very mild EOAD. The risk of Factor 2 symptoms: no. 9 (OR, 2.69; 95% CI, 1.08-6.71; p = 0.033) and 13 (OR, 2.12; 95% CI, 1.02-4.40; p = 0.043) was higher in moderate than mild EOAD. CONCLUSION We confirmed that depressive symptoms differ according to EOAD severity. When assessing depressive symptoms related to dementia progression, we recommend focusing on "hopelessness and ominousness" in very mild EOAD and "unhappiness and dissatisfaction" in mild EOAD.

Background: Only a few studies have investigated disease progression in patients with early-onset Alzheimer’s disease (EOAD). Therefore, the aim of this study was to investigate disease progression in patients with EOAD and the influence of various factors, such as gender, education, and apolipoprotein E (APOE) genotype on disease progression. Methods: A total of 288 EOAD patients were enrolled in the study. Linear mixed models were used to investigate the rate of cognitive and functional decline in terms of age at onset, gender, education, follow-up period, and APOE genotype. Results: EOAD patients showed an annual decline of –1.54 points/years in the Korean version mini-mental examination score, an annual increase of 3.46 points/year in the Seoul instrumental activities of daily living (SIADL) score, and an annual increase of 1.15 points/year in the clinical dementia rating scale-sum of boxes score. After stratification, higher educated patients showed faster disease progression in all three parameters, and female patients demonstrated faster disease progression as assessed by the SIADL score. Age at onset and APOE genotype had no influence on disease progression. Conclusion: We confirmed the rate of disease progression in Korean patients with EOAD in real-life hospital-based clinical practice. The results of this study suggest that education and female gender, not APOE genotype, may be important as independent strong predictive factors for disease progression in patients with EOAD.

Background Although plasma amyloid-β (Aβ) levels have been evaluated as a possible diagnostic marker of Alzheimer's disease (AD), the findings are inconsistent. Objective The present study aimed to validate plasma levels of Aβ40, Aβ42, and the Aβ40/Aβ42 ratio as biomarkers of AD in subjects with early-onset AD (EOAD) without familial AD genetic mutations. Methods Patients with sporadic EOAD (sEOAD) were prospectively recruited by nine neurology clinics. Plasma levels of Aβ40 and Aβ42 were measured using a sandwich enzyme-linked immunosorbent assay (ELISA) in 100 sEOAD (50-69 year-old) and 46 age-matched normal control subjects (50-72 year-old). Cerebrospinal fluid (CSF) was obtained from 32 sEOAD subjects and 25 controls. The integrity of the blood-brain barrier was assessed using the CSF/plasma albumin ratio. Results The plasma levels of Aβ42 were significantly lower, while the Aβ40/Aβ42 ratio was significantly higher in sEOAD patients than in controls. The levels of Aβ40, Aβ42, and the Aβ40/Aβ42 ratio did not differ in relation to the APOEɛ4 allele. The CSF/plasma albumin ratio was comparable between the two groups, and the plasma parameters of Aβ proteins were not significantly associated. A multivariate analysis revealed that an increased Aβ40/Aβ42 ratio is valuable for the discrimination of sEOAD from controls (β=0.344, p=0.000). The area under the ROC curve for the Aβ40/Aβ42 ratio was 0.76, and a cut-off ratio of 5.87 was suggested to have 70% sensitivity and 68% specificity. Conclusion The plasma Aβ40/Aβ42 ratio had moderate validity for the discrimination of sEOAD patients from age-matched controls.

The aim of this study was to optimize extraction conditions for jujube pulp and seed in order to obtain maximum active ingredient yield and antioxidant activity, as well as to prepare chitosan nanoparticles loaded with jujube pulp and seed extracts for enhancing stability. The extraction conditions, i.e. temperature, time, and ethanol concentration, were optimized at the following respective values: 61.2 °C, 38 h, and 60.4% for pulp, and 58 °C, 34 h, and 59.2% for seed. The jujube nanoparticle size significantly increased with a higher chitosan/sodium tripolyphosphate ratio and extract concentration. Entrapment efficiency was greater than 80% regardless of preparation conditions. The stabilities of jujube pulp and seed extract in terms of total phenolic content and antioxidant activity were effectively enhanced by nanoencapsulation. In conclusion, jujube pulp and seed extracts prepared using optimal conditions could be useful as a natural functional food ingredient with antioxidant activity, and nanoencapsulation can be used to improve the stability of jujube extract. Therefore, these results could be used to promote the utilization of not only jujube pulp but also seed, by product.

Background: Contrary to the initial hypothesis, there is accumulating evidence that the pathogenesis of lacunar infarction (LI) is heterogeneous. LI is often accompanied by intracranial stenosis, and while the clinical significance of severe stenosis of the intracranial parent artery in LI has been demonstrated, that of mild stenosis in LI has not been. Thus the aim of this study was to determine the clinical relevance of mild intracranial stenosis in LI. Methods: Ninety-three consecutive patients with acute LI were enrolled between March 2011 and December 2013. The patients were divided according to the presence of intracranial stenosis in the parent artery into pure LI (PLI) and LI with mild intracranial stenosis (

BACKGROUND & OBJECTIVE Early-onset Alzheimer's disease (EOAD, onset age < 65 years) may differ from late-onset Alzheimer's disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. METHODS Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. RESULTS Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE e4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. CONCLUSION Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients.

We evaluate the longitudinal outcomes of amnestic mild cognitive impairment (aMCI) according to the modality of memory impairment involved. We recruited 788 aMCI patients and followed them up. aMCI patients were categorized into three groups according to the modality of memory impairment: Visual-aMCI, only visual memory impaired; Verbal-aMCI, only verbal memory impaired; and Both-aMCI, both visual and verbal memory impaired. Each aMCI group was further categorized according to the presence or absence of recognition failure. Risk of progression to dementia was compared with pooled logistic regression analyses while controlling for age, gender, education, and interval from baseline. Of the sample, 219 (27.8%) aMCI patients progressed to dementia. Compared to the Visual-aMCI group, Verbal-aMCI (OR = 1.98, 95% CI = 1.19-3.28, p = 0.009) and Both-aMCI (OR = 3.05, 95% CI = 1.97-4.71, p < 0.001) groups exhibited higher risks of progression to dementia. Memory recognition failure was associated with increased risk of progression to dementia only in the Visual-aMCI group, but not in the Verbal-aMCI and Both-aMCI groups. The Visual-aMCI without recognition failure group were subcategorized into aMCI with depression, small vessel disease, or accelerated aging, and these subgroups showed a variety of progression rates. Our findings underlined the importance of heterogeneous longitudinal outcomes of aMCI, especially Visual-aMCI, for designing and interpreting future treatment trials in aMCI.

Background: Rhabdomyolysis is a syndrome of skeletal muscle breakdown with leakage of muscle contents into blood stream. Variable disorders affecting muscle membrane or its energy supply can cause rhabdomyolysis. Case Report: We report a patient with rapidly progressive dementia who developed severe parkinsonism after rhabdomyolysis in the course of the illness. Functional neuroimaging studies revealed diffuse cortical hypometabolism and severe nigrostriatal dopaminergic dysfunction. Conclusion: This case suggests that the special attentions should be paid on evaluation for rhabdomyolysis in some demented patients. J Neurocrit Care 2014;7(1):56-59

Objective: Limbic encephalitis (LE) is characterized by rapid development of impaired cognitive function, seizure and psychiatric symptoms. Brain 18fluoro labelled deoxyglucose (18FDG)-positron emission tomography (PET) typically showed glucose hypermetabolism in the temporomesial region in the acute stage. Although several studies about brain 18FDG-PET in LE have been reported, serial 18FDG-PET findings during the course of the disease are limited. The purpose of this study is to analyze serial 18FDGPET findings in LE and to compare them with the results of neuropsychological test. Methods: We studied prospectively two patients diagnosed as LE using clinical criteria. They underwent serial brain magnetic resonance imaging (MRI) and 18FDG-PET scans. They also received detailed neuropsychological tests. Results: Initial 18FDG-PET presented glucose hypermetabolism in unilateral temporomesial region without obvious abnormalities in brain MRI. Follow-up 18FDG-PET images obtained three month later displayed hypometabolism in both temporomesial region. Correspondingly, neuropsychological studies revealed prominent visuospatial and verbal memory deficits. Conclusion: The initial 18FDG-PET was very sensitive in visualizing the disease process compared with MRI and suggesting more markedly functional impairment than structural damage in early stage of LE. This was well correlated with cognitive dysfunction measured by neuropsychological test such as anterograde episodic memory loss involving both verbal and non-verbal materials.

Seong Soo An,1,* Sun Ah Park,2,* Eva Bagyinszky,1 Sun Oh Bae,1 Yoon-Jeong Kim,2 Ji Young Im,2 Kyung Won Park,3 Kee Hyung Park,4 Eun-Joo Kim,5 Jee Hyang Jeong,6 Jong Hun Kim,7 Hyun Jeong Han,8 Seong Hye Choi,9 SangYun Kim10 1Department of Bionano Technology, Gachon University, Seongnam-si, 2Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, 3Department of Neurology, Dong-A University College of Medicine and Institute of Convergence Bio-Health, Busan, 4Department of Neurology, Gachon University Gil Medical Center, Incheon, 5Department of Neurology, Pusan National University Hospital, Busan, 6Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, 7Department of Neurology, Ilsan Hospital, National Health Insurance Corporation, 8Department of Neurology, Myongii Hospital, Goyang, 9Department of Neurology, Inha University School of Medicine, Incheon, 10Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam-si, Republic of Korea *These authors contributed equally tothiswork Abstract: Early-onset Alzheimer’s disease (EOAD) has distinct clinical characteristics in comparison to late-onset Alzheimer’s disease (LOAD). The genetic contribution is suggested to be more potent in EOAD. However, the frequency of causative mutations in EOAD could be variable depending on studies. Moreover, no mutation screening study has been performed yet employing large population in Korea. Previously, we reported that the rate of family history of dementia in EOAD patients was 18.7% in a nationwide hospital-based cohort study, the Clinical Research Center for Dementia of South Korea (CREDOS) study. This rate is much lower than in other countries and is even comparable to the frequency of LOAD patients in our country. To understand the genetic characteristics of EOAD in Korea, we screened the common Alzheimer’s disease (AD) mutations in the consecutive EOAD subjects from the CREDOS study from April2012 to February 2014. We checked the sequence of APP (exons16-17), PSEN1 (exons3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24EOAD subjects with a family history and 80 without a family history of dementia. PSEN1 T116I case demonstrated autosomal dominant trait of inheritance, with at least 11 affected individuals over 2 generations. However, there was no family history of dementia within first-degree relation in PSEN1 L226F and PSEN2 V214L cases. Approximately, 55.7% of the EOAD subjects had APOE ε4 allele, while none of the mutation-carrying subjects had the allele. The frequency of genetic mutation in this study is lower compared to the studies from other countries. The study design that was based on nationwide cohort, which minimizes selection bias, is thought to be one of the contributors to the lower frequency of genetic mutation. However, the possibility of the greater likeliness of earlier onset of sporadic AD in Korea cannot be excluded. We suggest early AD onset and not carrying APOE ε4 allele are more reliable factors for predicting an induced genetic mutation than the presence of the family history inKorean EOAD population. Keywords: Alzheimer’s disease, mutation, presenilin, apolipoprotein-E, sequencing, early onset Alzheimer’s disease, genetics

Background and purpose Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(-)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects. Methods Ten amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(-) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays. Results The level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH (p=1.000), but it did between AD and CN subjects (p=0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age. Conclusions Our results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(-) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.

Aside from the glucocerebrosidase gene, the genetic risk factors for cognitive decline in Parkinson's disease (PD) are controversial. We investigated whether the G2385R polymorphism in leucine-rich repeat kinase 2 gene (LRRK2), a risk variant for the development of PD in East Asians, is associated with cognitive dysfunction in PD. We recruited 299 PD patients, consisting of 23 carriers and 276 non-carriers of LRRK2 G2385R, from 14 centers. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). PD with cognitive dysfunction was defined as an MMSE Z score that, adjusting for age at study entry and years of education, was below -1.0 standard deviations. In multivariate analysis, PD duration, age at study entry and depression were significant risk factors for cognitive dysfunction as assessed by MMSE performance or the MoCA. In linear regression analysis of the association between MMSE Z scores and PD duration, there was no significant difference associated with the LRRK2 G2385R genotype. The interaction terms between PD duration and the LRRK2 G2385R genotype were not significant for the MMSE Z score but were significant for the MoCA. In conclusion, the LRRK2 G2385R genotype may not be associated with cognitive dysfunction in PD.

The imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms produced by the alternative splicing of tau exon 10 leads to neuronal instability and eventual neurodegeneration in tauopathy. However, the role of altered 3R/4R tau ratio in Alzheimer's disease (AD) remains controversial. It has been shown that the expression of 3R tau is modulated by peptide amyloid β (Aβ) and that 3R tau levels increase with the progression of AD. The incidence of AD increases in patients with type 2 diabetes mellitus (T2DM), and the comorbidity of these disorders is closely associated with both aging and disease duration. To investigate whether changes in 3R and 4R tau isoforms are involved in AD pathology pertaining to age-related T2DM, the expression of tau isoforms and their relationship with AD-like tau pathology were examined in a spontaneous T2DM model using aged Otsuka Long-Evans Tokushima Fatty (OLETF) rats with obesity. An AD-like pathology consisting of increased aggregates in the neuronal cytoplasm and a loss of synaptic proteins was observed in these rats. The aggregates were reactive with a 3R tau-specific, but not 4R tau-specific, antibody. In contrast to 4R tau, the level of 3R tau profoundly increased and the proteins were prone to taking toxic phosphorylated and truncated forms. Taken together, these findings suggest that increased 3R tau may contribute to AD-like tau pathology in a chronic T2DM model. Thus, the restoration of normal 3R tau expression should be considered as an important therapeutic strategy in the treatment of AD.

Metamorphopsia is a type of visual illusion, which has been reported as a rare ictal manifestation. The patient presented with a simple partial status epilepticus characterised by continuous facial metamorphopsia, intermittently accompanied by elementary visual hallucinations or other types of visual illusions. Subtraction single-photon emission computed tomography images showed an increased perfusion in the ventrolateral aspect of the right temporo-occipital junction (middle and inferior occipital, and inferior temporal gyri). The result suggests that the anatomical substrate involved in the generation of ictal facial metamorphopsia is located in the visual association areas at the right temporo-occipital junction.

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Summary: Purpose: To examine whether the distribution of interictal epileptiform discharges (IEDs) recorded from foramen ovale electrodes (FOEs) correlates with metabolite levels in medial structures of the temporal lobes in patients with mesial temporal lobe epilepsy (MTLE). Methods: We studied 34 patients with MTLE. The lateralization ratio of IEDs was calculated after counting IEDs recorded from FOEs during prolonged video-EEG monitoring. Metabolite ratio between N-acetylaspartate (NAA) and creatine (Cr) was calculated in each medial temporal structure. The correlation between the lateralization ratio of IEDs and metabolic ratio was evaluated. Results: The asymmetry indexes of IEDs correlated with the asymmetry index of NAA/Cr ratio in the medial temporal structure (ρ = –0.380; p = 0.027). Analysis of IEDs and metabolite ratio revealed a significant inverse relation in the contralateral side to the major epileptogenic focus (ρ = –0.360; p = 0.037); however, this significance was not present in the ipsilateral side (ρ = –0.018; p = 0.921). Conclusions: There is a correlation between the neuronal dysfunction or damage detected by MRS and the epileptic activity in the contralateral medial temporal structure. Our results suggest that the pathomechanism underlying the contralateral reduction of NAA/Cr ratio, frequently observed in patients with MTLE, might be related to the process of epileptogenesis generating the independent contralateral IEDs.

Purpose: This study was done to develop a measurement for stress experienced by patients with schizophrenia during hospitalization. Methods: The preliminary tool was developed through in-depth interviews and a validity verification test of content. For data collection, 15 inpatients with schizophrenia were selected as participants for in-depth interviews and 195 patients admitted to one of eight psychiatric hospitals in four provinces were recruited as participants to test reliability and validity of the preliminary tool. Results: The questionnaire was developed as a four-point Likert-type scale in a self-report form with 28 items. Factor analysis showed 28 items in six factors. Factors were named ‘Unjust human rights infringement’, ‘Futureless life’, ‘Alienation from other family members’, ‘Infringement of basic needs’, ‘Infringement of personal preference’ and ‘Inconvenience of shared living’. The six factors explained 63.5% of the total variance. Cronbach’s alpha for the total items was .93 and for the factors ranged from .65 to .87. Conclusion: A tool to measure stress in patients hospitalized with schizophrenic was developed based on identified hospitalization stress experiences. Study results indicate that this tool can be used to evaluate hospitalization stress in these patients and will contribute to establishing nursing interventions for relief of hospitalization stress.

Background: We investigated levels of the beta-amyloid 1-42 (A beta 42), total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau) in cerebrospinal fluid (CSF) of idiopathic normal pressure hydrocephalus (iNPH) patients and tried to find their clinical implications in the evaluation and treatment of iNPH. Method: Twenty-five possible iNPH patients were prospectively enrolled and their CSF was collected to analyze levels of A beta 42, T-tau and P-tau using ELISA method. Gait disturbance, urinary incontinence, and cognitive impairment were semi-quantified and detailed neuropsychological (NP) test was performed. Result: Eight iNPH patients were classified into the lower CSF A beta 42 group and 17 patients were classified into the higher CSF A beta 42 group. There was no difference in the iNPH grading score and its improvement after LP between the two groups. The lower CSF A beta 42 group showed more deficits in attention, visuospatial function and verbal memory in the baseline NP test and less improvement in phonemic categorical naming and frontal inhibitory function after LP. Conclusions: Our study suggested that concomitant AD in iNPH patients might contribute to lumbar puncture or shunt unresponsiveness, especially in the field of cognitive dysfunction.

The study was done to evaluate the effects a Stress Management Program (SMP) on stress, problem solving skills, and quality of life for hospitalized patients with Schizophrenia.A mixed method design was used: a combination of a repeated-measure design with a non-equivalent control group and qualitative data collection. The participants were 40 patients with schizophrenia admitted in three psychiatric hospitals. The experimental group (n=20) received the SMP twice a week for a total of 8 weeks.Study results revealed that the SMP was effective for stress (F=321.02, p.001), problem solving ability (F=246.28, p.001), and quality of life (F=63.35,p.001) for hospitalized persons with schizophrenia.The results suggest that a SMP can be an effective strategy to reduce patients' hospitalization stress, and improve problem solving skills and quality of life. Therefore, it is recommended that mental health nurses use this stress management program in clinical practice to assist adaptation to hospitalization for persons with schizophrenia.

Background and Purpose Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β proteins (Aβ). In this study we explored the correlation of plasma Aβ40 and Aβ42 concentrations with Aβ42, total tau (tTau) and phosphorylated tau 181 (pTau181) levels in cerebrospinal fluid (CSF) in AD and control subjects to further understand the characteristics of plasma Aβ proteins levels. Methods The consecutive subjects (44 AD and 47 controls) in this study were recruited. The plasma levels of Aβ40 and Aβ42 were measured using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA) kits. And the corresponding CSFs were analyzed in terms of Aβ42, tTau and pTau181 concentrations using INNOTEST ELISA kits. Further, the albumin levels were measured both in serum and CSF and albumin ratio was obtained to check the integrity of blood-brain barrier. Results CSF Aβ42 concentrations were significantly decreased while tTau and pTau181 levels were significantly increased in AD subjects. The plasma levels of Aβ42 were significantly lower (p=0.007), while the Aβ40/Aβ42 ratio was significantly higher (p

Background and Purpose The goal of this study was to estimate the efficacy and safety of the rivastigmine transdermal patch in patients with probable Alzheimer's disease (AD) who cannot tolerate or do not respond to oral cholinesterase inhibitors (ChEIs). Methods A 24-week, prospective, open-label, single-arm, multicenter study was conducted from June 2009 to June 2010 in patients with probable AD. The enrolled patients had either a poor response or a decline in global function after treatment with oral ChEIs, or they were not able to tolerate treatment with oral ChEIs due to adverse events such as nausea or vomiting. A poor response was defined as a decrease of at least 2 points on the Korean version of the Mini-Mental State Examination (K-MMSE) within the previous 6 months (the decline in global function was determined by the investigator or caregiver). The efficacy of treatment was assessed using a follow-up Clinical Global Impression of Change (CGIC) assessment and K-MMSE conducted after 24 weeks, and safety was measured by the occurrence of adverse events and patient disposition. Results In total, 164 patients aged 74.7±7.52 years (mean±SD) and with 5.12±3.64 years of education were included. The study was completed by 70% of the patients (n=116), with 12.2% discontinuing due to adverse events. The most frequently reported adverse events (11%) were skin lesions, such as erythema or itching, followed by gastrointestinal problems (1.2%). Either an improvement or no decline in CGIC scores was reported for 82% of the patients. Conclusions The immediate switching of patients from an oral ChEI to the rivastigmine transdermal patch without a washout period was safe and well tolerated by the probable-AD patients in this study.

Paramyotonia congenita (PC), first described in 1886 by Eulenberg, is characterized by cold and exercise-induced muscle stiffness and intermittent flaccid paresis not necessarily related to cold or myotonia. Several authors segregated a pure form of PC, which has no periodic paralysis, even after cold exposure. The existence of this phenotype has been debated in the literature. We describe electrophysiological and molecular genetic features of a patient with PC who had no history of periodic paralysis. Immersion in cold water or potassium load could not induce clinical paralysis. However, repetitive nerve stimulation and exercise test demonstrated a drop in compound muscle action potential amplitude. Genetic analysis revealed the substitution of valine for glycine on the human skeletal muscle sodium channel (SCN4A) gene. The G1306V mutation is rare in the classic form of PC, and moreover might be the first in pure paramyotonia.

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Aβ42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer's disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.

Background Cerebellar lesions revealed by abnormal signals on magnetic resonance images are extremely rare in acquired hepatocerebral degeneration (AHCD). Objective To report a case of AHCD with prominent cerebellar findings both clinically and radiologically. Design and Setting Case report and tertiary-care hospital. Patient A 46-year-old man complained of progressive speech difficulties of 5 months’ duration. Two years earlier, he had been diagnosed as having cirrhosis of the liver caused by alcoholism and hepatitis B virus infection. Results The patient had progressive ataxic dysarthria and limb and gait ataxia as manifestations of AHCD. Magnetic resonance imaging of the brain revealed distinctive symmetrical T2 high-signal intensities in the bilateral cerebellar hemispheres and brachium pontis, which were consistent with his neurologic deficits. Simultaneously, high T1 signals in the bilateral pallidum and ventral midbrain were noted, which are typical manifestations of AHCD. Follow-up magnetic resonance imaging 3 months later showed the same cerebellar signs and abnormal signals. Conclusions The cerebellar cortex and middle cerebellar peduncle are considered highly vulnerable structures to metabolic insults in liver disease. Findings from our patient suggest that dominant cerebellar deficits with compatible T2 high-signal lesions are another type of clinical manifestation in AHCD.

Thyroid related autoantibodies have been related to the development of encephalopathy, known as Hashimoto's encephalopathy. However, their relation with the encephalopathy occurring in patients with Graves' disease has not been well established. The case is reported of a 51 year old woman presenting with subacute progressive dementia with evidence of hyperthyroidism. She had Graves' disease associated with high titres of thyroid related autoantibodies. Her encephalopathy was not improved by antithyroid drugs, but promptly responded to corticosteroid treatment, and stabilised with a gradual reduction of thyroid related autoantibody titres. Brain positron emission tomography initially showed a diffuse and multifocal cerebral hypometabolism with subsequent normalisation on her clinical recovery, which was consistent with the acute and reversible cerebral inflammation probably mediated by autoimmune mechanisms.