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Abstract Brain endothelial LDL receptor-related protein 1 (LRP1) is involved in the clearance of Aβ peptides across the blood-brain barrier (BBB). Here we show that endothelial deficiency of ankyrin repeat and SAM domain containing 1 A (ANKS1A) reduces both the cell surface levels of LRP1 and the Aβ clearance across the BBB. Association of ANKS1A with the NPXY motifs of LRP1 facilitates the transport of LRP1 from the endoplasmic reticulum toward the cell surface. ANKS1A deficiency in an Alzheimer’s disease mouse model results in exacerbated Aβ pathology followed by cognitive impairments. These deficits are reversible by gene therapy with brain endothelial-specific ANKS1A. In addition, human induced pluripotent stem cell-derived BBBs (iBBBs) were generated from endothelial cells lacking ANKS1A or carrying the rs6930932 variant. Those iBBBs exhibit both reduced cell surface LRP1 and impaired Aβ clearance. Thus, our findings demonstrate that ANKS1A regulates LRP1-mediated Aβ clearance across the BBB.

Abstract This study aimed to evaluate the sensitivity and prognostic value of arterial spin labeling (ASL) in a large group of status epilepticus (SE) patients and compare them with those of other magnetic resonance (MR) sequences, including dynamic susceptibility contrast (DSC) perfusion imaging. We retrospectively collected data of patients with SE in a tertiary center between September 2016 and March 2020. 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). We included 51 SE patients and 46 patients with self-limiting seizures for comparison. Relevant changes in ASL 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 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, although the specificity of ASL was very low as 9.4% and 15.6%, respectively. ASL showed a better ability to detect SE and predict the prognosis than other MR sequences, therefore it can be valuable for the initial evaluation of patients with SE.

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.

The presence of protein inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), in the brain is the main feature of Parkinson’s disease (PD). Recent evidence that the prion-like propagation of α-synuclein (α-syn), as a major component of LBs and LNs, plays an important role in the progression of PD has gained much attention, although the molecular mechanism remains unclear. In this study, we evaluated whether neuronal ApoE regulates the cell-to-cell transmission of α-syn and explored its molecular mechanism using in vitro and in vivo model systems. We demonstrate that neuronal ApoE deficiency attenuates both α-syn uptake and release by downregulating LRP-1 and LDLR expression and enhancing chaperone-mediated autophagy activity, respectively, thereby contributing to α-syn propagation. In addition, we observed that α-syn propagation was attenuated in ApoE knockout mice injected with pre-formed mouse α-syn fibrils. This study will help our understanding of the molecular mechanisms underlying α-syn propagation.

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.

Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P

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 April 2012 to February 2014. We checked the sequence of APP (exons 16-17), PSEN1 (exons 3-12), and PSEN2 (exons 3-12) genes. We identified different causative or probable pathogenic AD mutations, PSEN1 T116I, PSEN1 L226F, and PSEN2 V214L, employing 24 EOAD 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 in Korean EOAD population. [ABSTRACT FROM AUTHOR]

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 Gómez-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Objective: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients.Methods: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value.Results: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD.Conclusions: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Women are subject to a disproportionate burden from Alzheimer's disease (AD) and sex differences exist in treatment response and prognosis of the disease. Yet gender-specific risk factors have not been widely studied. We aimed to investigate gender-specific risk factors for AD in subjects with mild cognitive impairment (MCI). Methods: Participants (n = 294) with MCI were recruited from a nationwide, prospective cohort study of dementia and were followed for a median (range) of 13.8 (6.0-36.0) months. Sex-stratified associations of progression to AD with baseline characteristics were explored. Results: Seventy-four individuals (25.2%) developed incident dementia (67 AD) during follow-up. Significant risk factors for probable AD differed by sex. In men, the significant risk factors were severe periventricular white matter hyperintensities, and poorer global cognitive function. In women, older age, clinically significant depressive symptoms at baseline, and positive APOE e4 alleles were the significant risk factors. Conclusions: Risk factors for progression from MCI to probable AD differed in men and women. These results may translate to genderspecific preventative or therapeutic strategies for patients with MCI. [ABSTRACT FROM AUTHOR]

The influence of a periodic Taylorvortex flow on the polymorphiccrystallization of sulfamerazine (SMZ), including polymorphic nucleationand phase transformation, was investigated using a Couette–Taylor(CT) crystallizer, and also compared with the influence of a randomturbulent flow in a mixing tank (MT) crystallizer. In the MT crystallizer,the induction of the metastable phase (form-I) occurred first, whichwas then followed by the induction of the stable phase (form-II) 10–85h later. However, this whole process was significantly reduced toa half hour in the CT crystallizer, demonstrating the high efficiencyof a Taylor vortex flow for the induction of polymorphic nucleation.The efficiency of the Taylor vortex flow was also enhanced when increasingthe rotation speed. As a result, the stable and metastable phaseswere simultaneously nucleated at the first induction with a rotationspeed above 300 rpm; plus the stable-phase fraction nucleated at thefirst induction increased when increasing the rotation speed. In addition,the polymorphic nucleation was facilitated when decreasing the dimensionof the Taylor vortex flow, which was proportional to the gap sizebetween the inner and outer cylinders. The periodic Taylor vortexflow was also more effective than the random turbulent flow for thephase transformation from the metastable phase to the stable phase.Thus, the time period for the complete phase transformation (calledthe reconstruction time) in the CT crystallizer was 5–10 timesshorter than that in the MT crystallizer. Furthermore, the phase transformationwas enhanced when decreasing the dimension of the Taylor vortex dueto the promotion of the mass transfer. Finally, the polymorphic nucleationand phase transformation that varied with the rotation speed and gapsize of the CT crystallizer were linearly correlated with one parameter:the viscous energy dissipation, representing the hydrodynamic intensityof the Taylor vortex flow. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: We investigated levels of the β-amyloid 1–42 (Aβ42), 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 Aβ42, 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 Aβ42 group and 17 patients were classified into the higher CSF Aβ42 group. There was no difference in the iNPH grading score and its improvement after LP between the two groups. The lower CSF Aβ42 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. [ABSTRACT FROM AUTHOR]

Numerous students perceive neuroanatomy as a particularly difficult subject due to its overwhelming complexity. Therefore, a neuroanatomy book that concentrates on easy-to-read stories with schematics rather than exhaustive details has been published. This study evaluates the effect of a trial of the new neuroanatomy book on student learning. From the book, a printout on the brainstem and cranial nerve was extracted. Medical students read the printout, and subsequently were examined on their knowledge of and interest in neuroanatomy. Students who read the extract answered examination questions relatively well and were more interested in neuroanatomy. The printout seemed to enhance the knowledge and concentration of the students. After grasping the fundamental information in the book, students are expected to be able to learn advanced concepts comfortably and confidently. In addition, the book with its concise and simple content is suitable not only for shortduration neuroanatomy courses but also for self-learning. [ABSTRACT FROM AUTHOR]

The authors report on an unusual case of extensive brain stem lesions as a manifestation of thrombotic thrombocytopenic purpura (TTP). A 28- year-old woman developed rapidly progressive neurologic deficits 5 days after a cesarean delivery. Her condition had been normal after delivery. Initial magnetic resonance imaging (MRI) revealed extensive T2 hyperintense lesions involving the entire brain stem; only part of the pons showed hyperintense abnormalities in a concomitantly taken diffusionweighted image. The hematologic evaluations and her clinical course revealed the diagnosis of TTP, so plasma exchange and methylprednisolone therapy were initiated. After 10 days of treatment, she developed neurologic improvement. A follow-up MRI on the 75th day revealed dramatically reduced brain stem lesions with only residual punctate lesions in the pons. Her remaining neurologic deficits were dysarthria, limb ataxia, and left hemiparesis. As demonstrated in this study, extensive brain stem involvement should be added as a possible neuroimaging feature of TTP. [ABSTRACT FROM AUTHOR]

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.

The recent discovery that the impairment of autophagic flux in non-alcoholic fatty liver disease (NAFLD) might be a strong determining factor in steatosis suggests the potential of therapeutic control of autophagic flux with natural agents in restoring NAFLD. We investigated the potential of Eucommia ulmoides leaf extract (EUL) to control dyslipidemia in NAFLD. EUL supplementation (200 mg/kg) promoted recovery from high fat diet (HFD)-induced lipid dysmetabolism. This hepatoprotective efficacy was accompanied by suppression of endoplasmic reticulum (ER) stress, enhancing lysosomal functions, and thereby increasing autophagic flux. We found a strong indication that inhibition of the mTOR-ER stress pathway was related to the enhanced autophagic flux. However, the direct antioxidative effect of EUL on cytoprotection cannot be ruled out as a significant contributing factor in NAFLD. Our findings will aid in further elucidating the mechanism of the anti-steatosis activity of EUL and highlight the therapeutic potential of EUL in the treatment of NAFLD.