Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association

Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer’s dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD’s diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.

Nucleocapsid and Spike Proteins of SARS-CoV-2 Drive Neutrophil Extracellular Trap Formation

Patients with severe coronavirus disease 2019 (COVID-19) demonstrate dysregulated immune responses including exacerbated neutrophil functions. Massive neutrophil infiltrations accompanying neutrophil extracellular trap (NET) formations are also observed in patients with severe COVID-19. However, the mechanism underlying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation has not yet been elucidated.Here we show that 2 viral proteins encoded by SARS-CoV-2, the nucleocapsid protein and the whole spike protein, induce NET formation from neutrophils. NET formation was ROSindependent and was completely inhibited by the spleen tyrosine kinase inhibition. The inhibition of p38 MAPK, protein kinase C, and JNK signaling pathways also inhibited viral protein-induced NET formation. Our findings demonstrate one method by which SARSCoV-2 evades innate immunity and provide a potential target for therapeutics to treat patients with severe COVID-19.

Executive Summary of the 2019 International Conference of Korean Dementia Association: Exploring the Novel Concept of Alzheimer's Disease and Other Dementia: a Report from the Academic Committee of the Korean Dementia Association

Because of repeated failures of clinical trials, the concept of Alzheimer's disease (AD) has been changing rapidly in recent years. As suggested by the National Institute on Aging and the Alzheimer's Association Research Framework, the diagnosis and classification of AD is now based on biomarkers rather than on symptoms, allowing more accurate identification of proper candidates for clinical trials by pathogenesis and disease stage. Recent development in neuroimaging has provided a way to reveal the complex dynamics of amyloid and tau in the brain in vivo, and studies of blood biomarkers are taking another leap forward in diagnosis and treatment of AD. In the field of basic and translational research, the development of animal models and a deeper understanding of the role of neuroinflammation are taking a step closer to clarifying the pathogenesis of AD. Development of big data and the Internet of Things is also incorporating dementia care and research into other aspects. Largescale genetic research has identified genetic abnormalities that can provide a foundation for precision medicine along with the aforementioned digital technologies. Through the first international conference of the Korean Dementia Association, experts from all over the world gathered to exchange opinions with association members on these topics. The Academic Committee of the Korean Dementia Association briefly summarizes the contents of the lectures to convey the depth of the conference and discussions. This will be an important milestone in understanding the latest trends in AD's pathogenesis, diagnostic and therapeutic research and in establishing a future direction.

A Therapeutic Strategy for Alzheimer's Disease Focused on Immune-inflammatory Modulation

Alzheimer's disease (AD), the most common form of dementia, has emerged as a major global public health challenge. However, the complexity of AD in its biological, genetic, and clinical aspects has hindered the development of effective therapeutic agents. Research plans that integrate new drug discoveries are urgently needed, including those based on novel and reliable biomarkers that reflect not only clinical phenotype, but also genetic and neuroimaging information. Therapeutic strategies such as stratification (i.e., subgrouping of patients having similar clinical characteristics or genetic background) and personalized medicine could be set as new directions for developing effective drugs for AD. In this review, we describe a therapeutic strategy that is based on immune-inflammation modulation for a subgroup of AD and related dementias, arguing that the use of stratification and personalized medicine is a promising way to achieve targeted medicine. The Korean AD Research Platform Initiative based on Immune-Inflammatory biomarkers (K-ARPI) has recently launched a strategy to develop novel biomarkers to identify a subpopulation of patients with AD and to develop new drug candidates for delaying the progression of AD by modulating toxic immune inflammatory response. Sphingosine kinase 1 (SphK1) and its metabolites, triggering receptor expressed on myeloid cells-2 (TREM2) related signals, and actin motility related proteins including Nck-associated protein 1 (Nap1) were selected as promising targets to modulate neuroinflammation. Their roles in stratification and personalized medicine will be discussed.

Two Siblings with Adolescent/Adult Onset Niemann-Pick Disease Type C in Korea

Niemann-Pick disease, type C (NP-C), is caused by NPC1 or NPC2 gene mutations. Progressive neurological, psychiatric, and visceral symptoms are characteristic. Here, we present cases of a brother (Case 1) and sister (Case 2) in their mid-20s with gait disturbance and psychosis. For the Case 1, neurological examination revealed dystonia, ataxia, vertical supranuclear-gaze palsy (VSGP), and global cognitive impairment. Case 2 showed milder, but similar symptoms, with cortical atrophy. Abdominal computed tomography showed hepatosplenomegaly in both cases. NPC1 gene sequencing revealed compound heterozygote for exon 9 (c.1552C>T [R518W]) and exon 18 (c.2780C>T [A927V]). Filipin-staining tests were also positive. When a young patient with ataxia or dystonia shows VSGP, NP-C should be considered.

Highly Efficient Reprogramming and Characterization of Induced Pluripotent Stem Cells by Using a Microwell Array

Reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) enables the possibility of generating patient-specific cells. However, the low efficiency issue associated with iPSCs generation has limited iPSCs usage in research and clinical applications. In this study, we developed a high efficiency system to generate iPSCs by using a polydimethylsiloxane stencil. This device could be applied to the localization and reprogramming of human fibroblasts. Herein, a well-defined culture system based on a stencil, which supported efficient reprogramming of fibroblasts into iPSCs with 2–4 fold increase in efficacy over conventional methods, is presented. Subsequently, we prepared a multiple analysis system, which used a micro-patterned scissile microarray to characterize iPSCs. The results showed that iPSCs could be cultured into micro-patterns in a precisely controlled manner on the scissile poly(ethylene terephthalate) sheet, which was cut into pieces for subsequent analyses, indicating that this method allows multiple analyses to establish iPSC pluripotency in the same sample. Our approach provides a simple, cost-effective, but highly efficient system for the generation and characterization of iPSCs, and will serve as a powerful tool for establishing patient- and disease-specific pluripotent stem cells.

Curcumin Stimulates Proliferation of Spinal Cord Neural Progenitor Cells via a Mitogen-Activated Protein Kinase Signaling Pathway

OBJECTIVE: The aims of our study are to evaluate the effect of curcumin on spinal cord neural progenitor cell (SC-NPC) proliferation and to clarify the mechanisms of mitogen-activated protein (MAP) kinase signaling pathways in SC-NPCs. METHODS: We established cultures of SC-NPCs, extracted from the spinal cord of Sprague-Dawley rats weighing 250 g to 350 g. We measured proliferation rates of SC-NPCs after curcumin treatment at different dosage. The immuno-blotting method was used to evaluate the MAP kinase signaling protein that contains extracellular signal-regulated kinases (ERKs), p38, c-Jun NH2-terminal kinases (JNKs) and beta-actin as the control group. RESULTS: Curcumin has a biphasic effect on SC-NPC proliferation. Lower dosage (0.1, 0.5, 1 microM) of curcumin increased SC-NPC proliferation. However, higher dosage decreased SC-NPC proliferation. Also, curcumin stimulates proliferation of SC-NPCs via the MAP kinase signaling pathway, especially involving the p-ERK and p-38 protein. The p-ERK protein and p38 protein levels varied depending on curcumin dosage (0.5 and 1 microM, p<0.05). CONCLUSION: Curcumin can stimulate proliferation of SC-NPCs via ERKs and the p38 signaling pathway in low concentrations.

Erratum: Bone regeneration of mouse critical-sized calvarial defects with human mesenchymal stem cells in scaffold / 한국실험동물학회지

At the request of the authors, the Acknowledgments information has been changed.

Bone regeneration of mouse critical-sized calvarial defects with human mesenchymal stem cells in scaffold / 한국실험동물학회지

Combination of tissue engineering and cell therapy represents a promising approach for bone regeneration. Human mesenchymal stem cells (hMSCs) have properties that include low immunogenicity, high proliferation rate, and multi-differentiation potential; therefore, they are an attractive seeding source for tissue engineering therapy. Here we found that hMSCs with a scaffold did not affect cell viability and osteogenic differentiation. We also investigated regenerative effect of hMSCs with the scaffold in a calvarial bone defect model. Formation of new bone was evaluated by micro-CT, histology and expression of osteogenic markers. The results clearly showed interesting evidence indicating that hMSCs with scaffold increased the formation of new bone and expression of osteogenic markers, compared to the empty and scaffold only groups. Overall, our results suggest that hMSCs with scaffold are suitable for stimulation of intense bone regeneration in critical-sized bone defects.

Reliability of Triggered EMG for Prediction of Safety during Pedicle Screw Placement in Adolescent Idiopathic Scoliosis Surgery

STUDY DESIGN: We performed a prospective study to evaluate the reliability of using triggered electromyography (EMG) for predicting pedicle wall breakthrough during the placement of pedicle screw in adolescent idiopathic scoliosis surgery. PURPOSE: We wanted to correlate pedicle wall breakthrough with the triggered EMG threshold of stimulation and the postoperative computed tomography (CT) findings. OVERVIEW OF LITERATURE: Pedicle wall breakthrough has been reported to be difficult to evaluate by radiographs. Triggered EMG had been found to be a more sensitive test to detect this breakthrough. METHODS: Seven patients who underwent the insertion of 103 pedicle screws were evaluated. The triggered EMG activity was recorded from several muscles depending on the level of screw placement. The postoperative CT scans were read by a spine surgeon who was a senior fellow in orthopedics, and a musculoskeletal radiologist. RESULTS: The mean age at surgery was 12.6 years (range, 11 to 17 years). The preoperative mean Cobb angle was 54.7degrees (range, 45 to 65degrees). There were 80 thoracic screws and 23 lumbar screws. All the screws had stimulation thresholds of > or = 6 mA, except 3 screws with the stimulation threshold of or = 6 mA were safe, with 90.3% reliability, as was assessed on the postoperative CT scans.

Bone Marrow-Derived Mesenchymal Stem Cells Improve the Functioning of Neurotrophic Factors in a Mouse Model of Diabetic Neuropathy / 한국실험동물학회지

Diabetic neuropathy is one of the most frequent and troublesome complications of diabetes. Although there has been a continuous increase in the incidence of diabetic neuropathy, treatments have yet to be found that effectively treat diabetic neuropathy. Neurotrophic factors are proteins that promote the survival of specific neuronal populations. They also play key roles in the regeneration of peripheral nervous system. Recent evidence from diabetic animal models and human diabetic subjects suggest that reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic neuropathy. One way to reverse this effect is to take advantage of the finding that bone marrow derived mesenchymal stem cells (BM-MSCs) promote peripheral nerve repair and the functioning of neurotrophic factors. Therefore, we speculated that treatment with BM-MSCs could be a viable therapeutic strategy for diabetic neuropathy. The present study was designed to examine the possible beneficial effect of BM-MSCs on functions of neurotrophic factors in diabetic neuropathy. To assess this possibility, we used an in vivo streptozotocin-induced diabetic neuropathy mouse model. Quantitative real-time polymerase-chain reacion showed that BM-MSCs significantly increase expression levels of neurotrophic factors. Also, BM-MSCs ameliorated nerve conduction velocity in streptozotocin-treated mice. These results may help to elucidate the mechanism by which BM-MSCs function as a cell therapy agent in diabetic neuropathy.

Polysaccharides isolated from Phellinus gilvus enhances dermal wound healing in streptozotocin-induced diabetic rats

Dermal wound healing is a complex process that involved inflammation leading to re-epithelialization, granulation tissue, and tissue remodeling. Previous studies from our laboratory have shown that polysaccharides isolated from fungus, Phellinus gilvus (PG) have various anti-inflammatory activities. In present study, we have assessed the effect of polysaccharides from PG on the dermal wound healing of polysaccharides from PG in streptozotocin-induced diabetic rat model. Six of 6-mm circular wounds were created with biopsy punch on the 4th day after induction of diabetes. After 24 hours, each test substance was applied to the wound twice a day for next 5 days. Circular wounds treated with PG showed significantly reduced wound contraction and complete reepithelialization, as compared to wounds of non-treated (p < 0.05). These results show that polysaccharides isolated from PG enhanced wound repair in diabetic impaired healing, and could be developed as a wound healing agent in such clinical settings.

An Experimental Study for the Effect of Interrupted(Intermittently-Repeated) versus Continuous Temporary Clipping on the Change of Arterial Wall of Rat / 대한뇌혈관학회지

The benefits of the use of temporary clipping for intracerebral aneurysm surgery were proved through many experimental and clinical studies. There are two techniques of temporary clipping which are interrupted and continuous clipping. In the study of cerebral perfusion, interrupted clipping reduced ischemic damage to the brain. However, the comparison of histological changes in the arterial wall between them is not reported yet. Temporary clipping on the iliac artery of 80 rats was performed using Yasargil temporary mini clip. The specimens were divided into two groups; Group I (intermittently repeated clipping for 5 minutes was done 3 times on the same site with resting interval for 5 minutes: total clipping time was 15 minutes) and Group II (continuous clipping for 15 minutes). Under the light microscope, the histological findings were examined in the specimens, which were obtained at each time-interval after clipping (0 hr, 3 hrs, 6 hrs, 12 hrs, 3 days, and 3 months). The histological changes of the arterial wall of rat by two techniques for temporary clipping were observed. Although there is no significant difference between two temporary clippings, there is a trend of milder and more delayed arterial change in intermittently-repeated temporary clipping.

Demyelinating Pseudotumor: A Case Report

The demyelinating diseases of the central nervous system(CNS), of which multiple sclerosis is the most common, have the characteristics which are selective loss of myelin with relative axonal preservation on the histopathologic findings, variable clinical findings and unknown pathophysiology. Occasionally, the clinical features, radiological and histopathological findings of patients with demyelinating disorders of the CNS mimic the brain tumor. Therefore, it may lead to erroneous surgical intervention as well as radiotherapy. The authors report a 26-year-old woman with demyelinating pseudotumor who presented with a generalized tonicclonic type seizure and left hemiparesis. Computerized tomography and magnetic resonance imaging of the patient revealed about 3X3X2cm sized enhanced mass lesion in the right frontal lobe with severe perifocal brain edema. This space-occupying lesion was resected subtotally and confirmed as the demyelinating pseudotumor via various neurohistochemical stains. Uncommonly, large focal cerebral demyelinating lesions presented as brain tumors clinically and radiologically. Therefore, it is mandatory to make a more careful diagnosis to differentiate the demyelinating pseudotumor from other true brain tumors before undergoing the surgery.