Treatment Outcome After Switching From Galcanezumab to Fremanezumab in Patients With Migraine

Background@#and PurposeMonoclonal antibodies (mAbs) targeting calcitonin-gene-related peptide (CGRP) or its receptor (anti-CGRP-R) have been widely administered to patients with migraine who show inadequate responses to preventive medications. Among patients in whom a particular anti-CGRP-R mAb is ineffective, switching between different anti-CGRP-R mAbs can be the next option. Few studies have investigated treatment outcomes for antibody switching, especially between mAbs with the same target of the CGRP ligand. We aimed to determine the treatment outcome after switching between two anti-CGRP mAbs (galcanezumab to fremanezumab). @*Methods@#We identified migraine patients in a prospective headache clinic registry who received galcanezumab for ≥3 months and were switched to fremanezumab for a further ≥3 months at a single university hospital. We defined a treatment response as a ≥50% reduction in the number of days with a moderate or severe headache at the third month of treatment relative to baseline. The treatment response after switching to fremanezumab was compared with the initial treatment response to galcanezumab. @*Results@#Among 21 patients identified in the registry, 7 (33.3%) were initial responders to galcanezumab. After switching to fremanezumab, 7 (33.3%) showed a treatment response. The treatment response rate was 28.6% in the initial responders and 71.4% in the nonresponders to galcanezumab (p>0.999). @*Conclusions@#Switching between anti-CGRP mAbs (galcanezumab to fremanezumab) yielded a treatment outcome comparable to that reported previously when switching from an anti-CGRP-R mAb (erenumab) to an anti-CGRP mAb (galcanezumab or fremanezumab). The treatment response to fremanezumab seems to be independent of the prior treatment response to galcanezumab. Our findings suggest that switching to another anti-CGRP mAb can be considered when a particular anti-CGRP mAb is ineffective or intolerable.

Caregiver Burden of Patients With Huntington’s Disease in South Korea

Objective@#This is the first prospective cohort study of Huntington’s disease (HD) in Korea. This study aimed to investigate the caregiver burden in relation to the characteristics of patients and caregivers. @*Methods@#From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We used the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associations of the ZBI-12 scores by linear regression analysis and investigated the differences between the low- and high-burden groups. @*Results@#Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study. The average age at onset of motor symptoms was 49.3 ± 12.3 years, with an average cytosine-adenine-guanine (CAG)n of 42.9 ± 4.0 (38–65). The median ZBI-12 score among our caregivers was 17.6 ± 14.2. A higher caregiver burden was associated with a more severe Shoulson–Fahn stage (p = 0.038) of the patients. A higher ZBI-12 score was also associated with lower independence scale (B = -0.154, p = 0.006) and functional capacity (B = -1.082, p = 0.002) scores of patients. The caregiving duration was longer in the high- than in the low-burden group. Caregivers’ demographics, blood relation, and marital and social status did not affect the burden significantly. @*Conclusion@#HD patients’ neurological status exerts an enormous impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need to establish an optimal support system for families dealing with HD in Korea. A future longitudinal analysis could help us understand how disease progression aggravates the caregiver burden throughout the entire disease course.

Efficacy and Safety of Galcanezumab as a Preventive Treatment for Episodic Migraine in South Korean Patients: A Post-Hoc Analysis of a Phase 3 Clinical Trial

Background@#and Purpose The estimated prevalence of migraines in South Korea is 6.0%, with affected patients having unmet needs. The efficacy, safety, and tolerability of galcanezumab, a humanized monoclonal antibody, for episodic migraine (EM) prevention was evaluated in South Korean patients. @*Methods@#During the double-blind period of the EVOLVE-2 phase 3 trial, patients with EM were randomized into placebo, 120 mg-galcanezumab, and 240-mg galcanezumab treatment groups. The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days during the 6-month double-blind period. We conducted a post-hoc analysis of the South Korean cohort in EVOLVE-2. @*Results@#Among 98 South Korean patients in the intent-to-treat population, significant changes from baseline were observed in the number of monthly migraine headache days in the 240-mg galcanezumab group compared with the placebo group (-2.64, p=0.013), in the percentage of patients with ≥50% reduction in the number of monthly migraine headache days (120 mg: odds ratio=2.43, p=0.030; 240 mg: odds ratio=2.60, p=0.019), in the number of monthly migraine headache days with acute medication use (120 mg: -2.22, p=0.006; 240 mg: -2.23, p=0.005), and in the Migraine-Specific Quality-of-Life Role Function-Restrictive (120 mg: 8.34, p=0.040). Numerical improvements from baseline were observed relative to the placebo group in at least one galcanezumab group for: the percentage of patients with ≥75% reduction in the number of monthly migraine headache days functional impairment, and disease severity. The most common treatment-emergent adverse event in the combined galcanezumab group was injection site reaction, which led to treatment discontinuation for one patient. @*Conclusions@#Galcanezumab treatment demonstrated efficacy and a favorable safety and tolerability profile in South Korean patients with EM.

Increased 10-Year Prevalence of Huntington’s Disease in South Korea: An Analysis of Medical Expenditure Through the National Healthcare System

Background@#and PurposeThis study aimed to determine the updated 10-year prevalence of Huntington’s disease (HD) in South Korea and the medical and economic burdens across the duration of the disease. @*Methods@#Data from the National Health Insurance database during 2010–2019 were analyzed. We identified HD cases using predefined criteria. Information on age at diagnosis, sex, and common nonneurological comorbidities were collected. We analyzed individual patterns of the use of medical services and yearly medical expenditure. Incidence rates, 10-year prevalence rates, and longitudinal medical expenditure changes were assessed. @*Results@#New patients with HD (average=152.10) were detected every year, with an annual incidence of 0.29 per 100,000. The estimated 10-year prevalence of HD was 2.2 per 100,000. The most common ages at the time of diagnosis were 50–59 years (23.3%). In 2019, 56.4% of patients with HD were followed-up at referral or general hospitals, and 32.2% were managed at long-term-care hospitals. The annual medical cost for an individual was KRW 6,569,341±895,097 (mean±SD) (mean≈USD 5,653). Medical expenditure was the highest in those aged 60–79 years, and lowest in those younger than 30 years. However, in all age groups, the annual medical expenditure was highest during the 9 years following a diagnosis. @*Conclusions@#This study found that the actual prevalence of HD in South Korea was higher than previously thought and that patients are in a situation with high medical expenditure that persists over time.

Association of Zolpidem With Increased Mortality in Patients With Brain Cancer: A Retrospective Cohort Study Based on the National Health Insurance Service Database

Background@#and Purpose Zolpidem is one of the most common hypnotics prescribed to treat insomnia worldwide. However, there are numerous reports of a positive association between zolpidem and mortality, including an association with increased cancer-specific mortality found in a Taiwanese cohort study. This study aimed to determine the association between zolpidem use and brain-cancer-specific mortality in patients with brain cancer. @*Methods@#This population-based, retrospective cohort study analyzed data in the National Health Insurance Service database. All incident cases of brain cancer at an age of ≥18 years at the time of brain cancer diagnosis over a 15-year period (2003–2017) were included. A multivariate Cox regression analysis after adjustment for covariables was performed to evaluate the associations of zolpidem exposure with brain-cancer-specific and all-cause mortality. @*Results@#This study identified 38,037 incident cases of brain cancer, among whom 11,823 (31.1%) patients were exposed to zolpidem. In the multivariate Cox regression model, the brain-cancer-specific mortality rate was significantly higher in patients who were prescribed zolpidem than in those with no zolpidem prescription (adjusted hazard ratio [HR]=1.14, 95% confidence interval [CI]=1.08–1.21, p<0.001). Zolpidem exposure was significantly associated with increased brain-cancer-specific mortality after adjustment in younger adults (age 18– 64 years; adjusted HR=1.37, 95% CI=1.27–1.49) but not in older adults (age ≥65 years; adjusted HR=0.94, 95% CI=0.86–1.02). @*Conclusions@#Zolpidem exposure was significantly associated with increased brain-cancerspecific mortality in patients with brain cancer aged 18–64 years. Further prospective studies are warranted to understand the mechanism underlying the effect of zolpidem on mortality in patients with brain cancer.

Gene Therapy for Huntington’s Disease: The Final Strategy for a Cure?

Huntington’s disease (HD) has become a target of the first clinical trials for gene therapy among movement disorders with a genetic origin. More than 100 clinical trials regarding HD have been tried, but all failed, although there were some improvements limited to symptomatic support. Compared to other neurogenetic disorders, HD is known to have a single genetic target. Thus, this is an advantage and its cure is more feasible than any other movement disorder with heterogeneous genetic causes. In this review paper, the authors attempt to cover the characteristics of HD itself while providing an overview of the gene transfer methods currently being researched, and will introduce an experimental trial with a preclinical model of HD followed by an update on the ongoing clinical trials for patients with HD.

Cognitive improvement effect of gintonin might be associated with blood-brain barrier permeability enhancement: dynamic contrastenhanced MRI pilot study

Along with the multiple neuroprotective effect, recent studies suggest that gintonin might increase the blood brain barrier permeability. We evaluated the effect of gintonin on the vascular permeability changes in different brain segments, using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). In this 8-week, randomized, open label pilot study, ten participants with subjective memory impairment but preserved cognitive function assigned to gintonin-enriched fraction (GEF) 300 mg/day or placebo groups. Korean versions of the Alzheimer's disease assessment scale (ADAS-K) and DCE-MRI parameters including Ktrans and Vp in different brain segments were evaluated at baseline and at 8 weeks after treatment. Nine participants completed the study protocol. No adverse events occurred during the observation period for 8 weeks in both groups. Following gintonin administration, increment trends of the brain permeability that did not reach a statistical significance were observed in the left hippocampus (Ktrans and Vp , both, p = 0.062), left thalamus and in left putamen (Ktrans , p = 0.062), and left insula and right amygdala (Vp , p = 0.062), but not in the control placebo group. The increment of the Ktrans value in the left thalamus from the baseline was highly correlated with the change of the ADAS scores (r = −0.900, p = 0.037). Gintonin might enhance the blood-brain barrier (BBB) permeability in the brain structures involved in cognitive functions. Further efficacy exploration for the synergistic effect of gintonin's BBB permeability enhancement to its other cognitive enhancing mechanisms are warranted.

Comorbid Depression Is Associated with a Negative Treatment Response in Idiopathic REM Sleep Behavior Disorder

Background@#and PurposeThe first-line medications for the symptomatic treatment of rapid eye movement sleep behavior disorder (RBD) are clonazepam and melatonin taken at bedtime. We aimed to identify the association between depression and treatment response in patients with idiopathic RBD (iRBD). @*Methods@#We reviewed the medical records of 123 consecutive patients (76 males; age, 66.0±7.7 years; and symptom duration, 4.1±4.0 years) with iRBD who were treated with clonazepam and/or melatonin. Clonazepam and melatonin were initially administered at 0.25–0.50 and 2 mg/day, respectively, at bedtime, and the doses were subsequently titrated according to the response of individual patients. Treatment response was defined according to the presence or absence of any improvement in dream-enacting behaviors or unpleasant dreams after treatment. @*Results@#Forty (32.5%) patients were treated with clonazepam, 56 (45.5%) with melatonin, and 27 (22.0%) with combination therapy. The doses of clonazepam and melatonin at followup were 0.5±0.3 and 2.3±0.7 mg, respectively. Ninety-six (78.0%) patients reported improvement in their RBD symptoms during a mean follow-up period of 17.7 months. After adjusting for potential confounders, depression was significantly associated with a negative treatment response (odds ratio=3.76, 95% confidence interval=1.15–12.32, p=0.029). @*Conclusions@#We found that comorbid depression is significantly associated with a negative response to clonazepam and/or melatonin in patients with iRBD. Further research with larger numbers of patients is needed to verify our observations and to determine the clinical implications of comorbid depression in the pathophysiology of iRBD.

Flow cytometric immunophenotyping of canine adipose-derived mesenchymal stem cells (ADMSCs) and feline ADMSCs using anti-human antibodies / 대한수의학회지

Various trials have been conducted to develop therapies for serious untreatable diseases. Among these, those using stem cells have shown great promise, and adipose-derived mesenchymal stem cells (ADMSCs) are easier to obtain than other types of stem cells. Prior to clinical trials, characterization of ADMSCs with monoclonal antibodies should be performed. However, it is difficult to use species-specific antibodies for veterinarians. This study was conducted to confirm the panel of human antibodies applicable for use in immunophenotypic characterization of canine adipose-derived stem cells and feline ADMSCs extracted from subcutaneous adipose tissue collected during ovariohysterectomy. For flow cytometric immunophenotyping, the third passages of canine ADMSC and feline ADMSC and human CD31, CD34, CD42, CD44, CD62 and CD133 antibodies were used. Of these, CD133 reacted with canine cells (3.74%) and feline cells (1.34%). CD133 is known as a marker related with more primitive stem cell phenotype than other CD series. Because this human CD133 was not a species-specific antibody, accurate percentages of immunoreactivity were not confirmed. Nevertheless, the results of this study confirmed human CD133 as a meaningful marker in canine and feline ADMSCs.

Flow cytometric immunophenotyping of canine adipose-derived mesenchymal stem cells (ADMSCs) and feline ADMSCs using anti-human antibodies

Various trials have been conducted to develop therapies for serious untreatable diseases. Among these, those using stem cells have shown great promise, and adipose-derived mesenchymal stem cells (ADMSCs) are easier to obtain than other types of stem cells. Prior to clinical trials, characterization of ADMSCs with monoclonal antibodies should be performed. However, it is difficult to use species-specific antibodies for veterinarians. This study was conducted to confirm the panel of human antibodies applicable for use in immunophenotypic characterization of canine adipose-derived stem cells and feline ADMSCs extracted from subcutaneous adipose tissue collected during ovariohysterectomy. For flow cytometric immunophenotyping, the third passages of canine ADMSC and feline ADMSC and human CD31, CD34, CD42, CD44, CD62 and CD133 antibodies were used. Of these, CD133 reacted with canine cells (3.74%) and feline cells (1.34%). CD133 is known as a marker related with more primitive stem cell phenotype than other CD series. Because this human CD133 was not a species-specific antibody, accurate percentages of immunoreactivity were not confirmed. Nevertheless, the results of this study confirmed human CD133 as a meaningful marker in canine and feline ADMSCs.

High-Fat Diet and Voluntary Chronic Aerobic Exercise Recover Altered Levels of Aging-Related Tryptophan Metabolites along the Kynurenine Pathway

Tryptophan metabolites regulate a variety of physiological processes, and their downstream metabolites enter the kynurenine pathway. Age-related changes of metabolites and activities of associated enzymes in this pathway are suggestable and would be potential intervention targets. Blood levels of serum tryptophan metabolites in C57BL/6 mice of different ages, ranging from 6 weeks to 10 months, were assessed using high-performance liquid chromatography, and the enzyme activities for each metabolic step were estimated using the ratio of appropriate metabolite levels. Mice were subjected to voluntary chronic aerobic exercise or high-fat diet to assess their ability to rescue age-related alterations in the kynurenine pathway. The ratio of serum kynurenic acid (KYNA) to 3-hydroxylkynurenine (3-HK) decreased with advancing age. Voluntary chronic aerobic exercise and high-fat diet rescued the decreased KYNA/3-HK ratio in the 6-month-old and 8-month-old mice groups. Tryptophan metabolites and their associated enzyme activities were significantly altered during aging, and the KYNA/3-HK ratio was a meaningful indicator of aging. Exercise and high-fat diet could potentially recover the reduction of the KYNA/3-HK ratio in the elderly.

Prolonged Effect of OnabotulinumtoxinA on Chronic Migraine in 87 Koreans

No abstract available.

Exosome-Based Delivery of miR-124 in a Huntington's Disease Model

OBJECTIVE: Huntington's disease (HD) is a genetic neurodegenerative disease that is caused by abnormal CAG expansion. Altered microRNA (miRNA) expression also causes abnormal gene regulation in this neurodegenerative disease. The delivery of abnormally downregulated miRNAs might restore normal gene regulation and have a therapeutic effect. METHODS: We developed an exosome-based delivery method to treat this neurodegenerative disease. miR-124, one of the key miRNAs that is repressed in HD, was stably overexpressed in a stable cell line. Exosomes were then harvested from these cells using an optimized protocol. The exosomes (Exo-124) exhibited a high level of miR-124 expression and were taken up by recipient cells. RESULTS: When Exo-124 was injected into the striatum of R6/2 transgenic HD mice, expression of the target gene, RE1-Silencing Transcription Factor, was reduced. However, Exo-124 treatment did not produce significant behavioral improvement. CONCLUSION: This study serves as a proof of concept for exosome-based delivery of miRNA in neurodegenerative diseases.

Applications of CRISPR/Cas9 for Gene Editing in Hereditary Movement Disorders

Gene therapy is a potential therapeutic strategy for treating hereditary movement disorders, including hereditary ataxia, dystonia, Huntington's disease, and Parkinson's disease. Genome editing is a type of genetic engineering in which DNA is inserted, deleted or replaced in the genome using modified nucleases. Recently, clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 (CRISPR/Cas9) has been used as an essential tool in biotechnology. Cas9 is an RNA-guided DNA endonuclease enzyme that was originally associated with the adaptive immune system of Streptococcus pyogenes and is now being utilized as a genome editing tool to induce double strand breaks in DNA. CRISPR/Cas9 has advantages in terms of clinical applicability over other genome editing technologies such as zinc-finger nucleases and transcription activator-like effector nucleases because of easy in vivo delivery. Here, we review and discuss the applicability of CRISPR/Cas9 to preclinical studies or gene therapy in hereditary movement disorders.

Ginseng may modify the progression of degenerative cerebellar ataxia: A report of two case

Cerebellar degeneration is a group of diseases that manifests as progressive ataxia, that finally led to death without specific treatment. We report here two patients with cerebellar degeneration, who had shown an improvement and less progressive course, which is associated with panax ginseng intake. Patient 1 was a 60-year-old woman with multisystem atrophy (MSA) type C with 5 year history of ginseng ingestion. Patient 2 was a 54-year-old woman with spinocerebellar ataxia (SCA) type 6, who had a history of ginseng intake for 30 months. Both the patients showed atrophic change in the cerebellum by brain magnetic resonance imaging. Cerebellar functions had been semi-quantified by International Cooperative Ataxia Rating Scale (ICARS) and monitored before and after the ginseng ingestion every 6 to 12 months. In Patient 1 with MSA type C, ICARS had improved from 21 to 17.5 ± 1.8 in the following 5 years. In Patient 2 with SCA, ICARS also showed an improvement from 22 to 6.0 ± 1.0 over 30 months. However, when she stopped taking ginseng, it progressed up to 13 points in two years. These observations provide a potential disease-modifying effect of ginseng on patients with cerebellar degeneration.

Magnetic resonance angiographic screening of aneurysms in migraine

Objective: The purpose of the present study was to screen the prevalence of aneurysms in migraineurs; to differentiate presenting features in migraineurs with and without aneurysm; and also to correlate the locations of aneurysm to the clinical features of migraine. Methods: A total of 4,416 subjects were interviewed and completed self-reported questionnaires on headache. Of these, 1,773 subjects diagnosed to have migraines based on the International Classification of Headache Disorders II (ICHD-II) criteria were screened for aneurysm by magnetic resonance angiography (MRA). When aneurysm was suspected, further investigation with trans femoral cerebral angiography (TFCA) or three dimensional computerized tomography (CT) angiography was performed. Based upon MRA findings, subjects were grouped into unruptured aneurysm migraine patients (UAMP) and no aneurysm migraine patients (NAMP). Results: The prevalence of aneurysm was 3.6% (63 of 1,773) with the mean age of 56.0 years, which were not different from those of general population. There was no difference in migraine subtypes between UAMP and NAMP. Aggravation of headache by estrogen replacement therapy during menopause (p=.039), history of migraine in young age (p= .021), diplopia (p=.026), and retroauricular pain (p=.025) were significantly associated with presence of aneurysm. Although aneurysms were detected more in anterior circulation, there was no correlation between aneurysm site and headache location. The average size of aneurysm was 3.5 ± 2.1 mm and none were ruptured. Interventional therapy of aneurysm did not alter the feature of migraine. Conclusions: The incidence of aneurysm was not different in migraine patients as compared to the general population. Some features which significantly differentiate whether migrainuers have aneurysm or not warrant further study to have a predictive and localizing value.

In Vivo Roles of a Patient-Derived Induced Pluripotent Stem Cell Line (HD72-iPSC) in the YAC128 Model of Huntington's Disease

Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can provide immense opportunities to model human diseases, which may lead to develop novel therapeutics. Huntington's disease (HD) is a devastating neurodegenerative genetic disease, with no available therapeutic options at the moment. We recently reported the characteristics of a HD patient-derived iPSC carrying 72 CAG repeats (HD72-iPSC). In this study, we investigated the in vivo roles of HD72-iPSC in the YAC128 transgenic mice, a commonly used HD mouse model carrying 128 CAG repeats. To do this, we transplanted HD72-iPSC-derived neural precursors into the striatum of YAC128 mice bilaterally and observed a significant behavioral improvement in the grafted mice. Interestingly, the transplanted HD72-iPSC-derived neural precursors formed GABAeric neurons efficiently, but no EM48-positive protein aggregates were detected at 12 weeks after transplantation. Taken together, these results indicate no HD pathology was developed from the grafted cells, or no transmission of HD pathology from the host to the graft occurred at 12 weeks post-transplantation.

Multiple left subclavian venous catheterizations in premature infant / 대한마취과학회지

No abstract available.

Inhibitory control of angiotensin-converting enzyme by ramipril in migraine

Background: Renin-angiotensin systems (RAS) are involved in the physiology of migraine. Ramipril is an angiotensin-converting enzyme inhibitor. We tested whether ramipril has an effect on migraine. Methods: The study was designed as a prospective open-labeled trial in a single center. All patients were asked to maintain a headache diary. Ramipril was administered at 5mg/day (2.5mg twice a day) and subjects were checked every 4 weeks up to 12 weeks. Results: The mean number of headache days was 19.9 ± 11.2 days per month at baseline, and 12.0 ± 11.5 at 12 weeks (p vs. <15 days a month) did not show a difference. Mean blood pressure was not altered. Conclusions: Ramipril prevented migraine attacks independently from blood pressure. This result supports a link between renin-angiotensin system and migraine pathophysiology (Clinicaltrials.gov identifier: NCT01402479).

Suitability of autologous serum for expanding rabbit adipose-derived stem cell populations

Adipose-derived stem cells (ASCs) are believed to have potential use for treating many illnesses. Most cells, including ASCs, are generally cultured in medium containing fetal bovine serum (FBS). However, FBS, which could induce an immune response or infection, is not recommended for clinical applications. In the present study, we evaluated the morphology, proliferation rate, and characterization of rabbit ASCs grown in medium containing autologous serum (AS) and compared these cells to ones cultured with FBS. Morphological changes were monitored by microscopy and flow cytometry. Proliferation rates were assessed with cell counting and ASC phenotypes were characterized by flow cytometry using representative surface markers (CD44 and CD45). Expression of epidermal growth factor, brain-derived neurotrophic factor, and vascular endothelial growth factor was measured by reverse transcription-polymerase chain reaction. Results of our study showed that ASCs had a greater expansion rate in AS without developing morphological heterogeneity than cells grown in FBS. AS-cultured ASCs expressed representative growth factors, CD44 but not CD45, similar to cells cultured in FBS. Expression levels of some growth factors were different between AS and FBS. In conclusion, our findings indicated that AS could potentially be used as a culture medium supplement for the expansion of autologous ASCs.