Amyloid-Targeting Drugs for the Treatment of Alzheimer Disease

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by cognitive impairment, neurobehavioral changes, and loss of functional ability. Current therapeutic options for AD are limited to medications that contribute to modest symptomatic improvement. The amyloid β (Aβ) peptide is central to the pathogenesis, so that immunotherapy targeting Aβ has been focused as a putative disease-modifying treatment for AD. In this review, I review the ongoing Aβ -directed immunotherapies, including aducanumab, which is the new AD medication since 2003 as well as the first disease-modifying treatment on the market approved by the Food and Drug Administration.

Validation of the Korean version of the Boston Autonomic Symptom Questionnaire

Background@#and Purpose The Boston Autonomic Symptom Questionnaire (BASQ) is a quantitative tool using a numeric rating scale to assess the symptoms of systemic dysautonomia, including cardiovascular, gastrointestinal, urinary, sudomotor, vasomotor, and sexual functions. The aim of this study was to validate the Korean version of the BASQ (KBASQ). @*Methods@#Prospectively enrolled subjects who submitted to autonomic function tests, including tests for cardiovagal, adrenergic, and sudomotor functions, also completed the KBASQ and the Korean version of the Orthostatic Grading Scale (KOGS), a validated questionnaire for assessing orthostatic symptoms.Twenty-eight subjects completed the KBASQ twice to assess test-retest reliability. We classified the subjects to dysautonomia or normal control group according to dysautonomic symptoms and the results of autonomic function tests. @*Results@#This study enrolled 225 subjects aged 54.0±18.1 years (mean±standard deviation), with a male/female ratio of 1/1.03. The internal validity of the KBASQ was excellent (Cronbach’s α=0.922), and that of each of its subscales ranged from excellent to acceptable (Cronbach’s α=0.709–0.952). The test-retest reliability was good, with correlation coefficients ranging from 0.354 to 0.917. The subcategory scores for the KBASQ were significantly higher in the dysautonomia group than in the normal control group. There were significant correlations among the items in the KBASQ and KOGS. There was also a significant correlation between KBASQ scores and the results of the autonomic function tests. @*Conclusions@#The internal validity and reliability of the KBASQ were good, indicating that it may be a useful screening tool for the systematic evaluation of autonomic symptoms in patients with dysautonomia.

Amyloid-Targeting Drugs for the Treatment of Alzheimer Disease

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by cognitive impairment, neurobehavioral changes, and loss of functional ability. Current therapeutic options for AD are limited to medications that contribute to modest symptomatic improvement. The amyloid β (Aβ) peptide is central to the pathogenesis, so that immunotherapy targeting Aβ has been focused as a putative disease-modifying treatment for AD. In this review, I review the ongoing Aβ -directed immunotherapies, including aducanumab, which is the new AD medication since 2003 as well as the first disease-modifying treatment on the market approved by the Food and Drug Administration.

Validation of the Korean version of the Boston Autonomic Symptom Questionnaire

Background@#and Purpose The Boston Autonomic Symptom Questionnaire (BASQ) is a quantitative tool using a numeric rating scale to assess the symptoms of systemic dysautonomia, including cardiovascular, gastrointestinal, urinary, sudomotor, vasomotor, and sexual functions. The aim of this study was to validate the Korean version of the BASQ (KBASQ). @*Methods@#Prospectively enrolled subjects who submitted to autonomic function tests, including tests for cardiovagal, adrenergic, and sudomotor functions, also completed the KBASQ and the Korean version of the Orthostatic Grading Scale (KOGS), a validated questionnaire for assessing orthostatic symptoms.Twenty-eight subjects completed the KBASQ twice to assess test-retest reliability. We classified the subjects to dysautonomia or normal control group according to dysautonomic symptoms and the results of autonomic function tests. @*Results@#This study enrolled 225 subjects aged 54.0±18.1 years (mean±standard deviation), with a male/female ratio of 1/1.03. The internal validity of the KBASQ was excellent (Cronbach’s α=0.922), and that of each of its subscales ranged from excellent to acceptable (Cronbach’s α=0.709–0.952). The test-retest reliability was good, with correlation coefficients ranging from 0.354 to 0.917. The subcategory scores for the KBASQ were significantly higher in the dysautonomia group than in the normal control group. There were significant correlations among the items in the KBASQ and KOGS. There was also a significant correlation between KBASQ scores and the results of the autonomic function tests. @*Conclusions@#The internal validity and reliability of the KBASQ were good, indicating that it may be a useful screening tool for the systematic evaluation of autonomic symptoms in patients with dysautonomia.

Home-Visiting Cognitive Intervention for the Community-Dwelling Elderly Living Alone

Methods@#HCI was conducted from April 2016 to November 2019. Every elder who lived alone and 2 matched partners met for 8 weeks once a week. The partners visited participants' home and did the HCI which composed of cognitive training and cognitive stimulation activities. The Mini-Mental State Examination-dementia screening (MMSE), Geriatric Depression Scale (GDS), the Korean version of instrumental activities of daily living (K-IADL), and the Social Support Scale (SSS) were evaluated before and after HCI to compare the effect of HCI. @*Results@#A total of 258 participants showed significant improvements in MMSE, GDS, K-IADL, and SSS. The MMSE and GDS scores were significantly improved after HCI in both the normal cognition (NC, n=210) and cognitive impairment (CI, n=48) groups. The cognitive effect of HCI for CI was higher than for NC. Among the NC, the magnitude of cognitive improvement was greater in the higher educated group (above 7 years) than in the other groups. @*Conclusions@#Active cognitive interventions could provide possible benefits to improve cognition, emotion, and functional abilities. Regular cognitive-care services like HCI are necessary to reduce dementia risk for the elderly who live alone in the community.

Clinical Utility of Seoul Neuropsychological Screening Battery-Core for Dementia Management Project in the Community

BACKGROUND: The increasing number of dementia patients is increasing the importance of identifying them and also those at a high risk of dementia. The early diagnosis and management of dementia can slow the progression of the disease and reduce the socioeconomic burden. For these purposes, the Local Dementia Centers established in all regions of Korea are working on the early detection of dementia using neuropsychological batteries. This study investigated the utility of the Seoul Neuropsychological Screening Battery-Core (SNSB-C) in a dementia management project performed in the local community. METHODS: This study was conducted in two parts. The first part used data from the Local Dementia Centers to investigate the accuracy of detecting cognitive impairment in SNSB-C compared with the Seoul Neuropsychological Screening Battery-Second Edition (SNSB-II). The second part of this study which data from hospital examined the accuracy of diagnosing dementia using SNSB-C. RESULTS: Data were collected from 508 participants at the Local Dementia Centers in Daejeon and 50 participants at a hospital. SNSB-C had a high sensitivity and specificity for detecting cognitive impairment, and also a high sensitivity, high specificity, and positive predictive value for diagnosing dementia. CONCLUSIONS: The sensitivity in diagnosing dementia was as high for SNSB-C as for SNSB-II while taking less time. SNSB-C could therefore be a good diagnostic evaluation tool for use in local dementia centers.

Characteristics of Cerebral Microbleeds

Cerebral microbleeds (CMBs) are increasingly recognized neuroimaging findings, occurring with cerebrovascular disease, dementia, and aging. CMBs are associated with subsequent hemorrhagic and ischemic stroke, and also with an increased risk of cognitive deterioration and dementia. They occur in the setting of impaired small vessel integrity due to hypertension or cerebral amyloid angiopathy. This review summarizes the concepts, cause or risk factors, histopathological mechanisms, and clinical consequences of CMBs.

Orthostatic Hypotension and Cognitive Function in Parkinson's Disease

BACKGROUND: Although orthostatic hypotension (OH) and cognitive impairment (CI) are common non-motor symptoms of Parkinson's disease (PD), the relationship between OH and CI remains to be clarified. This study was aimed to investigate the relationship between OH and CI in PD. METHODS: We recruited 192 patients who were diagnosed as PD based on the UK Brain Bank diagnostic criteria. The Hoehn & Yahr stages were ranged I to III and patients underwent extensive clinical evaluation, including brain magnetic resonance imaging (MRI) for cerebral white matter hyperintensity (WMH), tilt table test, the Korean version of Montreal Cognitive Assessments and the Korean version of Mini-Mental Status Examination in one month from the first clinic visit. The participants were divided into two groups according to the presence of OH (OH+ vs. OH−) and cognitive function (cognitive normal, CN vs. CI), respectively. RESULTS: Significant relationship between OH and cognitive function (p=0.04) was found in our patients. The patients with OH+ had higher risk of CI by 2.6 times than that of OH+ patients. Maximum heart rate change during tilt table test was correlated with cognitive function and white matter changes, whereas blood pressure change during tilt table test showed no correlation with those parameters. CONCLUSIONS: There was significant relationship between OH and CI in PD. Therefore, PD patients with either symptom may need periodic evaluation and proper management for OH and cognitive functions.

National Responsibility Policy for Dementia Care: Current and Future

With the world's fastest-growing aged population, dementia care has become a major public health concern in Korea, prompting the emergence of the policy of national responsibility for dementia care. Over the past one year since the introduction of the new policy, it has shown its strengths and weaknesses. Now is the time for us to put the current status of this policy into perspective in terms of the benefits for patients and caregivers as well as the cost-effectiveness in the management of dementia. In addition, we will suggest the optimal quality control system and education program for dementia care hospitals, highlighting the critical role of neurologists for the success of the national responsibility policy for dementia care.

Correlation of Driving-related Cognition and Cognitive Impairment in Drivers over the Age of 60

BACKGROUND: A rate of traffic accidents by elderly drivers increased by 70% between 2011 and 2015 in Korea. Elderly drivers with cognitive impairment are more susceptible to be involved traffic accidents than cognitively normal individuals. This study aimed to evaluate the correlation of driving-related cognition and cognitive impairment in drivers over the age of 60 using the standardized program developed by the Road Traffic Authority (RTA). METHODS: Current drivers older than 60 years were recruited for the study. All participants were tested using the Mini-Mental Status Examination (MMSE), Rey Complex Figure Test (RCFT)-copy, and Digit Symbol Substitution Test (DSST) for cognitive function assessments. The driving aptitude test (DAT) for the elderly developed by RTA consists of 4 different tasks including speed and distance driving tests (SD), visuospatial memory driving tests (VM), sustained attention driving tests (SA), and divided attention driving tests (DA). The participants were divided into two groups by their MMSE score (normal cognition, CN; cognitive impairment, CI). RESULTS: One hundred fourteen participants were enrolled in the study and 57 of them were assigned to the CI group. In comparison, drivers in CI showed worse scores at DSST, SD, VM, and DA than those in CN. DSST and DA were worsened with increasing age. DSST was the best predictive assessment to be the risk or caution grade in DAT. CONCLUSIONS: We could find a correlation between DAT and cognitive function in drivers over the age 60. These results could be used as the basis of investigating optimal tools for decreasing driving risks in the cognitive impaired elderly.

Postprandial Dizziness/Syncope Relieved by Alfa-Glucosidase Inhibitor: A Case Report / 대한평형의학회지

A 74-year-old man presented with positional vertigo and prandial dizziness and syncope. He had experienced episodes of frequent dizziness and loss of consciousness for several months. He underwent total gastrectomy with esophagojejunostomy and brown anastomosis 30 years ago. Thirteen years ago, subtotal colectomy with ileo-descending colostomy was done due to colon cancer. And he also had mitral valve replacement and maze operation due to severe mitral valve stenosis and atrial fibrillation. After cardiac operation, he has suffered from sudden dizziness with diaphoresis and chalky face, which usually occurs especially within 30 minutes from the onset of eating. Sometimes, this event was followed by several seconds of loss of consciousness, which caused recurrent events of falling. Neurological examination showed positional nystagmus compatible with benign paroxysmal positional vertigo arising from posterior semicircular canal of the right ear. The positional vertigo disappeared immediately after canalith repositioning maneuver. We tried to monitor vital signs and serum level of glucose during eating. Hyperglycemia (range, 210–466 mg/dL) was noted during eating, which was accompanied by postprandial and prandial hypotension, up to 60/40 mmHg. The patient was prescribed 100 mg of the alfa-glucosidase, acarbose to be taken half an hour before each meal. Eventually, the treatment with acarbose ameliorated the prandial dizziness and hypotension associated with hyperglycemia. Our patient suggests the acarbose could prevent postprandial dizziness and hypotension.

Gaze-Evoked and Perverted Head-Shaking Nystagmus in a Patient with Polycythemia Vera / 대한평형의학회지

Polycythemia vera (PV) is well known chronic myeloproliferative neoplasm, caused by clonal expansion of an abnormal hematopoietic stem cell. Patients with PV may present diverse neurologic symptoms including headache, dizziness or vertigo, tinnitus. However, the attention has not been directed to the neurootological findings in patients with PV. Here, we present a 71-year-old male patient with PV suffered from vertigo and headache. He demonstrated gaze-evoked nystagmus and perverted head shaking nystagmus. Transcranial Doppler showed decrement of blood flow velocity in posterior circulation. The patient's neuro-otologic findings were normalized as polychethemia and blood flow improved with repetitive phlebotomy and medications such as hydroxyurea and aspirin. Considering the neurological and hemodynamic findings in our patient, the mechanism of vertigo in PV could be explained by central vestibulopathy because of vascular insufficiency rather than peripheral vestibulopathy because of inner ear blood hyperviscosity.

Comparison of Somatic and Sudomotor Nerve Fibers in Type 2 Diabetes Mellitus

BACKGROUND AND PURPOSE: The objective of this study was to find a sensitive method for the early detection of diabetic polyneuropathy (DPN) and determine the relationship between the functions of somatic and autonomic small nerve fibers in DPN. METHODS: Patients with type 2 diabetes mellitus and DPN based on clinical symptoms, signs, intraepidermal nerve fiber density (IENFD), and findings in the quantitative sudomotor axon reflex test (QSART) were enrolled retrospectively. Neurological examinations and nerve conduction studies were performed on all patients. Heart-rate variability during deep breathing (DB ratio) and the Valsalva maneuver (Valsalva ratio) were used to quantify the cardiovagal function. Patients were divided into two groups: 1) normal nerve conduction, defined as small-fiber neuropathy (SFN) and 2) abnormal nerve conduction, defined as mixed-fiber neuropathy. RESULTS: In total, 82 patients were enrolled (age: 60.7±10.7 years, mean±SD). A decreased IENFD was the most frequent abnormality across all of the patients, followed by abnormalities of the QSART and cardiovagal function. A decreased IENFD was more sensitive than the QSART, DB ratio, and Valsalva ratio for detecting diabetic SFN. The DB ratio was significantly correlated with the duration of diabetes mellitus and clinical symptoms and signs. There was no correlation between the IENFD and the findings of the QSART for the distal leg. CONCLUSIONS: Measuring the IENFD was a more sensitive method than the QSART for the early detection of DPN. The degree of involvement of the somatic small nerve fibers and sudomotor nerve fibers was independent in DPN.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated with Membranous Glomerulonephritis and Tendinitis

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated progressive or relapsing demyelinating peripheral neuropathy. Other autoimmune diseases may be associated with CIDP. A 38-year-old man developed CIDP, which was subsequently associated with membranous glomerulonephritis (MGN) and tendinitis. He was treated with intravenous immunoglobulin, rituximab, and prednisone, which resulted in improvement of the clinical symptoms. This is a case report of CIDP associated with MGN and tendinitis.

Factors Affecting Cognitive Impairment and Depression in the Elderly Who Live Alone: Cases in Daejeon Metropolitan City

BACKGROUND AND PURPOSE: With the rapid increase in the number of elderly people in Korea, multiple socio-economic problems have emerged. In 2015, 6.4 million people accounting for about 13% of the total population in Korea were aged 65 years and over. As the elderly population continues to grow, the elderly who live alone are also increasing. They have potential risks in medical and neuropsychological aspects. The purpose of this study was to investigate the association between cognition and socio-environmental status in the elderly who live alone. METHODS: This study was conducted on 512 people who live alone (equivalent to 1% of the total elderly people) in Daejeon Metropolitan City between April and November 2015. Structured questionnaires were used to investigate the general characteristics, socio-economic status, physical status, and mood for participants. Simple tests using Mini-Mental Status Examination-Demetia Screening, Geriatric Depression Scale and Korean-instrumental activities of daily living were also performed. RESULTS: Among the 512 participants, 109 participants (21.3%) had cognitive impairment, and 128 participants (25.0%) had depression. The number of daily meals, frequency of meeting with family, and depression were independent risk factors for cognitive impairment. Factors including the duration of living alone, cognitive impairment, poor self-perceived health status, frequency of meeting with family and duration of education were considered an independent risk factor for depression. CONCLUSIONS: This study showed that the elderly who live alone are susceptible to cognitive impairment and depression, and factors including the number of daily meals, social contact, and self-perceived health status may affect cognition and depressive mood. Thus, physicians need to pay attention to management of major factors that may cause cognition impairment and depression in the elderly who live alone; in addition, they require ongoing community interest and support.

Treatment of Alzheimer's Disease with Repetitive Transcranial Magnetic Stimulation Combined with Cognitive Training: A Prospective, Randomized, Double-Blind, Placebo-Controlled Study

BACKGROUND AND PURPOSE: Repetitive transcranial magnetic stimulation (rTMS) has been examined as a potential treatment for many neurological disorders. High-frequency rTMS in particular improves cognitive functions such as verbal fluency and memory. This study explored the effect of rTMS combined with cognitive training (rTMS-COG) on patients with Alzheimer's disease (AD). METHODS: A prospective, randomized, double-blind, placebo-controlled study was performed with 27 AD patients (18 and 8 in the treatment and sham groups, respectively, and 1 drop-out). The participants were categorized into mild [Mini-Mental State Examination (MMSE) score=21-26] and moderate (MMSE score=18-20) AD groups. The rTMS protocols were configured for six cortical areas (both dorsolateral prefrontal and parietal somatosensory associated cortices and Broca's and Wernicke's areas; 10 Hz, 90-110% intensity, and 5 days/week for 6 weeks). Neuropsychological assessments were performed using the AD Assessment Scale-cognitive subscale (ADAS-cog), Clinical Global Impression of Change (CGIC), and MMSE before, immediately after, and 6 weeks after the end of rTMS-COG treatment. RESULTS: Data from 26 AD patients were analyzed in this study. There was no significant interactive effect of time between the groups. The ADAS-cog score in the treatment group was significantly improved compared to the sham group (4.28 and 5.39 in the treatment group vs. 1.75 and 2.88 in the sham group at immediately and 6 weeks after treatment, respectively). The MMSE and CGIC scores were also improved in the treatment group. Based on subgroup analysis, the effect of rTMS-COG was superior for the mild group compared to the total patients, especially in the domains of memory and language. CONCLUSIONS: The present results suggest that rTMS-COG represents a useful adjuvant therapy with cholinesterase inhibitors, particularly during the mild stage of AD. The effect of rTMS-COG was remarkable in the memory and language domains, which are severely affected by AD.

Isolated Tongue Paralysis as Presentation of Seropositive Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is characterized by a characteristic clinical presentation or positivity for the anti-aquaporin-4 antibody. Lesions involving the dorsal medulla are typical of NMOSD, but isolated tongue paralysis has not been reported previously. We report a rare case of NMOSD presenting with isolated tongue paralysis and swelling due to intrinsic tongue muscle paralysis, which was caused by bilateral involvement of the hypoglossal nuclei in the lower dorsal medulla oblongata.

Mild Cognitive Impairment

Mild cognitive impairment (MCI) is an intermediate cognitive state between normal aging and dementia. It has disparate features in activities of daily life which is interfered notably in dementia. Recently, there have been consistent reports of MCI which is predementia, however significant controversy exist. In this review, we make out the diagnostic criteria, classification, risk factor, prevalence, diagnostic test including neuroimaging and biomarkers, management, and prognosis of MCI. This review will cover current knowledge and future directions on MCI.

High Frequency Repetitive Transcranial Magnetic Stimulation for Freezing of Gait and Nonmotor Symptoms in Parkinson's Disease

BACKGROUND: To investigate the effect of high frequency repetitive transcranial magnetic stimulation (rTMS) on motor symptoms especially freezing of gait (FoG), and nonmotor symptoms in Parkinson disease (PD). METHODS: In this randomized, double-blind, sham-controlled study, fifteen PD patients were enrolled. For 10 days, 5 Hz, both motor cortices and dorsolateral prefrontal cortex (DLPFC) were stimulated. The motor symptoms and FoG were evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS) part III, FoG questionnaire (FoG-Q), variable parameters of FoG, and kinematic gait analysis. Nonmotor symptoms were evaluated by the Korean version of non-Motor Symptoms Scale (K-NMSS), 39-item Parkinson disease questionnaire (K-PDQ39), Mini-Mental Status examination (K-MMSE), Montreal Cognitive Assessment (K-MoCA), and Frontal assessment battery (FAB). RESULTS: Finally, 12 patients (real:8, sham:4) data were analyzed. FoG-Q and UPDRS part III were improved (p=0.002, 0.022) and variable parameters of FoG was improved after 10 days stimulation in real treatment group. In addition, their effects maintained until 6 weeks from the baseline. In nonmotor symptoms, K-NMSS and K-PDQ 39 were improved until 6 weeks in real treatment group (p=0.002, 0.002), however no changes were shown in cognitive function test. CONCLUSIONS: The high frequency rTMS was effective for FoG, in addition to motor and a few nonmotor symptoms in PD.

Reversible Cerebellar Leukoencephalopathy Associated With Oral Methotrexate

Methotrexate (MTX)-induced leukoencephalopathy is the most often reported leukoencephalopathy following intrathecal or intravenous administration. A 72-year-old woman developed leukoencephalopathy localized to the cerebellum after treatment with oral MTX at a dose of 15 mg/week for 3 years. She complained of subtle imbalance during walking and reported having fallen. Her symptoms improved after discontinuation of MTX, and the leukoencephalopathy resolved. This is therefore a case report of selective cerebellar reversible leukoencephalopathy associated with oral MTX.