A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer's Disease in a Real-World Setting.

Background: Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. Objective: To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. Methods: This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups. Results: In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). Conclusions: The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making.Trial Registration: ClinicalTrials.gov (NCT03448445).

Effects of GV1001 on Language Dysfunction in Patients With Moderate-to-Severe Alzheimer's Disease: Post Hoc Analysis of Severe Impairment Battery Subscales.

Background and Purpose: The efficacy and safety of GV1001 have been demonstrated in patients with moderate-to-severe Alzheimer's disease (AD). In this study, we aimed to further demonstrate the effectiveness of GV1001 using subscales of the Severe Impairment Battery (SIB), which is a validated measure to assess cognitive function in patients with moderate-to-severe AD. Methods: We performed a post hoc analysis of data from a 6 month, multicenter, phase 2, randomized, double-blind, placebo-controlled trial with GV1001 (ClinicalTrials.gov, NCT03184467). Patients were randomized to receive either GV1001 or a placebo for 24 weeks. In the current study, nine subscales of SIB-social interaction, memory, orientation, language, attention, praxis, visuospatial ability, construction, and orientation to name- were compared between the treatment (GV1001 1.12 mg) and placebo groups at weeks 12 and 24. The safety endpoints for these patients were also determined based on adverse events. Results: In addition to the considerable beneficial effect of GV1001 on the SIB total score, GV1001 1.12 mg showed the most significant effect on language function at 24 weeks compared to placebo in both the full analysis set (FAS) and per-protocol set (PPS) (p=0.017 and p=0.011, respectively). The rate of adverse events did not differ significantly between the 2 groups. Conclusions: Patients with moderate-to-severe AD receiving GV1001 had greater language benefits than those receiving placebo, as measured using the SIB language subscale.

Transferability of Alzheimer Disease Polygenic Risk Score Across Populations and Its Association With Alzheimer Disease-Related Phenotypes.

Importance: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry. Objective: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations. Design, Setting, and Participants: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases and 41 944 controls). This PRS was tested for an association with AD dementia and its related phenotypes in 1634 Korean individuals, who were recruited from 2013 to 2019. The association of a PRS based on a GWAS of a Japanese population (the National Center for Geriatrics and Gerontology; 3962 AD cases and 4074 controls) and a transancestry meta-analysis of European and Japanese GWASs was also evaluated. Data were analyzed from December 2020 to June 2021. Main Outcomes and Measures: Risk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid ß deposition (Aß). Results: A total of 1634 Korean patients (969 women [59.3%]), including 716 individuals (43.6%) with AD dementia, 222 (13.6%) with aMCI, and 699 (42.8%) cognitively unimpaired controls, were analyzed in this study. The mean (SD) age of the participants was 71.6 (9.0) years. Higher PRS was associated with a higher risk of AD dementia independent of APOE ɛ4 status in the Korean population (OR, 1.95; 95% CI, 1.40-2.72; P < .001). Furthermore, PRS was associated with aMCI, earlier symptom onset, and Aß deposition independent of APOE ɛ4 status. The PRS based on a transancestry meta-analysis of data sets comprising 2 distinct ancestries showed a slightly improved accuracy. Conclusions and Relevance: In this cohort study, a PRS derived from a European GWAS identified individuals at a high risk for AD dementia in the Korean population. These findings emphasize the transancestry transferability and clinical value of PRSs and suggest the importance of enriching diversity in genetic studies of AD.

A case of CSF1R-related leukoencephalopathy: serial neuroimaging and neuropsychological tests.

Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is one of the most common causes of adult-onset leukodystrophy and is caused by mutation of the CSF1R gene. Brain magnetic resonance imaging (MRI) findings in asymptomatic patients have not been well recognized. We report on the case of a patient with CSF1R-related leukoencephalopathy who had a novel missense variant of the CSF1R gene with a family history of early onset dementia. This is a representative case of CSF1R-related leukoencephalopathy, which shows the progression of brain MRI and cognitive decline from an asymptomatic state.

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 or 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.

Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer's disease already receiving donepezil: a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial.

BACKGROUND: Our previous studies showed that GV1001 has various protective effects against ß-amyloid and other stressors. Based on these findings, we hypothesized that GV1001 might have beneficial effects in patients with Alzheimer's disease (AD). METHODS: A phase 2, double-blind, parallel-group, placebo-controlled, 6-month randomized clinical trial was performed to evaluate the safety and efficacy of subcutaneously administered GV1001. Between September 2017 and September 2019, 13 centers in South Korea recruited participants. A total of 106 patients were screened, and 96 patients with moderate-to-severe AD were randomized 1:1:1 to the placebo (group 1, n = 31), GV1001 0.56 mg (group 2, n = 33), and 1.12 mg (group 3, n = 32) groups. GV1001 was administered every week for 4 weeks (4 times), followed by every 2 weeks until week 24 (10 times). The primary endpoint was the change in the Severe Impairment Battery (SIB) score from baseline to week 24. The key secondary efficacy endpoints were the change in the Clinical Dementia Rating Sum of Box (CDR-SOB), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, and Global Deterioration Scale scores. The safety endpoints were also assessed based on adverse events, laboratory test results, vital signs, and other observations related to safety. RESULTS: Group 3 showed less decrease in the SIB score at 12 and 24 weeks compared with group 1 (P < 0.05). These were not significantly observed in group 2. Among the secondary endpoints, only the NPI score showed significantly better improvement in group 2 than in group 3 at week 12; however, there were no other significant differences between the groups. Although the ADCS-ADL and CDR-SOB scores showed a pattern similar to SIB scores, a statistically significant result was not found. Adverse events were similar across all three groups. CONCLUSIONS: The results indicate that GV1001 1.12 mg met the primary endpoint of a statistically significant difference. GV1001 was well tolerated without safety concerns. This study warrants a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03184467 . Registered on June 12, 2017.

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

BACKGROUND AND PURPOSE: The elderly living alone feel lonelier and more isolated than do those live with others, and they are at higher risk for cognitive decline and depression. This study aimed to assess whether a home-visiting cognitive intervention (HCI) can have positive effects on cognitive improvement for the elderly who 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.

Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease.

BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.

Sex-Related Reserve Hypothesis in Alzheimer's Disease: Changes in Cortical Thickness with a Five-Year Longitudinal Follow-Up.

BACKGROUND: Sex effects on the progression of Alzheimer's disease (AD) have received less attention than other demographic factors, including onset age and education. OBJECTIVE: The aim of this study was to investigate whether sex affected cortical thinning in the disease progression of AD. METHODS: We prospectively recruited 36 patients with early-stage AD and 14 people with normal cognition. All subjects were assessed with magnetic resonance imaging at baseline, Year 1, Year 3, and Year 5. We performed cortical thickness analyses using surface-based morphometry on magnetic resonance imaging. RESULTS: Women with AD showed more rapid cortical thinning in the left dorsolateral frontal cortex, left superior temporal gyrus, bilateral temporo-parietal association cortices, bilateral anterior cingulate gyri, bilateral medial frontal cortices, and bilateral occipital cortices over 5 years than men with AD, even though there was no difference in cortical thickness at baseline. In contrast, there were no regions of significantly more rapid atrophy in men with AD. CONCLUSIONS: Our findings suggest that women deteriorate faster than men in the progression of AD.

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.

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.

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.

Effect of galantamine on attention in patients with Alzheimer's disease combined with cerebrovascular disease.

AIM: Patients with Alzheimer's disease (AD) and cerebrovascular disease (CVD) show greater attentional deficits compared with AD patients without CVD. The aim of the present study was to investigate the effect of galantamine on attention in AD patients with CVD. METHODS: In this open trial, 1512 patients with AD and CVD were recruited from 71 nationwide hospitals. The patients were given galantamine for 16 weeks. The primary outcome measure was the score on the Attention Questionnaire Scale (AQS), which measures the patients' attention in their daily lives. The secondary outcome measures were the scores on the Korean Mini-Mental State Examination, the Clinical Dementia Rating scale and the Global Deterioration Scale. Efficacy measures were calculated both at baseline and at the end of the treatment (week 16). RESULTS: The responders rate on the AQS (change of the AQS from baseline >0) was 60.6% in AD patients with CVD. At the end of the treatment, both the AQS (15.0 ± 5.7 vs 16.3 ± 5.8, P < 0.001) and the Korean Mini-Mental State Examination scores (17.8 ± 4.8 vs 18.1 ± 5.1, P < 0.001) showed a significant improvement relative to the baseline performance. The Clinical Dementia Rating (1.25 ± 0.59 vs 1.22 ± 0.63 P = 0.025) and Global Deterioration Scale (3.82 ± 0.94 vs 3.76 ± 0.96, P = 0.002) scores also showed a significant decrease at the end of the treatment. CONCLUSIONS: Galantamine is effective in improving attention in the daily lives of AD patients with CVD. Geriatr Gerontol Int 2017; 17: 1661-1668.

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.

Anti-aquaporin-4 antibody-positive dorsal midbrain syndrome.

Neuromyelitis optica spectrum disorders (NMOSD) can cause various ocular motor disorders in addition to optic neuritis. Ocular motor findings associated with NMOSD include spontaneous vertical and gaze-evoked nystagmus, wall-eyed bilateral internuclear ophthalmoplegia, and trochlear nerve palsy. The association between dorsal midbrain syndrome and anti-aquaporin-4 antibody seropositivity has not been reported. Here, we report a patient displaying typical dorsal midbrain syndrome and anti-aquaporin-4 antibody seropositivity.

Transient Positive Horizontal Head Impulse Test in Pregabalin Intoxication.

Head impulse test (HIT) is helpful to understanding high-frequency vestibulo-ocular reflex in patients with dizziness and imbalance. There are some reports on abnormal HITs in cerebellar disorder. To our knowledge, there was no report of transient bilateral positive head impulse related to antiepileptic drugs. A 65-year-old woman developed dizziness and imbalance after treatment with pregabalin for pain control of radiation cystitis. Neurological examination exhibited positive bilateral HIT results, in addition to ataxia and gaze-evoked rebound nystagmus. Pregabalin intoxication can evoke transient positive horizontal head impulse test as another indicator of cerebellar dysfunction.

10-minute delayed recall from the modified mini-mental state test predicts Alzheimer's disease pathology.

We compared the sensitivity and specificity of two delayed recall scores from the Modified Mini-Mental State (3MS) test with consensus clinical diagnosis to differentiate cognitive impairment due to Alzheimer's disease (AD) versus non-AD pathologies. At a memory disorders clinic, 117 cognitively impaired patients were administered a baseline 3MS test and received a contemporaneous consensus clinical diagnosis. Their brains were examined after death about 5 years later. Using logistic regression with forward selection to predict pathologically defined AD versus non-AD, 10-min delayed recall entered first (p = 0.001), followed by clinical diagnosis (p = 0.02); 1-min delayed recall did not enter. 10-min delayed recall scores ≤4 (score range = 0-9) were 87% sensitive and 47% specific in predicting AD pathology; consensus clinical diagnosis was 82% sensitive and 45% specific. For the 57 patients whose initial Mini-Mental State Examination scores were ≥19 (the median), 3MS 10-min delayed recall scores ≤4 showed some loss of sensitivity (80%) but a substantial gain in specificity (77%). In conclusion, 10-min delayed recall score on the brief 3MS test distinguished between AD versus non-AD pathology about 5 years before death at least as well as consensus clinical diagnosis that requires much more comprehensive information and complex deliberation.