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Background: Preclinical studies in transgenic models of Alzheimer’s disease (AD) suggest that DHP1401 has neuroprotective and memory-enhancing effects. Objective: To evaluate the efficacy and safety of DHP1401 in AD patients treated with donepezil Methods: Methods: In a double-blind study, patients with mild-to-moderate AD were randomized (1:1:1) to receive a twice daily total dose of 500 mg or 1000 mg DHP1401 or placebo for 24 weeks. Tolerability and safety were monitored at baseline and weeks 12 and 24. Results: total of 180 patients were randomized to Active 1 (500 mg: n = 62), Active 2 (1000 mg: n = 53), and control groups (n = 65) in 16 sites in Korea. There was no significant difference in the Alzheimer’s Disease Assessment Scale (ADAS-cog) score, the primary efficacy endpoint, from baseline. However, in the subgroup with mild AD patients (MMSE, 20–26) who received the high dose of DHP1401 and the group that received donepezil 5 mg, the ADAS-cog scores improved. MMSE and K-TMT-e type B were significant in both active groups at week 24. The most frequently observed symptom was dizziness (2.78%), and the most commonly observed reactions were related to metabolism and nutrition disorders (5.00%). No remarkable adverse events were observed for 24 weeks. Conclusion: Although the effectiveness of DHP1401 was not proved to be superior as the primary efficacy endpoint, the secondary endpoints, MMSE and K-TMT-e type B, showed significant beneficial effects. Also, the subgroups showed that ADAS-cog scores significantly were improved. DHP1401 could be proven beneficial for the AD treatment by further clinical trials.

Introduction: Alzheimer's disease dementia (ADD) has now become a crucial concern for modern society as a result of increased life expectancy. However, it is often difficult for a majority of the population to afford expensive medical imaging tests for accurate diagnosis. As a solution, quantitative analysis of electroencephalography (EEG) that aids in a sufficient description of brain activities can be employed as a cost-effective, safe and objective diagnostic tool. In the presented research, we employed diverse QEEG features at both channel- and source-level to enhance the robustness of our previously established artificial intelligence (AI) model that distinguishes non-ADD (NADD) data from ADD data.Method 594 NADD and 137 ADD subjects’ EEG data were employed for the presented research. artifact-free data were obtained through the application of independent component analysis (ICA) and bad epoch rejection. Absolute and relative power spectra at 19 channels were first computed, followed by the estimation of source-level power spectra through standardized low-resolution brain electromagnetic tomography (s-LORETA). Through further feature engineering, functional brain networks were also obtained. The established channel-level features were transformed into images that spatially allocate absolute and relative spectral powers, which were utilized for the training of deep neural network structures. Moreover, source-level spectral powers and functional brain networks were adopted for the training of a tree-based machine learning algorithm. Prediction probabilities of the established classification models were ensembled through the voting method and returned the final classification result.Results The best classification accuracies of the absolute and relative channel-level spectral power image-based deep neural network models were 85.3% and 86.5% respectively. The tree-based model that has been trained with source-level features resulted in an accuracy of 87.7%. The accuracy of the ensemble model was 88.5%, which demonstrates the compensatory interaction among the models.Conclusions The promising classification results indicate the potential behind EEG-AI models for the analysis of neurodegenerative disorders. Through continuous analysis of several independent QEEG features of varying aspects, we may soon be able to more aptly diagnose several neurological disorders.

Background Individuals with the behavioral variant of frontotemporal dementia (bvFTD) exhibit various levels of abulia, disinhibition, impaired judgment, and decline in executive function. Empirical evidence has shown that individuals with bvFTD also often exhibit difficulty using honorific speech, which expresses respect to another party or addressee. Objective To analyze differences in the ability to use honorific speech among individuals with bvFTD, individuals with dementia of the Alzheimer type (AD dementia), and individuals with normal cognition (NC). Method A total of 53 native Korean speakers (13 bvFTD, 20 AD dementia, and 20 NC) completed an experimental honorific speech task (HST) that involved both expressive and receptive tasks. We analyzed the number of correct responses and error patterns separately for an expressive task and for a receptive task. Results The bvFTD group had significantly fewer correct responses on the HST compared with the AD dementia and NC groups. The bvFTD group exhibited more misjudgment errors in identifying nonhonorific speech as honorific speech in the expressive task, and significantly longer response times in the receptive task, than the AD dementia and NC groups. Significant associations were identified between HST scores and cortical atrophy in the temporal and frontotemporal lobes. Conclusion A decline in the ability to use honorific speech may be a diagnosable behavioral and psychiatric symptom for bvFTD in Korean-speaking individuals. This decline in individuals with bvFTD could be attributed to multiple factors, including social manners (politeness) and impaired social language use ability (pragmatics).

BACKGROUND AND PURPOSE Reportedly 30-50% of patients being treated for chronic illnesses do not adhere to their medication regimen. We assessed the impact of a nurse-led education program for caregivers of Korean de novo Alzheimer's disease patients who had newly been prescribed donepezil. METHODS This multicenter study analyzed 93 participants in a caregiver education group and 92 participants in a caregiver no-education group. At every visit up to the end of the study (1 year), caregivers in the education group were given educational brochures regarding Alzheimer's disease and the efficacy and adverse events of donepezil treatment. The primary endpoint was the discontinuation rate of donepezil treatment during the 1-year observation period. The secondary endpoints included the effect of education on compliance with donepezil treatment assessed at each visit using a clinician rating scale (CRS) and visual analog scale (VAS), and changes from baseline in cognitive assessment tests. RESULTS The donepezil discontinuation rates at 1 year were 5.38% (5/93) and 6.52% (6/92) in the caregiver education and no-education groups, respectively (p=0.742). No significant between-group differences in donepezil compliance rates on the CRS and VAS were observed, but significant changes were observed in some cognitive tests from baseline to the end of the study. CONCLUSIONS Caregiver education had no significant effect on treatment discontinuation, but this may have been due to the low severity of cognitive impairment among the included population at baseline. In addition, the low discontinuation rates meant that no significant difference in treatment compliance was observed.

BACKGROUND AND PURPOSE The rate of donepezil discontinuation and the underlying reasons for discontinuation in Asian patients with Alzheimer's disease (AD) are currently unknown. We aimed to determine the treatment discontinuation rates in AD patients who had newly been prescribed donepezil in routine clinical practice in Asia. METHODS This 1-year observational study involved 38 institutions in seven Asian countries, and it evaluated 398 participants aged 50-90 years with a diagnosis of probable AD and on newly prescribed donepezil monotherapy. The primary endpoint was the rate of donepezil discontinuation over 1 year. Secondary endpoints included the reason for discontinuation, treatment duration, changes in cognitive function over the 1-year study period, and compliance as assessed using a clinician rating scale (CRS) and visual analog scale (VAS). RESULTS Donepezil was discontinued in 83 (20.9%) patients, most commonly due to an adverse event (43.4%). The mean treatment duration was 103.67 days in patients who discontinued. Among patients whose cognitive function was assessed at baseline and 1 year, there were no significant changes in scores on the Mini-Mental State Examination, Montreal Cognitive Assessment, and Trail-Making Test-Black and White scores, whereas the Clinical Dementia Rating score increased significantly (p

Background: Frontotemporal dementia (FTD) syndrome is a genetically heterogeneous group of diseases. Pathogenic variants in the chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) genes are mainly associated with genetic FTD in Caucasian populations. Objective: To understand the genetic background of Korean patients with FTD syndrome. Methods: We searched for pathogenic variants of 52 genes related to FTD, amyotrophic lateral sclerosis, familial Alzheimer’s disease, and other dementias, and hexanucleotide repeats of the C9orf72 gene in 72 Korean patients with FTD using whole exome sequencing and the repeat-primed polymerase chain reaction, respectively. Results: One likely pathogenic variant, p.G706R of MAPT, in a patient with behavioral variant FTD (bvFTD) and 13 variants of uncertain significance (VUSs) in nine patients with FTD were identified. Of these VUSs, M232R of the PRNP gene, whose role in pathogenicity is controversial, was also found in two patients with bvFTD. Conclusions: These results indicate that known pathogenic variants of the three main FTD genes (MAPT, GRN, and C9orf72) in Western countries are rare in Korean FTD patients.

We investigated whether telomere length (TL) reflecting physical rather than chronological aging is associated with disease progression in the different cognitive stages of Alzheimer's disease (AD). Study participants included 89 subjects with amyloid pathology (A+), determined through amyloid PET or cerebrospinal fluid analysis, including 26 cognitively unimpaired (CU A+) individuals, 28 subjects with mild cognitive impairment (MCI A+), and 35 subjects with AD dementia (ADD A+). As controls, 104 CU A- individuals were selected. The participants were evaluated annually over two years from baseline. Compared to the highest TL quartile group of MCI A+ participants, the lowest TL quartile group yielded 2-year differences of -9.438 (95% confidence interval [CI] = -14.567 ~ -4.309), -26.708 (-41.576 ~ -11.839), 3.198 (1.323 ~ 5.056), and 2.549 (0.527 ~ 4.571) on the Mini-Mental State Examination, Consortium to Establish a Registry for AD, Clinical Dementia Rating-Sum of Boxes, and Blessed Dementia Scale-Activities of Daily Living, respectively. With this group, the lowest TL quartile group had a significantly greater probability of progressing to ADD than the highest TL quartile group (hazard ratio = 13.16, 95% CI = 1.11 ~ 156.61). Telomere shortening may be associated with rapid cognitive decline and conversion to dementia in MCI A+.

Background Neuropsychological tests (NPTs) are important tools for informing diagnoses of cognitive impairment (CI). However, interpreting NPTs requires specialists and is thus time-consuming. To streamline the application of NPTs in clinical settings, we developed and evaluated the accuracy of a machine learning algorithm using multi-center NPT data. Methods Multi-center data were obtained from 14,926 formal neuropsychological assessments (Seoul Neuropsychological Screening Battery), which were classified into normal cognition (NC), mild cognitive impairment (MCI) and Alzheimer’s disease dementia (ADD). We trained a machine learning model with artificial neural network algorithm using TensorFlow (https://www.tensorflow.org) to distinguish cognitive state with the 46-variable data and measured prediction accuracies from 10 randomly selected datasets. The features of the NPT were listed in order of their contribution to the outcome using Recursive Feature Elimination. Results The ten times mean accuracies of identifying CI (MCI and ADD) achieved by 96.66 ± 0.52% of the balanced dataset and 97.23 ± 0.32% of the clinic-based dataset, and the accuracies for predicting cognitive states (NC, MCI or ADD) were 95.49 ± 0.53 and 96.34 ± 1.03%. The sensitivity to the detection CI and MCI in the balanced dataset were 96.0 and 96.0%, and the specificity were 96.8 and 97.4%, respectively. The ‘time orientation’ and ‘3-word recall’ score of MMSE were highly ranked features in predicting CI and cognitive state. The twelve features reduced from 46 variable of NPTs with age and education had contributed to more than 90% accuracy in predicting cognitive impairment. Conclusions The machine learning algorithm for NPTs has suggested potential use as a reference in differentiating cognitive impairment in the clinical setting.

Background and Purpose: Cerebral small vessel disease is characterized by progressive cerebral white matter changes (WMCs). This study aimed to compare the effects of cilostazol and aspirin on changes in WMC volume in patients with cerebral small vessel disease. Methods: In a multicenter, double-blind, randomized controlled trial, participants with moderate or severe WMCs and at least one lacunar infarction detected on brain magnetic resonance imaging were randomly assigned to the cilostazol and aspirin groups in a 1:1 ratio. Cilostazol slow release (200 mg) or aspirin (100 mg) capsules were administered once daily for 2 years. The primary outcome was the change in WMC volume on magnetic resonance images from baseline to 2 years. Secondary imaging outcomes include changes in the number of lacunes or cerebral microbleeds, fractional anisotropy, and mean diffusivity on diffusion tensor images, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all ischemic vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability. Results: Between July 2013 and August 2016, 256 participants were randomly assigned to the cilostazol (n=127) and aspirin (n=129) groups. Over 2 years, the percentage of WMC volume to total WM volume and the percentage of WMC volume to intracranial volume increased in both groups, but neither analysis showed significant differences between the groups. The peak height of the mean diffusivity histogram in normal-appearing WMs was significantly reduced in the aspirin group compared with the cilostazol group. Cilostazol significantly reduced the risk of ischemic vascular event compared with aspirin (0.5 versus 4.5 cases per 100 person-years; hazard ratio, 0.11 [95% CI, 0.02–0.89]). Conclusions: There was no significant difference between the effects of cilostazol and aspirin on WMC progression in patients with cerebral small vessel disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01932203.

ImportancePolygenic 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.ObjectiveTo 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 ParticipantsThis 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 MeasuresRisk of AD dementia, amnestic mild cognitive impairment (aMCI), earlier symptom onset, and amyloid β deposition (Aβ).ResultsA 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 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 RelevanceIn 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.

In this study we aimed to find the association between neuropsychological performance and body mass index (BMI) in patients with mild cognitive impairment (MCI). In addition, we investigated the effects of the apolipoprotein E (APOE) genotype in the relationship between the BMI and cognition in MCI.We enrolled a cohort of 3,038 subjects with MCI aged 65-90 from the Clinical Research Center for Dementia of South Korea and a dementia cohort of the Ewha Womans University Mokdong Hospital. MCI patients were classified into three subgroups according to the Asian standard of BMI. We compared cognitive performances between groups by one-way analysis of variance. To investigate the effects of the APOE genotype, we used multivariate linear regression models after adjusting for possible confounders.Even though normal BMI groups were younger, had more females, and had less comorbidities, the higher BMI groups had better cognitive functions. Among subjects with APOE ε4 carriers, there was a positive relationship between the BMI and the memory task alone.Our findings suggested that higher BMI in patients with MCI were associated with better cognitive performance. The effects of the APOE ε4 genotype in the associations between BMI and cognition were distinguishing. Therefore, according to physical status, APOE ε4 genotype-specific strategies in the assessments and treatments may be necessary in elderly patients with MCI.

The relationship between sleep parameters and longitudinal shortening of telomere length is unclear. This study aimed to investigate the relationship between sleep parameters and the shortening of leukocyte telomere length (LTL) over a year.Among the participants in the validation cohort of the Korea Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, participants who measured both baseline and follow-up (two years later) of LTL were analyzed. They were dichotomized according to the degree of LTL attrition over two years. Clinical characteristics were compared between the faster and slower LTL shortening groups (cut-off points: -0.710 kbp,A total of 238 participants, aged 55-88 years, were included. Participants with faster LTL shortening had a shorter duration of sleep (Poor sleep quality, specifically short sleep duration, long sleep latency, and low sleep efficiency were associated with faster longitudinal shortening of LTL.

To develop and validate the Distress Screening Tool (DST) for child and adolescent cancer survivors. In part 1, items of the DST were generated through literature search and group interviews. Initially, the DST was tested on pediatric cancer survivors and their caregivers. In part 2, the modified version of the DST was retested with a different set of participants. Lastly, the psychometric properties and cutoff scores of the DST were evaluated on a separate set of survivors and caregivers. In part 1, six items of the DST self- and caregiver-report versions were generated. The initial 6 DST items of both versions showed acceptable internal consistency, but low inter-item correlation. Following the item modification, both versions of the DST showed improved inter-item correlation. In part 2, the modified DST had acceptable internal consistency and convergent validity, with acceptable psychometric properties. Cutoff scores were also generated. The DST could be a useful tool for pediatric cancer survivors.

Purpose: The objective of this study was to report the incidence of falls in hospitals and analyze the risk factors for falls. Methods: This study used data on 1,216 patients who experienced falls from 2015 to 2017 during their hospitalization. The data was collected from the falls incident reports ...

Background Telomeres are repetitive DNA sequences of TTAGGG at the ends of chromosomes. Many studies have shown that telomere shortening is associated with aging-related diseases, such as cardiovascular diseases, hypertension, diabetes, cancer, and various neurodegenerative diseases, including Alzheimer's disease, vascular dementia, Parkinson's disease, and dementia with Lewy bodies. However, changes in telomere length (TL) in patients with frontotemporal dementia (FTD) syndrome are unclear. Accordingly, in this study, we assessed TL in blood samples from patients with FTD syndrome. Methods Absolute TL was measured in peripheral blood leukocytes from 53 patients with FTD syndromes (25 with behavioral variant FTD, 19 with semantic variant primary progressive aphasia [PPA], six with nonfluent/agrammatic variant PPA, and three with amyotrophic lateral sclerosis [ALS] plus) and 28 cognitively unimpaired (CU) controls using terminal restriction fragment analysis. Results TL was significantly longer in the FTD group than in the CU group. All FTD subtypes had significantly longer TL than controls. There were no significant differences in TL among FTD syndromes. No significant correlations were found between TL and demographic factors in the FTD group. Conclusions Longer telomeres were associated with FTD syndrome, consistent with a recent report demonstrating that longer telomeres are related to ALS. Therefore, our results may support a shared biology between FTD and ALS. More studies with larger sample sizes are needed.

Background Spirituality is a fundamental, intrinsic aspect of human beings and should be a core component of quality palliative care. There is an urgent need to train hospice palliative care teams (HPCTs) to enhance their ability to provide spiritual care. This study aimed to develop and evaluate a meaning-centered, spiritual care training program (McSCTP) for HPCTs (McSCTP-HPCTs). Methods The modules’ content was informed by Viktor Frankl’s meaning-centered logotherapy with its emphasis on spiritual resources, as well as the spiritual care model of the Interprofessional Spiritual Care Education Curriculum (ISPEC). Following development, we conducted a pilot test with four nurses. We used the results to inform the final program, which we tested in an intervention involving 13 members of HPCTs. We took measurements using self-administered questionnaires at three points before and after the intervention. Using descriptive statistics, the Mann-Whitney U test, and the Kruskal-Wallis test, we analyzed the participants’ demographic and career-related characteristics, as well as the degree of variance between three outcome variables: compassion fatigue (CF), spiritual care competencies (SCCs), and spiritual care therapeutics (SCT). Results We divided the McSCTP-HPCTs into five modules. Module I: The HPCTs’ SCC evaluation, understanding the major concepts of spiritual care and logotherapy; Modules II-IV: Meaning-centered interventions (MCIs) related to spiritual needs (existential, relational, and transcendental/religious); Module V: The process of meaning-centered spiritual care. The preliminary evaluation revealed significant differences in all three outcome variables at the posttest point (CF, p = 0.037; SCCs, p = 0.005; SCT, p = 0.002). At the four-week follow-up test point, we only found statistical significance with the SCCs (p = 0.006). Conclusions The McSCTP-HPCTs is suitable for use in clinical settings and provides evidence for assessing the SCCs of HPCTs.

Background Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on β-amyloid (Aβ) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans. Methods Among 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n = 128 with overlapping CSF and Aβ-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. Aβ42, Aβ40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Aβ-PET, was evaluated. Results Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the Aβ-PET status in a subgroup without CSF (n = 143), and then when we applied CSF biomarker cutoffs determined based on the Aβ-PET status, the CSF biomarkers (cutoffs of 642.1 pg/mL for Aβ42, 0.060 for Aβ42/Aβ40, 0.315 for t-tau/Aβ42, and 0.051 for p-tau/Aβ42, respectively) showed good agreement with Aβ-PET (overall AUC ranges of 0.840–0.898). Use of the Aβ-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (Aβ42, Aβ42/Aβ40, t-tau/Aβ42, and p-tau/Aβ42) with overall AUC ranges of 0.876–0.952. During follow-up, participants with AD-like CSF signature determined by Aβ-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature. Conclusion CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Aβ-PET in Koreans. The Korean-specific Aβ-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.

We investigated the survival time of each clinical syndrome of frontotemporal dementia (FTD) and the impacts of behavioral and motor features on survival of FTD. A total of 216 patients with FTD [82 behavioral variant FTD (bvFTD), 78 semantic variant primary progressive aphasia (svPPA), 43 non-fluent/agrammatic variant PPA (nfvPPA), 13 FTD-motor neuron disease (MND)] were enrolled from 16 centers across Korea. Behaviors and parkinsonism were assessed using the Frontal Behavioral Inventory and Unified Parkinson’s Disease Rating Scale Part III, respectively. The Kaplan–Meier method was used for the survival analysis and the Cox proportional hazards model was applied for analysis of the effect of behavioral and motor symptoms on survival, after controlling vascular risk factors and cancer. An overall median survival of FTD was 12.1 years. The survival time from onset was shortest for FTD-MND and longest for svPPA. The median survival time of patients with bvFTD was unavailable but likely comparable to that of patients with nfvPPA. In the bvFTD group, negative behavioral symptoms and akinetic rigidity were significantly associated with survival. In the nfvPPA group, the presence of dysarthria had a negative impact on survival. These findings provide useful information to clinicians planning for care.

Background: Universal Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability could improve diagnostic accuracy and help predict disease progression. To determine the diagnostic cutoffs of CSF AD biomarkers measured with three immunoassay platforms, including fully automated Lumipulse based on b-amyloid (Ab) positron emission tomography (PET) status, to determine diagnostic utility and clinical predictability.Methods: Three hundred thirty-one Korean participants were enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD: 71 cognitively normal (CN), 99 with subjective cognitive decline (SCD), 89 with mild cognitive impairment (MCI), and 72 with AD. Among these 331 participants, 139 (29, 58, 29, and 23 from each group, respectively) provided CSF and 271 underwent baseline amyloid PET. Three annual cognitive and neuropsychiatric function tests were conducted. Ab42, Ab40, total-tau and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Ab-PET, were evaluated.Results: Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN > SCD > MCI > AD. Biomarker levels among immunoassays were strongly intercorrelated, and using the cutoffs for Ab-PET status with maximal AD diagnostic accuracy (n = 215), the levels showed excellent agreement with Ab-PET. Use of Ab-PET-based cutoffs for CSF biomarkers showed excellent diagnostic discrimination between AD and CN (Ab42, Ab42/Ab40, t-tau/Ab42 and p-tau/Ab42) with overall AUC ranges to discriminate AD and CN (0.876–0.952). During follow-up, participants with AD-like CSF signature determined by Ab-PET-based cutoffs from Lumipulse showed rapid progression of clinical scores, after adjustment for potential confounders, compared with those with a normal CSF signature.Conclusion: CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Ab-PET. Ab-PET-based CSF biomarker cutoffs measured by immunoassays, including the Lumipulse, strongly predict progression of cognitive decline. The clinical utility of CSF biomarkers from fully automated immunoassay platforms should be evaluated in larger, more diverse cohorts.

Individuals with the behavioral variant of frontotemporal dementia (bvFTD) exhibit various levels of abulia, disinhibition, impaired judgment, and decline in executive function. Empirical evidence has shown that individuals with bvFTD also often exhibit difficulty using honorific speech, which expresses respect to another party or addressee.To analyze differences in the ability to use honorific speech among individuals with bvFTD, individuals with dementia of the Alzheimer type (AD dementia), and individuals with normal cognition (NC).A total of 53 native Korean speakers (13 bvFTD, 20 AD dementia, and 20 NC) completed an experimental honorific speech task (HST) that involved both expressive and receptive tasks. We analyzed the number of correct responses and error patterns separately for an expressive task and for a receptive task.The bvFTD group had significantly fewer correct responses on the HST compared with the AD dementia and NC groups. The bvFTD group exhibited more misjudgment errors in identifying nonhonorific speech as honorific speech in the expressive task, and significantly longer response times in the receptive task, than the AD dementia and NC groups. Significant associations were identified between HST scores and cortical atrophy in the temporal and frontotemporal lobes.A decline in the ability to use honorific speech may be a diagnosable behavioral and psychiatric symptom for bvFTD in Korean-speaking individuals. This decline in individuals with bvFTD could be attributed to multiple factors, including social manners (politeness) and impaired social language use ability (pragmatics).

Background Although amyloid PET of typical Alzheimer’s disease (AD) shows diffuse ß-amyloid (Aß) deposition, some patients show focal deposition. The clinical significance of this focal Aß is not well understood. We examined the clinical significance of focal Aß deposition in terms of cognition as well as Aß and tau cerebrospinal fluid (CSF) levels. We further evaluated the order of Aß accumulation by visual assessment. Methods We included 310 subjects (125 cognitively unimpaired, 125 mild cognitive impairment, and 60 AD dementia) from 9 referral centers. All patients underwent neuropsychological tests and 18F-flutemetamol (FMM) PET. Seventy-seven patients underwent CSF analysis. Each FMM scan was visually assessed in 10 regions (frontal, precuneus and posterior cingulate, lateral temporal, parietal, and striatum of each hemisphere) and was classified into three groups: No-FMM, Focal-FMM (FMM uptake in 1–9 regions), and Diffuse-FMM (FMM uptake in all 10 regions). Results 53/310 (17.1%) subjects were classified as Focal-FMM. The cognitive level of the Focal-FMM group was better than that of Diffuse-FMM group and worse than that of No-FMM group. Among the Focal-FMM group, those who had FMM uptake to a larger extent or in the striatum had worse cognitive levels. Compared to the Diffuse-FMM group, the Focal-FMM group had a less AD-like CSF profile (increased Aß42 and decreased t-tau, t-tau/Aß42). Among the Focal-FMM group, Aß deposition was most frequently observed in the frontal (62.3%) and least frequently observed in the striatum (43.4%) and temporal (39.6%) regions. Conclusions We suggest that focal Aß deposition is an intermediate stage between no Aß and diffuse Aß deposition. Furthermore, among patients with focal Aß deposition, those who have Aß to a larger extent and striatal involvement show clinical features close to diffuse Aß deposition. Further longitudinal studies are needed to evaluate the disease progression of patients with focal Aß deposition.

There is a lack of research on the effects of physical activity (PA) on the progression of Alzheimer's disease (AD).We investigated whether PA is associated with progression of dementia and mortality in AD.In the present study, 934 patients with mild-to-moderate AD were included. PA was evaluated using a questionnaire written by the caregiver. The outcome measures were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), a global composite score of neuropsychological subtests, and mortality. They were evaluated annually and received a maximum of three follow-up examinations.Between-group differences compared with the no PA group in the change of CDR-SB scores were -0.431 (95% CI = -0.824∼-0.039; p = 0.031) for the moderate PA group (150-750 minutes per week of moderate intensity PA), and -1.148 (-1.656∼-0.639; p 0.001) for the high PA group (750 minutes per week). As PA increased, there was a significant trend to slow the rate of increase in the CDR-SB, S-IADL, and CGA-NPI scores. The patients with ≥150 minutes per week for each of non-recreational and recreational PAs had a lower risk of mortality compared to those with150 minutes per week for each of the PAs (hazard ratio 0.22, 95% CI = 0.05∼0.88; p = 0.033).More PA is associated with slower progression of dementia severity, functional decline, and abnormal behavior, and with a lower risk of mortality in AD.

BACKGROUND Balance impairments are common in patients with Alzheimer's disease (AD) dementia. OBJECTIVE We sought to determine the stage along the AD spectrum during which balance impairments appear and identify factors associated with a decline in balance function. METHODS Our cross-sectional study included 295 participants; 71 were cognitively normal (CN), 96 reported subjective cognitive decline (SCD), 72 had amnestic mild cognitive impairment (MCI), and 56 had AD dementia. The balance and mobility function was assessed using the Timed Up and Go test (TUG) and the One-Leg Standing Test (OLST). RESULTS Participants in the MCI and AD dementia groups were older than those in the cognitively normal and SCD groups. TUG and OLST test scores were linearly correlated with Mini-Mental Status Examination-Korean Version score (MMSE-KC). TUG score increased with greater AD spectrum severity (all p

BACKGROUND AND PURPOSE Visual assessment of medial temporal-lobe atrophy (MTA) has been quick, reliable, and easy to apply in routine clinical practice. However, one of the limitations in visual assessments of MTA is the lack of widely accepted age-adjusted norms and cutoff scores for MTA for a diagnosis of Alzheimer's disease (AD). This study aimed to determine the optimal cutoff score on a T1-weighted axial MTA Visual Rating Scale (VRS) for differentiating patients with AD from cognitively normal elderly people. METHODS The 3,430 recruited subjects comprising 1,427 with no cognitive impairment (NC) and 2003 AD patients were divided into age ranges of 50-59, 60-69, 70-79, and 80-89 years. Of these, 446 participants (218 in the NC group and 228 in the AD group) were chosen by random sampling for inclusion in this study. Each decade age group included 57 individuals, with the exception of 47 subjects being included in the 80- to 89-year NC group. The scores on the T1-weighted axial MTA VRS were graded by two neurologists. The cutoff values were evaluated from the area under the receiver operating characteristic curve. RESULTS The optimal axial MTA VRS cutoff score from discriminating AD from NC increased with age: it was ≥as ≥1, ≥2, and ≥3 in subjects aged 50-59, 60-69, 70-79, and 80-89 years, respectively (all p

Background We investigated the prevalence of parkinsonism in frontotemporal dementia (FTD) subtypes and the cognitive and behavioral differences between FTD with and without parkinsonism in a well-structured, prospective cohort. Methods One hundred and ninety-one FTD patients were enrolled and all patients underwent comprehensive neurological evaluations, neuropsychological tests, and the Unified Parkinson's Disease Rating Scale. Results The prevalence of parkinsonism was 38.7% (74 patients), and included 33 (46.5%) behavioral variant FTD (bvFTD), 16 (24.2%) semantic dementia (SD), 19 (45.2%) progressive nonfluent aphasia (PNFA), and 6 (50%) FTD associated with motor neuron disease (FTD-MND). SD patients with parkinsonism had higher CDR sum of boxes scores (9.7 ± 4.5 vs 6.2 ± 4.5, p = 0.024), frontal behavioral inventory total score (33.7 ± 20.5 vs 24.3 ± 14.5, p = 0.045), and executive function score of frontal executive dysfunction, disinhibition, and apathy (28.9 ± 13.7 vs 19.2 ± 12.9, p = 0.021) than those without parkinsonism. Seoul Instrumental Activities of Daily Living score (bvFTD: 23.5 ± 11.7 vs 17.3 ± 11.3, p = 0.031, SD: 23.1 ± 11.1 vs 11.3 ± 9.3, p = 0.005) was higher for bvFTD and SD with parkinsonism than for those without parkinsonism. Conclusions Parkinsonism is found to be more common in patients with bvFTD, PNFA, and FTD-MND patients than those with SD. Behavioral disturbances were more prominent in SD with parkinsonism than without. Additional studies are needed to determine the pathomechanism and optimal treatment of parkinsonism in different FTD subtypes.

We aimed to present the study design of an independent validation cohort from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (AD) (KBASE-V) and to investigate the baseline characteristics of the participants according to the AD clinical spectrum. We recruited 71 cognitively normal (CN) participants, 96 with subjective cognitive decline (SCD), 72 with mild cognitive impairment (MCI), and 56 with AD dementia (ADD). The participants are followed for three years. The Consortium to Establish a Registry for AD scores was significantly different between all of the groups. The logical memory delayed recall scores were significantly different between all groups, except between the MCI and ADD groups. The Mini-Mental State Examination score, hippocampal volume, and cerebrospinal fluid (CSF) amyloid-β42 level were significant difference among the SCD, MCI, and ADD groups. The frequencies of participants with amyloid pathology according to PET or CSF studies were 8.9%, 25.6%, 48.3%, and 90.0% in the CN, SCD, MCI, and ADD groups, respectively. According to ATN classification, A+/T+/N+ or A+/T+/N− was observed in 0%, 15.5%, 31.0%, and 78.3% in the CN, SCD, MCI, and ADD groups, respectively. The KBASE-V showed a clear difference according to the AD clinical spectrum in neuropsychological tests and AD biomarkers.

Background: Hepatic encephalopathy is usually accompanied by high signal intensities in the bilateral globus pallidus and the cerebral peduncle on T1-weighted brain images. Here, we present a case of fulminant hepatic failure along with hyperammonemia. Case Report: A 47-year-old man was admitted to our hospital due to decreased mental status. The laboratory tests showed increased aspartate transaminase, alanine transaminase, total bilirubin, ammonia levels and positive hepatitis A virus IgM antibody. Diffusion-weighted brain imaging revealed high signal intensities in diffuse cortical areas, including the insular cortex, cingulate gyrus, and bilateral thalami. However, there was no involvement of the perirolandic area and the occipital cortex. We diagnosed the patient with hyperammonemic encephalopathy with fulminant hepatitis A infection. Conclusion: We described a case of hyperammonemic encephalopathy with diffuse cerebral and thalamic involvement. This case emphasized the obvious implication that signal changes in the insular cortex and the cingulate gyrus could be a ‘sentinel sign’, and increased diffuse cortical and thalamic involvement may point to a more severe status.

BACKGROUND AND PURPOSE Only a few studies have investigated the relationship between different subtypes and disease progression or prognosis in patients with behavioral variant frontotemporal dementia (bvFTD). Since a localized injury often produces more focal signs than a diffuse injury, we hypothesized that the clinical characteristics differ between patients with bvFTD who show diffuse frontal lobe atrophy (D-type) on axial magnetic resonance imaging (MRI) scans versus those with focal or circumscribed frontal lobe atrophy (F-type). METHODS In total, 94 MRI scans (74 scans from bvFTD and 20 scans from age-matched normal controls) were classified into 35 D- and 39 F-type bvFTD cases based on an axial MRI visual rating scale. We compared baseline clinical characteristics, progression in motor and cognitive symptoms, and survival times between D- and F-types. Survival analyses were performed for 62 of the 74 patients. RESULTS While D-type performed better on neuropsychological tests than F-type at baseline, D-type had higher baseline scores on the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Evaluations of motor progression showed that the disease duration with motor symptoms was shorter in D-type than F-type. Moreover, the survival time was shorter in D-type (6.9 years) than F-type (9.4 years). Cox regression analyses revealed that a high UPDRS Part III score at baseline contributed to an increased risk of mortality, regardless of the pattern of atrophy. CONCLUSIONS The prognosis is worse for D-type than for those with F-type. Shorter survival in D-type may be associated with the earlier appearance of motor symptoms.

Aim Memantine is known to be effective in the treatment of the behavioral symptoms of dementia, especially agitation in moderate to severe Alzheimer's disease (AD). However, memantine and rivastigmine patch combination therapy has not been well studied in determining treatment effectiveness with mild to moderate AD patients. Methods This was a multicenter, 24-week, prospective, randomized, open-label study design. A total 147 AD patients with Mini-Mental State Examination scores from 10 to 20 were randomly assigned to rivastigmine patch monotherapy and combination therapy with memantine groups. Agitation symptoms, using the Korean Version of the Cohen Mansfield Agitation Inventory were evaluated at baseline and at study end. Suppression and emergence of agitation symptoms were also evaluated. We carried out factor analyses to evaluate the interrelationship of agitation symptoms and to investigate treatment response in these symptoms. Results Factor analyses showed two symptom clusters: factor A – aggressive agitated behaviors – versus factor B – non-aggressive agitated behaviors. The rivastigmine patch monotherapy group showed significantly decreased factor B scores and had a tendency of decreased Korean Version of the Cohen Mansfield Agitation Inventory total scores and factor A scores. Conversely, the combination therapy group showed significantly increased Korean Version of the Cohen Mansfield Agitation Inventory total scores and factor B scores. Neither monotherapy nor combination therapy reduced the emergence of new agitation symptoms. Conclusions In this trial of mild to moderate AD patients, the rivastigmine patch monotherapy group experienced a reduction of non-aggressive agitated behaviors. However, combination therapy with memantine did not show any benefit on the agitation associated with mild to moderate AD. Geriatr Gerontol Int 2017; 17: 494–499.