Effect of Cognitive Training in Fully Immersive Virtual Reality on Visuospatial Function and Frontal-Occipital Functional Connectivity in Predementia: Randomized Controlled Trial.

BACKGROUND: Cognitive training can potentially prevent cognitive decline. However, the results of recent studies using semi-immersive virtual reality (VR)-assisted cognitive training are inconsistent. OBJECTIVE: We aimed to examine the hypothesis that cognitive training using fully immersive VR, which may facilitate visuospatial processes, could improve visuospatial functioning, comprehensive neuropsychological functioning, psychiatric symptoms, and functional connectivity in the visual brain network in predementia. METHODS: Participants over 60 years old with subjective cognitive decline or mild cognitive impairment from a memory clinic were randomly allocated to the VR (n=23) or the control (n=18) group. The VR group participants received multidomain and neuropsychologist-assisted cognitive training in a fully immersive VR environment twice a week for 1 month. The control group participants did not undergo any additional intervention except for their usual therapy such as pharmacotherapy. Participants of both groups were evaluated for cognitive function using face-to-face comprehensive neuropsychological tests, including the Rey-Osterrieth Complex Figure Test (RCFT) copy task; for psychiatric symptoms such as depression, apathy, affect, and quality of life; as well as resting-state functional magnetic resonance imaging (rsfMRI) at baseline and after training. Repeated-measures analysis of variance was used to compare the effect of cognitive training between groups. Seed-to-voxel-based analyses were used to identify the cognitive improvement-related functional connectivity in the visual network of the brain. RESULTS: After VR cognitive training, significant improvement was found in the total score (F1,39=14.69, P=.001) and basic components score of the RCFT copy task (F1,39=9.27, P=.005) compared with those of the control group. The VR group also showed improvements, albeit not significant, in naming ability (F1,39=3.55, P=.07), verbal memory delayed recall (F1,39=3.03, P=.09), and phonemic fluency (F1,39=3.08, P=.09). Improvements in psychiatric symptoms such as apathy (F1,39=7.02, P=.01), affect (F1,39=14.40, P=.001 for positive affect; F1,39=4.23, P=.047 for negative affect), and quality of life (F1,39=4.49, P=.04) were found in the VR group compared to the control group. Improvement in the RCFT copy task was associated with a frontal-occipital functional connectivity increase revealed by rsfMRI in the VR group compared to the control group. CONCLUSIONS: Fully immersive VR cognitive training had positive effects on the visuospatial function, apathy, affect, quality of life, and increased frontal-occipital functional connectivity in older people in a predementia state. Future trials using VR cognitive training with larger sample sizes and more sophisticated designs over a longer duration may reveal greater improvements in cognition, psychiatric symptoms, and brain functional connectivity. TRIAL REGISTRATION: Clinical Research Information Service KCT0005243; https://tinyurl.com/2a4kfasa.

[¹8F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [¹8F]THK5351 in MCI subgroups. METHODS: This study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [¹8F]THK5351 PET, and detailed neuropsychological tests. [¹8F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [¹8F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [¹8F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses. RESULTS: [¹8F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [¹8F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [¹8F]THK5351 retention. CONCLUSIONS: [¹8F]THK5351 PET might be useful for identifying distinct topographic patterns of [¹8F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.

Risk Factors for Serious Suicide Attempts: Difference Between Older and Younger Attempters in the Emergency Department.

Objective: Suicide attempts of the older adults are known to be more serious than that of the younger adults. Despite its major social impact in South Korea, the behavioral mechanism of serious suicide attempt (SSA) in old people remains to be elucidated. Thus, we investigated the risk factors for SSA in older and younger suicide attempters in the emergency department. Methods: Demographic data, clinical information, and the level of seriousness of suicide with Risk Rescue Rating Scale were compared between older (age ≥65) and younger (age <65) adults who visited the emergency department for a suicide attempt. Regression analyses were performed to identify the risk factors for SSA in these two groups. Results: Among 370 patients, 37 were older adults (10%; aged 74.41 ± 6.78), more likely to have another medical disease (p < 0.001), and a higher suicide completion rate (16.2 vs. 5.4%, p = 0.023). In the younger group, old age (B = 0.090, p < 0.001), male sex (B = -0.038, p = 0.019), and impression of schizophrenia (B = 0.074, p = 0.027) were associated with a higher risk-rescue ratio and interpersonal stress condition was associated with a lower risk-rescue ratio (B = -0.045, p = 0.006). In the older group, however, no variables were included significant in the regression model for the Risk Rescue Rating Scale. Conclusions: Demographic and clinical factors such as old age, male sex, interpersonal stress, and impression of schizophrenia were associated with lethality in the younger suicide attempters. However, no factors were associated with SSA in the older adult group. Different mechanisms may underly the lethality in old age suicide.

Identification of Heterogeneous Subtypes of Mild Cognitive Impairment Using Cluster Analyses Based on PET Imaging of Tau and Astrogliosis.

Background: Mild cognitive impairment (MCI) is a condition with diverse causes and clinical outcomes that can be categorized into subtypes. [18F]THK5351 has been known to detect reactive astrogliosis as well as tau which is accompanied by neurodegenerative changes. Here, we identified heterogeneous groups of MCI patients using THK retention patterns and a graph theory approach, allowing for the comparison of risk of progression to dementia in these MCI subgroups. Methods: Ninety-seven participants including 60 MCI patients and individuals with normal cognition (NC, n = 37) were included and undertook 3T MRI, [18F]THK5351 PET, and detailed neuropsychological tests. [18F]Flutemetamol PET was also performed in 62 participants. We calculated similarities between MCI patients using their regional standardized uptake value ratio of THK retention in 75 ROIs, and clustered subjects with similar retention patterns using the Louvain method based on the modularity of the graph. The clusters of patients identified were compared with an age-matched control group using a general linear model. Dementia conversion was evaluated after a median follow-up duration of 34.6 months. Results: MCI patients were categorized into four groups according to their THK retention patterns: (1) limbic type; (2) diffuse type; (3) sparse type; and (4) AD type (retention pattern as in AD). Subjects of the limbic type were characterized by older age, small hippocampal volumes, and reduced verbal memory and frontal/executive functions. Patients of the diffuse type had relatively large vascular burden, reduced memory capacity and some frontal/executive functions. Co-morbidity and mortality were more frequent in this subgroup. Subjects of the sparse type were younger and declined only in terms of visual memory and attention. No individuals in this subgroup converted to dementia. Patients in the AD type group exhibited the poorest cognitive function. They also had the smallest hippocampal volumes and the highest risk of progression to dementia (90.9%). Conclusion: Using cluster analyses with [18F]THK5351 retention patterns, it is possible to identify clinically-distinct subgroups of MCI patients and those at greater risk of progression to dementia.

Topographical Heterogeneity of Alzheimer's Disease Based on MR Imaging, Tau PET, and Amyloid PET.

Alzheimer's disease (AD) patients are known to have heterogeneous clinical presentation and pathologic patterns. We hypothesize that AD dementia can be categorized into subtypes based on multimodal imaging biomarkers such as magnetic resonance imaging (MRI), tau positron emission tomography (PET), and amyloid PET. We collected 3T MRI, 18F-THK5351 PET, and 18F-flutemetamol (FLUTE) PET data from 83 patients with AD dementia [Clinical Dementia Rating (CDR) ≤1] and 60 normal controls (NC), and applied surface-based analyses to measure cortical thickness, THK5351 standardized uptake value ratio (SUVR) and FLUTE SUVR for each participant. For the patient group, we performed an agglomerative hierarchical clustering analysis using the three multimodal imaging features on the vertices (n = 3 × 79,950). The identified AD subtypes were compared to NC using general linear models adjusting for age, sex, and years of education. We mapped the effect size within significant cortical regions reaching a corrected p-vertex <0.05 (random field theory). Our surface-based multimodal framework has revealed three distinct subtypes among AD patients: medial temporal-dominant subtype (MT, n = 44), parietal-dominant subtype (P, n = 19), and diffuse atrophy subtype (D, n = 20). The topography of cortical atrophy and THK5351 retention differentiates between the three subtypes. In the case of FLUTE, three subtypes did not show distinct topographical differences, although cortical composite retention was significantly higher in the P type than in the MT type. These three subtypes also differed in demographic and clinical features. In conclusion, AD patients may be clustered into three subtypes with distinct topographical features of cortical atrophy and tau deposition, although amyloid deposition may not differ across the subtypes in terms of topography.

Exposure to ambient fine particles and neuropsychiatric symptoms in cognitive disorder: A repeated measure analysis from the CREDOS (Clinical Research Center for Dementia of South Korea) study.

There is a growing concern that air pollution, especially those particles <2.5 µm (PM2.5), could increase the risk of cognitive impairment and mental disorders. However, the relationship between ambient PM2.5 and neuropsychiatric symptoms in people with cognitive impairment is still undetermined. This longitudinal study included 645 pairs of cognitively impaired subjects, who had not changed residence within Seoul, and their caregivers from the Clinical Research Center for Dementia of South Korea study cohort between September 2005 and June 2010 (1763 days). Neuropsychiatric symptoms were measured by the Korean version of the Neuropsychiatry Inventory, and caregiver burden was examined by the Neuropsychiatry Inventory Caregiver Distress Scale at the first and second visits at the outpatient clinic. District-specific PM2.5 concentrations were constructed over 1 month to 1 year prior to each visit. A log-linear regression using generalized estimating equations to account for repeated measures was used to assess the relationship between PM2.5 exposure and neuropsychiatric symptoms or caregiver burden. Aggravated neuropsychiatric symptoms were associated with exposure to high PM2.5 levels (adjusted percent change: 16.7% [95% confidence interval (CI), 5.0-29.7] per 8.3 µg/m3 increase in 1-month moving averages). Increased caregiver burden was associated with high PM2.5 exposures only in caregivers for patients with Alzheimer's disease (adjusted percent change: 29.0% [95% CI, 8.1-53.9] per 8.3 µg/m3 increase in 1-month moving averages). The present results indicate that PM2.5 exposure is associated with aggravated neuropsychiatric symptoms and increased caregiver burden in subjects with cognitive impairment. The findings in this study suggest that the role of air pollution deserves great consideration in the aging population with cognitive impairment.

18F-THK5351 PET Imaging in the Behavioral Variant of Frontotemporal Dementia.

BACKGROUND AND PURPOSE: Behavioral variant frontotemporal dementia (bvFTD) is a subtype of frontotemporal dementia, which has clinical symptoms of progressive personality and behavioral changes with deterioration of social cognition and executive functions. The pathology of bvFTD is known to be tauopathy or TDP-43 equally. We analyzed the 18F-THK5351 positron emission tomography (PET) scans, which were recently developed tau PET, in patients with clinically-diagnosed bvFTD. METHODS: Forty-eight participants, including participants with behavioral variant frontotemporal dementia (bvFTD, n=3), Alzheimer's disease (AD, n=21) and normal cognition (NC, n=24) who completed 3T magnetic resonance images, 18F-THK5351 PET scans, and detailed neuropsychological tests were included in the study. Voxel-wise statistical analysis and region of interest (ROI)-based analyses were performed to evaluate the retention of THK in bvFTD patients. RESULTS: In the voxel-based and ROI-based analyses, patients with bvFTD showed greater THK retention in the prefrontal, medial frontal, orbitofrontal, anterior cingulate, insula, anterior inferior temporal and striatum regions compared to NC participants. Left-right asymmetry was noted in the bvFTD patients. A patient with extrapyramidal symptoms showed much greater THK retention in the brainstem. CONCLUSIONS: The distribution of THK retention in the bvFTD patients was mainly in the frontal, insula, anterior temporal, and striatum regions which are known to be the brain regions corresponding to the clinical symptoms of bvFTD. Our study suggests that 18F-THK5351 PET imaging could be a supportive tool for diagnosis of bvFTD.

Tau positron emission tomography using [18F]THK5351 and cerebral glucose hypometabolism in Alzheimer's disease.

This study aims to evaluate the clinical validity of [18F]THK5351 positron emission tomography (PET) for the assessment of disease progression and symptoms in Alzheimer's disease (AD). Fifty-one patients with AD dementia, 30 patients with amnestic mild cognitive impairment (aMCI), and 43 controls with normal cognition (NC) were included. All subjects underwent [18F]THK5351 PET, 3.0-T magnetic resonance imaging, and detailed neuropsychological tests. Regions of interest and voxel-based statistical analyses were performed. In patients with AD dementia, [18F]THK5351 retention was greater in most association cortices as well as the limbic area compared to NC or aMCI participants. Patients with aMCI also showed higher THK5351 retention in those areas compared to NC. [18F]THK5351 retention significantly correlated with neuropsychological test results. Negative correlations between [18F]THK5351 and [18F] fluorodeoxyglucose were observed in AD dementia and aMCI groups. Mirror images of [18F]THK5351 retention and glucose hypometabolism in [18F] fluorodeoxyglucose were noticeable in the focal variants of AD. [18F]THK5351 PET reflects disease severity and symptoms in AD. Our results suggest [18F]THK5351 is reflective of tau-related AD pathology.

Dementia Care by Healthy Elderly Caregivers Is Associated with Improvement of Patients' Memory and the Caregivers' Quality of Life: A Before and After Study.

OBJECTIVE: The provision of care for elderly people with dementia by healthy elderly caregivers is one of the new health-care paradigms in South Korea. The aim of this study was to determine whether this type of care, which includes cognitive stimulation, would improve the cognitive function of dementia patients and the quality of life of the healthy elderly caregiver. METHODS: Totals of 132 dementia patients and 197 healthy elderly caregivers participated in this study. We evaluated the cognitive function of the dementia patients at baseline and after providing the program for 6 months using the Korean version of the Consortium to Establish a Registry for Alzheimer's disease, 1st Edition (CERAD-K). We also evaluated the quality of life of the healthy elderly caregivers using the World Health Organization Quality of Life-Short Version (WHOQOL-BREF) at baseline and after 6 months. RESULTS: The word-list memory results of CERAD-K for the included dementia patients improved after 6 months (Z=-2.855, p=0.004). The WHOQOL-BREF score among the elderly caregiver also improved significantly (Z=-2.354, p=0.019). CONCLUSION: These data suggest that dementia care is associated with improvements in both the cognitive function of dementia patients and the quality of life of the healthy elderly caregivers.

Stem Cell Therapy for Alzheimer's Disease: A Review of Recent Clinical Trials.

Stem cell therapy has been noted to be a disease-modifying treatment for Alzheimer's disease (AD). After the failure to develop new drugs for AD, the number of studies on stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), has increased from the early 2000 s. Issues pertaining to stem cells have been investigated in many animal studies in terms of stem cell origin, differentiation potency, method of culture, tumor formation, injection route, and mobility. Since 2010, mainly in East Asia, researchers began clinical trials investigating the use of stem cells for AD. Two phase I trials on moderate AD have been completed; though they revealed no severe acute or long-term side effects, no significant clinical efficacy was observed. Several studies, which involve more sophisticated study designs using different injection routes, well-established scales, and biomarkers such as amyloid positron emission tomography, are planned for mild to moderate AD patients. Here, we review the concept of stem cell therapy for AD and the progress of recent clinical trials.

Comparison of efficacy and safety of milnacipran and fluoxetine in Korean patients with major depression.

OBJECT: To compare efficacy and safety of milnacipran and fluoxetine in a population of Korean patients with major depression. RESEARCH DESIGN AND METHODS: The design was a multi-centre, randomised, comparative clinical study. Patients with major depression (DSM-IV diagnostic criteria) scoring over 17 points on the 17-item Hamilton Depression Scale (HAM-D) and over 21 points on the Montgomery-Asberg Depression Rating Scale (MADRS) were recruited and randomised to receive milnacipran (50 mg/day increasing after 1 week to 100 mg/day) or fluoxetine (20 mg/day) for 6 weeks. All previous medication was stopped at least 7 days before entry into the study. Patients were evaluated (HAM-D, MADRS and clinical global impression scale, CGI) at baseline and after 1, 2, 4 and 6 weeks of treatment. All adverse events which developed during the study period were recorded. RESULTS: 70 patients (milnacipran 39; fluoxetine 31) were included in the study. Total score on both HAM-D, MADRS and CGI decreased significantly in both groups after 1 week and continued to decrease throughout the study. There was no significant difference between the two groups for any measurement at any time point. Both antidepressants were well tolerated. In the milnacipran group, 13 patients reported 28 adverse reactions, and in the fluoxetine group 11 patients reported 18 adverse reactions. Two patients discontinued due to adverse events in the milnacipran group and three in the fluoxetine group. There were no clinically significant modifications in vital signs, routine blood laboratory tests, biochemistry or ECG throughout the study. Nausea and headache were the most frequently reported adverse events with milnacipran while digestive disturbances, diarrhoea and insomnia were more common with fluoxetine. CONCLUSION: Milnacipran, like fluoxetine, was found to be effective and well tolerated for the treatment of major depression in this population of depressed Korean patients. Principal limitations of the study were its open design, its small sample size and its relatively short duration.

A longitudinal study of Alzheimer's disease: rates of cognitive and functional decline.

OBJECTIVE: To measure rates of decline in cognition and function in patients with Alzheimer's disease (AD) and to investigate their accelerating risk factors in Korea. METHODS: This study presents longitudinal data on a community-based sample of 107 patients with AD, followed at 6 months and 12 months. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini Mental State Examination (MMSE) and the Disability Assessment for Dementia Scale (DAD) were given. Mixed model analyses were conducted using the following independent variables: times of repeated assessment (0, 6 or 12 months), severity of dementia assessed by the Functional Assessment Staging (FAST) and individual indicators as covariates. RESULTS: Average annual rates of decline in the MMSE, the ADAS-cog and the DAD were 2.3, 11.4 and 15.1 points, respectively. Neither gender, duration of formal education, nor duration of AD since onset was significant predictors of cognitive and functional decline. Patterns of functional decline in total DAD, instrumental ADLs, planning and organization and performance subscale are linear as MMSE score declines, while those of the basic ADLs and the initiation are curvilinear. CONCLUSION: This naturalistic observational study measured rates of cognitive and functional decline in AD, and can provide reference data for further longitudinal studies or clinical trials. Further study will be necessary to determine whether linear or curvilinear pattern in functional decline is due to progression of AD itself or statistical artifact.

A randomized, double-blind, crossover comparison of risperidone and haloperidol in Korean dementia patients with behavioral disturbances.

OBJECTIVE: Behavioral disturbances in dementia are extremely prominent and distressful, and often result in serious physical, social, and economic consequences. The authors compared the efficacy and tolerability of risperidone and haloperidol in the treatment of behavioral and psychological symptoms of dementia (BPSD) in institutionalized elderly Korean patients with Alzheimer disease, vascular dementia, or mixed dementia. METHODS: This was an 18-week double-blind, crossover study involving 120 patients who were randomly assigned to receive flexible doses (0.5-1.5 mg/day) of risperidone or haloperidol. BPSD were assessed using the Korean version of the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD-K), the Korean version of the Cohen-Mansfield Agitation Inventory (CMAI-K), and the Clinical Global Impression of Change scale (CGI-C). Safety and tolerability assessments included the Extrapyramidal Symptom Rating Scale and the incidence of adverse events. RESULTS: Both risperidone and haloperidol were efficacious in alleviating BPSD. However, when receiving risperidone, patients showed significantly greater improvement than when receiving haloperidol in the total and subscale scores of the BEHAVE-AD-K, the total and subscale scores of the CMAI-K, and the scores on the CGI-C scale. Also, risperidone had an additional benefit on aggressiveness and anxieties/phobias. The risk of antipsychotic-induced parkinsonism throughout this study was significantly lower with risperidone than with haloperidol. CONCLUSION: Risperidone had a favorable efficacy and tolerability profile compared with haloperidol in the treatment of BPSD in this patient population.