Investigating the impact of environmental enrichment on proteome and neurotransmitter-related profiles in an animal model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with behavioral and cognitive impairments. Unfortunately, the drugs the Food and Drug Administration currently approved for AD have shown low effectiveness in delaying the progression of the disease. The focus has shifted to non-pharmacological interventions (NPIs) because of the challenges associated with pharmacological treatments for AD. One such intervention is environmental enrichment (EE), which has been reported to restore cognitive decline associated with AD effectively. However, the therapeutic mechanisms by which EE improves symptoms associated with AD remain unclear. Therefore, this study aimed to reveal the mechanisms underlying the alleviating effects of EE on AD symptoms using histological, proteomic, and neurotransmitter-related analyses. Wild-type (WT) and 5XFAD mice were maintained in standard housing or EE conditions for 4 weeks. First, we confirmed the mitigating effects of EE on cognitive impairment in an AD animal model. Then, histological analysis revealed that EE reduced Aß accumulation, neuroinflammation, neuronal death, and synaptic loss in the AD brain. Moreover, proteomic analysis by liquid chromatography-tandem mass spectrometry showed that EE enhanced synapse- and neurotransmitter-related networks and upregulated synapse- and neurotransmitter-related proteins in the AD brain. Furthermore, neurotransmitter-related analyses showed an increase in acetylcholine and serotonin concentrations as well as a decrease in polyamine concentration in the frontal cortex and hippocampus of 5XFAD mice raised under EE conditions. Our findings demonstrate that EE restores cognitive impairment by alleviating AD pathology and regulating synapse-related proteins and neurotransmitters. Our study provided neurological evidence for the application of NPIs in treating AD.

Therapeutic Potential of Traditional Oriental Medicines in Targeting Tau Pathology: Insights from Cell-free and Cell-based Screening.

BACKGROUND: Traditional Oriental Medicines (TOMs) formulated using a variety of medicinal plants have a low risk of side effects. In previous studies, five TOMs, namely Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, Palmijihwanghwan, and Jowiseungchungtang have been commonly used to treat patients with Alzheimer's disease. However, only a few studies have investigated the effects of these five TOMs on tau pathology. OBJECTIVE: This study aimed to examine the effect of five TOMs on various tau pathologies, including post-translational modifications, aggregation and deposition, tau-induced neurotoxicity, and tau-induced neuroinflammation. METHODS: Immunocytochemistry was used to investigate the hyperphosphorylation of tau induced by okadaic acid. In addition, the thioflavin T assay was used to assess the effects of the TOMs on the inhibition of tau K18 aggregation and the dissociation of tau K18 aggregates. Moreover, a water-soluble tetrazolium-1 assay and a quantitative reverse transcription polymerase chain reaction were used to evaluate the effects of the TOMs on tau-induced neurotoxicity and inflammatory cytokines in HT22 and BV2 cells, respectively. RESULTS: The five TOMs investigated in this study significantly reduced okadaic acid-induced tau hyperphosphorylation. Hwanglyeonhaedoktang inhibited the aggregation of tau and promoted the dissociation of tau aggregates. Dangguijakyaksan and Hwanglyeonhaedoktang attenuated tau-induced neurotoxicity in HT22 cells. In addition, Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, and Palmijihwanghwan reduced tauinduced pro-inflammatory cytokine levels in BV2 cells. CONCLUSION: Our results suggest that five TOMs are potential therapeutic candidates for tau pathology. In particular, Hwanglyeonhaedoktang showed the greatest efficacy among the five TOMs in cell-free and cell-based screening approaches. These findings suggest that Hwanglyeonhaedoktang is suitable for treating AD patients with tau pathology.

Korean red ginseng polysaccharide as a potential therapeutic agent targeting tau pathology in Alzheimer's disease.

Tau is a microtubule-associated protein that plays a critical role in the stabilization and modulation of neuronal axons. Tau pathology is stronger associated with cognitive decline in patients with Alzheimer's disease (AD) than amyloid beta (Aß) pathology. Hence, tau targeting is a promising approach for the treatment of AD. Previous studies have demonstrated that the non-saponin fraction with rich polysaccharide (NFP) from Korean red ginseng (KRG) can modulate tau aggregation and exert a therapeutic effect on AD. Therefore, we investigated the efficacy of NFP isolated from KRG on tau pathology in experimental models of AD. Our results showed that NFP from KRG ameliorated deposition and hyperphosphorylation of tau in the brain of 3xTg mice. Moreover, NFP from KRG modulated the aggregation and dissociation of tau K18 in vitro. We demonstrated the alleviatory effects of NFP from KRG on hyperphosphorylated tau and tau kinase in okadaic acid-treated HT22 cells. Furthermore, NFP from KRG mitigated Aß deposition, neurodegeneration, and neuroinflammation in 3xTg mice. We revealed the neuroprotective effects of NFP from KRG on tau-induced neuronal loss in HT22 cells. Our results indicate that NFP extracted from KRG is a novel therapeutic agent for the treatment of AD associated with tau pathology.

An exploratory study on the role of occupational therapists in home-based rehabilitation team in South Korea.

Introduction: Cooperation among rehabilitation team members is essential in the home-based rehabilitation setting. Q-methodology that can quantitatively analyze the subjectivity of members of the rehabilitation team was used to explore the role of occupational therapists (OTs) in home-based rehabilitation. Methods: The Q-methodology process was implemented in five steps: Step 1 - Representative statements about the role of OTs were collected through in-depth interviews, open questionnaires, and literature reviews (Q-sample); Step 2 - A total of 34 rehabilitation team members (physical therapists, OTs, social workers, nutritionists) were recruited (P-sample); Step 3 - The statements were classified according to their subjective perspective (Q-sort); Step 4 - Factor analysis was performed based on the correlation among the responses from the participants (Q-factor analysis); Step 5 - The awareness factor for roles was interpreted (Interpretation of awareness factors). Results: The roles of OTs perceived by members of the home-based rehabilitation team were formed into five factors (A) Adaptation within home environments; (B) Professional development; (C) Reliable service execution; (D) Client needs resolution; and (E) Focus on activity participation. In all factors, perspectives on the role of OTs in helping clients participate in their roles and activities at home were included. These factors included issues and directions addressed in prior literature on the development of occupational therapy. Conclusions: In home-based rehabilitation, OTs must play a professional role in ensuring clients live fully at home, and cooperate with team members for an effective rehabilitation approach.

Effects of assistive technology-based occupational therapy on community-dwelling people recovering from stroke.

PURPOSE: The purpose of this study was to investigate the effect of assistive technology-based occupational therapy on occupational performance, satisfaction, and psychosocial impacts of community-dwelling people recovering from stroke. METHODS: A total of eleven community-dwelling people recovering from stroke participated in an occupational therapy intervention based on the core concepts of the Human Activity Assistive Technology (HAAT) model. The intervention involved the adoption of assistive technology devices (ATDs) to perform individual goal activities in the daily lives of people recovering from stroke. The intervention was conducted weekly as a 30-min session for a total of 4 weeks, in the home where each participant actually resided. RESULTS: All participants in the intervention showed statistically significant improvements in occupational performance, satisfaction, and goal attainment level with regard to the individually meaningful activities, between pretest, posttest, and follow-up. User satisfaction with the ATDs and associated services was generally 'satisfactory,' and the mean score significantly increased from post-intervention to follow-up. The psychosocial impact of assistive technologies significantly improved from post-intervention to follow-up evaluation. CONCLUSION: Interventions involving concepts, processes, and strategies based on the HAAT model should be continuously performed to select and adopt appropriate interventions involving assistive technologies.

The Effect of a Multimodal Occupational Therapy Program with Cognition-Oriented Approach on Cognitive Function and Activities of Daily Living in Patients with Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Non-pharmacological intervention, which includes a broad range of approaches, may be an alternative treatment for Alzheimer's disease (AD). Multimodal non-pharmacological intervention alleviates cognitive dysfunction and the impairment of activities of daily living (ADL) in AD patients. However, it is still unclear which combination of non-pharmacological interventions is preferred. We selected a non-pharmacological intervention combined with occupational therapy (OT). We investigated the effect of a multimodal OT program with cognition-oriented approach on cognitive dysfunction and impairments of ADL in patients with AD. Four electronic databases were searched from January 2000 to August 2020. The studies were assessed for heterogeneity, quality assessment, effect size and publication bias. A total of seven randomized controlled trials examining multimodal OT programs with cognition-oriented approach in AD patients were included in the meta-analysis. Compared with the control group, the multimodal OT program with cognition-oriented approach group was statistically beneficial for cognitive dysfunction (95% CI: 0.25-0.91). However, compared with the control group, the multimodal OT program with cognition-oriented approach group tended to be beneficial for basic ADL, and instrumental ADL. These results suggest that the multimodal OT program with cognition-oriented approach might be the optimal multimodal non-pharmacological intervention for improving cognitive dysfunction in AD patients.

Neurological Mechanisms of Animal-Assisted Intervention in Alzheimer's Disease: A Hypothetical Review.

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with aggregation of amyloid-beta (Aß) and tau as the pathological hallmarks. AD is the most common form of dementia and is characterized by a progressive decline of cognition. The failure of pharmacological approaches to treat AD has resulted in an increased focus on non-pharmacological interventions that can mitigate cognitive decline and delay disease progression in patients with AD. Animal-assisted intervention (AAI), a non-pharmacological intervention, improves emotional, social, and cognitive dysfunction in patients with neurodegenerative diseases. In particular, AAI is reported to mitigate the effects of cognitive impairment in patients with AD. Despite the positive effects of AAI on cognitive dysfunction in patients with AD, there have been no studies on how AAI affects AD-related pathologies. This review postulates potential neurological mechanisms of emotional or social interaction through AAI in countering AD-related pathologies, such as Aß deposition, tau hyperphosphorylation, neuroinflammation, and impaired adult hippocampal neurogenesis (AHN), and proposes insights for future research by organizing accumulated previous evidence.

Platycodon grandiflorum Root Protects against Aß-Induced Cognitive Dysfunction and Pathology in Female Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by irreversible cognitive dysfunction. Amyloid beta (Aß) peptide is an important pathological factor that triggers the progression of AD through accumulation and aggregation, which leads to AD-related pathologies that consequently affect cognitive functions. Interestingly, several studies have reported that Platycodon grandiflorum root extract (PGE), besides exhibiting other bioactive effects, displays neuroprotective, anti-neuroinflammatory, and cognitive-enhancing effects. However, to date, it is not clear whether PGE can affect AD-related cognitive dysfunction and pathogenesis. Therefore, to investigate whether PGE influences cognitive impairment in an animal model of AD, we conducted a Y-maze test using a 5XFAD mouse model. Oral administration of PGE for 3 weeks at a daily dose of 100 mg/kg significantly ameliorated cognitive impairment in 5XFAD mice. Moreover, to elucidate the neurohistological mechanisms underlying the PGE-mediated alleviative effect on cognitive dysfunction, we performed histological analysis of hippocampal formation in these mice. Histopathological analysis showed that PGE significantly alleviated AD-related pathologies such as Aß accumulation, neurodegeneration, oxidative stress, and neuroinflammation. In addition, we observed a neuroprotective and antioxidant effect of PGE in mouse hippocampal neurons. Our findings suggest that administration of PGE might act as one of the therapeutic agents for AD by decreasing Aß related pathology and ameliorating Aß induced cognitive impairment.

Animal-Assisted and Pet-Robot Interventions for Ameliorating Behavioral and Psychological Symptoms of Dementia: A Systematic Review and Meta-Analysis.

Patients with dementia suffer from psychological symptoms such as depression, agitation, and aggression. One purpose of dementia intervention is to manage patients' inappropriate behaviors and psychological symptoms while taking into consideration their quality of life (QOL). Animal-assisted intervention (AAI) and pet-robot intervention (PRI) are effective intervention strategies for older people with cognitive impairment and dementia. In addition, AAI and PRI have been shown to have positive effects on behavioral and psychological symptoms of dementia (BPSD). However, studies into the association between AAI/PRI and BPSD have elicited inconsistent results. Thus, we performed a meta-analysis to investigate this association. We analyzed nine randomized controlled trials on AAI and PRI for dementia patients published between January 2000 and August 2019 and evaluated the impact of AAI/PRI on agitation, depression, and QOL. We found that AAI and PRI significantly reduce depression in patients with dementia. Subsequent studies should investigate the impact of AAI and PRI on the physical ability and cognitive function of dementia patients and conduct a follow-up to investigate their effects on the rate of progression and reduction of symptoms of dementia. Our research will help with neuropsychological and environmental intervention to delay or improve the development and progression of BPSD.

Neuroprotective and Anti-Inflammatory Effects of Low-Moderate Dose Ionizing Radiation in Models of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-ß (Aß) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aß accumulation and Aß-mediated pathology. To investigate the short-term effects of low-moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aß-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aß accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aß1-42 (2 µM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aß and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects.

Bilingualism for Dementia: Neurological Mechanisms Associated With Functional and Structural Changes in the Brain.

As the number of older adults increases, the prevalence of dementias, such as Alzheimer's dementia (AD), vascular dementia, dementia with Lewy bodies, and frontotemporal dementias, also increases. Despite research into pharmacological approaches for treating diverse diseases, there is still no cure. Recently, novel non-pharmacological interventions are attracting attention. Non-pharmacological approaches include cognitive stimulation, alterations in diet, physical activity, and social engagement. Cognitive stimulating activities protect against the negative effects of cognitive decline caused by age-related neurogenerative diseases. Bilingualism is one form of cognitive stimulation that requires multiple aspects of brain activity and has been shown to delay the onset of dementia symptoms in patients by approximately 4-5 years as compared with monolingual patients through cognitive reserve. The purpose of this review was to bilingualism protects against cognitive decline associated with AD and other dementias. We discuss potential underlying neurological mechanisms, including: (1) stimulating adult neurogenesis, (2) enhancing synaptogenesis, (3) strengthening functional connectivity that bilingualism may delay clinical AD symptoms, (4) protecting white matter integrity, and (5) preserving gray matter density.

Topographical Visualization of the Reciprocal Projection between the Medial Septum and the Hippocampus in the 5XFAD Mouse Model of Alzheimer's Disease.

It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer's disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at the mesoscale level. In this study, we adopted AD animal model, five familial AD mutations (5XFAD) mice, and anterograde and retrograde tracers, BDA and DiI, respectively, to visualize the pathology-related changes in topographical connectivity of the SHS loop in the 5XFAD brain. By comparing 4.5-month-old and 14-month-old 5XFAD mice, we successfully identified key circuit components of the SHS loop altered in 5XFAD brains. Remarkably, the SHS loop began to degenerate in 4.5-month-old 5XFAD mice before the onset of neuronal loss. The impairment of connectivity between the MS and hippocampus was accelerated in 14-month-old 5XFAD mice. These results demonstrate, for the first time, topographical evidence for the degradation of the interconnection between the MS and hippocampus at the mesoscale level in a mouse model of AD. Our results provide structural and functional insights into the interconnectivity of the MS and hippocampus, which will inform the use and development of various therapeutic approaches that target neural circuits for the treatment of AD.

A comparison of the swallowing function and quality of life by oral intake level in stroke patients with dysphagia.

[Purpose] This study was conducted to compare the swallowing function and quality of life (QOL) in stroke patients with dysphagia by oral intake level. [Subjects and Methods] Seventy-nine stroke patients with dysphagia were enrolled. All subjects were evaluated by using the Swallowing Function Test (SFT) and the Swallowing Quality of Life (SWAL-QOL) questionnaire. The subjects were divided into two group based on the SFT score: oral intake (OI) and non-oral intake (NOI) groups. The SFT and SWAL-QOL scores were then compared between the groups. [Results] There were significant differences in items in the SFT, except for the respiratory item, between the OI group and the NOI group. There were significant differences in all items on the SWAL-QOL, except for the sleep item, between the OI group and the NOI group. [Conclusion] Oral intake was positively associated the swallowing function and QOL in stroke patients with dysphagia. Safe intervention using oral intake treatments during dysphagia rehabilitation may have a positive effect on the patients' swallowing function and QOL.

Clinical usefulness of the clock drawing test applying rasch analysis in predicting of cognitive impairment.

[Purpose] This study examined the clinical usefulness of the clock drawing test applying Rasch analysis for predicting the level of cognitive impairment. [Subjects and Methods] A total of 187 stroke patients with cognitive impairment were enrolled in this study. The 187 patients were evaluated by the clock drawing test developed through Rasch analysis along with the mini-mental state examination of cognitive evaluation tool. An analysis of the variance was performed to examine the significance of the mini-mental state examination and the clock drawing test according to the general characteristics of the subjects. Receiver operating characteristic analysis was performed to determine the cutoff point for cognitive impairment and to calculate the sensitivity and specificity values. [Results] The results of comparison of the clock drawing test with the mini-mental state showed significant differences in according to gender, age, education, and affected side. A total CDT of 10.5, which was selected as the cutoff point to identify cognitive impairement, showed a sensitivity, specificity, Youden index, positive predictive, and negative predicive values of 86.4%, 91.5%, 0.8, 95%, and 88.2%. [Conclusion] The clock drawing test is believed to be useful in assessments and interventions based on its excellent ability to identify cognitive disorders.

Usefulness of the driveABLE cognitive assessment in predicting the driving risk factor of stroke patients.

[Purpose] This study examined the usefulness of the DriveABLE cognitive assessment tool (DCAT) in predicting the driving risk factor of stroke patients, and compared the cognitive and driving functions of two groups discriminated by DCAT. [Subjects and Methods] A total of forty-two stroke patients with a driver's license participated in this study. Two participants with communication problems were excluded. DCAT was used to evaluate the risk potential to the driver, and the subjects were classified into two groups according to the probability of driving risk estimated by the DCAT evaluation. The safe driver group (SDG) and unsafe driver group (USDG) underwent a driving simulator and cognitive function assessments. [Results] The results of the SDG and USDG were compared. The SDG showed higher cognitive function than the USDG. In addition, the SDG showed higher ability than the USDG in most of the tests associated with the driving function (pedal reaction time, average reaction time, centerline crossing, road edge excursion, off-road accidents, collisions). [Conclusion] DCAT is a useful tool for predicting the risk of driving. In addition, it can predict the driving ability of stroke patients related to the cognitive function. Nevertheless, a multi-faceted study of associated with driving and cognitive functions for safe driving will be needed.

Effects of spaced retrieval training with errorless learning in the rehabilitation of patients with dementia.

[Purpose] Among the non-pharmacological interventions for dementia, spaced retrieval training (SRT) is a good method for rehabilitating cognition. The purpose of this study was to examine effects of SRT with errorless learning (EL) in the rehabilitation of patients with dementia. [Subjects and Methods] Twenty-nine participants with vascular dementia (VD) and Alzheimer's disease (AD) participated in the present study. The Korean version of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K) and Modified Barthel Index (MBI) were performed to assess the changes in the neuropsychological performance and the independent activities of daily living after SRT with EL. All tests were administered both before and after SRT with EL. Each SRT with EL intervention was performed for 30 minutes per day for 5 weeks. SPSS for Windows version 18.0 was used for statistical analysis. [Results] All items of the CERAD-K score of the VD group except for constructional praxis increased significantly after the SRT with EL intervention, but no significant differences from the AD group were found. The Korean version of the geriatric depression scale (GDS-K) of the VD group increased significantly after the SRT with EL intervention. The mean MBI scores of each group showed no significant difference after the intervention. [Conclusion] SRT with EL is an effective intervention for memory training of patients with dementia. Future research using sufficient sample sizes will be needed to obtain strong evidence for comparing not only the before and after intervention data but also between the groups.

Effects of upper limb robot-assisted therapy in the rehabilitation of stroke patients.

[Purpose] The aim of this study was to examine the effects of upper limb robot-assisted therapy in the rehabilitation of stroke patients. [Subjects and Methods] Fifteen stroke patients with no visual or cognitive problems were enrolled. All subjects received robot-assisted therapy and comprehensive rehabilitation therapy for 30 minutes each. The experimental group received a conventional therapy and an additional half hour per weekday of robot therapy. The patients participated in a total of 20 sessions, each lasting 60 minutes (conventional therapy 30 min, robot-assisted therapy 30 min), which were held 5 days a week for 4 weeks. [Result] The patients showed a significant difference in smoothness and reach error of the point to point test, circle size and independence of the circle in the circle test, and hold deviation of the playback static test between before and after the intervention. On the other hand, no significant difference was observed in the displacement of the round dynamic test. The patients also showed significant improvement in the Fugl-Meyer Assessment and Modified Barthel Index after the intervention. [Conclusion] These kinematic factors can provide good information when analyzing the upper limb function of stroke patients in robot-assisted therapy. Nevertheless, further research on technology-based kinematic information will be necessary.

The Standardization of the Clock Drawing Test (CDT) for People with Stroke Using Rasch Analysis.

[Purpose] The aim of this study was to standardize the clock drawing test (CDT) for people with stroke using Rasch analysis. [Subjects and Methods] Seventeen items of the CDT identified through a literature review were performed by 159 stroke patients. The data was analyzed with Winstep version 3.57 using the Rasch model to examine the unidimensionality of the items' fit, the distribution of the items' difficulty, and the reliability and appropriateness of the rating scale. [Result] Ten out of the 159 participations (6.2%) were considered misfit subjects, and one item of the CDT was determined to be a misfit item based on Rasch analysis. The rating scales were judged as suitable because the observed average showed an array of vertical orders and MNSQ values < 2. The separate index and reliability of the subject (1.98, 0.80) and item (6.45, 0.97) showed relatively high values. [Conclusion] This study is the first to examine the CDT scale in stroke patients by Rasch analysis. The CDT is expected to be useful for screening stroke patients with cognitive problems.