Sympathetic dysfunction as an early indicator of autonomic involvement in Parkinson's disease.

PURPOSE: The specific characteristics of autonomic involvement in patients with early Parkinson's disease (PD) are unclear. This study aimed to evaluate the characteristics of autonomic dysfunction in drug-naïve patients with early-stage PD without orthostatic hypotension (OH) by analyzing Valsalva maneuver (VM) parameters. METHODS: We retrospectively analyzed drug-naïve patients without orthostatic hypotension (n = 61) and controls (n = 20). The patients were subcategorized into early PD (n = 35) and mid-PD (n = 26) groups on the basis of the Hoehn and Yahr staging. VM parameters, including changes in systolic blood pressure at late phase 2 (∆SBPVM2), ∆HRVM3, Valsalva ratio (VR), pressure recovery time, adrenergic baroreflex sensitivity, and vagal baroreflex sensitivity, were assessed. RESULTS: In the early PD group, ∆SBPVM2, a marker of sympathetic function, was significantly lower compared with that in controls (risk ratio = 0.95, P = 0.027). Receiver operating characteristic (ROC) curve analysis showed an optimal cut-off value of -10 mmHg for ∆SBPVM2 [P = 0.002, area under the curve (AUC): 0.737]. VR exhibited an inverse relationship with Unified Parkinson's Disease Rating Scale Part 3 scores in the multivariable regression analysis (VR: P = 0.038, ß = -28.61), whereas age showed a positive relationship (age: P = 0.027, ß = 0.35). CONCLUSION: The ∆BPVM2 parameter of the VM may help detect autonomic nervous system involvement in early-PD without OH. Our results suggest that sympathetic dysfunction is an early manifestation of autonomic dysfunction in patients with PD.

The semicircular canal function is preserved with little impact on falls in patients with mild Parkinson's disease.

INTRODUCTION: Postural instability is a cardinal symptom of Parkinson's disease (PD), which suggests the vestibular system may be affected in PD. This study aimed to determine whether vestibular dysfunction is associated with the risk of falls in PD. METHODS: We prospectively recruited patients with de-novo PD at a tertiary medical center between December 2019 and March 2023. During initial assessment, each patient was queried about falls within the preceding year. All patients underwent evaluation of video head-impulse tests (video-HITs), motion analysis, mini-mental state examination (MMSE), and Montreal Cognitive Assessment (MOCA). We determined whether head impulse gain of the vestibulo-ocular reflex (VOR) was associated with clinical severity of PD or risk of falls. RESULTS: Overall, 133 patients (mean age ± SD = 68 ± 10, 59 men) were recruited. The median Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (MDS-UPDRS-III) was 23 (interquartile range = 16-31), and 81 patients (61 %) scored 2 or less on the Hoehn and Yahr scale. Fallers were older (p = 0.001), had longer disease duration (p = 0.001), slower gait velocity (p = 0.009), higher MDS-UPDRS-III (p < 0.001) and H&Y scale (p < 0.001), lower MMSE (p = 0.018) and MOCA scores (p = 0.001) than non-fallers. Multiple logistic regression showed that MDS-UPDRS-III had a positive association with falling (p = 0.004). Falling was not associated with VOR gain (p = 0.405). The VOR gain for each semicircular canal showed no correlation with the MDS-UPDRS-III or disease duration. CONCLUSIONS: The semicircular canal function, as determined by video-HITs, is relatively spared and has little effect on the risk of falls in patients with mild-to-moderate PD.

Scale for Ocular Motor Disorders in Ataxia (SODA) in Patients with Multiple System Atrophy.

A clinical scale fully dedicated to evaluating ocular motor abnormalities is required for now. We investigated the utility of a recently developed Scale for Ocular motor Disorders in Ataxia (SODA) in patients with multiple system atrophy (MSA). We prospectively assessed SODA in consecutive patients with MSA between August 2021 and August 2023 at the Korea University Medical Center. The results of the clinical exam-based SODA were compared with those measured using video-oculography (VOG-guided SODA). We also compared the findings with other established clinical scales targeting patients with MSA, including the Unified Multiple System Atrophy Rating Scale (UMSARS) I-II, Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (UPDRS-III), Scale for Assessment of Rating of Ataxia (SARA), Composite Autonomic Symptom Score-31 (COMPASS-31), and Composite Autonomic Severity Score (CASS). Twenty patients were enrolled in our study (17 with cerebellar-type MSA and three with Parkinson-type MSA). Scores ranged from 1 to 14 (median [interquartile range (IQR)] = 8 [5-10]). Among the subscales, saccades had a median score of 2.5 (IQR = 1-3), followed by ocular pursuit (1 [0-1]), nystagmus (1 [0-2]), saccadic intrusions (1 [0-1]), vestibulo-ocular reflex (VOR) (0.5 [0-1]), ocular alignment (0 [0-1]), and VOR cancellation (1 [0-1]). The clinical-exam-based SODA (p = 0.020) and VOG-guided SODA (p = 0.034) positively correlated with disease duration. No correlation was found between clinical exam-based SODA and other scales. Skew deviation, gaze-evoked nystagmus, VOR cancellation, and smooth pursuit had the highest precision among the items. Ocular misalignment and spontaneous and positional nystagmus were frequently false positive and were poorly detected with clinical exam-based SODA. Six patients with repeated evaluation exhibited higher scores, along with deterioration documented on other clinical scales. The SODA can reliably predict neurodegeneration as an additional clinical surrogate in MSA.

Photoactive MOF-Derived Bimetallic Silver and Cobalt Nanocomposite with Enhanced Antibacterial Activity.

Conventional antibiotic-based treatment of bacterial infections remains one of the most difficult challenges in medicine because of the threat of multidrug resistance caused by indiscriminate abuse. To solve these problems, it is essential to develop an effective antibacterial agent that can be used at a small dose while minimizing the occurrence of multiple resistance. Metal-organic frameworks (MOFs), which are hyper-porous hybrid materials containing metal ions linked by organic ligands, have recently attracted attention because of their strong antibacterial activity through metal-ion release, unlike conventional antibiotics. In this study, we developed a photoactive MOF-derived cobalt-silver bimetallic nanocomposite (Ag@CoMOF) by simply depositing silver nanoparticles on a cobalt-based MOF through nanoscale galvanic replacement. The nanocomposite structure continuously releases antibacterial metal ions (i.e., Ag and Co ions) in the aqueous phase and exhibits a strong photothermal conversion effect of Ag nanoparticles, accompanied by a rapid temperature increase of 25-80 °C under near-infrared (NIR) irradiation. Using this MOF-based bimetallic nanocomposite, superior antibacterial activities were achieved by 22.1-fold for Escherichia coli and 18.3-fold for Bacillus subtilis enhanced inhibition of bacterial growth in a liquid culture environment compared with the generally used chemical antibiotics. In addition, we confirmed the synergistic enhancement of the antibacterial ability of the bimetallic nanocomposite induced by NIR-triggered photothermal heating and bacterial membrane disruption even when using a small amount of the nanocomposites. We envision that this novel antibacterial agent using MOF-based nanostructures will replace traditional antibiotics to circumvent multidrug resistance and present a new approach to antibiotic development.

Ocular Motor Findings Aid in Differentiation of Spinocerebellar Ataxia Type 17 from Huntington's Disease.

Differentiation of spinocerebellar ataxia type 17 (SCA17) from Huntington's disease (HD) is often challenging since they share the clinical features of chorea, parkinsonism, and dystonia. The ocular motor findings remain to be elucidated in SCA17, and may help differentiating SCA17 from HD. We retrospectively compared the ocular motor findings of 11 patients with SCA17 with those of 10 patients with HD. In SCA17, abnormal ocular motor findings included impaired smooth pursuit (9/11, 82%), dysmetric saccades (9/11, 82%), central positional nystagmus (CPN, 7/11, 64%), abnormal head-impulse tests (4/11, 36%), and horizontal gaze-evoked nystagmus (GEN, 3/11, 27%). Among these, CPN was more frequently observed in SCA17 than in HD (7/11 (64%) vs. 0/10 (0%), p = 0.004) while saccadic slowing was more frequently observed in HD than in SCA17 (8/10 (80%) vs. 2/11 (18%), p = 0.009). Of six patients with follow-up evaluation, five later developed bilateral saccadic hypermetria (n = 4), GEN (n = 1), CPN (n = 1), bilaterally abnormal smooth pursuit (n = 1), and hyperactive head-impulse responses (n = 1) along with a clinical decline. Ocular motor abnormalities can be utilized as a diagnostic marker for differentiation of SCA17 from HD as well as a surrogate marker for clinical decline in SCA17.

Regional Metabolic Changes Influencing Three-Dimensional Perception in Parkinson's Disease.

BACKGROUND AND PURPOSE: Stereopsis refers to the perception of depth and awareness of the distance of an object from the observer that results from the brain receiving visual stimuli from both eyes in combination. Patients with idiopathic Parkinson's disease (PD patients) typically experience problems with vision, eyeball movements, and visual perception due to degeneration of the cells that generate dopamine in the brain. We therefore hypothesized that stereopsis is affected more by visual cortical dysfunction in idiopathic PD than by retina and subcortical structural dysfunction. METHODS: We analyzed stereopsis in 12 PD patients and 7 healthy controls using a three-dimensional (3D) television (TV). Before allowing patients to watch TV, we examined their visual acuity and strabismus using the Titmus Stereo Fly Test, and evaluated their cognitive function using cognitive tests. The patients watched 3D and two-dimensional (2D) versions of a movie with an approximate duration of 17 minutes, and then completed a questionnaire about stereopsis. All subjects underwent brain F-18 fluorodeoxyglucose (FDG) positron-emission tomography after watching the 3D version of the movie. One week later, subjects watched the 2D version of the same movie under the same conditions. Each scan was analyzed using statistical parametric mapping (version 8) software. RESULTS: The visual cortex was activated less in the PD patients than in the healthy controls when watching the 2D or 3D movie. However, there was no significant difference between watching 2D and 3D movies in the PD patients or healthy controls. CONCLUSIONS: The lower activation of the primary visual cortex in PD patients suggests the presence of dysfunction of the visual cortex. In addition, there was less activation of the visual association cortex in PD patients when watching a 3D movie than in controls under the same conditions. This might be one reason why PD patients do not recognize real and dynamic stereopsis. These findings have clinical significance since they suggest that safety needs to be considered when making devices or programs using 3D or virtual reality for use by patients with various cerebral degenerative diseases.

Differentiating amnestic from non-amnestic mild cognitive impairment subtypes using graph theoretical measures of electroencephalography.

The purpose of this study was to explore different patterns of functional networks between amnestic mild cognitive impairment (aMCI) and non-aMCI (naMCI) using electroencephalography (EEG) graph theoretical analysis. The data of 197 drug-naïve individuals who complained cognitive impairment were reviewed. Resting-state EEG data was acquired. Graph analyses were performed and compared between aMCI and naMCI, as well as between early and late aMCI. Correlation analyses were conducted between the graph measures and neuropsychological test results. Machine learning algorithms were applied to determine whether the EEG graph measures could be used to distinguish aMCI from naMCI. Compared to naMCI, aMCI showed higher modularity in the beta band and lower radius in the gamma band. Modularity was negatively correlated with scores on the semantic fluency test, and the radius in the gamma band was positively correlated with visual memory, phonemic, and semantic fluency tests. The naïve Bayes algorithm classified aMCI and naMCI with 89% accuracy. Late aMCI showed inefficient and segregated network properties compared to early aMCI. Graph measures could differentiate aMCI from naMCI, suggesting that these measures might be considered as predictive markers for progression to Alzheimer's dementia in patients with MCI.

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IIb Clinical Study to Evaluate the Safety and Efficacy of DHP1401 in Patients with Mild to Moderate Alzheimer's Disease Treated with Donepezil: DHP1401 Randomized Trial in Mild to Moderate Alzheimer's Disease (DRAMA).

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 donepezilMethods: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.

Head-impulse tests aid in differentiation of multiple system atrophy from Parkinson's disease.

The integrity of the vestibulo-ocular reflex (VOR) remains to be delineated in patients with parkinsonism. We aimed to define the findings of the VOR using head-impulse tests (HITs) and their differential diagnostic value in patients with Parkinson's disease (PD) and multiple system atrophy (MSA). From December 2019 to January 2021, 30 patients with PD and 23 patients with MSA (17 with cerebellar-type MSA and 6 with parkinsonian-type MSA) had a video-oculographic recording of HITs at two university hospitals in South Korea. Reversed (p = 0.034) and perverted (p = 0.015) catch-up saccades were more frequently observed in MSA than in PD during HITs. The gain difference between the ACs and the PCs were larger in MSA than in PD (p = 0.031), and positively correlated with the disease duration in patients with MSA (Spearman's coefficient = 0.512, p = 0.012). Multivariate logistic regression analysis showed that reversed (p = 0.044) and perverted (p = 0.039) catch-up saccades were more frequently associated with MSA than with PD during HITs. In conclusion, HITs aid in differentiation of MSA from PD, and may serve as a surrogate marker for the clinical decline.

Automated Classification of Normal Control and Early-Stage Dementia Based on Activities of Daily Living (ADL) Data Acquired from Smart Home Environment.

With the global trend toward an aging population, the increasing number of dementia patients and elderly living alone has emerged as a serious social issue in South Korea. The assessment of activities of daily living (ADL) is essential for diagnosing dementia. However, since the assessment is based on the ADL questionnaire, it relies on subjective judgment and lacks objectivity. Seven healthy seniors and six with early-stage dementia participated in the study to obtain ADL data. The derived ADL features were generated by smart home sensors. Statistical methods and machine learning techniques were employed to develop a model for auto-classifying the normal controls and early-stage dementia patients. The proposed approach verified the developed model as an objective ADL evaluation tool for the diagnosis of dementia. A random forest algorithm was used to compare a personalized model and a non-personalized model. The comparison result verified that the accuracy (91.20%) of the personalized model was higher than that (84.54%) of the non-personalized model. This indicates that the cognitive ability-based personalization showed encouraging performance in the classification of normal control and early-stage dementia and it is expected that the findings of this study will serve as important basic data for the objective diagnosis of dementia.

Erratum: Validation Study of the Official Korean Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

This corrects the article on p. 633 in vol. 16, PMID: 33029970.

The link to polysulfides and their applications.

This article highlights recent discoveries within the field of polysulfides which are created from waste sulfur through inverse vulcanisation. Due to the current environmental climate, making materials from renewable resources or industrial waste is highly desirable. Sulfur is an impurity refined out of petroleum and gas reserves at a rate of more than 70 million tonnes a year and is currently used in the rubber, fertiliser and chemical industries. However, even with these applications, the usage is significantly below the amount refined each year, leading to large stockpiles of sulfur. Inverse vulcanisation is an attractive method to synthesize new sulfur based materials by trapping the polysulfide using crosslinkers containing diene functionalities. A wide variety of unsaturated crosslinkers can be incorporated into polysulfide materials resulting in inorganic rubbers, combining the benefits of both components. The materials produced have been shown to selectively absorb mercury, are prominsing replacements for existing mid IR lenses, and can be used as capsules for controlled release fertilisers. An overview of the field, including the breadth of crosslinkers employed, synthetic strategies, and the properties and potential applications of polysulfides created through inverse vulcanisation, is captured.

Regional Gray Matter Volume Changes in Parkinson's Disease with Orthostatic Hypotension.

Neurodegenerative change in the central nervous system has been suggested as one of the pathophysiological mechanisms of autonomic nervous system dysfunction in Parkinson's disease (PD). We analyzed gray matter (GM) volume changes and clinical parameters in patients with PD to investigate any involvement in the brain structures responsible for autonomic control in patients with PD having orthostatic hypotension (OH). Voxel-based morphometry was applied to compare regional GM volumes between PD patients with and without OH. Multivariate logistic regression analysis using a hierarchical model was carried out to identify clinical factors independently contributing to the regional GM volume changes in PD patients with OH. The Sobel test was used to analyze mediation effects between the independent contributing factors to the GM volume changes. PD patients with OH had more severe autonomic dysfunction and reduction in volume in the right inferior temporal cortex than those without OH. The right inferior temporal volume was positively correlated with the Qualitative Scoring MMSE Pentagon Test (QSPT) score, reflecting visuospatial/visuoperceptual function, and negatively correlated with the Composite Autonomic Severity Score (CASS). The CASS and QSPT scores were found to be factors independently contributing to regional volume changes in the right inferior temporal cortex. The QSPT score was identified as a mediator in which regional GM volume predicts the CASS. Our findings suggest that a decrease in the visuospatial/visuoperceptual process may be involved in the presentation of autonomic nervous system dysfunction in PD patients.

Validation Study of the Official Korean Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

BACKGROUND AND PURPOSE: The Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is widely used for estimating the symptoms of Parkinson's disease. Translation and validation of the MDS-UPDRS is necessary for non-English speaking countries and regions. The aim of this study was to validate the Korean version of the MDS-UPDRS. METHODS: Altogether, 362 patients in 19 centers were recruited for this study. We translated the MDS-UPDRS to Korean using the translation-back translation method and cognitive pretesting. We performed both confirmatory and exploratory factor analyses to validate the scale. We calculated the comparative fit index (CFI) for confirmatory factor analysis, and used unweighted least squares for exploratory factor analysis. RESULTS: The CFI was higher than 0.90 for all parts of the scale. Exploratory factor analysis also showed that the Korean MDS-UPDRS has the same number of factors in each part as the English version. CONCLUSIONS: The Korean MDS-UPDRS has the same overall structure as the English MDS-UPDRS. Our translated scale can be designated as the official Korean MDS-UPDRS.

Artificial Intelligence Approaches to Social Determinants of Cognitive Impairment and Its Associated Conditions.

BACKGROUND AND PURPOSE: This study uses an artificial-intelligence model (recurrent neural network) for evaluating the following hypothesis: social determinants of disease association in a middle-aged or old population are different across gender and age groups. Here, the disease association indicates an association among cerebrovascular disease, hearing loss and cognitive impairment. METHODS: Data came from the Korean Longitudinal Study of Ageing (2014-2016), with 6,060 participants aged 53 years or more, that is, 2,556 men, 3,504 women, 3,640 aged 70 years or less (70-), 2,420 aged 71 years or more (71+). The disease association was divided into 8 categories: 1 category for having no disease, 3 categories for having 1, 3 categories for having 2, and 1 category for having 3. Variable importance, the effect of a variable on model performance, was used for finding important social determinants of the disease association in a particular gender/age group, and evaluating the hypothesis above. RESULTS: Based on variable importance from the recurrent neural network, important social determinants of the disease association were different across gender and age groups: 1) leisure activity for men; 2) parents alive, income and economic activity for women; 3) children alive, education and family activity for 70-; and 4) brothers/sisters cohabiting, religious activity and leisure activity for 70+. CONCLUSIONS: The findings of this study support the hypothesis, suggesting the development of new guidelines reflecting different social determinants of the disease association across gender and age groups.