Neck rigidity: a pitfall for video head-impulse tests in Parkinson's disease.

Video head impulse tests (video-HITs) are commonly used for vestibular evaluation; however, the results can be contaminated by various artifacts, including technical errors, recording problems, and participant factors. Although video-HITs can be used in patients with Parkinson's disease (PD), the effect of neck rigidity has not been systematically investigated. This study aimed to investigate the effect of neck rigidity on video-HIT results in patients with PD. We prospectively recruited 140 consecutive patients with PD (mean age ± standard deviation = 68 ± 10 years, 69 men) between September 2021 and April 2024 at Korea University Medical Center. The video-HIT results were compared with those of 19 age- and sex-matched healthy participants. Neck rigidity was stratified as a subdomain of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor part (MDS-UPDRS-III). In 59 patients, the vestibulo-ocular reflex (VOR) gain was overestimated in at least one canal plane (58/140, 41%), mostly in the anterior canal (AC, n = 44), followed by the horizontal (HC, n = 15) and posterior canals (PC, n = 7). VOR gain overestimation was also observed in patients with no (18/58, 35%), subtle (20/58, 34%), or mild (17/58, 29%) neck rigidity. Multivariable logistic regression analysis showed that VOR overestimation was positively associated with neck rigidity (odds ratio [OR] [95% confidence interval] = 1.51 [1.01-2.25], p = 0.043). The head velocities of patients decreased during head impulses for the AC (p = 0.033 for the right AC; p = 0.014 for the left AC), whereas eye velocities were similar to those of healthy participants. Our findings suggest that neck rigidity may be a confounder that can contaminate video-HIT results. Thus, the results of video-HITs, especially for the AC, should be interpreted with the context of head velocity during head impulses in patients with neck rigidity.

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.

Distinct plasma phosphorylated-tau proteins profiling for the differential diagnosis of mild cognitive impairment and Alzheimer's disease by plasmonic asymmetric nanobridge-based biosensor.

The differential diagnosis between mild cognitive impairment (MCI) and Alzheimer's disease (AD) has been highly demanded for its effectiveness in preventing and contributing to early diagnosis of AD. To this end, we developed a single plasmonic asymmetric nanobridge (PAN)-based biosensor to differentially diagnose MCI and AD by quantitative profiling of phosphorylated tau proteins (p-tau) in clinical plasma samples, which revealed a significant correlation with AD development and progression. The PAN was designed to have a conductive junction and asymmetric structure, which was unable to be synthesized by the traditional thermodynamical methods. For its unique morphological characteristics, PAN features high electromagnetic field enhancement, enabling the biosensor to achieve high sensitivity, with a limit of detection in the attomolar regime for quantitative analysis of p-tau. By introducing support vector machine (SVM)-based machine learning algorithm, the improved diagnostic system was achieved for prediction of healthy controls, MCI, and AD groups with an accuracy of 94.47 % by detecting various p-tau species levels in human plasma. Thus, our proposed PAN-based plasmonic biosensor has a powerful potential in clinical utility for predicting the onset of AD progression in the asymptomatic phase.

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.

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

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

Precise profiling of exosomal biomarkers via programmable curved plasmonic nanoarchitecture-based biosensor for clinical diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease of complex pathogenesis, with overt symptoms following disease progression. Early AD diagnosis is challenging due to the lack of robust biomarkers and limited patient access to diagnostics via neuroimaging and cerebrospinal fluid (CSF) tests. Exosomes present in body fluids are attracting attention as diagnostic biomarkers that directly reflect neuropathological features within the brain. In particular, exosomal miRNAs (exomiRs) signatures are involved in AD pathogenesis, showing a different expression between patients and the healthy controls (HCs). However, low yield and high homologous nature impede the accuracy and reproducibility of exosome blood-based AD diagnostics. Here, we developed a programmable curved plasmonic nanoarchitecture-based biosensor to analyze exomiRs in clinical serum samples for accurate AD diagnosis. To allow the detection of exomiRs in serum at attomolar levels, nanospaces (e.g., nanocrevice and nanocavity) were introduced into the nanostructures to dramatically increase the spectral sensitivity by adjusting the bending angle of the plasmonic nanostructure through sodium chloride concentration control. The developed biosensor classifies individuals into AD, mild cognitive impairment (MCI) patients, and HCs through profiling and quantifying exomiRs. Furthermore, integrating analysis expression patterns of multiple exosomal biomarkers improved serum-based diagnostic performance (average accuracy of 98.22%). Therefore, precise, highly sensitive serum-derived exosomal biomarker detection-based plasmonic biosensor has a robust capacity to predict the molecular pathologic of neurodegenerative disease, progression of cognitive decline, MCI/AD conversion, as well as early diagnosis and treatment.

Deep Learning Algorithm of 12-Lead Electrocardiogram for Parkinson Disease Screening.

BACKGROUND: Although idiopathic Parkinson's disease (IPD) is increasing with the aging population, there is no adequate screening test for early diagnosis of IPD. Cardiac autonomic dysfunction begins in the early stages of IPD, and an electrocardiogram (ECG) contains precise information on the heart. OBJECTIVE: This study is to develop an ECG deep learning algorithm that can efficiently screen for IPD. METHODS: Data were collected from 751 IPD patients (2,138 ECGs), 751 age and sex-matched non-IPD patients (2,673 ECGs) as a control group, and 297 drug-induced Parkinsonism (DPD) patients (875 ECGs) as a disease control group. ECG data were randomly divided into training set, validation set, and test set at a ratio of 6:2:2. We developed a deep-convolutional neural network (CNN) consisting of 16 layers with Bayesian optimization that classified IPD patients by ECG data. The robustness of the deep learning model was verified through 5-fold cross-validation. RESULTS: The AUROC of the model for detection of IPD was 0.924 (95% CI, 0.913-0.936) in the test set. That for detecting DPD was 0.473 (95% CI, 0.453-0.504). The sensitivities of the model according to Unified Parkinson's Disease Rating Scale III and Hoehn & Yahr scale were also similar. CONCLUSION: In conclusion, the CNN-based deep learning model using ECG data showed quite good performance in identifying IPD patients. Standardized 12-lead ECG test could be one of the clinically feasible candidate methods for early screening of IPD in the future.

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.

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.

Impact of an Education Program for Caregivers of Patients with Alzheimer's Disease on Treatment Discontinuation and Compliance in Korea.

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.

Discontinuation Rate of Newly Prescribed Donepezil in Alzheimer's Disease Patients in Asia.

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<0.001). Treatment compliance at 1 year was 96.8% (306/316) on the CRS and 92.6±14.1% (mean±standard deviation) on the VAS. CONCLUSIONS: In patients on newly prescribed donepezil, the primary reason for discontinuation was an adverse event. Cognitive assessments revealed no significant worsening at 1 year, indicating that continuous donepezil treatment contributes to the maintenance of cognitive function.

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

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

Validation of a New Screening Tool for Dementia: The Simple Observation Checklist for Activities of Daily Living.

BACKGROUND AND PURPOSE: Screening tests for dementia such as the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment are widely used, but there are drawbacks to their efficient use. There remains a need for a brief and easy method of assessing the activities of daily living (ADL) that can be administered to elderly individuals by healthcare workers. We have therefore developed a new scale named the Simple Observation Checklist for Activities of Daily Living (SOC-ADL). METHODS: We developed the SOC-ADL scale as a team of experts engaged in caring for individuals with dementia. This scale comprises eight items and was designed based on the Korean instrumental activities of daily living (K-IADL) scale and the Barthel activities of daily living scale (Barthel Index). The new scale was validated by enrolling 176 patients with cognitive dysfunction across 6 centers. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were performed. We assessed its concurrent validity by performing comparisons with the Korean-MMSE, Clinical Dementia Rating, Clinical Dementia Rating-Sum of Boxes, K-IADL, and Barthel Index, and its criterion validity by performing comparisons between mild cognitive impairment (MCI) and dementia. We also used Cronbach's alpha to assess the interitem reliability. The appropriate cutoff values were determined by analyzing receiver operating characteristic curves, including the areas underneath them. RESULTS: EFA extracted one factor and CFA revealed that all of the model fits exceeded the minimum acceptable criteria. The SOC-ADL scores were strongly correlated with those of the other tools for dementia and could be used to differentiate MCI from dementia. Cronbach's alpha values indicated that the results were reliable. The optimal cutoff value of the SOC-ADL for discriminating dementia from MCI was 3 points, which provided a sensitivity and specificity of 74.5% and 75.7%, respectively. CONCLUSIONS: Our results demonstrate that the SOC-ADL is a valid and reliable tool for differentiating dementia from MCI based on an assessment of ADL. This new tool can be used for screening ADL in elderly subjects who have difficulty communicating, and to increase the efficiency of dementia screening at the population level.