Movement Disorder Society-Unified Parkinson's Disease Rating Scale Research Articles

Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested. The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD. We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study. Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P=0.008) and II (both P=0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition. Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society.

Assessment of Parkinson's Disease Severity From Videos Using Deep Architectures.

Parkinson's disease (PD) diagnosis is based on clinical criteria, i.e., bradykinesia, rest tremor, rigidity, etc. Assessment of the severity of PD symptoms with clinical rating scales, however, is subject to inter-rater variability. In this paper, we propose a deep learning based automatic PD diagnosis method using videos to assist the diagnosis in clinical practices. We deploy a 3D Convolutional Neural Network (CNN) as the baseline approach for the PD severity classification and show the effectiveness. Due to the lack of data in clinical field, we explore the possibility of transfer learning from non-medical dataset and show that PD severity classification can benefit from it. To bridge the domain discrepancy between medical and non-medical datasets, we let the network focus more on the subtle temporal visual cues, i.e., the frequency of tremors, by designing a Temporal Self-Attention (TSA) mechanism. Seven tasks from the Movement Disorders Society - Unified PD rating scale (MDS-UPDRS) part III are investigated, which reveal the symptoms of bradykinesia and postural tremors. Furthermore, we propose a multi-domain learning method to predict the patient-level PD severity through task-assembling. We show the effectiveness of TSA and task-assembling method on our PD video dataset empirically. We achieve the best MCC of 0.55 on binary task-level and 0.39 on three-class patient-level classification.

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

The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has become the gold standard for evaluating different domains in Parkinson's disease (PD), and it is commonly used in clinical practice, research, and clinical trials. The objectives are to validate the Arabic-translated version of the MDS-UPDRS and to assess its factor structure compared with the English version. The study was carried out in three phases: first, the English version of the MDS-UPDRS was translated into Arabic and subsequently back-translated into English by independent translation team; second, cognitive pretesting of selected items was performed; third, the Arabic version was tested in over 400 native Arabic-speaking PD patients. The psychometric properties of the translated version were analyzed using confirmatory factor analysis (CFA) as well as exploratory factor analysis (EFA). The factor structure of the Arabic version was consistent with that of the English version based on the high CFIs for all four parts of the MDS-UPDRS in the CFA (CFI ≥0.90), confirming its suitability for use in Arabic. The Arabic version of the MDS-UPDRS has good construct validity in Arabic-speaking patients with PD and has been thereby designated as an official MDS-UPDRS version. The data collection methodology among Arabic-speaking countries across two continents of Asia and Africa provides a roadmap for validating additional MDS rating scale initiatives and is strong evidence that underserved regions can be energically mobilized to promote efforts that apply to better clinical care, education, and research for PD. © 2022 International Parkinson and Movement Disorder Society.

Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson’s disease focusing on correlations with motor symptoms

The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson’s disease (PD) supporting the theory that PACAP could have an important role in the pathomechanism of the disorder affecting mostly older patients. Earlier studies found changes in PACAP levels in neurological disorders; therefore, the aim of our study was to examine PACAP in plasma samples of PD patients. Peptide levels were measured with ELISA and correlated with clinical parameters, age, stage of the disorder based on the Hoehn and Yahr (HY) scale, subtype of the disease, treatment, and specific scores measuring motor and non-motor symptoms, such as movement disorder society-unified Parkinson’s disease rating scale (MDS-UPDRS), Epworth sleepiness scale (ESS), Parkinson’s disease sleep scale (PDSS-2), and Beck depression inventory (BDI). Our results showed significantly decreased PACAP levels in PD patients without deep brain stimulation (DBS) therapy and in akinetic-rigid subtype; additionally we also observed a further decrease in the HY stage 3 and 4. Elevated PACAP levels were found in patients with DBS. There were no significant correlations between PACAP level with MDS-UPDRS, type of pharmacological treatment, PDSS-2 sleepiness, or depression (BDI) scales, but we found increased PACAP level in patients with more severe sleepiness problems based on the ESS scale. Based on these results, we suggest that following the alterations of PACAP with other frequently used clinical biomarkers in PD patients might improve strategic planning of further therapeutic interventions and help to provide a clearer prognosis regarding the future perspective of the disease.

Effects of rasagiline on Parkinson's Disease Questionnaire (PDQ-39) emotional well-being domain in patients with Parkinson's disease: A post-hoc analysis of clinical trials in Japan.

BackgroundIdentifying the factors that influence health-related quality of life (HRQoL) is of great scientific interest, but a potential causal relationship between treatment and HRQoL has yet to be fully elucidated. Japanese patients reported better HRQoL outcomes on the Parkinson’s Disease Questionnaire (PDQ-39) emotional well-being domain, a 6-question subset of the PDQ-39 which is considered to reflect the emotional aspects of the disease-specific HRQoL, when treated with rasagiline, than placebo, in both a monotherapy clinical trial (NCT02337725) and an adjunctive therapy clinical trial in patients with wearing-off phenomena (NCT02337738).ObjectiveTo investigate how rasagiline exerts its effect on the PDQ-39 emotional well-being domain in Japanese patients with Parkinson’s disease.MethodsA path analysis was performed to assess the direct treatment effects of rasagiline on the PDQ-39 emotional well-being domain and the effects mediated indirectly through the influence on items related to motor symptoms by a post-hoc analysis of two clinical trials in Japan.ResultsIn the monotherapy trial, the PDQ-39 emotional well-being domain was mainly affected indirectly through items related to motor symptoms (80.7%) composed of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II (67.2%) and Part III (13.5%). In the adjunctive therapy trial, the PDQ-39 emotional well-being domain was also mainly influenced indirectly through effects on items related to motor symptoms (1 mg/day: 54.7%, 0.5 mg/day: 57.6%) composed of MDS-UPDRS Part II (1 mg/day: 35.6%, 0.5 mg/day: 40.9%), Part III (1 mg/day: 8.0%, 0.5 mg/day: 8.3%) and mean daily OFF-time (1 mg/day: 11.1%, 0.5 mg/day: 8.4%).ConclusionsThe effects of rasagiline on the PDQ-39 emotional well-being domain were mediated primarily by influence on the subjective aspects of motor experiences of daily living.

Effects of task prioritization on a postural-motor task in early-stage Parkinson's disease: EEG connectivity and clinical implication.

Appropriate attentional resource allocation could minimize exaggerated dual-task interference due to basal ganglia dysfunction in Parkinson's disease (PD). Here, we assessed the electroencephalography (EEG) functional connectivity to investigate how task prioritization affected posture-motor dual-tasks in PD. Sixteen early-stage PD patients and 16 healthy controls maintained balance in narrow stance alone (single-posture task) or while separating two interlocking rings (postural dual-task). The participants applied a posture-focus or supraposture-focus strategy in the postural dual-task. Postural sway dynamics, ring-touching time, and scalp EEG were analyzed. Both groups exhibited smaller postural sway size, postural determinism, and ring-touching time with the supraposture-focus versus posture-focus strategy. PD patients exhibited higher mean inter-regional connectivity strength than control subjects in both single and dual-task postural conditions. To cope with dual-task interference, PD patients increased inter-regional connectivity (especially with the posture-focus strategy), while control subjects reduced inter-regional connectivity. The difference in mean connectivity strength between the dual-task condition with supraposture-focus and single-posture condition was negatively correlated to the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III total scores and hand-related sub-scores. Our findings suggest differential task prioritization effects on dual-task performance and cortical reorganization between early-stage PD and healthy individuals. Early-stage PD patients are advocated to use a supraposture-focus strategy during a postural dual-task. In addition, with a supraposture-focus strategy, PD patients with mild motor severity could increase compensatory inter-regional connectivity to cope with dual-task interference.

A Smartphone Application as an Exploratory Endpoint in a Phase 3 Parkinson’s Disease Clinical Trial: A Pilot Study

Background: Smartphones can generate objective measures of Parkinson’s disease (PD) and supplement traditional in-person rating scales. However, smartphone use in clinical trials has been limited. Objective: This study aimed to determine the feasibility of introducing a smartphone research application into a PD clinical trial and to evaluate the resulting measures. Methods: A smartphone application was introduced part-way into a phase 3 randomized clinical trial of inosine. The application included finger tapping, gait, and cognition tests, and participants were asked to complete an assessment battery at home and in clinic alongside the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Results: Of 236 eligible participants in the parent study, 88 (37%) consented to participate, and 59 (27 randomized to inosine and 32 to placebo) completed a baseline smartphone assessment. These 59 participants collectively completed 1,292 batteries of assessments. The proportion of participants who completed at least one smartphone assessment was 61% at 3, 54% at 6, and 35% at 12 months. Finger tapping speed correlated weakly with the part III motor portion (r = −0.16, left hand; r = −0.04, right hand) and total (r = −0.14) MDS-UPDRS. Gait speed correlated better with the same measures (r = −0.25, part III motor; r = −0.34, total). Over 6 months, finger tapping speed, gait speed, and memory scores did not differ between those randomized to active drug or placebo. Conclusions: Introducing a smartphone application midway into a phase 3 clinical trial was challenging. Measures of bradykinesia and gait speed correlated modestly with traditional outcomes and were consistent with the study’s overall findings, which found no benefit of the active drug.

Association of Fecal and Plasma Levels of Short-Chain Fatty Acids With Gut Microbiota and Clinical Severity in Patients With Parkinson Disease.

Background and ObjectivesShort-chain fatty acids (SCFAs) are gut microbial metabolites that promote the disease process in a rodent model of Parkinson disease (PD), but fecal levels of SCFAs in patients with PD are reduced. Simultaneous assessments of fecal and plasma SCFA levels, and their interrelationships with the PD disease process, are scarce. We aimed to compare fecal and plasma levels of different SCFA subtypes in patients with PD and healthy controls to delineate their interrelations and link to gut microbiota changes and clinical severity of PD.MethodsA cohort of 96 patients with PD and 85 controls were recruited from National Taiwan University Hospital. Fecal and plasma concentrations of SCFAs were measured using chromatography and mass spectrometry. Gut microbiota was analyzed using metagenomic shotgun sequencing. Body mass index and medical comorbidities were evaluated and dietary information was obtained using a food frequency questionnaire. To assess motor and cognitive impairment, we used the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Mini-Mental Status Examination (MMSE).ResultsCompared with controls, patients with PD had lower fecal but higher plasma concentrations of acetate, propionate, and butyrate. After adjustment for age, sex, disease duration, and anti-PD medication dosage, MDS-UPDRS part III motor scores correlated with reduced fecal levels of acetate (ρ = −0.37, p = 0.012), propionate (ρ = −0.32, p = 0.036), and butyrate (ρ = −0.40, p = 0.004) and with increased plasma propionate concentrations (ρ = 0.26, p = 0.042) in patients with PD. MMSE scores negatively correlated with plasma levels of butyrate (ρ = −0.09, p = 0.027) and valerate (ρ = −0.032, p = 0.033) after adjustment for confounders. SCFAs-producing gut bacteria correlated positively with fecal levels of SCFAs in healthy controls but revealed no association in patients with PD. In the PD patient group, the abundance of proinflammatory microbes, such as Clostridiales bacterium NK3B98 and Ruminococcus sp AM07-15, significantly correlated with decreased fecal levels and increased plasma levels of SCFAs, especially propionic acid.DiscussionReductions in fecal SCFAs but increased plasma SCFAs were observed in patients with PD and corelated to specific gut microbiota changes and the clinical severity of PD.Classification of EvidenceThis study provides Class III evidence that gut metabolite SCFAs distinguish between patients with PD and controls and are associated with disease severity in patients with PD.

Efficacy of safinamide as add-on therapy after subthalamic nucleus deep brain stimulation in Parkinson disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective surgical treatment for advanced Parkinson's disease (PD). However, some patients still experience motor fluctuations or dyskinesia after STN-DBS. Safinamide is approved as add-on treatment to levodopa in fluctuating PD patients. In this study, we evaluated the effect of safinamide as adjunctive therapy in PD patients still experiencing motor fluctuations and dyskinesias after STN-DBS. PD patients treated for at least 2 years with bilateral STN-DBST and with troublesome motor fluctuation and/or dyskinesias were examined by means of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the quality of life questionnaire Parkinson's Disease Questionnaire-8 (PDQ-8) and the Non-Motor Symptoms Scale (NMSS) at baseline (T0), after 1 month of treatment with safinamide 50 mg daily (T1) and after another month of treatment with safinamide 100 mg daily (T2). Twenty-nine PD patients were examined. An improvement of the MDS-UPDRS IV score (motor complications) was observed between T0 and T1, T0 and T2, and T1 and T2. The time spent in the OFF state, the functional impact and the complexity of motor fluctuations significantly improved between T0 and T1 and T0 and T2. The mean levodopa equivalent daily dose significantly decreased from T0 to T1 and from T0 to T2. Regarding non-motor symptoms, an improvement on mood and pain was observed. Safinamide seems to be an effective adjunctive treatment in PD patients treated with bilateral STN-DBS, leading to an improvement of motor complications, mood and pain.

GaitForeMer: Self-Supervised Pre-Training of Transformers via Human Motion Forecasting for Few-Shot Gait Impairment Severity Estimation.

Parkinson's disease (PD) is a neurological disorder that has a variety of observable motor-related symptoms such as slow movement, tremor, muscular rigidity, and impaired posture. PD is typically diagnosed by evaluating the severity of motor impairments according to scoring systems such as the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Automated severity prediction using video recordings of individuals provides a promising route for non-intrusive monitoring of motor impairments. However, the limited size of PD gait data hinders model ability and clinical potential. Because of this clinical data scarcity and inspired by the recent advances in self-supervised large-scale language models like GPT-3, we use human motion forecasting as an effective self-supervised pre-training task for the estimation of motor impairment severity. We introduce GaitForeMer, Gait Forecasting and impairment estimation transforMer, which is first pre-trained on public datasets to forecast gait movements and then applied to clinical data to predict MDS-UPDRS gait impairment severity. Our method outperforms previous approaches that rely solely on clinical data by a large margin, achieving an F1 score of 0.76, precision of 0.79, and recall of 0.75. Using GaitForeMer, we show how public human movement data repositories can assist clinical use cases through learning universal motion representations. The code is available at https://github.com/markendo/GaitForeMer.

Self-Report versus Clinician Examination in Early Parkinson's Disease.

BackgroundEvaluating the discrepancies between patient‐reported measures and clinician examination has implications for formulating individual treatment regimens.ObjectiveThis study investigated the association between health outcomes and level of self‐reported motor‐related function impairment relative to clinician‐examined motor signs.MethodsRecently diagnosed PD patients were evaluated using the Parkinson's Progression Marker Initiative (PPMI, N = 420) and the PASADENA phase II clinical trial (N = 316). We calculated the average normalized difference between each participant's part II and III MDS‐UPDRS (Movement Disorder Society Unified Parkinson's Disease Rating Scale) scores. Individuals with score differences <25th or >75th percentiles were labeled as low‐ and high‐self‐reporters, respectively (those between ranges were labeled intermediate‐self‐reporters). We compared a wide range of clinical/biomarker readouts among these three groups, using Kruskal–Wallis nonparametric and Pearson's χ2 tests. Spearman's correlations were tested for associations between MDS‐UPDRS subscales.ResultsIn both cohorts, high‐self‐reporters reported the largest impairment/symptom experience for most motor and nonmotor patient‐reported variables. By contrast, these high‐self‐reporters were similar to or less impaired on clinician‐examined and biomarker measures. Patient‐reported nonmotor symptoms on MDS‐UPDRS part IB showed the strongest positive correlation with self‐reported motor‐related impairment (PPMI rs = 0.54, PASADENA rs = 0.52). This correlation was numerically stronger than the part II and clinician‐examined MDS‐UPDRS part III correlation (PPMI rs = 0.38, PASADENA rs = 0.28).ConclusionSelf‐reported motor‐related impairments reflect not only motor signs/symptoms but also other self‐reported nonmotor measures. This may indicate (1) a direct impact of nonmotor symptoms on motor‐related functioning and/or (2) the existence of general response tendencies in how patients self‐rate symptoms. Our findings suggest further investigation into the suitability of MDS‐UPDRS II to assess motor‐related impairments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Efficacy and safety of istradefylline in patients with Parkinson's disease presenting with postural abnormalities: Results from a multicenter, prospective, and open-label exploratory study in Japan

Postural abnormalities in Parkinson's disease (PD) can devastatingly impair the quality of life, especially in patients with advanced disease, and are generally refractory to dopaminergic agents. The objective of this exploratory study was to investigate the efficacy and safety of istradefylline for the treatment of postural abnormalities in PD. In this open-label, 24-week, single-arm prospective trial, PD patients with postural abnormalities experiencing the wearing-off phenomenon on levodopa-containing therapies were enrolled and received a starting dose of 20 mg/day istradefylline orally for 4 weeks, which was then increased to 40 mg/day. The primary endpoint was the change from baseline to week 24 in the 14-item Unified Dystonia Rating Scale (UDRS) total score. Pivotal secondary endpoints were changes in the sub-items of UDRS, Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, and adverse drug reactions (ADRs). Overall, 24/31 enrolled patients completed the study; mean (standard deviation) age and duration of motor complications were 73.3 (7.7) years and 3.2 (4.4) years, respectively. Mean (95% confidence interval [CI]) change in the UDRS total score was 4.84 (1.97, 7.71; P = 0.002), with significant improvements in the neck, right distal arm and hand, and trunk severity scores. Mean (95% CI) change in the MDS-UPDRS part III score was 7.84 (4.34, 11.34; P < 0.001). The most common ADRs were malaise, dyskinesia exacerbation, and visual hallucinations in 2 (6.5%) patients each. This exploratory study demonstrated that istradefylline could be efficacious for postural abnormalities and was generally well tolerated in patients with PD experiencing the wearing-off phenomenon with levodopa-containing therapies.

Computer-vision based method for quantifying rising from chair in Parkinson's disease patients

BackgroundThe ability to arise from a sitting to a standing position is often impaired in Parkinson's disease (PD). This impairment is associated with an increased risk of falling, and higher risk of dementia. We propose a novel approach to estimate Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) ratings for “item 3.9” (arising from chair) using a computer vision-based method, whereby we use clinically informed reasoning to engineer a small number of informative features from high dimensional markerless pose estimation data. MethodsWe analysed 447 videos collected via the KELVIN-PD™ platform, recorded in clinical settings at multiple sites, using commercially available mobile smart devices. Each video showed an examination for item 3.9 of the MDS-UPDRS and had an associated severity rating from a trained clinician on the 5-point scale (0, 1, 2, 3 or 4).The deep learning library OpenPose was used to extract pose estimation key points from each frame of the videos, resulting in time-series signals for each key point. From these signals, features were extracted which capture relevant characteristics of the movement; velocity variation, smoothness, whether the patient used their hands to push themselves up, how stooped the patient was while sitting and how upright the patient was when fully standing. These features were used to train an ordinal classification system (with one class for each of the possible ratings on the UPDRS), based on a series of random forest classifiers. ResultsThe UPDRS ratings estimated by this system, using leave-one-out cross validation, corresponded exactly to the ratings made by clinicians in 79% of videos, and were within one of those made by clinicians in 100% of cases. The system was able to distinguish normal from Parkinsonian movement with a sensitivity of 62.8% and a specificity of 90.3%. Analysis of misclassified examples highlighted the potential of the system to detect potentially mislabelled data. ConclusionWe show that our computer-vision based method can accurately quantify PD patients’ ability to perform the arising from chair action. As far as we are aware this is the first study estimating scores for item 3.9 of the MDS-UPDRS from singular monocular video. This approach can help prevent human error by identifying unusual clinician ratings, and provides promise for such a system being used routinely for clinical assessments, either locally or remotely, with potential for use as stratification and outcome measures in clinical trials.

Combining Repetitive Transcranial Magnetic Stimulation and Video Game-Based Training to Improve Dexterity in Parkinson's Disease: Study Protocol of a Randomized Controlled Trial.

Introduction: Patients with Parkinson's disease (PD) often exhibit difficulties with dexterity during the performance of activities of daily living (ADL) due to dysfunctional supplementary motor area (SMA). The aim of this clinical trial protocol work is to describe how the effectiveness of a combined repetitive transcranial magnetic stimulation (rTMS) over SMA and video-game-based skill training (VBT) in PD will be evaluated. The short and long-term benefits are assessed.Methods and analysis: A single-blind (patients) stratified (based on Hoehn & Yahr) parallel randomized sham-controlled rTMS-VBT study with a baseline and two follow-up measurements (3 and 12 weeks) is being conducted. These measurements include the dexterity questionnaire 24 (DextQ-24) as a primary outcome, and nine hole peg test and coin rotation task as main secondary dexterity outcomes. Further secondary outcomes will be the subscale II of the movement disorders society unified PD rating scale (MDS-UPDRS) to assess improvements on overall ADL and the Parkinson's Disease Questionnaire-39 to assess quality of life. Thirty-six outpatients (from one neurorehabilitation center) with PD (diagnosis based on brain bank criteria) will be recruited who report difficulties with dexterity in performing ADL. All PD patients will receive a 45-min VBT three times a week for 3 weeks. The PD patients randomized in the experimental group will receive VBT preceded by real rTMS, being intermittent theta burst (iTBS) stimulation sessions. The PD patients randomized to the control group receive a VBT with sham rTMS.Discussion: The study will provide evidence to determine whether a combined iTBS and VBT skill intervention is more effective than a VBT intervention alone to improve dexterity in PD.Ethics and dissemination: The study was approved by the Ethics Committee for Northwest and Central Switzerland (EKNZ), Switzerland 2019–00433. The study will be conducted in accordance with the Helsinki Declaration and the Guidelines of Good Clinical Practice. Informed consent will be signed prior to subject enrolment. Dissemination will include submission to international peer-reviewed professional journals and presentation at international congresses.The study protocol has been registered in the clinicaltrials.gov registry with the identification code: NCT04699149.

The Association of Olfactory Dysfunction With Depression, Cognition, and Disease Severity in Parkinson's Disease.

Background: Non-motor subtypes of Parkinson's disease (PD) include the limbic, cognitive, and brainstem phenotype, which may have different pathological pathways with olfaction. In this work, we aim to clarify the association between olfactory dysfunction, depression, cognition, and disease severity in PD.Methods: A total of 105 PD subjects were included and divided into anosmia and non-anosmic groups, using the University of Pennsylvania Smell Identification Test (UPSIT). All patients were evaluated with the movement disorder society unified Parkinson's disease rating scale (MDS-UPDRS), the Beck depression inventory (BDI)-II, and the Montreal cognitive assessment (MoCA).Results: The BDI-II and UPSIT scores had a trend of reverse correlation without statistical significance (β-coefficient −0.12, p = 0.232). However, the odds ratio (OR) in anosmia was 2.74 (95% CI 1.01–7.46) for depression and 2.58 (95% CI 1.06–6.29) for cognitive impairment. For the MDS-UPDRS total and Part 3 score, the anosmia had a β-coefficient of 12.26 (95% CI 5.69–18.82) and 8.07 (95% CI 3.46–12.67), respectively. Neither depression nor cognitive impairment is associated with motor symptoms.Conclusion: More severe olfactory dysfunction in PD is associated with cognitive impairment and greater disease severity. Depression in PD may involve complex pathways, causing relatively weak association with olfactory dysfunction.

Clinical Efficacy and Dosing of Vibrotactile Coordinated Reset Stimulation in Motor and Non-motor Symptoms of Parkinson's Disease: A Study Protocol.

Enhanced neuronal synchronization of the subthalamic nucleus (STN) is commonly found in PD patients and corresponds to decreased motor ability. Coordinated reset (CR) was developed to decouple synchronized states causing long lasting desynchronization of neural networks. Vibrotactile CR stimulation (vCR) was developed as non-invasive therapeutic that delivers gentle vibrations to the fingertips. A previous study has shown that vCR can desynchronize abnormal brain rhythms within the sensorimotor cortex of PD patients, corresponding to sustained motor relief after 3 months of daily treatment. To further develop vCR, we created a protocol that has two phases. Study 1, a double blinded randomized sham-controlled study, is designed to address motor and non-motor symptoms, sensorimotor integration, and potential calibration methods. Study 2 examines dosing effects of vCR using a remote study design. In Study 1, we will perform a 7-month double-blind sham-controlled study including 30 PD patients randomly placed into an active vCR or inactive (sham) vCR condition. Patients will receive stimulation for 4 h a day in 2-h blocks for 6 months followed by a 1-month pause in stimulation to assess long lasting effects. Our primary outcome measure is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off medication after 6 months of treatment. Secondary measures include a freezing of gait (FOG) questionnaire, objective motor evaluations, sensorimotor electroencephalography (EEG) results, a vibratory temporal discrimination task (VTDT), non-motor symptom evaluations/tests such as sleep, smell, speech, quality of life measurements and Levodopa Equivalent Daily Dose (LEDD). Patients will be evaluated at baseline, 3, 6, and 7 months. In the second, unblinded study phase (Study 2), all patients will be given the option to receive active vCR stimulation at a reduced dose for an additional 6 months remotely. The remote MDS-UPDRS part III off medication will be our primary outcome measure. Secondary measures include sleep, quality of life, objective motor evaluations, FOG and LEDD. Patients will be evaluated in the same time periods as the first study. Results from this study will provide clinical efficacy of vCR and help validate our investigational vibrotactile device for the purpose of obtaining FDA clearance.Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04877015.

Repeated infusion of autologous adipose tissue-derived stem cells for Parkinson's disease.

Mesenchymal stem cells are expected to have a therapeutic effect on progressive neurodegenerative diseases for which there is currently no fundamental treatment. The aim is to confirm that repeated infusion of autologous adipose tissue-derived stem cells (ADSCs) can be safely administered to patients with Parkinson's disease, and to investigate the effects of this as a pilot study. Three patients with Parkinson's disease received five or six repeated infusions of ADSCs at intervals of approximately one month. Observations were based on medical examinations by a neurologist and interviews with the patient and caregivers. The severity of Parkinson's disease was assessed using the Hoehn & Yahr staging scale and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). No adverse events were observed during the observation period from the start of treatment to six months after the end of the last dose. MDS-UPDRS improved in all three patients. Repeated administration of Autologous ADSCs for Parkinson's disease was safe and feasible. The results of this pilot study provide insight into the value of further research.

Dose optimization of apomorphine sublingual film for treating “OFF” episodes in Parkinson's disease

IntroductionApomorphine sublingual film is approved for the “on-demand” treatment of “OFF” episodes in Parkinson's disease (PD). Patients must undergo dose titration to determine their most effective and tolerable dose. We assessed whether higher doses than those that provide an initial “ON” response could yield more effective treatment. MethodsPatients with PD were assessed in the “OFF” state and the apomorphine sublingual film dose was titrated to a level that provided a tolerable “ON” response. The dose was then increased by up to two dose levels, if tolerated. A comparison in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores was made following administration of the dose that provided the initial “ON” response and following the higher dose. Treatment-emergent adverse events were also reported. ResultsThirty-five patients were titrated to higher apomorphine sublingual film doses than those that provided an initial “ON” response. A mean improvement in MDS-UPDRS Part III score was observed compared with the initial dose of 5.6 points (P = 0.034), 4.4 points (P = 0.009), and 3.7 points (P = 0.018) at 30, 60, and 90 min postdose, respectively. Adverse events were mild or moderate and resolved with dose reduction without concomitant treatment. ConclusionHigher doses of apomorphine sublingual film than those initially perceived to provide an “ON” response can be tolerated and provide additional improvement in motor function in many patients.

Predictive Value of Verbatim Parkinson's Disease Patient-Reported Symptoms of Postural Instability and Falling.

Background:Postural instability is an intractable sign of Parkinson’s disease, associated with poor disease prognosis, fall risk, and decreased quality of life.Objective:1) Characterize verbatim reports of postural instability and associated symptoms (gait disorder, balance, falling, freezing, and posture), 2) compare reports with responses to three pre-specified questions from Part II of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), and 3) examine postural instability symptoms and MDS-UPDRS responses as predictors of future falls.Methods:Fox Insight research participants reported their problems attributed to PD in their own words using the Parkinson Disease Patient Reports of Problems (PD-PROP). Natural language processing, clinical curation, and data mining techniques were applied to classify text into problem domains and clinically-curated symptoms. Baseline postural instability symptoms were mapped to MDS-UPDRS questions 2.11–2.13. T-tests and chi-square tests were used to compare postural instability reporters and non-reporters, and Cochran-Armitage trend tests were used to evaluate associations between PD-PROP and MDS-UPDRS responses; survival methods were utilized to evaluate the predictive utility of PD-PROP and MDS-UPDRS responses in time-to-fall analyses.Results:Of participants within 10 years of PD diagnosis, 9,692 (56.0%) reported postural instability symptoms referable to gait unsteadiness, balance, falling, freezing, or posture at baseline. Postural instability symptoms were significantly associated with patient-reported measures from the MDS-UPDRS questions. Balance problems reported on PD-PROP and MDS-UPDRS 2.11–2.13 measures were predictive of future falls.Conclusion:Verbatim-reported problems captured by the PD-PROP and categorized by natural language processing and clinical curation and MDS-UPDRS responses predicted falls. The PD-PROP output was more granular than, and as informative as, the categorical responses.

S1913 Antibiotic Combination Therapy Improves Symptoms of Parkinson’s Disease in Individuals With Chronic Constipation

Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons with motor symptoms of tremor, rigidity, bradykinesia and postural instability alongside non-motor symptoms such as constipation. Here we explore the effects of a novel antibiotic combination therapy (ACT) comprising Metronidazole, Vancomycin and Rifaximin for the treatment of constipation, which improved symptoms of PD in two cases. Our findings were validated by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) to rank the burden of disease ranging from normal=0 to most severe=272. Case description/methods: Case 1 A 69 y/o male presented with PD and severe constipation including straining to initiate a bowel movement and inability to defecate for up to 1wk. Before commencing ACT, preliminary MDS-UPDRS was 38 and symptoms included asymmetric tremor, cogwheel rigidity, bradykinesia and shuffling gait despite treatment with Levodopa and Carbidopa. At 1yr review on ACT, constipation had abated with daily bowel motions not requiring Movicol. The MDS-UPDRS fell to 21 indicating a 45% reduction even with an unchanged PD medication regimen. Strikingly, there was a diminished tremor, milder cog-wheeling tone and minimal impairment of gait. After concluding ACT, the patient slowly regressed in line with the natural progression of disease. Case 2 A 62 y/o female presented with PD and a 10yr history of constipation, passing a bowel motion once every 4d with bloating and flatulence. Before ACT with added Colchicine was commenced, baseline MDS-UPDRS was 37 and symptoms included asymmetric tremor, rigidity, postural instability and decreased arm swing despite treatment with Pramipexole and Rasagiline. At 1yr follow-up on ACT, constipation had resolved with complete emptying daily and no bloating or flatulence. The MDS-UPDRS fell to 26 denoting a 30% reduction whilst the dosage of PD medication remained constant. Noticeably, there was a decreased frequency of tremor, absence of rigidity, improved balance and greater arm swing. Upon cessation of ACT, the patient had a sustained response and gained further success with self-initiated thiamine injections. Discussion: ACT successfully treated constipation and improved neurological symptoms of PD in two cases. Our findings suggest that treatments modulating the gut microbiota may play a role in reducing the severity and progression of PD as well as ameliorating non-motor symptoms such as constipation.Table 1.: Two cases with Parkinson’s Disease and Chronic Constipation who were treated with Antibiotic Combination Therapy PD: Parkinson’s Disease, MDS-UPDRS: Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (ranging from normal=0 to most severe=272), w: With, w/o: Without, BNO: Bowels not open, BO: Bowels open, i: One ii: Two, mg: Milligram, qd: Once a day, bd: Twice a day, qid: Four times a day.