Unified Parkinson's Rating Scale Research Articles

Topological patterns of motor networks in Parkinson's disease with different sides of onset: A resting-state-informed structural connectome study.

Parkinson's disease (PD) has a characteristically unilateral pattern of symptoms at onset and in the early stages; this lateralization is considered a diagnostically important diagnosis feature. We aimed to compare the graph-theoretical properties of whole-brain networks generated by using resting-state functional MRI (rs-fMRI), diffusion tensor imaging (DTI), and the resting-state-informed structural connectome (rsSC) in patients with left-onset PD (LPD), right-onset PD (RPD), and healthy controls (HCs). We recruited 26 patients with PD (13 with LPD and 13 with RPD) as well as 13 age- and sex-matched HCs. Rs-fMRI and DTI were performed in all subjects. Graph-theoretical analysis was used to calculate the local and global efficiency of a whole-brain network generated by rs-fMRI, DTI, and rsSC. Two-sample t-tests and Pearson correlation analysis were conducted. Significantly decreased global and local efficiency were revealed specifically in LPD patients compared with HCs when the rsSC network was used; no significant intergroup difference was found by using rs-fMRI or DTI alone. For rsSC network analysis, multiple network metrics were found to be abnormal in LPD. The degree centrality of the left precuneus was significantly correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) score and disease duration (p = 0.030, r = 0.599; p = 0.037, r = 0.582). The topological properties of motor-related brain networks can differentiate LPD and RPD. Nodal metrics may serve as important structural features for PD diagnosis and monitoring of disease progression. Collectively, these findings may provide neurobiological insights into the lateralization of PD onset.

Zonisamide add-on in tremor-dominant Parkinson's disease- A randomized controlled clinical trial

Introductionand objective: Tremor is a disabling symptom of PD that usually responds poorly to available standard pharmacological agents. This study aimed to assess the effect of Zonisamide 25 mg on tremor in tremor-dominant PD patients as compared to placebo. MethodsThis was a randomized, placebo-controlled, double-blind study. Parkinson's disease patients were allocated either to the intervention group (standard treatment along with Zonisamide 25 mg add-on) or the placebo group (standard treatment along with placebo). Baseline Unified Parkinson's Disease Rating Scale (UPDRS) and Tremor Research Group Essential Tremor Rating Scale (TETRAS) scores, as well as accelerometric tremor analysis were done and follow-up assessments of the same were done after 12 weeks of intervention. Percentage change from baseline in the UPDRS tremor score was the primary outcome whereas percentage change from baseline of total UPDRS score, UPDRS rigidity and bradykinesia scores, TETRAS score, and accelerometric tremor analysis values were the secondary outcomes. ResultsThere was no significant difference in the percentage change from baseline UPDRS tremor scores between the two groups (placebo: 8.33 [-19.89–23.86] vs drug: 26.14 [-35.58 to −16.07], p-value: 0.164, CI: 0.157–0.171). Best-case analysis for missing values showed a significant improvement in the drug group, compared to the placebo group (p-value: < 0.001, CI: <0.001 - <0.001). ConclusionZonisamide at a dose of 25 mg per day did not improve tremor in tremor-dominant PD patients, however, a positive trend was seen as compared to Placebo in the UPDRS tremor score. Larger studies are required to confirm this finding.

Cannabidiol-enriched cannabis extraction product in Parkinson's disease: A randomized, double-blind, and placebo-controlled trial in Buriram Hospital.

The objective of this study was to assess cannabidiol-enriched cannabis extraction product (CBDEP) efficacy in patients with Parkinson's disease (PD). Forty patients with PD were randomly assigned to the sublingual CBDEP (n = 20) or placebo (n = 20) group. All patients were prescribed a low initial dose with gradual titration within 2 weeks based on individual response - including side effects - followed by 6 weeks of stable dosing. The primary outcome was the Unified Parkinson's Disease Rating Scale (UPDRS) score. The secondary outcomes were as follows: Quality of life (QOL) evaluated by the EQ-5D-5L, timed up and go (TUG) test, 5 times sit to stand (FTSTS) test, gait velocity, hospital anxiety and depression scale (HADS), renal and liver function indices, and adverse events. All outcomes were measured at baseline and at 8 weeks. The generalized estimating equation adjusted for baseline scores was used to compare the values at baseline and at 8 weeks, and between the groups. Four patients were lost to follow-up (CBDEP group, n = 1; placebo group, n = 3) and 36 were included in the analysis (CBDEP group, n = 19; placebo group, n = 17). The CBDEP group received mean cannabidiol and tetrahydrocannabinol dosages of 15.59 ± 5.04 mg/day and 0.61 ± 0.19 mg/day, respectively. No significant differences were found between the groups in terms of the UPDRS, TUG test, FTSTS test, gait velocity, HADS-anxiety, and HADS-depression. The placebo group had significantly improved EQ-5D-5L scores for QOL (P = 0.004). The CBDEP group showed significantly improved blood urea nitrogen (BUN), serum albumin, serum globulin levels, and albumin/globulin ratio (P = 0.037, P < 0.001, P = 0.011, and P = 0.002, respectively) compared with the placebo group. Neither group had serious side effects. No evidence was found that CBDEP can reduce disease severity or improve functional performance, anxiety, or depression in PD. However, CBDEP is safe and can improve the levels of BUN, serum albumin, serum globulin, and albumin/globulin ratio in patients with PD. Thai Clinical Trials Registry (registration number: TCTR 20210303005).

Reproductive Lifespan and Motor Progression of Parkinson's Disease.

Objectives: Estrogen not only plays a key role in the decreased risk of Parkinson’s disease (PD) but also influences its severity. We aimed to explore the effect of the reproductive lifespan on the motor progression of PD female patients in a large prospective cohort study. Methods: A competing risk analysis with a Fine and Gray model on 491 female and 609 male patients with PD was conducted. We regarded the chance of faster motor progression (as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) III increasing by ≥16 points during follow-up) and the chance of death as competing risks. The reproductive lifespan was regarded as the variable of interest, while faster motor progression was set as the primary outcome. Results: In the multivariable competing risk analysis, the male sex was not significantly associated with faster motor progression (subdistribution hazard ratio (SHR) 0.888, 95% CI 0.652–1.209, p = 0.450), while a shorter reproductive lifespan was associated with faster motor progression in women (SHR 0.964, 95% CI 0.936–0.994, p = 0.019). Sensitivity analysis indicated that a shorter reproductive lifespan was also significantly associated with faster motor progression in the 48 female patients who reported menopause after the onset of PD (SHR 0.156, 95% CI 0.045–0.542, p = 0.003). A linear mixed model also revealed the significant main effects of a short reproductive lifespan on the higher UPDRS III score in PD female patients at the last visit (p = 0.026). Conclusions: Our study indicates that a short reproductive lifespan contributes to faster motor progression in PD female patients, which has important implications for understanding the role of endogenous estrogen exposure in female PD and is beneficial to select appropriate patients in clinical trials.

Digital phenotyping by wearable-driven artificial intelligence in older adults and people with Parkinson's disease: Protocol of the mixed method, cyclic ActiveAgeing study.

BackgroundActive ageing is described as the process of optimizing health, empowerment, and security to enhance the quality of life in the rapidly growing population of older adults. Meanwhile, multimorbidity and neurological disorders, such as Parkinson’s disease (PD), lead to global public health and resource limitations. We introduce a novel user-centered paradigm of ageing based on wearable-driven artificial intelligence (AI) that may harness the autonomy and independence that accompany functional limitation or disability, and possibly elevate life expectancy in older adults and people with PD.MethodsActiveAgeing is a 4-year, multicentre, mixed method, cyclic study that combines digital phenotyping via commercial devices (Empatica E4, Fitbit Sense, and Oura Ring) with traditional evaluation (clinical assessment scales, in-depth interviews, and clinical consultations) and includes four types of participants: (1) people with PD and (2) their informal caregiver; (3) healthy older adults from the Helgetun living environment in Norway, and (4) people on the Helgetun waiting list. For the first study, each group will be represented by N = 15 participants to test the data acquisition and to determine the sample size for the second study. To suggest lifestyle changes, modules for human expert-based advice, machine-generated advice, and self-generated advice from accessible data visualization will be designed. Quantitative analysis of physiological data will rely on digital signal processing (DSP) and AI techniques. The clinical assessment scales are the Unified Parkinson’s Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), Apathy Evaluation Scale (AES), and the REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ). A qualitative inquiry will be carried out with individual and focus group interviews and analysed using a hermeneutic approach including narrative and thematic analysis techniques.DiscussionWe hypothesise that digital phenotyping is feasible to explore the ageing process from clinical and lifestyle perspectives including older adults and people with PD. Data is used for clinical decision-making by symptom tracking, predicting symptom evolution, and discovering new outcome measures for clinical trials.

Traditional Chinese medicine Pingchan granule for motor symptoms and functions in Parkinson's disease: A multicenter, randomized, double-blind, placebo-controlled study

BackgroundPingchan granule (PCG) is a traditional Chinese medicine for Parkinson's disease (PD). Hypothesis/PurposeThis was the first study aiming to evaluate the efficacy and safety of PCG for motor symptoms, gait impairments and quality of life in PD. Study Design and MethodsIn this multicenter, randomized, double-blind, placebo-controlled trial, 292 participants were included and followed for 9 months, randomly assigned at a 1:1 ratio to receive PCG or placebo. The primary outcome was the severity of motor symptoms assessed by Movement Disorder Society Unified Parkinson's Rating Scale III (MDS-UPDRS-III) motor score. Secondary outcomes included timed up and go test (TUG), functional gait assessment (FGA), freezing of gait (FOG), and quality of life assessed by Parkinson's disease questionnaire (PDQ-39). Assessments were done at baseline (T0), 3 months (T1), 6 months (T2) and 9 months (T3). Trial registration: Chinese Clinical Trial Register, ChiCTR-INR-1,701,194. ResultsGeneralized estimating equation analyses revealed that PCG group had significantly better improvement in MDS-UPDRS-III motor score than placebo group, as well as its domain scores of axial symptoms, bradykinesia, rigidity, and tremor. Improvements of TUG time, FGA, FOG questionnaire (FOGQ), and PDQ39 scores were also observed. ConclusionPCG had a long-lasting efficacy for motor symptoms and function in PD with good tolerance, supporting that PCG might be a viable alternative in the management of PD.

A quantitative systems pharmacology model for simulating OFF-Time in augmentation trials for Parkinson's disease: application to preladenant.

The clinical impact of therapeutic interventions in Parkinson's disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion channel effector proteins based on experimentally observed intracellular signaling. The calculated beta/gamma (b/g) power spectrum of the local field potentials in the subthalamic nucleus was previously calibrated on the clinically relevant Unified Parkinson's Disease Rating Scale (UPDRS). When combining this QSP model with PK modeling of different formulations of L-DOPA, we calculated the b/g fluctuations over a 16h awake period and used a weighted distance from a specific threshold to determine the cumulative liability of OFF-Time. Prediction of OFF-time with clinical observations of different L-DOPA formulations showed a significant correlation. Simulations show that augmentation with the adenosine A2A antagonist preladenant reduces OFF-time with 6min for carbidopa/levodopa 950mg 5-times daily to 37min for 100mg L-DOPA - 3 or 5 times daily. Exploring delays between preladenant and L-DOPA intake did not improve the outcome. Hypothetical A2A antagonists with an ideal PK and pharmacology profile can achieve OFF-Time reductions ranging from 9.5min with DuoDopa to 55min with low dose L-DOPA formulations. Combination of the QSP model with PK modeling can predict the anticipated OFF-Time reduction of novel A2A antagonists with standard of care. With the large number of GPCR in the model, this combination can support both the design of clinical trials with new therapeutic agents and the optimization of combination therapy in clinical practice.

Is 18F-DOPA a valid cardiac sympathetic neuroimaging agent?

18F-Dopamine positron emission tomography is a validated method for identifying cardiac noradrenergic deficiency, a characteristic feature of Lewy body forms of neurogenic orthostatic hypotension; however, 18F-dopamine is a research drug. Brain 18F-DOPA positron emission tomography is FDA-approved. Since 18F-DOPA is converted to 18F-dopamine in the heart, 18F-DOPA might be useful for cardiac sympathetic neuroimaging. We compared 18F-DOPA with 18F-dopamine in patients who either had or did not have low 18F-dopamine-derived radioactivity. Brain and cardiac 18F-DOPA scanning and cardiac 18F-dopamine scanning were done on separate days in patient groups with neurogenic orthostatic hypotension or Parkinsonism or control subjects across a range of values for 18F-dopamine-derived radioactivity. The lower limit of normal for myocardial 18F-dopamine-derived radioactivity was 6000Bq-kg/cc-MBq. We also examined inter-relationships among cardiac 18F-DOPA-derived radioactivity, cardiac 18F-dopamine-derived radioactivity, putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity, and Unified Parkinson Disease Rating Scale scores in patients with or without Parkinsonism. For putamen/occipital cortex ratios, the cutoff value was 2.70. Twelve subjects had severely decreased and eight normal cardiac 18F-dopamine-derived radioactivity. Cardiac 18F-DOPA-derived radioactivity did not distinguish the two groups and was unrelated to 18F-dopamine-derived radioactivity. Left ventricular myocardial 18F-DOPA-derived radioactivity was poorly resolved from that in the chamber. Putamen/occipital cortex ratios of 18F-DOPA-derived radioactivity were negatively correlated with Unified Parkinson Disease Rating Scale scores (-0.67, p = 0.0015). 18F-DOPA does not seem to be a valid cardiac sympathetic neuroimaging agent, although brain 18F-DOPA scanning provides a biomarker of Parkinsonism.

Mixed kernel SVR addressing Parkinson's progression from voice features.

Parkinson’s Disease (PD) is a progressive neurodegenerative disease with multiple motor and non-motor characteristics. PD patients commonly face vocal impairments during the early stages of the disease. In this article, the aim is to explain the Unified Parkinson’s Disease Rating Scale (UPDRS) as a measure of the progression of Parkinson’s disease using a set of covariates obtained from voice signals. In particular, a Support Vector Regression (SVR) model based on a combination of kernel functions is introduced. Theoretically, this proposal, that relies on a mixed kernel (global and local) produces an admissible kernel function. The optimal fitting was obtained for the combination given by the product of radial and polynomial basis. Important results are the non-linear relationships inferred from the features to the response, as well as a considerable improvement in prediction performance metrics, when compared to other learning approaches. Furthermore, with knowledge on factors such as age and gender, it is possible to describe the dynamics of patients’ UPDRS from the data collected during their monitoring. In summary, these advances could expand learning processes and intelligent systems to assist in monitoring the evolution of Parkinson’s disease.

Clinical factors and dopamine transporter availability for the prediction of outcomes after globus pallidus deep brain stimulation in Parkinson’s disease

We aimed to investigate the predictive value of preoperative clinical factors and dopamine transporter imaging for outcomes after globus pallidus interna (GPi) deep brain stimulation (DBS) in patients with advanced Parkinson’s disease (PD). Thirty-one patients with PD who received bilateral GPi DBS were included. The patients underwent preoperative [18F] FP-CIT positron emission tomography before DBS surgery. The Unified Parkinson’s Disease Rating Scale (UPDRS) were used to assess outcomes 12 months after DBS. Univariate and multivariate linear regression analysis were performed to investigate the association between clinical variables including sex, age at onset of PD, disease duration, cognitive status, preoperative motor severity, levodopa responsiveness, daily dose of dopaminergic medication, and dopamine transporter availability in the striatum and outcomes after GPi DBS. Younger age at onset of PD was associated with greater DBS motor responsiveness and lower postoperative UPDRS III score. Greater levodopa responsiveness, lower preoperative UPDRS III score and lower striatal dopamine transporter availability were associated with lower postoperative UPDRS III score. Younger age at onset was also associated with greater decrease in UPDRS IV score and dyskinesia score after GPi DBS. Our results provide useful information to select DBS candidates and predict therapeutic outcomes after GPi DBS in advanced PD.

Effect of acupuncture for non-motor symptoms in patients with Parkinson's disease: A systematic review and meta-analysis.

BackgroundAlthough non-motor symptoms of Parkinson’s disease (PD) are serious, effective treatments are still lacking. Acupuncture may have clinical benefits for non-motor symptoms of PD patients, but high-quality evidence supporting this possibility is still limited. Hence, we conducted this meta-analysis to evaluate the effect of acupuncture treatment on non-motor symptoms in patients with PD.MethodsRandomized controlled trials (RCTs) of acupuncture treatment for PD were retrieved from the following electronic databases: Medline (OVID), Embase (OVID), Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese BioMedical Literature Database, Chonqing VIP (CQVIP), and Wangfang database. Studies evaluating non-motor symptoms of PD were retrieved. Methodological quality was assessed using the Cochrane Handbook for Systematic Reviews of Interventions.ResultsA total of 27 RCTs were included, among which 8 outcomes related to non-motor symptoms were evaluated. The results showed that acupuncture combined with medication had benefits for PD-related insomnia relative to medication alone or sham acupuncture [standardized mean difference (SMD) = 0.517; 95% confidence interval (CI) = 0.242–0.793; p = 0.000], and acupuncture treatment had benefits at 8 weeks (SMD = 0.519; 95% CI = 0.181–0.857; p = 0.003). Regarding depression, acupuncture treatment was more effective (SMD = −0.353; 95% CI = −0.669 to −0.037; p = 0.029) within 2 months (SMD = −0.671; 95% CI = −1.332 to −0.011; p = 0.046). Regarding cognition, quality of life, and Unified Parkinson’s Disease Rating Scale (UPDRS) I and II scores, acupuncture treatment was effective [SMD = 0.878, 95% CI = 0.046–1.711, p = 0.039; SMD = −0.690, 95% CI = −1.226 to −0.155, p = 0.011; weighted mean difference (WMD) = −1.536, 95% CI = −2.201 to −0.871, p = 0.000; WMD = −2.071, 95% CI = −3.792 to −0.351, p = 0.018; respectively]. A significant difference was not found in terms of PD-related constipation. Only one study evaluated PD-related fatigue.ConclusionThe results of the analysis suggested that acupuncture treatment could ameliorate the symptoms of depression, quality of life, cognition, total mentation, behavior and mood, and activities of daily living in PD patients. Nevertheless, more prospective, well-designed RCTs with larger sample sizes are required to confirm our findings.

Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis.

BackgroundPimavanserin, a selective 5-HT2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis.AimWe aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis.MethodsThis analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined.ResultsThe pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [−2.4 (0.69)] and placebo [−2.3 (0.60)] (95% Confidence Interval [CI]:−1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 (n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was −1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label (n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses.ConclusionsPimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.

Psychiatric Symptoms in Parkinson's Disease Patients before and One Year after Subthalamic Nucleus Deep Brain Stimulation Therapy: Role of Lead Positioning and Not of Total Electrical Energy Delivered.

Parkinson’s disease (PD) patients may experience neuropsychiatric symptoms, including depression, anxiety, sleep disturbances, psychosis, as well as behavioral and cognitive symptoms during all the different stages of the illness. Deep Brain Stimulation (DBS) therapy has proven to be successful in controlling the motor symptoms of PD and its possible correlation with the occurrence or worsening of neuropsychiatric symptoms has been reported. We aimed to assess the neuropsychiatric symptoms of 14 PD patients before and after one year of Subthalamic Nucleus (STN)-DBS and to correlate the possible changes to the lead placement and to the total electrical energy delivered. We assessed PD motor symptoms, depression, anxiety, apathy, impulsivity, and suicidality using clinician- and/or self-administered rating scales and correlated the results to the lead position using the Medtronic SuretuneTM software and to the total electrical energy delivered (TEED). At the 12-month follow-up, the patients showed a significant improvement in PD symptoms on the UPDRS (Unified Parkinson’s disease Rating Scale) (−38.5%; p < 0.001) and in anxiety on the Hamilton Anxiety Rating Scale (HAM-A) (−29%; p = 0.041), with the most significant reduction in the physiological anxiety subscore (−36.26%; p < 0.001). A mild worsening of impulsivity was detected on the Barratt Impulsiveness Scale (BIS-11) (+9%; p = 0.048), with the greatest increase in the attentional impulsiveness subscore (+13.60%; p = 0.050). No statistically significant differences were found for the other scales. No correlation was found between TEED and scales’ scores, while the positioning of the stimulating electrodes in the different portions of the STN was shown to considerably influence the outcome, with more anterior and/or medial lead position negatively influencing psychiatric symptoms.

S1548 GI Dysmotility Symptoms Are Not Associated With Increased L-Dopa Requirements in Parkinson’s Disease Patients

Introduction: Gastrointestinal (GI) motility disorders like gastroparesis or small bowel bacterial overgrowth are thought to impair efficacy of L-dopa, which is absorbed in the proximal small intestine, resulting in motor fluctuations among Parkinson’s Disease (PD) patients that prompt dosage increases. While symptoms of dysmotility are frequently reported in PD, results are mixed concerning their effect, if any, on L-dopa pharmacokinetics. In this study, we compare L-dopa equivalent daily dose (LEDD) and motor function among patient with 5 upper GI symptoms to study the possible relationship between dysmotility symptoms and increased L-dopa requirement. Methods: Two hundred PD patients evaluated by outpatient neurology at Mass General Brigham Healthcare between 2018-2019 were included. History of 5 upper GI symptoms (dysphagia, nausea, vomiting, epigastric pain, and bloating), as well as LEDD were obtained from the medical record. Unified PD Rating Scale (UDPRS) part III motor exam scores off medication were extracted from clinical notes. Differences between LEDD and UDPRS motor scores among patients with and without a history of each of the 5 GI symptoms were calculated via Student t-tests. Results: Dysphagia was significantly associated with increased LEDD (230mg, P=0.0067) as well as increased motor severity (4.6 UDPRS, P=0.036). In contrast, nausea was associated with decreased LEDD (-187 mg, P=0.030) despite similar motor severity (1.1 UDPRS, P=0.63) to those without nausea (Table). There were no differences in LEDD and UDPRS scores among patients with and without vomiting, epigastric pain, and bloating. Conclusion: Except dysphagia, we found that GI dysmotility symptoms were not associated with increased LEDD nor increased motor severity. This suggests that symptomatic GI dysmotility may not be directly related to poor L-dopa absorption, a common clinical question for PD patients referred to GI. While dysphagia was linked with higher LEDD, this may have stemmed from higher UDPRS scores in this population. Interestingly, those with nausea required lower LEDD despite comparable motor severity. Nausea, a frequent symptom of delayed intestinal transit, may extend absorption time leading to better motor outcomes on less L-dopa. However, further studies are needed to discern any underlying mechanism. Our results nonetheless indicate that clinical management of dysmotility may not reduce motor fluctuations and the need for increased L-dopa as previously presumed. Table 1. - Changes in L-dopa Requirements and Motor Severity in the Presence of Dysmotility Symptoms GI Symptom ΔLEDD, mg (SD) P value ΔUDPRS III (SD) P value Nausea -187 (86) 0.03 1 (2) 0.633 Vomiting 11 (95) 0.91 -2 (2) 0.343 Dysphagia 230 (84) 0.007 5 (2) 0.036 Epigastric pain 101 (104) 0.33 0 (3) 0.881 Bloating 62 (99) 0.533 1 (2) 0.764 LEDD—L-dopa equivalent daily dose UDPRS—Unified Parkinson's Disease Rating Scale.

Feasibility and usefulness of a consumer-grade device for physical activity monitoring for patients with Parkinson's disease and Parkinsonism

The identification of the best measures to improve quality of life, awareness and care management for senior users with neurodegenerative diseases, and the implementation of personalized recommendations to support the user through gamification techniques and to adopt healthy habits, to maintain a good daily routine and to follow the prescribed actions by professionals for maintaining and improving their health condition, are the main contributions of PROCare4Life, an EU funded project. In fact, by proposing an integrated scalable and interactive care ecosystem, this solution can be easily adapted to the reality of several chronic diseases. The ability to passively track continuous ambulatory activity over time in a real-world scenario in patients with Parkinson’s disease (PD) has many potential uses. Wrist-worn physical activity monitors may be a valuable tool for tracking and/or increasing physical activity among patients with Parkinson. Because of differences in technology acceptance associated with age, and variable clinical conditions, feasibility and usefulness of Fitbits may vary among these subjects. The purpose of this study was to evaluate the patients’ adherence during the period of physical activity monitoring and to analyze the correlation between steps counts and clinical parameters. Patients with idiopathic PD (Parkinson’s disease) or Parkinsonism were recruited at Casa di Cura del Policlinico (Milan, Italy). Participants attended one assessment session at hospital with an expert neurologist. Age, gender, disease duration, falls history and medication intake were collected by an interview. Disease severity was measured using the Unified Parkinson’s Disease Rating Scale (UPDRS) and stage of disease rated using Hoehn and Yahr scale (H&Y). All participants signed an informed consent. All research procedures were approved by the Local Ethics Committee. Patients’ physical activity monitoring was performed by means of the wearable sensor Fitbit Versa 2 (Fitbit Inc, San Francisco, California, USA), a small wearable activity tracker that is worn like a watch with a triaxial accelerometer and that displays step count. The activity tracker was provided to patients at the time of enrollment together with the instructions for use. Patients were asked to wear it at all times for 60 days, excluding while bathing and sleeping. Step count was recorded while participants wore the smartwatch. While no specific recommendations were given on amount of physical activity and there was no daily step target, patients were invited to follow their daily routine for the period of the monitoring. Correlation between step count data from the Fitbit, demographic indicators and clinical scales were examined using Pearson’s correlation coefficient. 13 subjects were enrolled (73.23 ± 6.56 years; 8 males; 10 with diagnosis of PD; UDPRS at baseline: 67.92 ± 35.30; H&Y: 2.69 ± 0.75). Three of the 13 participants did not complete the study due to wristband’s usability problems. Among the subjects that completed the study, the number of mean daily steps during the monitoring period was 4879.76 ± 3385.69, with individual participants’ means ranging from 62.54 to 11727.86. The majority of subjects (60%) could be classified as sedentary (i.e., mean daily steps lower than 5000) [1]. Using the adherence definition of >100 steps, on average the participants wore wristband 49.80 ± 16.86 days, with an adherence of 83.00 ± 28.11% of the 60-day study period. Noteworthy, for the quasi-totality of subjects (70%) the adherence was very high (96.67 ± 5.69%), for two participants was high (68.33-75.00%) and for one participant very low (10.00%). A significant correlation between steps taken and UPDRS (R= -0.76, p=0.010) at the end of the monitoring period was found. Removing the subjects with very low adherence and the one that never reached 5000 steps per day, a high significant correlation for steps taken and H&Y scale (R = 0.71, p = 0.047) resulted. An additional high significant correlation was found between steps taken and the differences in global score of UPDRS (R = 0.75, p = 0.031) assessed at the beginning and at the end of the monitoring period. The preliminary results show that the use of a consumer-grade device in patients with neurodegenerative disease is feasible with reasonable adherence. The positive correlation between steps taken and modification in UPDRS scales means that higher steps correspond to a smaller worsening in UPDRS scale assessment. These preliminary results, if confirmed in large scale scenario, could be useful in the framework of the PROCare4Life project, in order to develop and validate an ICT-based integrated care ecosystem that will improve the quality of life of the users in their care delivery, and by improving social and medical services through automation and digitalisation.

Soluble LRP-1 in Parkinson’s disease: clues for paradoxical effects

Background: Low density lipoprotein receptor-related protein-1 (LRP-1) is highly expressed in the central nervous system and plays a role in neurodegenerative disorders. The available data on this subject-matter seem to support the presence of a correlation between LRP-1 levels and abnormal aggregation of a plurality of proteins, including tau, amyloid, and α‑synuclein. Understanding the molecular mechanisms underlying Parkinson’s disease (PD) is critical for development of new therapies. Aim: To investigate serum soluble LRP-1 (sLRP-1) concentrations in patients with PD and explored their potential role as a biomarker in diagnosis and prognosis of disease. Methods: Based on well-defined inclusion and exclusion criteria, we have included 133 PD patients and 45 healthy controls. The clinical severity was assessed using Hoehn Yahr and Unified PD Rating Scale (UPDRS). Following a fasting period, venous blood samples were taken, and centrifuged. Serum samples were stored until analysis. sLRP-1 was measured by ELISA assay. Results: The median of serum sLRP-1 levels was higher in PD patients compared to that in healthy controls, but without reaching a statistical significance. There was a positive, but statistically insignificant, correlation between sLRP-1 levels and duration of disease. sLRP-1 levels had a significant correlation with UPDRS Parts I and IV. Patients with hypertension showed lower levels of sLRP-1. Conclusion: The present study suggests that serum sLRP-1 concentrations are associated with the factors influencing prognosis of PD and disease severity. Further studies are needed to definitively determine whether or not sLRP-1 can be utilized as a diagnostic and prognostic biomarker for PD.

Spine kinematics in patients with Parkinson's disease with and without Freezing of Gait

Despite the importance of spine and upper limb movements in walking, most of previous studies on human locomotion focused exclusively on lower limbs [1]. Patients with Parkinson’s disease (PD) are characterized by trunk postural alterations and reduced limb movements [2,3]. It is still unclear to what extent postural alterations in PD concur to, or counteract, poor balance [3]. Specifically, their contribution to the occurrence of freezing of gait (FoG), an episodic failure of forward stepping exposing patients to high risk of falls, is yet to be fully elucidated. We aimed at characterizing spine kinematics in PD patients with and without FoG during walking and standing. We investigated linear gait in a cohort of 14 patients with PD. They were grouped into patients with (PDF, N=6, Unified Parkinson Disease Rating Scale part III [UPDRS-III]: 35(23-49)) and without FoG (PDNF, N=7, UPDRS-III: 31(12-48)), based on their clinical history. All patients performed the experimental protocol after overnight suspension of all dopaminergic drugs (meds-off). They were instructed to perform at least three trials of barefoot walking at self-selected speed on a walkway of 8 meters. A session of quiet standing of about 60 s ended the experiment. Kinematics was monitored by means of a full body marker protocol [4]. Three markers placed on the seventh cervical vertebrae (C7), the maximum kyphosis, and a virtual marker reconstructed in correspondence of the coccyx served as reference points for the calculation of the lordosis and kyphosis spine angles. Specifically, the coccyx was reconstructed in the pelvis reference system based on previous radiography studies [5]. The distance between the C7 and the middle point between the posterior-superior iliac spines (MID-PSIS) was used to estimate the rachis length. Height of the C7 and MID-PSIS were also computed. Trunk inclination was defined as the angle between the vertical axis of the laboratory and the line connecting C7 and MID-PSIS. The shoulder-pelvis angle was computed as the angle between the line connecting the two acromion and the line connecting the anterior superior iliac spines and projected to the frontal and horizontal planes of the pelvis reference system. For the walking sessions, all variables were computed and averaged across gait cycles at steady-state velocity. For the standing sessions, variables were averaged over time. A Kruskal–Wallis test identified differences between groups for each condition (i.e., walking and standing). A Wilcoxon matched-pair test was used to compare standing and walking conditions inside each group. Threshold for statistical significance was set at 0.05. No differences between groups were found in the spine variables during standing and walking. PDF showed higher values of the shoulder-pelvis angles in the frontal plane only during the standing condition. During walking, the average height of the MID-PSIS decreased with respect to standing in both groups, while C7 height decreased selectively in the PDNF group, despite a trend was present also in the PDF group. Only PDNF patients showed increased trunk inclination during walking with respect to standing. Our analyses did not show a clear difference in the spine kinematics during gait and standing between PDF and PDNF patients. We speculate that trunk postural alterations may not be at the basis of the occurrence of FoG, but rather be compensatory (ineffective) attempts to overcome this symptom. Considering the small sample size employed in our study, further analyses on larger cohorts are warranted to confirm these preliminary results.

Assessment of severity of Parkinson’s disease by optical coherence tomography

Background: Parkinson’s disease (PD) is the second most common movement disorder after essential tremor. Diminished visual acuity, color vision, and contrast sensitivity are also described in PD. Optical coherence tomography (OCT), a producible test for axonal degeneration, helps in prognosticating diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis. Aims and Objectives: To assess the severity of Parkinson’s disease with the changes in various variables of OCT. The objective is to evaluate variables such as (RNFL, CMT, TMV) of both eyes with SD – OCT. Materials and Methods: It is a hospital-based cross-sectional study conducted for a period of 22 months at the department of neurology. A total of 55 PD patients and 30 age- and sex-matched controls were evaluated. Results: There was a significant difference between patients and controls in average retinal nerve fiber layer (RNFL) and all RNFL quadrants in both the eyes (P&lt;0.001). A significant negative correlation was found between the RNFL thickness and Unified Parkinson’s Disease Rating Scale (UPDRS) motor score and Hoehn and Yahr (H&amp;Y) score in both the eyes (P&lt;0.001). A significant negative correlation was found between total macular volume (TMV) and central macular thickness (CMT) with UPDRS motor score in both the eyes (P&lt;0.001). A significant negative correlation was found between CMT and H&amp;Y stage in both the eyes (P&lt;0.001). There was a significant difference between patients and controls in CMT and TMV in both the eyes (P&lt;0.001). Conclusion: A significant negative correlation between severity and stage of the PD with OCT values was identified, which may suggest the possibility of dopaminergic depletion in the retina corresponding with basal ganglia dopamine depletion.

Association Between Asymmetry of Substantia Nigra Hyperechogenicity and Clinical Characteristics in Different Parkinson Disease Subtypes: A 5-Year Follow-up Study.

Our study focused on three aspects to determine whether bilateral substantia nigra hyperechogenicity (SN+) is asymmetrical, whether the asymmetry of SN+ is related to the clinical features and whether there is variation in SN+ asymmetry during the progression of Parkinson disease (PD). This follow-up study included 234 patients with PD, who were divided into tremor PD (TD, n=67) and non-tremor PD (NTD, n=167) groups based on the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. All participants underwent transcranial sonography (TCS) and clinical assessment. In both the TD and NTD groups, the initial SN+ was larger than the non-initial SN+. The initial SN+ was associated with Hoehn and Yahr (H&amp;Y) stage, PD duration and initial UPDRS III, and the SN+ asymmetry index was associated with motor asymmetry index in the TD group. In the NTD group, the initial SN+ was associated only with initial UPDRS III. After a 5-year follow-up, the area of SN+ on both sides was gradually inclining to symmetry in the NTD group. Our study determined that SN+ asymmetry could reflect asymmetrical characteristics of PD. Furthermore, we inferred that the dynamic change in SN+ asymmetry might reflect a dynamic change in motor asymmetry in the NTD group.

Initial Vestibular Function May Be Associated with Future Postural Instability in Parkinson's Disease.

Backgrounds: We aimed to understand the association between initial vestibular function examination and postural instability (PI) development in Parkinson’s disease (PD). Methods: After screening 51 PD patients, we divided 31 patients into 2 groups based on the presence of PI at the follow-up visit and compared the clinical features and vestibular-evoked myogenic potential (VEMP) variables. Results: The mean values of Hoehn and Yahr stage, Unified Parkinson’s Disease Rating Scale (UPDRS) part III, and item 30 (postural stability) of UPDRS were larger in patients with PI at a follow-up visit (p = 0.000, 0.006, 0.048, respectively). In VEMP analyses, the onset latencies of left and right cervical VEMPs were significantly reduced in patients with PI (p = 0.013, 0.040, respectively). Conclusion: We found that the initial VEMP test may be associated with later postural imbalance in PD, suggesting the baseline evaluation may help predict future PI occurrence. A more significant number of patients and more long-term follow-ups are likely to be required for confirmation.