Levodopa Dose Research Articles

“Frailty” in patients with Parkinsonian Spectrum Disorders: an observation from a tertiary care teaching hospital

Patients with movement disorders are in a pre-frail state due to the physical limitation or reduction in tolerance to physical stress. The study was conducted in the Department of Neurology of a tertiary care teaching hospital in Northern-east Rajasthan with 50 patients. Inclusion criteria: patients with parkinsonian features aged >18 years; and willing to give consent regarding participation in the study. Exclusion criteria: patients with age <18 years; not willing to participate in the study; and exclusion of alternative diagnosis. Frailty and pre-frailty states were assessed using the Fried’s criteria. Modified Frailty Index (MFI) was used to classify it as mild, moderate, and severe. Unified Parkinson's Disease Rating Scale (UPDRS), Multisystem Atrophy Rating Scale (MSARS), and Progressive Supranuclear Palsy Rating Scale (PSPRS) were used for respective disorders. The data was compiled using an MS Excel sheet, and SPSS 20 was used for statistical analysis. Thirty-nine patients fulfilled the criteria for “frailty-phenotype”; only 9 were “pre-frail”, and 2 were non-frail. On the MFI, patients with atypical parkinsonism had severe frailty with a mean index score of 0.54, where the mean scores were higher in the progressive supranuclear palsy (PSP) group (0.57) than in the multisystem atrophy (MSA) group (0.5). Patients with idiopathic Parkinson’s disease (IPD) had mild to moderate frailty with a mean score of 0.29 (Range 0.17-0.51). With a higher UPDRS score, the frailty index score in IPD patients was also higher, as was PSPRS in patients with PSP and UMSARS in patients with MSA. The mean MMSE score was also lower in the group with a higher frailty index. The levodopa dose requirement was higher in the frail group than in the non-frail or prefrail group (125mg/day vs. 625mg/day; p<0.05). Frailty is part and parcel of neurodegenerative movement disorders, including movement disorders, and adds to the burden of disease.

Deep brain stimulation in Parkinson disease, a switch for on/off dystonia

BackgroundDystonia is common in Parkinson’s disease (PD) patients, affecting about 30% of them. Bilateral subthalamic nucleus deep brain stimulation (DBS) can sometimes lead to dystonia, but this relationship is not well understood. ObjectiveTo provide a better understanding of dystonia's causes and its connection to deep brain stimulation. MethodsWe conducted a retrospective analysis of clinical data from 80 PD patients who underwent bilateral subthalamic nucleus stimulation, focusing on dystonia before and after surgery and its relation to medication state (on/off-dystonia). ResultsAfter deep brain stimulation, off-dystonia had a higher recovery rate than on-dystonia (43.5% versus 9.1%). Among patients suffering for on-dystonia, 74.4% had it for the first time after-surgery; these patients assumed higher doses of levodopa before DBS. ConclusionsPatients with off-dystonia before surgery tend to improve after DBS. Otherwise, deep brain stimulation could have the role of “additive boost” in the process of sensitization of striato-pallidal pathways and lead to on-dystonia in particular patients.

Efficacy and safety of safinamide in Parkinson's disease patients with motor fluctuations without levodopa dosage escalation over 18 weeks: KEEP study.

This multicentre, prospective, single-arm study evaluated safinamide as add-on therapy to levodopa in Korean patients with Parkinson's disease (PD) with motor fluctuations with≥1.5 h of "off" time daily, who took levodopa≥3 times/day (n = 199). Baseline levodopa and dopamine agonist doses were maintained without escalation during the 18-week treatment period. Participants received safinamide 50 mg/day for 2 weeks and 100 mg/day thereafter. PD diaries and questionnaires (Parkinson's Disease Questionnaire, PDQ-39; Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale, MDS-UPDRS part 3 and part 4; King's Parkinson's Disease Pain Scale, KPPS; Mini-Mental State Examination, MMSE) were assessed at baseline and at week 18. Treatment-emergent adverse events (TEAEs) were recorded. Mean disease duration was 6.6 years, and mean levodopa equivalent daily dose was 721.1 mg/day. At week 18, significant improvements from baseline were seen for the co-primary endpoints, mean daily "off" time (-1.3±2.4 h, p<0.001) and quality of life (QoL) based on PDQ-39 summary index (-2.7±10.3, p<0.001), Moreover, significant improvements were seen in motor symptoms and motor complications (MDS-UPDRS part 3 and 4), daily "on" time without dyskinesia (all p<0.001) and pain (KPPS; p = 0.013). TEAEs occurred in 40.2% of patients, with most being mild in severity. In conclusion, safinamide at a dosage of 100 mg/day significantly improved motor symptoms, QoL, and pain, and demonstrated a favourable safety profile without levodopa dosage escalation during the 18-week treatment period in Korean patients with PD.Trial registration number and date: NCT05312632, First Posted: April 5, 2022.

Evaluating efficacy and safety of Saffron add-on treatment in improvement of motor and depressive symptoms of patients with Parkinson’s disease: A randomized, double-blind, placebo-controlled clinical trial

AimEvidence has highlighted neuroprotective effects of saffron in animal models of Parkinson’s disease (PD). The present study investigated the efficacy and safety of add-on saffron on motor and depressive symptoms of patients with PD. MethodsThis study was an 8-week, randomized, double-blind, and parallel-group clinical trial. Known cases of PD with depression were randomized to receive either a routine treatment (levodopa or levodopa-equivalent dose of a dopamine agonist) plus saffron capsule (15 mg bid) or routine treatment plus placebo. All participants were assessed using the Hamilton Depression Rating Scale (HAMD), Geriatric Depression Scale-30 (GDS-30), item 3 of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 1, MDS-UPDRS part 3, and H and Y scale at baseline and at week 8. ResultsA total of 52 patients (25 in saffron and 27 in placebo groups) were included. Our results demonstrated that saffron could not improve motor symptoms of PD patients (F=0.53, df=1, p=0.424). However, repeated-measures analysis showed a significant effect of time × treatment (F=8.24, df=1, p=0.006) on HAMD scores, indicating a greater improvement of depressive symptoms in saffron compared to placebo groups. Our study showed nonsignificant findings regarding the secondary outcome measures (GDS-30, item 3 of MDS-UPDRS part 1, and H and Y scale). We showed that treatment with saffron is safe in PD. ConclusionWe substantiated that add-on treatment with saffron significantly improved depression, but not motor symptoms, in PD. Further trials with larger sample sizes and longer follow-ups are needed to confirm our findings.

CVN424, a GPR6 inverse agonist, for Parkinson's disease and motor fluctuations: a double-blind, randomized, phase 2 trial

CVN424 is a GPR6 inverse agonist that provides selective pharmacological control of the indirect striatopallidal pathway. We assessed the safety and efficacy of CVN424 as an adjunctive treatment to levodopa for reducing OFF-time in individuals with Parkinson's disease (PD) experiencing motor-fluctuations. This was a randomised, double-blind, placebo-controlled study conducted at 21 sites across the United States to evaluate two doses of CVN424 (NCT04191577). Patients with PD (Hoehn and Yahr stages 2-4) who were on a stable dose of levodopa and experiencing ≥2h of daily OFF-time were randomised (1:1:1) to receive either once-daily CVN424 (50mg or 150mg) or placebo for a 28-day treatment period. The primary endpoints were safety and tolerability. The key secondary endpoint was the change from baseline to Day 27 in OFF-time. The study was conducted from December 23, 2019, to October 14, 2021. Out of 198 participants screened, 141 eligible participants were randomised to one of the three treatment groups (n=47 per group), and 127 participants completed the 28-day treatment period. The most common treatment emergent adverse events (TEAEs) were headache (2% with CVN424 50mg, 9% with CVN424 150mg, and 2% with placebo) and nausea (4% with CVN424 50mg, 6% with CVN424 150mg and 2% with placebo). No serious treatment-related adverse events were reported. On Day 27, the mean±standard deviation (SD) change from baseline in daily OFF-time was-1.3±3.0h in the CVN424 50mg group,-1.6±2.5h in the CVN424 150mg group, and-0.5±2.9h in the placebo group. The placebo-adjusted LS mean±standard error (SE) treatment difference was significant for the CVN424 150mg dose (1.3±0.56h, [95 CI%-2.41 to-0.19], nominal p=0.02). Treatment with CVN424 was safe and well-tolerated. Despite the short study duration and small sample size, the 150mg CVN424 dose provided a clinically meaningful reduction in daily OFF-time. This study supports the development of CVN424 for the treatment of PD. Cerevance.

Sleep Quality in Parkinson Disease: Clinical Insights and PSQI Reliability Assessment

AbstractSleep disturbances are prevalent in Parkinson disease (PD), encompassing a spectrum from parasomnias like REM sleep behavior disorder to symptoms of sleep-wake cycle dysregulation, such as insomnia and daytime sleepiness. This research investigates sleep quality in PD patients compared with a matched healthy control group and explores the relationships between PD clinical characteristics and sleep parameters. Additionally, the study assesses the reliability of the Pittsburgh Sleep Quality Index (PSQI) for PD patients by examining internal consistency. The study comprises 52 participants, 27 in the PD group and 25 in the healthy control group, matched for sex and age. Sleep quality revealed that PD patients experienced significantly poorer sleep quality than the control group (p = 0.009). Weak correlations were found between PSQI scores and the modified Hoehn and Yahr scale (p = 0.062), with no correlation observed with the daily equivalent dose of levodopa (L-DOPA). The prevalence of poor sleep quality (PSQI score &gt; 5) was 85.1% for PD patients and 68% for the control group. The internal consistency analysis of the PSQI yielded a Cronbach's α of 0.588 for the PD group. While the PSQI demonstrates utility in detecting general sleep abnormalities and gauging patient perceptions of sleep quality in PD, its limitation as a global score is emphasized. The index prioritizes sleep habits and may not fully capture important sleep disorders in this population. These findings underscore the complex relationship between PD and sleep quality, suggesting the need for a comprehensive approach to assess and address sleep disturbances in PD patients.

The Effect of Chronic Treatment with the Inhibitor of Phosphodiesterase 5 (PDE5), Sildenafil, in Combination with L-DOPA on Asymmetric Behavior and Monoamine Catabolism in the Striatum and Substantia Nigra of Unilaterally 6-OHDA-Lesioned Rats.

The use of phosphodiesterase inhibitors in the treatment of Parkinson's disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra.

Does Delaying Levodopa Prevent Motor Complications in Parkinson's Disease? A Meta-Analysis.

There has been a long debate whether delaying treatment with levodopa prevents motor complications in Parkinson's disease (PD). We performed a meta-analysis on randomized clinical trials (RCTs) that compared early- versus delayed-start treatment with levodopa in PD. A systematic review was conducted in PubMed, EMBASE, and Web of Science databases from inception to July 1, 2023. Only RCTs that compared early and delayed levodopa treatment in PD were included. Non-randomized comparisons from follow-up studies were included as well. Our primary outcomes were occurrence of overall motor complications, motor fluctuations, and dyskinesias. Seven studies with a total of 1149 patients (636 in the early-start group and 513 in the delayed-start) were included in our analysis. There was no difference between groups regarding motor complications (OR 1.39; 95% CI: 0.68-1.72; P = 0.37) or dyskinesias (OR 1.52; 95% CI: 0.90-2.57; P = 0.11). Motor fluctuations occurred less frequently in the early-start group (OR 0.70; 95% CI: 0.52-0.95; P = 0.02). Nonetheless, on subgroup analysis of dopamine agonists, rate of dyskinesias was smaller in the delayed-start group (OR 1.82; 95% CI: 1.08-3.07; P = 0.03). Delaying treatment with levodopa does not seem to prevent levodopa-related motor complications in PD. Adjunct treatment with dopamine agonists may reduce the need for higher doses of levodopa and thus reduce the risk for dyskinesias but this practice is often associated with a higher frequency of adverse effects related to dopamine agonists.

Opicapone for the treatment of early wearing-off in levodopa-treated Parkinson’s disease: pooled analysis of patient level data from two randomized open-label studies

BackgroundThe wearing-off phenomenon is a key driver of medication change for patients with Parkinson’s disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies.MethodsThe ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3–4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled.ResultsThe adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was − 62.8 min [8.8] in the opicapone group and − 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (− 29.0 [− 53.8, − 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society—Unified Parkinson’s Disease Rating Scale Part III subscore (− 4.1 with opicapone vs − 2.5 with levodopa 100 mg), also favored opicapone (− 1.7 [− 3.3, − 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%).ConclusionsIn these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off.

Classification of Parkinson's disease by deep learning on midbrain MRI.

Susceptibility map weighted imaging (SMWI), based on quantitative susceptibility mapping (QSM), allows accurate nigrosome-1 (N1) evaluation and has been used to develop Parkinson's disease (PD) deep learning (DL) classification algorithms. Neuromelanin-sensitive (NMS) MRI could improve automated quantitative N1 analysis by revealing neuromelanin content. This study aimed to compare classification performance of four approaches to PD diagnosis: (1) N1 quantitative "QSM-NMS" composite marker, (2) DL model for N1 morphological abnormality using SMWI ("Heuron IPD"), (3) DL model for N1 volume using SMWI ("Heuron NI"), and (4) N1 SMWI neuroradiological evaluation. PD patients (n = 82; aged 65 ± 9 years; 68% male) and healthy-controls (n = 107; 66 ± 7 years; 48% male) underwent 3 T midbrain MRI with T2*-SWI multi-echo-GRE (for QSM and SMWI), and NMS-MRI. AUC was used to compare diagnostic performance. We tested for correlation of each imaging measure with clinical parameters (severity, duration and levodopa dosing) by Spearman-Rho or Kendall-Tao-Beta correlation. Classification performance was excellent for the QSM-NMS composite marker (AUC = 0.94), N1 SMWI abnormality (AUC = 0.92), N1 SMWI volume (AUC = 0.90), and neuroradiologist (AUC = 0.98). Reasons for misclassification were right-left asymmetry, through-plane re-slicing, pulsation artefacts, and thin N1. In the two DL models, all 18/189 (9.5%) cases misclassified by Heuron IPD were controls with normal N1 volumes. We found significant correlation of the SN QSM-NMS composite measure with levodopa dosing (rho = -0.303, p = 0.006). Our data demonstrate excellent performance of a quantitative QSM-NMS marker and automated DL PD classification algorithms based on midbrain MRI, while suggesting potential further improvements. Clinical utility is supported but requires validation in earlier stage PD cohorts.

Neuroprotective effects of L-Dopa-modified zinc oxide nanoparticles on the rat model of 6-OHDA-ınduced Parkinson’s disease

Parkinson’s disease (PD) is a chronic neurodegenerative case. As the disease progresses, the response time to doses of levodopa (L-Dopa) becomes shorter and the effects of the drug are severely limited by some undesirable side effects such as the ‘on–off’ phenomenon. In several diseases, including Parkinson’s, nanoparticles can deliver antioxidant compounds that reduce oxidative stress. This study evaluates and compares the neuroprotective effects of L-Dopa-modified zinc nanoparticles (ZnNPs) in the 6-hydroxydopamine (6-OHDA)-induced PD rat model. For this purpose, the synthesis of NPs was carried out. Scanning electron microscopy, X-ray diffraction and Fourier transform infrared spectrophotometer were used for characterization. The rats were randomized into 9 experimental groups: control, lesion group (6-OHDA), 6-OHDA + 5 mg/kg L-Dopa, 6-OHDA + 10 mg/kg L-Dopa, 6-OHDA + 20 mg/kg L-Dopa, 6-OHDA + 20 mg/kg ZnNPs, 6-OHDA + 40 mg/kg ZnNPs, 6-OHDA + 30 mg/kg ZnNPs + L-Dopa, and 6-OHDA + 60 mg/kg ZnNPs + L-Dopa. Behavioral tests were performed on all groups 14 days after treatment. Phosphatase and tensin homolog, Excitatory amino acid transporter 1/2, and Glutamine synthetase gene analyses were performed on brain samples taken immediately after the tests. In addition, histological and immunohistochemical methods were used to determine the general structure and properties of the tissues. We obtained important findings that L-Dopa-modified ZnNPs increased the activity of glutamate transporters. Our experiment showed that glutamate increases neuronal cell vitality and improves behavioral performance. Therefore, L-Dopa-modified ZnNPs can be used to prevent neurotoxicity. According to what we found, results show that L-Dopa-modified ZnNPs will lend to the effective avoidance and therapy of PD.

Probiotic Supplements For Depression In Parkinson’s Disease (Pro-Park): A Randomized, Triple-Blind, Placebo-Controlled, Phase IIb Trial Protocol

Introduction: Parkinson’s disease (PD) is the second most prevalent degenerative neurological disorder globally. Comorbid major depressive disorder (MDD) is a common occurrence which adds considerably to disease burden. This protocol presents a study designed to investigate the effect of add-on probiotic supplementation on MDD in patients with PD. Methods: We designed a phase IIb, randomized, triple-blind, placebo-controlled study to evaluate the efficacy and safety of probiotics as an adjuvant treatment to selective serotonin reuptake inhibitors (SSRI) for patients with mild to moderate PD and MDD. Participants will be randomized to probiotics (n=62) or placebo (n=62) arms using a permuted block randomization approach. Co-primary outcomes include changes in Montgomery-Åsberg Depression Rating Scale (MADRS)scores and SSRI equivalent doses, which will be compared between groups using a bivariate joint model. Secondary outcomes will include changes in both Beck Depression Inventory-II (BDI-II) score and levodopa dose, which will be analyzed using t-tests or Mann-Whitney tests as appropriate. Concurrent validity between MADRS and BDI-II will be assessed using Pearson’s or Spearman’s correlation tests. Safety will be evaluated by comparing discontinuation rates and adverse events between groups using chi-square. Data will be analyzed using intention-to-treat and per-protocol analyses, and missing data will be addressed using multiple imputation methods. Discussion: Probiotics represent a potential new approach to managing depression in patients with PD by targeting the gut-brain axis. The results will offer crucial information about the safety and efficacy of a low-cost and readily available supplement that may alleviate depression in this vulnerable population.

Oral Levodopa Stimulates Copeptin Secretion in Children and Adolescents with Intact Posterior Pituitary Function

BackgroundCopeptin stimulation tests can be used in the differential diagnosis of polyuria-polydipsia syndrome. Current stimulation methods rely on intravenous or subcutaneous administration. Oral stimulus can further simplify the diagnostic approach. The levodopa stimulation test is widely used in the evaluation of growth hormone deficiency, and the dopamine pathway was reported to be associated with arginine vasopressin secretion. This study aims to investigate the effect of oral levodopa on copeptin secretion. MethodsThis study was a prospective observational single-center cohort study. Patients <18 years old with short stature and no symptoms of polyuria or polydipsia undergoing the levodopa stimulation test for suspected growth hormone deficiency were recruited from May 2023 to Nov 2023. Copeptin and growth hormone were measured at 0, 30, 60, 90, and 120 min during the levodopa test. The insulin tolerance test with copeptin and growth hormone measured at the same time points was conducted in part of patients. ResultsForty-four participants were included in the final analysis. In the levodopa stimulation test, the median (interquartile range) copeptin concentration increased from 5.20 (3.51, 8.25) pmol/L to a maximum of 19.36 (8.97, 108.08) pmol/L (P < .001), 3.94 (1.41, 13.88) times that of the baseline (P < .001). Compared with the insulin tolerance test, peak copeptin in the levodopa test was significantly higher (34.61 [13.67, 98.96] vs 8.88 [7.14, 15.42] pmol/L, P = .009). Higher copeptin was associated with a larger dose of levodopa. ConclusionsOral levodopa could be used to stimulate copeptin.

Precision Dopaminergic Treatment in a Cohort of Parkinson's Disease Patients Carrying Autosomal Recessive Gene Variants: Clinical Cohort Data and a Mini Review.

Parkinson's disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152-1810) in PRKN carriers and 765 ± 96.6 (range 660-850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Levodopa-induced dyskinesia in Parkinson's disease: Insights from cross-cohort prognostic analysis using machine learning

BackgroundProlonged levodopa treatment in Parkinson's disease (PD) often leads to motor complications, including levodopa-induced dyskinesia (LID). Despite continuous levodopa treatment, some patients do not develop LID symptoms, even in later stages of the disease. ObjectiveThis study explores machine learning (ML) methods using baseline clinical characteristics to predict the development of LID in PD patients over four years, across multiple cohorts. MethodsUsing interpretable ML approaches, we analyzed clinical data from three independent longitudinal PD cohorts (LuxPARK, n = 356; PPMI, n = 484; ICEBERG, n = 113) to develop cross-cohort prognostic models and identify potential predictors for the development of LID. We examined cohort-specific and shared predictive factors, assessing model performance and stability through cross-validation analyses. ResultsConsistent cross-validation results for single and multiple cohort analyses highlighted the effectiveness of the ML models and identified baseline clinical characteristics with significant predictive value for the LID prognosis in PD. Predictors positively correlated with LID include axial symptoms, freezing of gait, and rigidity in the lower extremities. Conversely, the risk of developing LID was inversely associated with the occurrence of resting tremors, higher body weight, later onset of PD, and visuospatial abilities. ConclusionsThis study presents interpretable ML models for dyskinesia prognosis with significant predictive power in cross-cohort analyses. The models may pave the way for proactive interventions against dyskinesia in PD by optimizing levodopa dosing regimens and adjunct treatments with dopamine agonists or MAO-B inhibitors, and by employing non-pharmacological interventions such as dietary adjustments affecting levodopa absorption for high-risk LID patients.

Risk factors for 3-year mortality in selected patients with Parkinson's disease from a Romanian cohort.

This study aimed to identify and analyze factors associated with a higher risk of 3-year mortality in patients with Parkinson's disease (PD) within a Romanian cohort, focusing on individuals with more advanced disease stages as indicated by the Hoehn and Yahr scale. We conducted a cross-sectional observational study on 42 patients with PD treated at the Neurology Clinic I, Cluj-Napoca County Emergency Clinical Hospital, between October 2019 and January 2021. All participants were at stages 2.5 or 3 on the Hoehn and Yahr scale at baseline. Various clinical, neuropsychological, and neurophysiological assessments were performed, including evaluations for motor and non-motor symptoms such as anhedonia (via the Snaith-Hamilton Pleasure Scale - SHAPS) and cognitive impairment. The use of antiparkinsonian medications and antidepressants was also recorded. Factors associated with higher mortality risk included a higher anhedonia score (SHAPS > 34; P = 0.03), higher levodopa doses (cutoff = 937.5 mg; P = 0.001), and the administration of mirtazapine (P = 0.04). These findings indicate that non-motor symptoms like anhedonia, along with higher medication doses and specific treatments, play a significant role in influencing mortality risk in advanced PD. This study highlights the multifaceted nature of mortality risk in patients with PD, particularly emphasizing the role of non-motor symptoms and pharmacological treatment. Tailored therapeutic strategies, including closer monitoring of anhedonia and careful management of medication dosages, may be essential in reducing mortality and improving patient outcomes in advanced stages of PD.

Levodopa modulates semantic fluency and uniqueness in non-demented patients with progressive supranuclear palsy.

Semantic fluency is the ability to name items from a given category within a limited time, which relies on semantic knowledge, working memory, and executive function. Similar to patients with Parkinson's disease (PD), patients with progressive supranuclear palsy (PSP) scored lower than healthy adults in the well-established semantic fluency test. However, it is unclear how unique are the produced words. This study examined the relationship between semantic fluency and words' uniqueness in patients with PSP. Twenty-seven patients with PSP Richardson's syndrome (PSP-RS), 37 patients with PD, and 41 healthy controls (HC) performed a standard semantic fluency test (animals), and their verbal responses were audio-recorded. We used the uniqueness to reflect the ability to produce both original and effective work, that is, creativity. The PSP-RS group produced fewer correct words and fewer unique words than the PD and HC groups. Moreover, the correlation between fluency and uniqueness was positive in the HC and PD groups but negative in the PSP-RS group. Importantly, the actual levodopa dose was positively correlated with the fluency but negatively correlated with the uniqueness in PSP-RS. The PSP-RS patients who took a greater dose of levodopa tended to produce more correct words but fewer unique words. These results suggested that levodopa may modulate semantic fluency and uniqueness in the early stages of PSP-RS.

Motor improvement of remote programming in patients with Parkinson's disease after deep brain stimulation: a 1-year follow-up.

Remote programming (RP) is an emerging technology that enables the adjustment of implantable pulse generators (IPGs) via the Internet for people with Parkinson's disease (PwPD) who have undergone deep brain stimulation (DBS). Previous studies have not comprehensively explored the effectiveness of RP in managing motor symptoms, often omitting assessments such as the rigidity and retropulsion tests during the follow-up. This study evaluates the comprehensive improvements in motor performance and the potential cost benefits of RP for PwPD with DBS. A retrospective analysis was conducted on two groups of patients-those who received RP and those who received standard programming (SP). Clinical outcomes including motor improvement, quality of life, and daily levodopa dosage were compared between the groups during a 12 (± 3)-month in-clinic follow-up. A total of 44 patients were included in the study, with 18 in the RP group and 26 in the SP group. No significant differences were observed in the frequency of programming sessions or clinical outcomes between the groups (p > 0.05). However, the RP group experienced significantly lower costs per programming session than the SP group (p < 0.05), despite patients in the former group living further from our center (p < 0.05). Our findings suggest that RP could significantly reduce the costs of programming for PwPD with DBS, especially without compromising the effectiveness of treatment across all motor symptoms in the short term.

Oxycodone or Higher Dose of Levodopa for the Treatment of Parkinsonian Central Pain: OXYDOPA Trial.

Among the different types of pain related to Parkinson's disease (PD), parkinsonian central pain (PCP) is the most disabling. We investigated the analgesic efficacy of two therapeutic strategies (opioid with oxycodone- prolonged-release (PR) and higher dose of levodopa/benserazide) compared with placebo in patients with PCP. OXYDOPA was a randomized, double-blind, double-dummy, placebo-controlled, multicenter parallel-group trial run at 15 centers within the French NS-Park network. PD patients with PCP (≥30 on the Visual Analogue Scale [VAS]) were randomly assigned to receive oxycodone-PR (up to 40 mg/day), levodopa/benserazide (up to 200 mg/day) or matching placebo three times a day (tid) for 8 weeks at a stable dose, in add-on to their current dopaminergic therapy. The primary endpoint was the change in average pain intensity over the previous week rated on VAS from baseline to week-10 based on modified intention-to-treat analyses. Between May 2016 and August 2020, 66 patients were randomized to oxycodone-PR (n = 23), levodopa/benserazide (n = 20) or placebo (n = 23). The mean change in pain intensity was -17 ± 18.5 on oxycodone-PR, -8.3 ± 11.1 on levodopa/benserazide, and -14.3 ± 18.9 in the placebo groups. The absolute difference versus placebo was -1.54 (97.5% confidence interval [CI], -17.0 to 13.90; P = 0.8) on oxycodone-PR and +7.79 (97.5% CI, -4.99 to 20.58; P = 0.2) on levodopa/benserazide. Similar proportions of patients in each group experienced all-cause adverse events. Those leading to study discontinuation were most frequently observed with oxycodone-PR (39%) than levodopa/benserazide (5%) or placebo (15%). The present trial failed to demonstrate the superiority of oxycodone-PR or a higher dose of levodopa in patients with PCP, while oxycodone-PR was poorly tolerated. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mitigating gut microbial degradation of levodopa and enhancing brain dopamine: Implications in Parkinson’s disease

Parkinson’s disease is managed using levodopa; however, as Parkinson’s disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson’s disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson’s disease patients have varying levels of these bacteria. Thus, decreasing bacterial metabolism is a promising therapeutic approach to enhance the bioavailability of levodopa in the brain. In this work, we show that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa—alone or combined with carbidopa—to dopamine. Mito-ortho-HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.