Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.

Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

Association of dopamine receptor D3 polymorphism with Levodopa-induced Dyskinesia: A study on Parkinson's disease patients from India.

INTRODUCTION: Levodopa-induced dyskinesia (LID) is a debilitating motor feature in a subset of patients with Parkinson's disease (PD) after prolonged therapeutic administration of levodopa. Preliminary animal and human studies are suggestive of a key role of dopamine type 3 (D3) receptor polymorphism (Ser9Gly; rs6280) in LID. Its contribution to development of LID among Indian PD patients has remained relatively unexplored and merits further investigation. METHODS AND MATERIALS: 200 well-characterised PD patients (100 without LID and 100 with LID) and 100 age-matched healthy controls were recruited from the outpatient department of Institute of Neurosciences Kolkata. MDS-UPDRS (Unified Parkinson's Disease Rating Scale from International Movement Disorder Society) Part III and AIMS (abnormal involuntary movement scale) were performed for estimation of severity of motor features and LID respectively in the ON state of the disease. Participants were analysed for the presence of Ser9Gly single nucleotide variant (SNV) (rs6280) by polymerase chain reaction followed by restriction fragment length polymorphism techniques. RESULTS: The frequency of AA genotype (serine type) was more frequently present in PD patients with LID compared to PD patients without LID (50 % vs 28 %; P = 0.002; OR = 2.57, 95 % CI: 1.43 - 4.62). The abnormal involuntary movement scale score was significantly higher in PD patients with AA genotype compared to carriers of glycine allele (AG + GG) (4.08 ± 3.35; P = 0.002). CONCLUSION: We observed a significant association of serine type SNV (rs6280) in D3 receptor gene in a cohort of PD patients with LID from India. More severe motor severity was found in patients with glycine substitution of the same SNV. The current study emphasised the role of D3 receptor in the pathogenesis of LID.

Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

Buspirone and Zolmitriptan Combination for Dyskinesia: A Randomized, Controlled, Crossover Study.

BACKGROUND: Preclinical evidence suggests that co-administration of the 5-HT1A agonist buspirone and the 5-HT1B/1D agonist zolmitriptan act synergistically to reduce dyskinesia to a greater extent than that achieved by either drug alone. OBJECTIVES: Assess the therapeutic potential of a fixed-dose buspirone and zolmitriptan combination in Parkinson's disease (PD) patients with levodopa-induced dyskinesia. METHODS: Single-center, randomized, placebo-controlled, two-way crossover study (NCT02439203) of a fixed-dose buspirone/zolmitriptan regimen (10/1.25 mg three times a day) in 30 patients with PD experiencing at least moderately disabling peak-effect dyskinesia. RESULTS: Seven days of treatment with buspirone/zolmitriptan added to levodopa significantly reduced dyskinesia as assessed by Abnormal Involuntary Movement Scale scores versus placebo (mean treatment effect vs. placebo: -4.2 [-6.1, -2.3]) without significantly worsening Unified Parkinson's Disease Rating Scale (UPDRS) Part III (ON) scores (mean treatment effect vs. placebo: 0.6 [-0.1, 1.3]). No serious adverse events were reported. CONCLUSIONS: In this proof-of-concept study, addition of buspirone/zolmitriptan to the patients' PD medication regimen significantly reduced dyskinesia severity without worsening motor function. © 2024 International Parkinson and Movement Disorder Society.

Striatal Serotonin 4 Receptor is Increased in Experimental Parkinsonism and Dyskinesia.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Cinpanemab in Early Parkinson Disease: Evaluation of Biomarker Results From the Phase 2 SPARK Clinical Trial.

BACKGROUND AND OBJECTIVES: Sensitive, reliable, and scalable biomarkers are needed to accelerate the development of therapies for Parkinson disease (PD). In this study, we evaluate the biomarkers of early PD diagnosis, disease progression, and treatment effect collected in the SPARK. METHODS: Cinpanemab is a human-derived monoclonal antibody binding preferentially to aggregated forms of extracellular α-synuclein. SPARK was a randomized, double-blind, placebo-controlled, phase 2 multicenter trial evaluating 3 cinpanemab doses administered intravenously every 4 weeks for 52 weeks with an active treatment dose-blind extension period for up to 112 weeks. SPARK enrolled 357 participants diagnosed with PD within 3 years, aged 40-80 years, ≤2.5 on the modified Hoehn and Yahr scale, and with evidence of striatal dopaminergic deficit. The primary outcome was change from baseline in the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale total score. Secondary and exploratory biomarker outcomes evaluated change from baseline at week 52 relative to placebo. Dopamine transporter SPECT and MRI were used to quantify changes in the nigrostriatal dopamine pathway and regional atrophy. CSF and plasma samples were used to assess change in total α-synuclein levels, α-synuclein seeding, and neurofilament light chain levels. SPARK was conducted from January 2018 to April 2021 and terminated due to lack of efficacy. RESULTS: Approximately 3.8% (15/398) of SPECT-imaged participants did not have evidence of dopaminergic deficit and were screen-failed. Binary classification of α-synuclein seeding designated 93% (110/118) of the enrolled CSF subgroup as positive for α-synuclein seeds at baseline. Clinical disease progression was observed, with no statistically significant difference in cinpanemab groups compared with that in placebo. Ninety-nine percent of participants with positive α-synuclein seeding remained positive through week 52. No statistically significant changes from baseline were observed between treatment groups and placebo across biomarker measures. Broadly, there was minimal annual change with high interindividual variability across biomarkers-with striatal binding ratios of the ipsilateral putamen showing the greatest mean change/SD over time. DISCUSSION: Biomarker results indicated enrollment of the intended population with early PD, but there was no significant correlation with disease progression or clear evidence of a cinpanemab treatment effect on biomarker measures. Suitable biomarkers for evaluating disease severity and progression in early PD trials are still needed. TRIAL REGISTRATION INFORMATION: NCT03318523 (clinicaltrials.gov/ct2/show/NCT03318523); Submitted October 24, 2017; First patient enrolled January 2018.

Advanced Parkinson's disease treatment patterns in Italy: an observational study interim analysis.

BACKGROUND: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. PATIENTS AND METHODS: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. RESULTS: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). CONCLUSION: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.

Patients with Parkinson's disease (PD) often exhibit fluctuations in their response to oral levodopa; however, real-world studies on the management of these fluctuations are lacking. This planned interim analysis of the real-world, multicentre, observational PD Fluctuations treatment Pathway (PD-FPA) study found that adequate levodopa dosing and adjunctive medications can stabilize Italian patients with advanced PD and improve their quality of life.

Comparison of two types of extension tubes for people with Parkinson's disease in advanced treatment with levodopa-entacapone-carbidopa intestinal gel infusions: a prospective, crossover quality study.

BACKGROUND: Within Parkinson's disease (PD) management, a pivotal juncture often arises when individuals with PD (PwP) necessitate advanced therapies to stabilise symptom fluctuations and reduce off-periods, which are intrinsic to living with PD. One such intervention is the infusion of duodenal levodopa-entacapone-carbidopa intestinal gel (LECIG), which confers a more dependable levodopa plasma concentration compared with conventional oral therapy. It involves the insertion of a percutaneous endoscopic gastrojejunostomy (PEG-J) tube, facilitating direct access to the stomach and jejunum. Then, a slender tube extends into the small intestine, facilitating the continuous delivery of LECIG via a portable pump. The PEG-J incorporates an extension tube that permits patients with PD to connect the medication pump. OBJECTIVE: The objective of this study was to assess and compare two types of extension tubes a standard; a standard tube and the ENFit extension tube. METHOD: Employing a prospective, crossover design at a single centre in Denmark. Each participant evaluated both extension tubes for 14 days. The primary outcome measure was patient-reported evaluation measures through a nine-item questionnaire using a 5-point Likert scale and 10th open-ended qualitative question. RESULTS: Of the 12 recruited PwP, 10 successfully completed both testing periods and submitted self-reported questionnaires. The participants, with an average age of 70.3 years, comprised three men and seven women. Among them, five had a spouse or cohabitant, while five lived independently (with one residing in a nursing home). The average duration of PD diagnosis was 16.4 years, with an average of 2.6 years since the implantation of the medication pump. The ENFit tube outperformed the standard tube across all nine evaluation criteria, particularly excelling in terms of usability (items 4-6), safety (item 2) and overall product preference (item 9).

Starting with 24-h levodopa carbidopa intestinal gel at initiation in a large cohort of advanced Parkinson's disease patients.

Continuous intra-jejunal infusion of levodopa-carbidopa intestinal gel (LCIG) is a long-term proven and effective treatment in advanced Parkinson's Disease (APD). Efficacy and safety of 16-h administration of LCIG has already been established. Additional benefits of 24-h LCIG administration have been reported in several case series and small clinical studies. The aim of this retrospective study was to compare the characteristics of patients who needed 24-h LCIG from the beginning of the DAT (device-aided treatment) with those who remained with the standard 16-h LCIG treatment and to identify particular motives if any. We initiated LCIG in 150 patients out of which in case of 62 patients (41,3%) due to unsatisfactory initial clinical benefits continuous 24-h LCIG was deemed necessary. Despite the subjective complaints and more severe clinical condition, at baseline evaluation we found statistically significant differences between 16-h LCIG cohort and 24-h LCIG cohort only in case of incidence of freezing (47% vs 65%, p = 0.03) and sudden off (32% vs 48%, p = 0.04). Wake hours/daytime LCIG does not always sufficiently improve the patient's quality of life in some patients due to persistent nighttime troublesome symptoms. Instead of labeling the patient as a non-responder, it is worth trying the 24-h LCIG dosage in a carefully selected group of patients, as there is currently no consensus on reliable criteria that serve the decision in these patients.

Intrinsic auricular muscle zone stimulation for Parkinson disease: The EARSTIM-PD Phase II multi-center pilot study results.

BACKGROUND: Studies have suggested that intrinsic auricular muscle zones (IAMZ) stimulation alleviates motor features of Parkinson disease (PD). METHODS: A randomized, blinded, active sham-controlled pilot trial was conducted to evaluate the safety and dose-response-time curve of Earstim using a 3-treatment, 3-period crossover design in PD patients experiencing OFF time on levodopa. Treatments were: short (20-min) IAMZ stimulation; long (60-min) IAMZ stimulation; and 20-min active sham stimulation of non-muscular areas. Assessment time points were: prior to treatment, and 20, 40, 60, 90, and 120 min after treatment onset. Primary safety endpoints were adverse events frequency and severity. Primary efficacy endpoint was the change in MDS-UPDRS motor score at 20 min after treatment onset in the IAMZ treatment groups versus sham. RESULTS: Forty-six individuals consented; 38 were randomized (average age 64 years, 65 % male, mean 8.2 years from diagnosis). No serious adverse events or significant device-related events occurred. At 20 min after treatment onset, motor improvements did not differ between IAMZ treatments versus sham. However, at 60 min after treatment onset, motor improvement peaked on IAMZ treatments compared to sham (difference: 3.1 [-5.9 to 0.3], p = 0.03). While the difference in 120-min AUC change between IAMZ treatments versus sham was not significant, the short-stimulation IAMZ treatment showed the largest aggregate motor score improvement (AUC = -456 points, 95 % CI -691 to -221) compared to sham. CONCLUSION: Earstim was well-tolerated. The greatest motor improvement occurred at 60 min after stimulation onset in the short-stimulation IAMZ treatment, and supports its further study to alleviate OFF periods.

Parkinson's Disease and Driving Fitness: A Systematic Review of the Existing Guidelines.

BACKGROUND: Motor/nonmotor symptomatology and antiparkinsonian drugs deteriorate the driving ability of Parkinson's disease (PD) patients. OBJECTIVES: Treating neurologists are frequently asked to evaluate driving fitness of their patients and provide evidence-based consultation. Although several guidelines have been published, the exact procedure along with the neurologist's role in this procedure remains obscure. METHODS: We systematically reviewed the existing guidelines, regarding driving fitness evaluation of PD patients. We searched MEDLINE and Google Scholar and identified 109 articles. After specified inclusion criteria were applied, 15 articles were included (nine national guidelines, five recommendation papers, and one consensus statement). RESULTS: The treating physician is proposed as the initial evaluator in 8 of 15 articles (neurologist in 2 articles) and may refer patients for a second-line evaluation. The evaluation should include motor, cognitive, and visual assessment (proposed in 15, 13, and 8 articles, respectively). Specific motor tests are proposed in eight articles (cutoff values in four), whereas specific neuropsychological and visual tests are proposed in seven articles each (cutoff values in four and three articles, respectively). Conditional licenses are proposed in 11 of 15 articles, to facilitate driving for PD patients. We summarized our findings on a graphic of the procedure for driving fitness evaluation of PD patients. CONCLUSIONS: Neurological aspects of driving fitness evaluation of PD patients are recognized in most of the guidelines. Motor, neuropsychological, visual, and sleep assessment and medication review are key components. Clear-cut instructions regarding motor, neuropsychological, and visual tests and relative cutoff values are lacking. Conditional licenses and periodical reevaluation of driving fitness are important safety measures.

Decreased hepatic enzymes reflect the decreased vitamin B6 levels in Parkinson's disease patients.

The study aims to investigate the vitamin B6 levels in Parkinson's disease (PD) patients and their association with liver enzymes and evaluate how much dysregulation is associated with levodopa dose. Furthermore, to evaluate the effect of Opicapone, a catechol-o-methyl-transferase inhibitor, on vitamin B6 levels by monitoring the AST and ALT levels in patients treated with Levodopa-Carbidopa Intestinal Gel Infusion (LCIG). For these aims, serum vitamin B6 levels were measured (PD, n = 72 and controls, n = 31). The vitamin B6 level was compared with the total levodopa dose, clinical parameters, and blood homocysteine, albumin, and hemoglobin levels in PD patients. Correlations between vitamin B6 levels and AST and ALT levels, as well as the ratio ALT/AST, were analyzed. Changes in the AST and ALT levels and ALT/AST were analyzed in the patients treated with LCIG before and after the therapy (n = 24) and in the patients treated with LCIG + Opicapone before and after Opicapone treatment (n = 12). We found vitamin B6 levels were significantly lower in PD patients. Total levodopa dose and albumin levels were independently associated with vitamin B6 levels. Decreased vitamin B6 levels appeared as lower AST and ALT levels and ALT/AS. Treatment with LCIG decreased the AST and ALT levels and ALT/AST. Adjunctive therapy with Opicapone to LCIG ameliorated the decreased ALT and ALT/AST. We conclude that the ALT and ALT/AST can be useful parameters for monitoring vitamin B6 levels and Opicapone can ameliorate the dysregulated vitamin B6 in PD patients.

Weight loss in Parkinson's disease: A retrospective comparison between oral medication and device-assisted therapies.

OBJECTIVE: Weight loss (WL) is the most common symptom among patients with Parkinson's disease (PD) and has been reported to start several years before the diagnosis of PD. The relationship between WL and PD treatment is complex. This study aimed to characterize the impact of PD treatment on WL and find clues to establish the administration of nutrition for patients with PD. MATERIALS AND METHODS: Eighty-two patients with PD (mean age, 58.4 ± 10.2 years; mean Hoehn and Yahr stage, 3.2 ± 0.7) were recruited. Their treatments included deep brain stimulation (DBS) therapy (n = 34), levodopa/carbidopa intestinal gel (LCIG) therapy (n = 13), and oral medication alone (n = 35). Based on the medical records, the age of onset, disease duration, treatment options, videofluoroscopic dysphagia scale, blood test results, and weight change were collected. RESULTS: The median WL per year and rate of WL were -1.0 ± 2.8 kg and -1.9 ± 4.7 %, respectively. Most patients (93 %) were classified into normal nutrition and mild malnutrition groups by their CONUT scores. The median WL of the DBS group was significantly lower than that of the oral medication alone group (p < 0.01). The rate of WL showed a significant negative correlation with the age of onset (rho = -0.328, p = 0.003), but showed a significant positive correlation with the disease duration (rho = 0.231, p = 0.04). CONCLUSION: These results highlighted WL in the early stages of PD and suggested the need for adequate monitoring for patients undergoing device-aided therapy as well as oral medicine-treated patients with greater WL.

Design, Synthesis and In Vitro Evaluation of Levodopa Stearic Acid Hydrazide Conjugate for the Management of Parkinson's DiseaseNovel Conjugate for Parkinson's Disease.

Parkinson's disease is the highest prevalent neurodegenerative disease in elderly individuals after Alzheimer's disease. The pathological identification for Parkinson's disease is loss of dopaminergic neurons in substantia nigra region of the brain that in turn leads to dopamine deficiency that affects the body's normal physiological and neurological disorder. The important drawback in the modality of treatment is levodopa is only supplying depleted dopamine in the brain, it does not affect neurodegeneration. Even though levodopa manages the disease, an alternative treatment strategy is required to stop or prevent further degeneration of neuron. The compound with neuroprotector activity suits the requirement. Of them, stearic acid plays a vital role in protecting neurons against oxidative stress through a Phosphoinositide 3-kinase-dependent mechanism. Hence, our present study aimed to design, synthesize, and characterize the levodopa stearic acid hydrazide conjugate. Additionally, evaluate the cytotoxicity of synthesized compound in SHSY5Y: cell lines. In brief, levodopa was conjugated to the stearic acid successfully and was confirmed with Fourier-transform infrared spectroscopy, Nuclear magnetic resonance, and Mass Spectroscopy. In vitro cell viability study in SHSY5Y: cell lines showed elevated cell viability in 0.134 µm concentration of Conjugate, and 0.563 µm concentration of levodopa. Showing that the synthesized compound could offer an improved treatment strategy for Parkinson's disease.

Terminal Care in Parkinson's Disease: Real-Life Use of Continuous Subcutaneous Apomorphine Infusion to Improve Patient Comfort.

BACKGROUND: There are currently no recommendations on the therapeutic management of Parkinson's disease (PD) patients at the end of life. OBJECTIVE: To describe a cohort of patients with PD who benefited from continuous subcutaneous apomorphine infusion (CSAI) initiation at the end of their life as comfort care. METHODS: This real-life cohort includes 14 PD patients, who benefited from 24-h, low-dose CSAI (0.5-3 mg/h) in the context of terminal care. Patient's comfort (pain, rigidity, and/or ability to communicate) and occurrence of CSAI-related side-effects (nausea/vomiting, cutaneous and behavioral manifestations) were evaluated based on medical records. RESULTS: All patients (age 62-94 years, disease duration 2-32 years) presented with late-stage PD and a compromised oral route. Treatment lasted from a few hours to 39 days. CSAI led to substantial functional improvement, with a good safety profile. Overall clinical comfort was deemed improved by the medical team, the patient, and/or caregivers. CONCLUSIONS: CSAI might be a promising approach in PD terminal care, as it reduces motor symptoms and overall discomfort, with an apparent good safety profile. Use of the apomorphine pen, sublingual film or a classic syringe pump might be considered when apomorphine pumps are not available. Larger observational cohorts and randomized controlled trials are needed to establish the efficacy and tolerability of apomorphine in the context of terminal care and more broadly, in an advance care planning perspective.

Home-based monitoring of persons with advanced Parkinson's disease using smartwatch-smartphone technology.

Movement deterioration is the hallmark of Parkinson's disease (PD), characterized by levodopa-induced motor-fluctuations (i.e., symptoms' variability related to the medication cycle) in advanced stages. However, motor symptoms are typically too sporadically and/or subjectively assessed, ultimately preventing the effective monitoring of their progression, and thus leading to suboptimal treatment/therapeutic choices. Smartwatches (SW) enable a quantitative-oriented approach to motor-symptoms evaluation, namely home-based monitoring (HBM) using an embedded inertial measurement unit. Studies validated such approach against in-clinic evaluations. In this work, we aimed at delineating personalized motor-fluctuations' profiles, thus capturing individual differences. 21 advanced PD patients with motor fluctuations were monitored for 2 weeks using a SW and a smartphone-dedicated app (Intel Pharma Analytics Platform). The SW continuously collected passive data (tremor, dyskinesia, level of activity using dedicated algorithms) and active data, i.e., time-up-and-go, finger tapping, hand tremor and hand rotation carried out daily, once in OFF and once in ON levodopa periods. We observed overall high compliance with the protocol. Furthermore, we observed striking differences among the individual patterns of symptoms' levodopa-related variations across the HBM, allowing to divide our participants among four data-driven, motor-fluctuations' profiles. This highlights the potential of HBM using SW technology for revolutionizing clinical practices.

Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson's Disease.

Currently, available therapeutics for the treatment of Parkinson's disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon's therapeutic potential for the treatment of early through advanced PD.