Continuous subcutaneous foslevodopa/foscarbidopa infusion for the treatment of motor fluctuations in Parkinson's disease: Considerations for initiation and maintenance.

Background: As Parkinson's disease (PD) advances, management is challenged by an increasingly variable and inconsistent response to oral dopaminergic therapy, requiring special considerations by the provider. Continuous 24 h/day subcutaneous infusion of foslevodopa/foscarbidopa (LDp/CDp) provides steady dopaminergic stimulation that can reduce symptom fluctuation. Objective: Our aim is to review the initiation, optimization, and maintenance of LDp/CDp therapy, identify possible challenges, and share potential mitigations. Methods: Review available LDp/CDp clinical trial data for practical considerations regarding the management of patients during LDp/CDp therapy initiation, optimization, and maintenance based on investigator clinical trial experience. Results: LDp/CDp initiation, optimization, and maintenance can be done without hospitalization in the clinic setting. Continuous 24 h/day LDp/CDp infusion can offer more precise symptom control than oral medications, showing improvements in motor fluctuations during both daytime and nighttime hours. Challenges include infusion-site adverse events for which early detection and prompt management may be required, as well as systemic adverse events (eg, hallucinations) that may require adjustment of the infusion rate or other interventions. A learning curve should be anticipated with initiation of therapy, and expectation setting with patients and care partners is key to successful initiation and maintenance of therapy. Conclusion: Continuous subcutaneous infusion of LDp/CDp represents a promising therapeutic option for individuals with PD. Individualized dose optimization during both daytime and nighttime hours, coupled with patient education, and early recognition of certain adverse events (plus their appropriate management) are required for the success of this minimally invasive and highly efficacious therapy.

Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.

Construction of semi-supervised spatial projections to identify the source of beta- and high frequency oscillations in Parkinson's disease.

Traditional deep brain stimulation (DBS) treatment for Parkinson's disease (PD) targets the placement of DBS leads into subthalamic nucleus (STN). Extraction of neurobiomarkers from STN local field potential activity can be used for the optimization of DBS. Beta (12-30 Hz) and high frequency oscillations (200-450 Hz, HFO) of STN and their phase-amplitude coupling have been previously correlated with symptom severity in PD. The typical approach is to take bipolar derivations of electrode contacts in order to enhance recordings of local brain activity and suppress noise levels. This approach can often cancel the signals in correlated neighboring contacts and create ambiguity in which monopolar contact to select for the identification of the main source of the oscillatory signal. To improve local specificity and help identify the source of beta and HFO in terms of electrode contact, we propose a semi supervised blind-source separation method. This approach presents a novel perspective to investigate electrophysiology by projecting the recorded channels into a subspace of virtual channels. We show the contribution of each channel to the identified source and correlate the spatial information with imaging and postoperative programming parameters. We anticipate such a source identification strategy can be used in the future to investigate the distribution of beta and HFO on individual contacts of the DBS lead and can improve the interpretation of these signals.

Interactive mobile application for Parkinson's disease deep brain stimulation (MAP DBS): An open-label, multicenter, randomized, controlled clinical trial.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming. METHODS: We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements. RESULTS: We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (-7.0 ± 7.9) compared to SOC (-2.7 ± 6.9, p = 0.01) at six months. CONCLUSION: MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy.

Association of clinical outcomes and connectivity in awake versus asleep deep brain stimulation for Parkinson disease.

OBJECTIVE: Deep brain stimulation (DBS) for Parkinson disease (PD) is traditionally performed with awake intraoperative testing and/or microelectrode recording. Recently, however, the procedure has been increasingly performed under general anesthesia with image-based verification. The authors sought to compare structural and functional networks engaged by awake and asleep PD-DBS of the subthalamic nucleus (STN) and correlate them with clinical outcomes. METHODS: Levodopa equivalent daily dose (LEDD), pre- and postoperative motor scores on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III), and total electrical energy delivered (TEED) at 6 months were retroactively assessed in patients with PD who received implants of bilateral DBS leads. In subset analysis, implanted electrodes were reconstructed using the Lead-DBS toolbox. Volumes of tissue activated (VTAs) were used as seed points in group volumetric and connectivity analysis. RESULTS: The clinical courses of 122 patients (52 asleep, 70 awake) were reviewed. Operating room and procedure times were significantly shorter in asleep cases. LEDD reduction, MDS-UPDRS III score improvement, and TEED at the 6-month follow-up did not differ between groups. In subset analysis (n = 40), proximity of active contact, VTA overlap, and desired network fiber counts with motor STN correlated with lower DBS energy requirement and improved motor scores. Discriminative structural fiber tracts involving supplementary motor area, thalamus, and brainstem were associated with optimal clinical improvement. Areas of highest structural and functional connectivity with VTAs did not significantly differ between the two groups. CONCLUSIONS: Compared to awake STN DBS, asleep procedures can achieve similarly optimal targeting-based on clinical outcomes, electrode placement, and connectivity estimates-in more efficient procedures and shorter operating room times.

Quantitative mobility measures complement the MDS-UPDRS for characterization of Parkinson's disease heterogeneity.

INTRODUCTION: Emerging technologies show promise for enhanced characterization of Parkinson's Disease (PD) motor manifestations. We evaluated quantitative mobility measures from a wearable device compared to the conventional motor assessment, the Movement Disorders Society-Unified PD Rating Scale part III (motor MDS-UPDRS). METHODS: We evaluated 176 PD subjects (mean age 65, 65% male, 66% H&Y stage 2) during routine clinic visits using the motor MDS-UPDRS and a 10-min motor protocol with a body-fixed sensor (DynaPort MT, McRoberts BV), including the 32-ft walk, Timed Up and Go (TUG), and standing posture with eyes closed. Regression models examined 12 quantitative mobility measures for associations with (i) motor MDS-UPDRS, (ii) motor subtype (tremor dominant vs. postural instability/gait difficulty), (iii) Montreal Cognitive Assessment (MoCA), and (iv) physical functioning disability (PROMIS-29). All analyses included age, gender, and disease duration as covariates. Models iii-iv were secondarily adjusted for motor MDS-UPDRS. RESULTS: Quantitative mobility measures from gait, TUG transitions, turning, and posture were significantly associated with motor MDS-UPDRS (7 of 12 measures, p < 0.05) and motor subtype (6 of 12 measures, p < 0.05). Compared with motor MDS-UPDRS, several quantitative mobility measures accounted for a 1.5- or 1.9-fold increased variance in either cognition or physical functioning disability, respectively. Among minimally-impaired subjects in the bottom quartile of motor MDS-UPDRS, including subjects with normal gait exam, the measures captured substantial residual motor heterogeneity. CONCLUSION: Clinic-based quantitative mobility assessments using a wearable sensor captured features of motor performance beyond those obtained with the motor MDS-UPDRS and may offer enhanced characterization of disease heterogeneity.

Randomized, Double-Blind Assessment of LFP Versus SUA Guidance in STN-DBS Lead Implantation: A Pilot Study.

Background: The efficacy of deep brain stimulation (DBS) therapy in Parkinson's disease (PD) patients is highly dependent on the precise localization of the target structures such as subthalamic nucleus (STN). Most commonly, microelectrode single unit activity (SUA) recordings are performed to refine the target. This process is heavily experience based and can be technically challenging. Local field potentials (LFPs), representing the activity of a population of neurons, can be obtained from the same microelectrodes used for SUA recordings and allow flexible online processing with less computational complexity due to lower sampling rate requirements. Although LFPs have been shown to contain biomarkers capable of predicting patients' symptoms and differentiating various structures, their use in the localization of the STN in the clinical practice is not prevalent. Methods: Here we present, for the first time, a randomized and double-blinded pilot study with intraoperative online LFP processing in which we compare the clinical benefit from SUA- versus LFP-based implantation. Ten PD patients referred for bilateral STN-DBS were randomly implanted using either SUA or LFP guided targeting in each hemisphere. Although both SUA and LFP were recorded for each STN, the electrophysiologist was blinded to one at a time. Three months postoperatively, the patients were evaluated by a neurologist blinded to the intraoperative recordings to assess the performance of each modality. While SUA-based decisions relied on the visual and auditory inspection of the raw traces, LFP-based decisions were given through an online signal processing and machine learning pipeline. Results: We found a dramatic agreement between LFP- and SUA-based localization (16/20 STNs) providing adequate clinical improvement (51.8% decrease in 3-month contralateral motor assessment scores), with LFP-guided implantation resulting in greater average improvement in the discordant cases (74.9%, n = 3 STNs). The selected tracks were characterized by higher activity in beta (11-32 Hz) and high-frequency (200-400 Hz) bands (p < 0.01) of LFPs and stronger non-linear coupling between these bands (p < 0.05). Conclusion: Our pilot study shows equal or better clinical benefit with LFP-based targeting. Given the robustness of the electrode interface and lower computational cost, more centers can utilize LFP as a strategic feedback modality intraoperatively, in conjunction to the SUA-guided targeting.

Clinical Rating Scales and Quantitative Assessments of Movement Disorders.

This article reviews scales that have been developed for, validated in, and/or frequently used across multiple movement disorders with a focus on assessment of motor and nonmotor symptoms of Parkinson disease. Rating scales used in other disease states include those for essential tremor, dystonia (generalized dystonia, cervical dystonia, and blepharospasm), Tourette syndrome, Huntington disease, tardive dyskinesia, Wilson disease, ataxia, and functional movement disorders. Key features of each scale as well as cited criticisms and limitations of each scale are also discussed. Lastly, the article briefly discusses the emerging role of digital assessment tools (both wearable devices and digital interface applications).

Recent advances in understanding and treatment of Parkinson's disease.

Though primarily a sporadic condition, Parkinson's disease is increasingly recognized to be a multifactorial disease with a strong genetic component. At a cellular level, disruptions of protein trafficking and recycling, particularly by misfolding, accumulation, and aggregation of α-synuclein, mitochondrial dysfunction, oxidative stress, and other etiopathogenic mechanisms, have been found to result in the death of vulnerable neuronal populations and appear to drive the neurodegeneration underlying Parkinson's disease. The improved understanding of these mechanisms has led to the development of novel pathogenesis-targeted and potentially disease-modifying therapeutic approaches in Parkinson's disease. Until these treatments are fully developed and approved, clinicians must rely on therapies designed to improve quality of life of patients by treating various motor and non-motor symptoms of the disease.

VMAT2 Inhibitors in Neuropsychiatric Disorders.

The basal ganglia and dopaminergic pathways play a central role in hyperkinetic movement disorders. Vesicular monoamine transporter 2 (VMAT2) inhibitors, which deplete dopamine at presynaptic striatal nerve terminals, are a class of drugs that have long been used to treat hyperkinetic movement disorders, but have recently gained more attention following their development for specific indications in the United States. At present, there are three commercially available VMAT2 inhibitors: tetrabenazine, deutetrabenazine, and valbenazine. Pharmacokinetics, metabolism, and dosing vary significantly between the three drugs, and likely underlie the more favorable side effect profile of the newer agents (deutetrabenazine and valbenazine). Tetrabenazine and deutetrabenazine have demonstrated safety and efficacy in the treatment of chorea associated with Huntington's disease, including in randomized controlled trials, although direct comparison studies are limited. Both deutetrabenazine and valbenazine have demonstrated safety and efficacy in the treatment of tardive dyskinesia, with multiple double-blind, placebo-controlled trials, whereas tetrabenazine has been studied less rigorously. There have been no blinded, prospective trials with tetrabenazine in Tourette's syndrome (TS); however, double-blind, placebo-controlled trials in TS are ongoing for both deutetrabenazine and valbenazine. Given the favored side effect profile of newer VMAT2 inhibitors, clinicians should be aware of the distinctions between agents and become familiar with differences in their use, especially as there is potential for their utilization to increase across the range of hyperkinetic movement disorders.

Essential Tremor and Parkinson's Disease: Exploring the Relationship.

Background: There is longstanding controversy surrounding the possible link between essential tremor (ET) and Parkinson's disease (PD). Inconsistent and unreliable diagnostic criteria may in part account for some of the difficulties in defining the relationship between these two common movement disorders. Methods: References for this systematic review were identified using PubMed with the search terms "essential tremor" AND "Parkinson's disease" with articles published in English between 1960 and September 2018 included. Results: In this review we provide evidence that some patients diagnosed with ET have an increased risk of developing PD years or decades after onset of action tremor. There are several still unresolved questions about the link between the two disorders including lack of verifiable diagnostic criteria for the two disorders and marked overlap in phenomenology. Here we review clinical, epidemiologic, imaging, pathologic, and genetic studies that address the ET-PD relationship. Several lines of evidence support the association between ET and PD, including overlapping motor and non-motor features, relatively high prevalence of rapid eye movement sleep behavior disorder (26-43%) in ET patients, increased prevalence of PD in patients with longstanding antecedent ET, increased prevalence of ET in family members of patients with PD, and the presence of Lewy bodies in the brains of some ET patients (15-24%). Discussion: There is a substantial body of evidence supporting the association between ET and PD within at least a subset of patients, although the nature and possible pathogenic mechanisms of the relationship are not well understood.

Anosmia and Ageusia in Parkinson's Disease.

Anosmia, the loss of sense of smell, is a common nonmotor feature of Parkinson's disease (PD). Ageusia, the loss of sense of taste, is additionally an underappreciated nonmotor feature of PD. The olfactory tract is involved early in PD as indicated by frequent occurrence of hyposmia or anosmia years or decades before motor symptoms and by autopsy studies showing early synuclein pathology in the olfactory tract and anterior olfactory nucleus even in the early stages of PD. Testing for olfaction consists of evaluation of olfactory thresholds, smell identification and discrimination, and olfactory memory. Testing for gustation involves evaluating thresholds and discrimination of five basic tastes (salty, sweet, bitter, sour, and umami). The presence of a specific pattern of loss in both olfaction and gustation in PD has been proposed, but this has not yet been confirmed. Within PD, olfactory loss is strongly tied with cognitive status though links to other features of PD or a particular PD phenotype is debated. Hyposmia is more often present and typically more severe in PD patients than other parkinsonian syndromes, making it a potentially useful biomarker for the disease.

Diagnosis and Management of Parkinson's Disease.

Despite numerous efforts to identify specific and sensitive biomarkers, the diagnosis of Parkinson's disease (PD) is still based on clinical criteria that include the presence of a combination of cardinal motor features (tremor, rigidity, bradykinesia, and postural instability), other motor features (including freezing of gait and abnormal postures), and numerous nonmotor features. In addition, the presence of atypical features may suggest an alternative diagnosis. Levodopa therapy remains the gold standard in the management of motor features of PD. New formulations of levodopa and novel delivery systems are currently being evaluated and gradually introduced in clinical practice in an attempt to prevent or treat levodopa-related motor complications. Dopamine agonists also play an important role as monotherapy in mild or adjunctive therapy in moderately advanced disease. As the disease progresses and patients develop complications from levodopa therapy, specifically motor fluctuations and dyskinesias, deep brain stimulation becomes an alternative therapeutic option. Clinical trials of experimental therapeutics are currently fueling the PD therapeutic pipeline.