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.).

A Double-Blind, Randomized, Placebo-Controlled Trial of Bumetanide in Parkinson's Disease.

BACKGROUND: Acting on the main target of dopaminergic cells, the striatal γ-aminobutyric acid (GABA)-ergic cells, might be a new way to treat persons with Parkinson's disease (PD). OBJECTIVE: The objective of this study was to assess the efficacy of bumetanide, an Na-K-Cl cotransporter (NKCC1) inhibitor, to improve motor symptoms in PD. METHODS: This was a 4-month double-blind, randomized, parallel-group, placebo-controlled trial of 1.75 to 3 mg/day bumetanide as an adjunct to levodopa in 44 participants with PD and motor fluctuations. RESULTS: Compared to the baseline, the mean change in OFF Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score after 4 months of treatment (primary endpoint) did not improve significantly compared with placebo. No changes between participants treated with bumetanide and those treated with placebo were observed for most other outcome measures. Despite no relevant safety signals, bumetanide was poorly tolerated. CONCLUSIONS: There was no evidence in this study that bumetanide has efficacy in improving motor symptoms of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.

BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica.

Using the Accelerometers Integrated in Smartphones to Evaluate Essential Tremor.

Background/Aims: Evaluation of tremor constitutes a crucial step from the diagnosis to the initial treatment and follow-up of patients with essential tremor. The severity of tremor can be evaluated using clinical rating scales, accelerometry, or electrophysiology. Clinical scores are subjectively given, may be affected by intra- and interevaluator variations due to different experience, delays between consultations, and subtle changes in tremor severity. Existing medical devices are not routinely used: they are expensive, time-consuming, not easily accessible. We aimed at showing that a smartphone application using the accelerometers embedded in smartphones is effective for quantifying the tremor of patients presenting with essential tremor. Methods: We developed a free iPhone/iPod application, Itremor, and evaluated different parameters on 8 patients receiving deep brain stimulation of the ventral intermediate nucleus of the thalamus: average and maximum accelerations, time above 1 g of acceleration, peak frequency, typical magnitude of tremor, for postural and action tremors, on and off stimulation. Results: We demonstrated good correlations between the parameters measured with Itremor and clinical score in all conditions. Itremor evaluation enabled higher discriminatory power and degree of reproducibility than clinical scores. Conclusion: Itremor can be used for routine objective evaluation of essential tremor, and may facilitate adjustment of the treatment. © 2015 S. Karger AG, Basel.

Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging.

INTRODUCTION: Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [11C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [18F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status. METHODS: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [18F]-DPA714 and [11C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests. RESULTS: PD patients showed significantly higher [18F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [11C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction). CONCLUSION: [18F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients. TRIAL REGISTRATION: Trial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.

A French survey on the lockdown consequences of COVID-19 pandemic in Parkinson's disease. The ERCOPARK study.

BACKGROUND: In 2020 the coronavirus disease 19 (COVID-19) pandemic imposed a total and sudden lockdown. We aimed to investigate the consequences of the first COVID-19 lockdown (mid-March - mid-April 2020) on motor and non-motor symptoms (NMS) in a cohort of French people with Parkinson's disease (PwP). METHODS: PwP were enrolled either by an on-line survey sent from the national France Parkinson association (FP) to reach the French community of PwP or as part of outpatients' telemedicine visits followed by an hospital-based Parkinson Expert Center (PEC). All patients were evaluated using the same standardized questionnaire assessing motor and NMS (including a list of most disabling, new or worsened symptoms and Patient's Global Impression-Improvement scales [PGI-I]) psycho-social queries and quality of life. RESULTS: 2653 PwP were included: 441 (16.6%) in the PEC group and 2122 (83.4%) in the community-based group. Physiotherapy was interrupted among 88.6% of the patients. 40.9% referred a clinical modification of their symptoms. Based on the questionnaire, pain (9.3%), rigidity (9.1%) and tremor (8.5%) were the three most frequently new or worsened reported symptoms. Based on the PGI-I, the motor symptoms were the most affected domain, followed by pain and psychic state. PwP in community-based group tended to have more frequent worsening for motor symptoms, motor complications, pain and confusion than those of the PEC group. CONCLUSIONS: The first COVID-19 lockdown had a negative impact on motor and NMS of PwP. Efforts should be allocated to avoid interruption of care, including physiotherapy and physical activities and implement telemedicine. .

Clinical routine use of dopamine transporter imaging in 516 consecutive patients.

[(123)I]-FP-CIT is a single photon emission computed tomography (SPECT) ligand showing in vivo the loss of dopaminergic terminals in the brain and is now available in the market. Despite several systematic studies in clinically inconclusive cases, the use of such imaging in clinical routine is scarcely reported. We analyzed 516 files of subjects with movement disorders who were consecutively examined using [(123)I]-FP-CIT scan and determined whether the use of imaging was appropriate and if it improved clinical diagnosis or care of the patient. In addition, we determined if appropriate use was related to subspecialties in Neurology, e.g., movement disorders' specialists vs. general neurologists, and if appropriate use was increasing over time. Among the 516 scans, 18% were in agreement with the license, 62% were classified as appropriate and 37% were considered inappropriate. A change of management was obvious in 60% of patients, but in 92% of those with an appropriate request vs. 13% of patients with an inappropriate request. Movement disorders' specialists had more appropriate requests than other practitioners. Eventually, comparing the first 100 vs. the last 100 quantified SPECT, performed more than 2.5 years apart, we found no difference for the appropriateness of the examination. The use of [(123)I]-FP-CIT imaging in clinical routine does not fit a restrictive license. An inappropriate use is seen in nearly 40% of cases, which reduces the real cost-effectiveness of the technique suggesting a need for continuing medical education on the topic.

Optimized Quantification of Translocator Protein Radioligand ¹8F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers.

UNLABELLED: Translocator protein (TSPO) is expressed at a low level in healthy brain and is upregulated during inflammatory processes that may occur in neurodegenerative diseases. Thus, TSPO may be a suitable in vivo indicator of neurodegeneration. Here, we quantified the (18)F-DPA-714 radioligand in healthy TSPO-genotyped volunteers and developed a method to eliminate the need for invasive arterial blood sampling. METHODS: Ten controls (7 high-affinity binders [HABs] and 3 mixed-affinity binders [MABs]) underwent (18)F-DPA-714 PET with arterial and venous sampling. (18)F-DPA-714 binding was quantified with a metabolite-corrected arterial plasma input function, using the 1- and 2-tissue-compartment models (TCMs) as well as the Logan analysis to estimate total volume distribution (V(T)) in the regions of interest. Alternative quantification methods were tested, including tissue-to-plasma ratio or population-based input function approaches normalized by late time points of arterial or venous samples. RESULTS: The distribution pattern of (18)F-DPA-714 was consistent with the known distribution of TSPO in humans, with the thalamus displaying the highest binding and the cerebellum the lowest. The 2-TCM best described the regional kinetics of (18)F-DPA-714 in the brain, with good identifiability (percentage coefficient of variation < 5%). For each region of interest, V(T) was 47.6% ± 6.3% higher in HABs than in MABs, and estimates from the 2-TCM and the Logan analyses were highly correlated. Equilibrium was reached at 60 min after injection. V(T) calculated with alternative methods using arterial samples was strongly and significantly correlated with that calculated by the 2-TCM. Replacement of arterial with venous sampling in these methods led to a significant but lower correlation. CONCLUSION: Genotyping of subjects is a prerequisite for a reliable quantification of (18)F-DPA-714 PET images. The 2-TCM and the Logan analyses are accurate methods to estimate (18)F-DPA-714 V(T) in the human brain of both HAB and MAB individuals. Population-based input function and tissue-to-plasma ratio with a single arterial sample are promising alternatives to classic arterial plasma input function. Substitution with venous samples is promising but still requires methodologic improvements.

Spinal stimulation for movement disorders.

Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson's disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open-label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders.

Can nicotine be used medicinally in Parkinson's disease?

The risk of Parkinson's disease is reduced by cigarette smoking, which raises some unanswered questions. Nicotine, a major component of tobacco smoke, could exert either nonreceptor-mediated biological effects or, more importantly, act on the different subtypes of nicotinic brain receptors, in particular those associated with the nigrostriatal dopaminergic pathway. There is now robust experimental evidence for a neuroprotective effect of nicotine upon dopaminergic neurons. By contrast, in animal models of Parkinson's disease, nicotine alone has slight or no motor effects. However, nicotine may modulate dopamine transmission and has clear motor effects when associated with L-DOPA, reducing L-DOPA-induced dyskinesias. Clinical trials have yielded inconclusive results thus far and are hampered by different designs and small cohorts. Ongoing studies address either symptomatic motor or nonmotor symptoms, or neuroprotection. There is still no agreement on the daily dosage of nicotine or the method of administration. Together, these data suggest that nicotine or nicotinic receptor drugs have therapeutic potential for Parkinson's disease, although the specific treatment regimens remain to be determined.