Impaired sequence manipulation in non-demented patients with progressive supranuclear palsy.

PURPOSE: Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD. METHOD: Twenty-nine patients with PSP Richardson's syndrome (PSP-RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well-established neuropsychological tests, including digit span forward (DST-F), digit span backward (DST-B), and adaptive digit ordering tests (DOT-A). The DST-F required maintaining digit sequences, and the DST-B and DOT-A required maintaining and manipulating digit sequences. FINDING: The PSP-RS group scored lower than the PD and HC groups in the DST-B and DOT-A but not in the DST-F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP-RS patients. Moreover, in PSP-RS, the DST-B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST-B ordering cost (DST-F score vs. DST-B score). The PSP patients who took a greater dose of levodopa tended to have higher DST-B ordering cost. There was no effect of levodopa on DST-B or DOT-A in PD. CONCLUSION: These results suggested that the ability to manipulate sequence was already reduced in patients with PSP-RS and was worse than in patients with PD.

[Tremor-dominant form of Parkinson's disease]. / Tremor-dominantnaya forma bolezni Parkinsona.

The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.

Concomitant treatment with safinamide and antidepressant drugs: Safety data from real clinical practice.

BACKGROUND AND PURPOSE: The aim of this study was to assess the possible pharmacological interactions between safinamide and antidepressants, and in particular the appearance of serotonin syndrome with data from real life. METHODS: We conducted a retrospective observational study of patients with Parkinson's disease from our Movement Disorders Unit, who were under treatment with any antidepressant drug and safinamide. Specifically, symptoms suggestive of serotonin syndrome were screened for. Also, we collected time of simultaneous use, doses of levodopa and other antiparkinsonian drugs. RESULTS: Clinical records were reviewed for the study period of September 2018 to September 2019. Seventy-eight PD patients who were treated with safinamide of which 25 (32.05%) had a concomitant treatment with an antidepressant drug, being sertraline and escitalopram the most frequent. Mean age was 80 years±8.43 and H&Y stage was 3 [2-4]. Mean dose of levodopa used was 703.75mg±233.15. Median duration of concomitant treatment with safinamide and antidepressant drug was 6 months (IQR 20.5), and over eighteen months in 5 cases. No case of serotonin syndrome was recorded, neither was any of its typical manifestations combined or in isolation. CONCLUSIONS: Our real clinical practice study suggests that concomitant use of safinamide with antidepressant drugs in PD patients seemed to be safe and well tolerated, even in the long term. However, caution is warranted, individualizing treatment regimens and monitoring the potential appearance of adverse effects.

A decision support system based on recurrent neural networks to predict medication dosage for patients with Parkinson's disease.

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.

A neoteric annotation on the advances in combination therapy for Parkinson's disease: nanocarrier-based combination approach and future anticipation. Part I: exploring theoretical insights and pharmacological advances.

INTRODUCTION: Parkinson's disease (PD) is a neurological condition defined by a substantial reduction in dopamine-containing cells in the substantia nigra. Levodopa (L-Dopa) is considered the gold standard in treatment. Recent research has clearly shown that resistance to existing therapies can develop. Moreover, the involvement of multiple pathways in the nigrostriatal dopaminergic neuronal loss suggests that modifying the treatment strategy could effectively reduce this degeneration. AREAS COVERED: This review summarizes the key concerns with treating PD patients and the combinations, aimed at effectively managing PD. Part I focuses on the clinical diagnosis at every stage of the disease as well as the pharmacological treatment strategies that are applied throughout its course. It methodically elucidates the potency of multifactorial interventions in attenuating the disease trajectory, substantiating the rationale for co-administration of dual or multiple therapeutic agents. Significant emphasis is laid on evidence-based pharmacological combinations for PD management. EXPERT OPINION: By utilizing multiple drugs in a combination fashion, this approach can leverage the additive or synergistic effects of these agents, amplify the spectrum of treatment, and curtail the risk of side effects by reducing the dose of each drug, demonstrating significantly greater efficacy.

Evaluation of copeptin in children after stimulation with clonidine or L-Dopa.

OBJECTIVES: Arginine-stimulated serum copeptin has been proposed as a new method to diagnose arginine vasopressin (AVP) deficiency in children and adolescents. Herein we investigated the secretagogic potential of clonidine or L-Dopa on the copeptin serum levels in children. METHODS: Eight stimulation tests (4 with clonidine and 4 with L-Dopa) were performed in eight children (5 boys and 3 girls) with a median age of 6.5 years-old, evaluated for short stature due to possible growth hormone deficiency. Serum copeptin levels were measured at 30, 60, 90, and 120 min after administration of clonidine or L-Dopa. RESULTS: Copeptin levels in serum did not show any significant change in either test (clonidine or L-Dopa). The values of copeptin levels compared to the baseline value did not deviate more than 5 % in the clonidine arm (p=0.60) or 8 % in the L-Dopa arm (p=0.75) respectively. CONCLUSIONS: Data do not support the use of L-Dopa or clonidine as stimulants for evaluating AVP relating disorders in clinical pediatric practice.

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.

4'-fluorocannabidiol associated with capsazepine restrains L-DOPA-induced dyskinesia in hemiparkinsonian mice: Contribution of anti-inflammatory and anti-glutamatergic mechanisms.

We tested the efficacy of 4'-fluorocannabidiol (4'-F-CBD), a semisynthetic cannabidiol derivative, and HU-910, a cannabinoid receptor 2 (CB2) agonist in resolving l-DOPA-induced dyskinesia (LID). Specifically, we were interested in studying whether these compounds could restrain striatal inflammatory responses and rescue glutamatergic disturbances characteristic of the dyskinetic state. C57BL/6 mice were rendered hemiparkinsonian by unilateral striatal lesioning with 6-OHDA. Abnormal involuntary movements were then induced by repeated i.p. injections of l-DOPA + benserazide. After LID was installed, the effects of a 3-day treatment with 4'-F-CBD or HU-910 in combination or not with the TRPV1 antagonist capsazepine (CPZ) or CB2 agonists HU-308 and JWH015 were assessed. Immunostaining was conducted to investigate the impacts of 4'-F-CBD and HU-910 (with CPZ) on inflammation and glutamatergic synapses. Our results showed that the combination of 4'-F-CBD + CPZ, but not when administered alone, decreased LID. Neither HU-910 alone nor HU-910+CPZ were effective. The CB2 agonists HU-308 and JWH015 were also ineffective in decreasing LID. Both combination treatments efficiently reduced microglial and astrocyte activation in the dorsal striatum of dyskinetic mice. However, only 4'-F-CBD + CPZ normalized the density of glutamate vesicular transporter-1 (vGluT1) puncta colocalized with the postsynaptic density marker PSD95. These findings suggest that 4'-F-CBD + CPZ normalizes dysregulated cortico-striatal glutamatergic inputs, which could be involved in their anti-dyskinetic effects. Although it is not possible to rule out the involvement of anti-inflammatory mechanisms, the decrease in striatal neuroinflammation markers by 4'-F-CBD and HU-910 without an associated reduction in LID indicates that they are insufficient per se to prevent LID manifestations.

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.

Three-Dimensional Gait Analysis as a Biomarker for GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia.

BACKGROUND: GTP-cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) typically presents in childhood with dystonic posture of the lower extremities, gait impairment, and a significant response to levodopa. We performed three-dimensional gait analysis (3DGA) to quantitatively assess the gait characteristics and changes associated with levodopa treatment in patients with GTPCH1-deficient DRD. METHODS: Three levodopa-treated patients with GTPCH1-deficient DRD underwent 3DGA twice, longitudinally. Changes were evaluated for cadence; gait speed; step length; gait deviation index; kinematic data of the pelvis, hip, knee, and ankle joints; and foot progression angle. RESULTS: Levodopa treatment increased the cadence and gait speed in one of three patients and increased the gait deviation index in two of three patients. The kinematic data for each joint exhibited different characteristics, with some improvement observed in each of the three patients. There was consistent marked improvement in the abnormal foot progression angle; one patient had excessive external rotation of one foot, another had excessive bilateral internal rotation, and the other had excessive internal rotation of one foot and excessive external rotation of the opposite foot, all of which improved. CONCLUSION: The 3DGA findings demonstrate that the gait pathology and recovery process in GTPCH1-deficient DRD vary from case to case. Changes in the foot progression angle and gait deviation index can enable the effects of treatment to be more easily evaluated.

Effect of levodopa on postural blood pressure changes in Parkinson disease: a randomized crossover study.

PURPOSE: We investigated the effect of levodopa on postural blood pressure changes in individuals with Parkinson disease (PD) with (PD+OH) and without neurogenic OH (PD-OH). METHODS: We performed a prospective randomized crossover study with autonomic testing performed ON and OFF levodopa. The primary outcome was the change in systolic blood pressure (SBP) from supine to 70° tilt at 3 min (ΔSBP-3'). Secondary outcomes included indices of baroreflex function and blood pressure and heart rate during tilt. RESULTS: We enrolled 40 individuals with PD (21 PD+OH, 19 PD-OH), mean age (SD) 73.2 years (7.9), 13 women (32.5%)). There was no difference in age, sex, disease duration, and severity between PD+OH and PD-OH. Mean difference in ΔSBP-3' ON versus OFF levodopa in the whole study population was - 3.20 mmHg [- 7.36 to 0.96] (p = 0.14). Mean difference in ΔSBP-3' was - 2.14 mmHg [- 7.55 to 3.28] (p = 0.45) in PD+OH and - 5.14 mmHg [- 11.63 to 1.35] (p = 0.14) in PD-OH. Mean difference in ΔSBP ON versus OFF levodopa was greater at 7 and 10 min (- 7.52 mmHg [- 11.89 to - 3.15], p = 0.002, and - 7.82 mmHg [- 14.02 to - 1.67], p = 0.02 respectively). Levodopa was associated with lower absolute values of blood pressure in both PD+OH and PD-OH and cardiovascular noradrenergic baroreflex impairment. CONCLUSION: Levodopa decreases blood pressure in both PD with and without autonomic failure, but it does not cause a greater fall in blood pressure from supine to standing at 3 min. Levodopa-induced baroreflex sympathetic noradrenergic impairment may contribute to lower blood pressure. Lower standing blood pressure with levodopa may increase the risks of fall and syncope.

On Multiscaling of Parkinsonian Rest Tremor Signals and Their Classification.

Self-similar stochastic processes and broad probability distributions are ubiquitous in nature and in many man-made systems. The brain is a particularly interesting example of (natural) complex system where those features play a pivotal role. In fact, the controversial yet experimentally validated "criticality hypothesis" explaining the functioning of the brain implies the presence of scaling laws for correlations. Recently, we have analyzed a collection of rest tremor velocity signals recorded from patients affected by Parkinson's disease, with the aim of determining and hence exploiting the presence of scaling laws. Our results show that multiple scaling laws are required in order to describe the dynamics of such signals, stressing the complexity of the underlying generating mechanism. We successively extracted numeric features by using the multifractal detrended fluctuation analysis procedure. We found that such features can be effective for discriminating classes of signals recorded in different experimental conditions. Notably, we show that the use of medication (L-DOPA) can be recognized with high accuracy.

Neuronal intranuclear inclusion disease misdiagnosed as Parkinson's disease: a case report.

Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disease that mainly manifests as dementia, muscle weakness, sensory disturbances, and autonomic nervous dysfunction. Herein, we report a 68-year-old Chinese woman who was hospitalized because of resting tremor and bradykinesia that had been present for 7 years. Five years prior, bradykinesia and hypermyotonia had become apparent. She had urinary incontinence and rapid eye movement sleep behavior disorder. She was diagnosed with Parkinson's disease (PD) and received levodopa and pramipexole, which relieved her motor symptoms. During hospitalization, diffusion-weighted imaging revealed a high-intensity signal along the cortical medullary junction. Moreover, a skin biopsy revealed the presence of intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells. NIID was diagnosed by testing the Notch 2 N-terminal-like C (NOTCH2NLC) gene. We report this case to remind doctors to consider NIID when diagnosing patients with symptoms indicative of Parkinson's disease. Moreover, we note that further research is needed on the mechanism by which levodopa is effective for NIID.

AMPK-mediated autophagy pathway activation promotes ΔFosB degradation to improve levodopa-induced dyskinesia.

BACKGROUND: Parkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is one of the most prevalent motor complications, often characterized by abnormal involuntary movements, and the pathogenesis of LID is still unclear but recent studies have suggested the involvement of autophagy. METHODS: The onset of LID was mimicked by chronic levodopa treatment in a unilateral 6-hydroxydopamine (6-OHDA) -lesion rat model. Overexpression of ΔFosB in HEK293 cells to mimic the state of ΔFosB accumulation. The modulation of the AMP-activated protein kinase (AMPK)-mediated autophagy pathway using by metformin, AICAR (an AMPK activator), Compound C (an AMPK inhibitor) and chloroquine (an autophagy pathway inhibitor). The severity of LID was assessed by axial, limb, and orofacial (ALO) abnormal involuntary movements (AIMs) score and in vivo electrophysiology. The activity of AMPK pathway as well as autophagy markers and FosB-ΔFosB levels were detected by western blotting. RT-qPCR was performed to detect the transcription level of FosB-ΔFosB. The mechanism of autophagy dysfunction was further explored by immunofluorescence and transmission electron microscopy. RESULTS: In vivo experiments demonstrated that chronic levodopa treatment reduced AMPK phosphorylation, impaired autophagosome-lysosomal fusion and caused FosB-ΔFosB accumulation in the striatum of PD rats. Long-term metformin intervention improved ALO AIMs scores as well as reduced the mean power of high gamma (hγ) oscillations and the proportion of striatal projection neurons unstable in response to dopamine for LID rats. Moreover, the intervention of metformin promoted AMPK phosphorylation, ameliorated the impairment of autophagosome-lysosomal fusion, thus, promoting FosB-ΔFosB degradation to attenuate its accumulation in the striatum of LID rats. However, the aforementioned roles of metformin were reversed by Compound C and chloroquine. The results of in vitro studies demonstrated the ability of metformin and AICAR to attenuate ΔFosB levels by promoting its degradation, while Compound C and chloroquine could block this effect. CONCLUSIONS: In conclusion, our results suggest that long-term metformin treatment could promote ΔFosB degradation and thus attenuate the development of LID through activating the AMPK-mediated autophagy pathway. Overall, our results support the AMPK-mediated autophagy pathway as a novel therapeutic target for LID and also indicate that metformin is a promising therapeutic candidate for LID.

Effect of levodopa on pathological gait in Dravet syndrome: A randomized crossover trial using three-dimensional gait analysis.

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group. Levodopa/carbidopa hydrate was prescribed at a dose of 5 mg/kg/day (body weight <60 kg) or 300 mg/day (body weight ≥60 kg). The medication was taken for 4-6 weeks (4-week washout period). 3DGA was performed three times before the study, with and without levodopa. A mixed-effects model was used to evaluate the effectiveness of levodopa. The primary outcome was the change in the Gait Deviation Index (GDI). In addition, spatiotemporal gait parameters, 6-minute walking distance (6MD), and balance were evaluated. The correlation between the effectiveness of levodopa and age or gait performance before starting levodopa was analyzed. RESULTS: Levodopa improved the GDI by 4.2 points, (p = .029), 6MD by 52 m (p = .002), and balance test result by 4.1 mm (p = .011) in participants with DS. No severe adverse events were observed, with the exception of one participant, who exhibited fever and consequently stopped taking levodopa. Levodopa was more effective in younger participants with a higher baseline gait performance. SIGNIFICANCE: Our randomized crossover trial showed that levodopa has the potential to improve gait disturbance in people with DS.

Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease.

BACKGROUND: PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico-striato-pallido-thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications. OBJECTIVE: To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD). METHODS: Participants with idiopathic PD were administered the oral Symbol Digit Modalities Test (SDMT; n = 181) and the Stroop test (n = 172) in the off-medication and "best on" medication states. ANCOVA was used to test for differences between off-medication and on-medication scores corrected for age and years of education. RESULTS: After administration of symptomatic medications, scores worsened on the SDMT (F = 11.70, P < 0.001, d = -0.13), improved on the Stroop color (F = 26.89, P < 0.001, d = 0.184), word (F = 6.25, P = 0.013, d = 0.09), and color-word (F = 13.22, P < 0.001, d = 0.16) test components, and the Stroop difference and ratio-based interference scores did not significantly change. Longer disease duration correlated with lower scores on the SDMT, Stroop color, word, and color-word scores; however, longer disease duration and higher levodopa-equivalents correlated with higher Stroop difference-based interference scores. CONCLUSIONS: Symptomatic medication differentially affects performance on two cognitive tests in PD. After acute treatment, core Stroop measures improved, Stroop interference was unchanged, and SDMT performance worsened, likely reflecting complex changes in processing speed and executive function related to acute treatment. When considering motor symptom therapies in PD, an individual's cognitive demands and expectations, especially regarding executive function, should be considered.

Levodopa-Carbidopa-Entacapone Intestinal Gel in Advanced Parkinson Disease: A Multicenter Real-Life Experience.

BACKGROUND: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021. STUDY QUESTION: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD? STUDY DESIGN: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania. MEASURES AND OUTCOMES: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted. RESULTS: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications. CONCLUSIONS: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen.

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.

Connectome-guided initiation of dopamine agonists facilitates cognitive recovery after frontal lobe resection: A case report.

Abulia is a common problem that manifests following various brain conditions, including brain surgeries. Abulia is felt to be related to dysfunction with the brain's dopamine-dependent circuitry. The role of default mode network (DMN) in its pathogenesis is crucial. In this case report, we detail the presentation of abulia in an elderly woman following surgical resection of a right frontal glioblastoma involving the DMN. Connectomic imaging was used pre-operatively and post-operatively, demonstrating disruption of regions integral to the DMN and the central executive network. We observed a significant cognitive improvement following the administration of levodopa and carbidopa. Preoperative assessment of both anatomical and functional networks can help ensure surgical safety and predict postoperative deficits. This evaluation not only enhances preparedness and facilitates early case diagnosis but also expedites the initiation of prompt and potentially targeted treatments. This case highlights the potential efficacy of levodopa and carbidopa in addressing DMN dysfunction and broadly suggests the potential for connectomics-guided post-operative therapies.