Prosody matters: Preserved prominence marking strategies in people with Parkinson's disease independent of motor status.

While many studies focus on segmental variation in Parkinsonian speech, little is known about prosodic modulations reflecting the ability to adapt to communicative demands in people with Parkinson's disease (PwPD). This type of prosodic modulation is important for social interaction, and it involves modifications in speech melody (intonational level) and articulation of consonants and vowels (segmental level). The present study investigates phonetic cues of prosodic modulations with respect to different focus structures in mild dysarthric PwPD as a function of levodopa. Acoustic and kinematic speech parameters of 25 PwPD were assessed in two motor conditions. Speech production data from PwPD were collected before (medication-OFF) and after levodopa intake (medication-ON) by means of 3-D electromagnetic articulography. On the acoustic level, intensity, pitch, and syllable durations were analyzed. On the kinematic level, movement duration and amplitude were investigated. Spatio-temporal modulations of speech parameters were examined and compared across three different prosodic focus structures (out-of-focus, broad focus, contrastive focus) to display varying speech demands. Overall, levodopa had beneficial effects on motor performance, speech loudness, and pitch modulation. Acoustic syllable durations and kinematic movement durations did not change, revealing no systematic effects of motor status on the temporal domain. In contrast, there were spatial modulations of the oral articulators: tongue tip movements were smaller and lower lip movements were larger in amplitude under levodopa, reflecting a more agile and efficient articulatory movement under levodopa. Thus, respiratory-phonatory functions and consonant production improved, while syllable duration and tongue body kinematics did not change. Interestingly, prominence marking strategies were comparable between the medication conditions under investigation, and in fact, appear to be preserved in mild dysarthric PwPD.

Tricompartmental Microcarriers with Controlled Release for Efficient Management of Parkinson's Disease.

Parkinson's is a progressive neurodegenerative disease of the nervous system. It has no cure, but its symptoms can be managed by supplying dopamine artificially to the brain.This work aims to engineer tricompartmental polymeric microcarriers by electrohydrodynamic cojetting technique to encapsulate three PD (Parkinson's disease) drugs incorporated with high encapsulation efficiency (∼100%) in a single carrier at a fixed drug ratio of 4:1:8 (Levodopa (LD): Carbidopa(CD): Entacapone (ENT)). Upon oral administration, the drug ratio needs to be maintained during subsequent release from microparticles to enhance the bioavailability of primary drug LD. This presents a notable challenge, as the three drugs vary in their aqueous solubility (LD > CD > ENT). The equilibrium of therapeutic release was achieved using a combination of FDA-approved polymers (PLA, PLGA, PCL, and PEG) and the disc shape of particles. In vitro studies demonstrated the simultaneous release of all the three therapeutics in a sustained and controlled manner. Additionally, pharmacodynamics and pharmacokinetics studies in Parkinson's disease rats induced by rotenone showed a remarkable improvement in PD conditions for the microparticles-fed rats, thereby showing a great promise toward efficient management of PD.

Levodopa versus levodopa sparing in early parkinson's disease: can we meet halfway?

Monotherapy is the recommended initial treatment for early Parkinson's disease. The pharmacological options for initial treatment include dopaminergic agonists, monoamine oxidase B inhibitors, and levodopa formulations. Several factors should be considered when selecting the optimal treatment, such as disease severity, disease duration, age, activity level, and the risk of developing motor and non-motor complications. Early evidence on the potential role of levodopa formulations in the risk of dyskinesia led to levodopa aversion in the late 1990s and early 2000s, favoring the use of levodopa-sparing options like dopamine agonists. This shift resulted in an increase in behavioral adverse effects, such as impulse control disorders, leading to a subsequent dopamine agonist aversion in the mid-2000s. This review aims to provide a comprehensive evaluation of the existing literature regarding the benefits and drawbacks of levodopa versus levodopa-sparing strategies in drug-naive early-stage Parkinson's disease.

A Comprehensive Approach to Parkinson's Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects.

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.

Levodopa-based device-aided therapies for the treatment of advanced Parkinson's disease: a social return on investment analysis.

Introduction: Parkinson's disease (PD) is an incurable, progressive, neurodegenerative disorder. As PD advances and symptoms progress, patients become increasingly dependent on family and carers. Traditional cost-effectiveness analyses (CEA) only consider patient and payer-related outcomes, failing to acknowledge impacts on families, carers, and broader society. This novel Social Return on Investment (SROI) analysis aimed to evaluate the broader impact created by improving access to levodopa (LD) device-aided therapies (DATs) for people living with advanced PD (aPD) in Australia. Methods: A forecast SROI analysis over a three-year time horizon was conducted. People living with aPD and their families were recruited for qualitative interviews or a quantitative survey. Secondary research and clinical trial data was used to supplement the primary research. Outcomes were valued and assessed in a SROI value map in Microsoft Excel™. Financial proxies were assigned to each final outcome based on willingness-to-pay, economic valuation, and replacement value. Treatment cost inputs were sourced from Pharmaceutical Benefits Schedule (PBS) and Medicare Benefits Scheme (MBS) published prices. Results: Twenty-four interviews were conducted, and 55 survey responses were received. For every $1 invested in access to LD-based DATs in Australia, an estimated $1.79 of social value is created. Over 3 years, it was estimated $277.16 million will be invested and $406.77 million of social return will be created. This value is shared between people living with aPD (27%), their partners (22%), children (36%), and the Australian Government (15%). Most of the value created is social and emotional in nature, including reduced worry, increased connection to family and friends, and increased hope for the future. Discussion: Investment in LD-based DATs is expected to generate a positive social return. Over 50% of the value is created for the partners and children of people living with aPD. This value would not be captured in traditional CEA. The SROI methodology highlights the importance of investing in aPD treatment, capturing the social value created by improved access to LD-based DATs.

Risk for Mortality in High versus Low Antiparkinsonian Therapy Dose During the First Year of Parkinson's Disease: A Real-World Study.

INTRODUCTION: Early, simple predictors for long-term survival in Parkinson's disease (PD) may help identify patients at elevated risk and are crucial for more personalized treatment. METHODS: This large, retrospective study examined whether higher levodopa equivalent daily dose (LEDD) a year after diagnosis predicts long-term survival. RESULTS: Mortality risk was increased among 292 patients receiving ≥ 600 mg LEDD versus 2233 patients receiving < 600 mg LEDD (hazard ratio 1.5; 95% confidence interval 1.3-1.7), particularly among patients aged < 75 years (1.8; 1.4-2.4). CONCLUSION: In PD, higher LEDD can be an early risk marker of increased mortality, probably because it reflects more severe disease.

Study on the relationship between peripheral nerve fiber types and levodopa usage in Parkinson's disease.

Background and purpose:

The aim of this study is to comprehensively determine the types of affected fibers in Parkinson’s disease (PD) patients by employing nerve conduction studies (NCS), sympathetic skin response (SSR) examinations, and current perception threshold (CPT) testing and to analyze the correlation between levodopa use and nerve involvement.

This retrospective study included 36 clinically diagnosed PD patients who were recruited between January 2018 and April 2019. All patients underwent NCS, SSR testing, and CPT sensory examinations. Additionally, the PD patients were assessed for disease staging using the Hoehn and Yahr (H-Y) scale. 

Fifteen patients were included in the tremor-dominant subtype, ten patients in the rigid-dominant subtype, and eleven patients in the mixed subtype. Eleven patients were using levodopa, while twenty-five patients had never used any anti-Parkinson’s medication. Ten patients (28%) showed abnormal sympathetic skin responses (SSR). The CPT examination revealed sensory abnormalities in twenty-four patients (67%), with eighteen patients (75%) experiencing sensory hypersensitivity and six patients (25%) experiencing sensory hypoesthesia. Twelve patients (33%) had normal CPT results. Among the patients with abnormal CPT findings, seven cases (29%) involved large myelinated fiber damage, twenty-two cases (92%) involved small myelinated fiber damage, and nineteen cases (79%) involved unmyelinated fiber damage. The rate of sensory abnormalities was 64% (7/11) in the levodopa group and 68% (17/25) in the non-levodopa group, with no statistically significant difference between the two groups. 

The incidence of abnormal CPT findings in PD patients was higher than that of abnormal SSR responses, suggesting that nerve fiber damage primarily affects small fiber nerves (SFN).

Improved Outcomes When Home-Dose Carbidopa-Levodopa Is Continued in the Geriatric Emergency Department in Patients With Parkinson's Disease.

Parkinson's disease (PD) is a debilitating condition that affects 1.8% of people 65 years of age and older. Patients with PD often require hospitalization and are frequently admitted through the emergency department (ED). Notably, their hospital durations tend to be lengthier compared with patients without PD. The primary outcome of this research was to compare the length of stay (LOS) of patients who received carbidopa-levodopa (CL) in the ED with those who did not. Secondary outcomes included 30-day-readmission rates and administration of injectable for agitation. In addition, the percentage of patients receiving CL before and after an information management technology (IMT) alert implementation was compared in a sub-analysis. Patients that received CL during their inpatient stay were identified by a database report in this retrospective study. Patients were excluded if they were not admitted through the ED, younger than 65 years of age, or admitted to the intensive care unit after the ED. There was a total of 266 in the control group and 217 patients in the intervention group. The intervention group had a significantly shorter LOS than the control group (3.29 vs 5.37 days; P = 0.002), significantly less frequent 30-day readmissions (P = 0.032), and used fewer injectables for agitation (P = 0.035). The sub-analysis of the IMT alert revealed that prior to the alert's implementation, 28.5% of patients received CL in the ED; whereas post-alert, this percentage increased to 91.4% (P < 0.001). The results of this study found that the group of PD patients who received CL in the ED had shorter LOS, lower 30-day readmissions, and used less injectables for agitation compared with the group that did not receive CL in the ED. This improvement is possibly due to continuity of CL supply considering its short half-life and clinical importance for PD.

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

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

An Artificial Neural Network Predicts Gender Differences of Motor and Non-Motor Symptoms of Patients with Advanced Parkinson's Disease under Levodopa-Carbidopa Intestinal Gel.

Background and Objectives: Currently, no tool exists to predict clinical outcomes in patients with advanced Parkinson's disease (PD) under levodopa-carbidopa intestinal gel (LCIG) treatment. The aim of this study was to develop a novel deep neural network model to predict the clinical outcomes of patients with advanced PD after two years of LCIG therapy. Materials and Methods: This was a longitudinal, 24-month observational study of 59 patients with advanced PD in a multicenter registry under LCIG treatment from September 2019 to September 2021, including 43 movement disorder centers. The data set includes 649 measurements of patients, which make an irregular time series, and they are turned into regular time series during the preprocessing phase. Motor status was assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) Parts III (off) and IV. The NMS was assessed by the NMS Questionnaire (NMSQ) and the Geriatric Depression Scale (GDS), the quality of life by PDQ-39, and severity by Hoehn and Yahr (HY). Multivariate linear regression, ARIMA, SARIMA, and Long Short-Term Memory-Recurrent NeuralNetwork (LSTM-RNN) models were used. Results: LCIG significantly improved dyskinesia duration and quality of life, with men experiencing a 19% and women a 10% greater improvement, respectively. Multivariate linear regression models showed that UPDRS-III decreased by 1.5 and 4.39 units per one-unit increase in the PDQ-39 and UPDRS-IV indexes, respectively. Although the ARIMA-(2,0,2) model is the best one with AIC criterion 101.8 and validation criteria MAE = 0.25, RMSE = 0.59, and RS = 0.49, it failed to predict PD patients' features over a long period of time. Among all the time series models, the LSTM-RNN model predicts these clinical characteristics with the highest accuracy (MAE = 0.057, RMSE = 0.079, RS = 0.0053, mean square error = 0.0069). Conclusions: The LSTM-RNN model predicts, with the highest accuracy, gender-dependent clinical outcomes in patients with advanced PD after two years of LCIG therapy.

Pick's Disease Presenting as Tremulous Parkinsonism with Limited Levodopa Response-A Rare Cause of Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome is a clinical diagnosis and common pathological causes are corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease. OBJECTIVES: We would like to highlight a rare but important differential of corticobasal syndrome. METHODS: A 78-year-old female had a 4-year history of predominantly right-hand rest tremor, worsening of handwriting but no change in cognition. The clinical examination showed right upper limb postural and kinetic tremor, mild wrist rigidity and reduced amplitude of right-sided finger tapping. She was initially diagnosed as idiopathic Parkinson's disease. Five years after onset of symptoms, she demonstrated bilateral myoclonic jerks and right upper limb dystonic posturing. She could not copy movements with the right hand. The magnetic resonance imaging (MRI) revealed disproportionate atrophy in the parietal lobes bilaterally. The clinical diagnosis was changed to probable corticobasal syndrome. She passed away 11 years from onset of symptoms at the age of 85 years. She underwent a post-mortem. RESULTS: The anterior and posterior frontal cortex, anterior cingulate, temporal neocortex, hippocampus and amygdaloid complex demonstrated considerable tau-related pathology consisting of a dense background of neuropil threads, and rounded, paranuclear neuronal inclusions consistent with Pick bodies. The immunostaining for three microtubule binding domain repeats (3R) tau performed on sections from the frontal and temporal lobes, basal ganglia and midbrain highlighted several inclusions whilst no 4R tau was observed. She was finally diagnosed with Pick's disease. CONCLUSIONS: Pick's disease can rarely present with clinical features of corticobasal syndrome.

Evidence for a relationship between genetic polymorphisms of the L-DOPA transporter LAT2/4F2hc and risk of hypertension in the context of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) and hypertension are chronic diseases affecting a large portion of the population frequently coexistent and interdependent. The inability to produce/use adequate renal dopamine may contribute to the development of hypertension and renal dysfunction. The heterodimeric amino acid transporter LAT2/4F2hc (SLC7A8/SLC3A2 genes) promotes the uptake of L-DOPA, the natural precursor of dopamine. We examined the plausibility that SLC7A8/SLC3A2 gene polymorphisms may contribute to hypertensive CKD by affecting the L-DOPA uptake. METHODS: 421 subjects (203 men and 218 women, mean age of 78.9 ± 9.6 years) were recruited and divided in four groups according to presence/absence of CKD, defined as reduced estimated glomerular filtration rate (eGFR < 60 ml/min/m2) calculated using the creatinine-based Berlin Initiative Study-1 (BIS1) equation, and to presence/absence of hypertension (systolic blood pressure ≥ 140 and/or diastolic blood pressure ≥ 90 mmHg). Subjects were analysed for selected SNPs spanning the SLC7A8 and SLC3A2 loci by Sequenom MassARRAY iPLEX platform. RESULTS: The most significant SNP at the SLC3A2 (4F2hc) locus was rs2282477-T/C, with carriers of the C-allele having a lower chance to develop hypertension among CKD affected individuals [OR = 0.33 (CI 0.14-0.82); p = 0.016]. A similar association with hypertensive CKD was found for the SLC7A8 (LAT2) rs3783436-T/C, whose C-allele resulted associated with decreased risk of hypertension among subjects affected by CKD [OR = 0.56 (95% CI 0.35-0.90; p = 0.017]. The two variants were predicted to be potentially functional. CONCLUSIONS: The association between SLC3A2 and SLC7A8 variants to hypertension development in patients with renal failure could be linked to changes in L-DOPA uptake and consequently dopamine synthesis. Although the associations do not survive correction for Bonferroni multiple testing, and additional research is needed, our study opens new avenues for future basic and translational research in the field of hypertensive CKD.

Associations between gut microbiota characteristics and non-motor symptoms following pharmacological and surgical treatments in Parkinson's disease patients.

BACKGROUND: The gut microbiota has been implicated in Parkinson's disease (PD), with alterations observed in microbial composition and reduced microbial species richness, which may influence gastrointestinal symptoms in PD patients. It remains to be determined whether the severity of gastrointestinal symptoms correlates with microbiota variations in PD patients treated pharmacologically or with subthalamic nucleus deep brain stimulation (STN-DBS) therapy. This study aims to explore how these treatments affect gut microbiota and gastrointestinal symptoms in PD, identifying specific microbial differences associated with each treatment modality. METHODS: A total of 42 individuals diagnosed with PD, along with 38 age-matched household control participants, contributed stool samples for microbiota characterization. Differences in the gut microbiota across various groups of PD patients and their households were identified through comprehensive sequencing of the 16S rRNA gene amplicon sequencing. KEY RESULTS: Differences in microbial communities were observed between PD patients and controls, as well as between PD patients receiving pharmacological treatment and those with STN-DBS. Pharmacologically treated advanced PD patients have higher gastrointestinal dysfunctions. Gut microbiota profile linked to STN-DBS and reduced levodopa consumption, characterized by its anti-inflammatory properties, might play a role in diminishing gastrointestinal dysfunction relative to only pharmacological treatments. CONCLUSIONS & INFERENCES: Advanced PD patients on medication exhibit more gastrointestinal issues, despite relatively stable microbial diversity, indicating a complex interaction between gut microbiota, PD progression, and treatment effects. An imbalanced gut-brain axis, particularly due to reduced butyrate production, may lead to constipation by affecting the enteric nervous system, which emphasizes the need to incorporate gut microbiome insights into treatment strategies.

The Impact of Subthalamic Deep Brain Stimulation on Apathy in Parkinson's Disease Patients.

AIM: To investigate the impact of subthalamic deep brain stimulation (STN DBS) on apathy and the possible relationship between apathy, depression, and levodopa equivalent dosage (LED) in Parkinson's Disease (PD) patients. MATERIAL AND METHODS: A total of 26 patients have been evaluated via the Unified Parkinson Disease Rating Scale (UPDRS), Beck Depression Inventory (Beck D), and Beck Anxiety Inventory (Beck A), Montreal Cognitive Assessment (MoCA), Parkinson Disease Questionnaire (PDQ-39) just before and 6 months after DBS. RESULTS: Apathy scores (AES) showed a slight decrease from 54.00 ± 10.30 to 52.69 ± 8.88 without any statistical significance (p=0.502) after DBS therapy. No correlation was detected between the post-treatment changes in apathy and UPDRS scores, Beck D, Beck A. Although the direction of the correlation between changes in AES scores and LED values was negative, the results did not reach statistical significance. CONCLUSION: STN DBS therapy does not have a negative effect on apathy in PD Patients. Despite the satisfactory motor improvement, conservative dopaminergic dose reduction after surgery seems to be the main point to prevent apathy increase in PD patients after STN DBS.

The influence of sex on non-motor wearing-off in Parkinson's disease: A WORK-PD post-hoc study.

INTRODUCTION: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study. METHODS: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year. RESULTS: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms. DISCUSSION: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level.

Freezing of gait: pharmacological and surgical options.

PURPOSE OF REVIEW: The primary aim of this review is to describe and update the pathophysiological and relevant therapeutic strategies for freezing of gait (FoG) in patients with Parkinson's disease (PD). RECENT FINDINGS: FoG presumably involves dysfunction of multiple cortical and subcortical components, including dopaminergic and nondopaminergic circuits. In this regard, levodopa and physical therapy represent the first-choice therapeutic options for PD patients with FoG. However, the relationship between FoG and levodopa is not fully predictable. For those patients with levodopa-resistant FoG, there is promising but still controversial data on the benefits of bilateral high-frequency transcranial magnetic stimulation and deep brain stimulation on the subthalamic nuclei, substantia nigra pars reticulata, pedunculopontine nucleus, and the Fields of Forel. On the other hand, general exercise, gait training with a treadmill, focus attention on gait training, and conventional physiotherapy have demonstrated moderate to large benefits in FoG. SUMMARY: FOG requires different treatment strategies. The inclusion of adequate detection and prediction of FoG combined with double-blind, and statistically powered protocols are needed to improve patients' quality of life, the motor and nonmotor symptoms and societal burden associated with FoG.

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.

Dopamine synthesis and transport: current and novel therapeutics for parkinsonisms.

Parkinsonism is the primary type of movement disorder in adults, encompassing a set of clinical symptoms, including rigidity, tremors, dystonia, bradykinesia, and postural instability. These symptoms are primarily caused by a deficiency in dopamine (DA), an essential neurotransmitter in the brain. Currently, the DA precursor levodopa (synthetic L-DOPA) is the standard medication to treat DA deficiency, but it only addresses symptoms rather than provides a cure. In this review, we provide an overview of disorders associated with DA dysregulation and deficiency, particularly Parkinson's disease and rare inherited disorders leading predominantly to dystonia and/or parkinsonism, even in childhood. Although levodopa is relatively effective for the management of motor dysfunctions, it is less effective for severe forms of parkinsonism and is also associated with side effects and a loss of efficacy over time. We present ongoing efforts to reinforce the effect of levodopa and to develop innovative therapies that target the underlying pathogenic mechanisms affecting DA synthesis and transport, increasing neurotransmission through disease-modifying approaches, such as cell-based therapies, nucleic acid- and protein-based biologics, and small molecules.

The Effect of taVNS at 25 Hz and 100 Hz on Parkinson's Disease Gait-A Randomized Motion Sensor Study.

BACKGROUND: Transcutaneous electrostimulation of the auricular branch of the vagal nerve (taVNS) has the propensity to reach diffuse neuromodulatory networks, which are dysfunctional in Parkinson's disease (PD). Previous studies support the use of taVNS as an add-on treatment for gait in PD. OBJECTIVES: We assessed the effect of taVNS at 25 Hz (taVNS25), taVNS at 100 Hz (taVNS100), and sham earlobe stimulation (sVNS) on levodopa responsive (arm swing velocity, arm range of motion, stride length, gait speed) and non-responsive gait characteristics (arm range of motion asymmetry, anticipatory postural adjustment [APA] duration, APA first step duration, APA first step range of motion), and turns (first turn duration, double 360° turn duration, steps per turn) in advanced PD. METHODS: In our double blind sham controlled within-subject randomized trial, we included 30 PD patients (modified Hoehn and Yahr stage, 2.5-4) to assess the effect of taVNS25, taVNS100, and sVNS on gait characteristics measured with inertial motion sensors during the instrumented stand and walk test and a double 360° turn. Separate generalized mixed models were built for each gait characteristic. RESULTS: During taVNS100 compared to sVNS arm swing velocity (P = 0.030) and stride length increased (P = 0.027), and APA duration decreased (P = 0.050). During taVNS25 compared to sVNS stride length (P = 0.024) and gait speed (P = 0.021) increased and double 360° turn duration decreased (P = 0.039). CONCLUSIONS: We have found that taVNS has a frequency specific propensity to improve stride length, arm swing velocity, and gait speed and double 360° turn duration in PD patients. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.