Motor Symptoms Research Articles

Safinamide as adjunctive therapy to levodopa monotherapy for patients with Parkinson's disease with wearing-off: The Japanese observational J-SILVER study

BackgroundSafinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice. MethodsThis multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment. ResultsIn total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change −7.0 [p = 0.012], −2.4 [p = 0.007] and − 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild. ConclusionSafinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns. Study registrationUniversity Hospital Medical Information Network in Japan; study ID: UMIN000044341.

Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Evaluating the Effects of Bimanual Activities with and Without Motivational Strategies on Participation and Upper Extremity Function in Subjects with Parkinson's Disease: Study Protocol for a Randomized Controlled Trial

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms that can impact daily activities. Objectives: Activity-based interventions, particularly when combined with motivational strategies, may enhance upper extremity function and participation in people with PD. Methods: This study will include forty-five patients with PD aged 35 to 85 years, categorized as stages I to III according to the Hoehn and Yahr Scale. Patients will be recruited from neurological and rehabilitation centers and randomly assigned to one of three intervention groups: Activity-based interventions with motivational strategy, activity-based interventions without motivational strategy, and conventional interventions. All participants will undergo a 24-session intervention, three times a week. The study will assess various outcomes at multiple time points, including baseline, session 10, session 18, post-intervention (week 9), and follow-up (week 17). Primary outcome measures will focus on motor control of the upper extremity and participation, while secondary outcome measures will include cognitive function and quality of life. Results: This proposed randomized controlled trial (RCT) aims to investigate the potential beneficial effects of activity-based interventions, combined with motivational strategies, on upper extremity function and participation in activities of daily living (ADLs) for individuals with PD. Conclusions: The expected outcome of this study is to provide valuable insights that can assist occupational therapists in making informed decisions regarding intervention plans for people with PD.

Parkinson's disease with hyposmia and dysautonomia: does it represent a distinct subtype?

Olfactory dysfunction or dysautonomia is one of the earliest prodromal nonmotor symptoms of Parkinson's disease (PD). We aimed to investigate whether PD patients with dysautonomia and hyposmia at the de novo stage present different prognoses regarding PD dementia (PDD) conversion, motor complication development, and change in levodopa-equivalent doses (LED). In this retrograde cohort study, we included 105 patients with newly diagnosed PD patients who underwent cross-cultural smell identification test (CC-SIT), autonomic function tests (AFT), and dopamine transporter (DAT) scan at the de novo stage. PD patients were divided into Hyposmia + /Dysautonomia + (H + /D +) and Hyposmia - /Dysautonomia - (H - /D -) groups depending on the result of AFT and CC-SIT. Baseline clinical, cognitive, imaging characteristics, longitudinal risks of PDD development and motor complication occurrence, and longitudinal LED changes were compared between the two groups. When compared with the H - /D - group, the H + /D + group showed lower standardized uptake value ratios in all subregions, lower asymmetry index, and steeper ventral - dorsal gradient in the DAT scan. The H + /D + group exhibited poorer performance in frontal/executive function and a higher risk of PDD development. The risk of motor complications including levodopa-induced dyskinesia, wearing off, and freezing of gait, was comparable between the two groups. The analysis of longitudinal changes in LED using a linear mixed model showed that the increase of LED in the H + /D + group was more rapid. Our results suggest that PD patients with dysautonomia and hyposmia at the de novo stage show a higher risk of PD dementia conversion and rapid progression of motor symptoms.

RTMS of the Cerebellum Using an Accelerated Stimulation Protocol Improved Gait in Parkinson's Disease.

Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological and noninvasive brain stimulation technique that has been proven to be effective in Parkinson's disease (PD). The combination of rTMS and treadmill training improved gait function in PD greater than treadmill training alone. The aim of our study was to evaluate the combination of a novel high-intensity, short intervention rTMS treatment and a multimodal treatment protocol including of physiotherapy, occupational therapy and language therapy, the so-called Parkinson's Disease Multimodal Complex Treatment (PD-MCT), to improve motor function. In this randomized double-blind sham-controlled trial rTMS with 48 Hz or sham was applied over the cerebellum 3 times a day for 5 consecutive days. Patients were assessed at baseline (V0), after 5 days of treatment (V1), and 4 weeks later (V2). The primary clinical outcome measure was the motor sum-score of the Unified PD Rating Scale (UPDRSIII), secondary clinical outcomes were quantitative motor tasks. A total of 36 PD patients were randomly allocated either to rTMS (n = 20) or sham (n = 16), both combined with PD-MCT. rTMS improved the UDPRSIII score comparing baseline and V1 in the treatment group by -8.2 points (P = .004). The 8MW and dynamic posturography remained unchanged in both groups after intervention. Conclusion. Compressing weeks of canonical rTMS protocols into 5 days was effective and well tolerated. rTMS may serve as an add-on therapy for augmenting the multimodal complex treatment of motor symptoms, but seems to be ineffective to treat postural instability.

A Network Approach to Understanding the Role of Executive Functioning and Alpha Oscillations in Inattention and Hyperactivity-Impulsivity Symptoms of ADHD.

ADHD is a prevalent neurodevelopmental disorder characterized by symptoms of inattention and hyperactivity-impulsivity. Impairments in executive functioning (EF) are central to models of ADHD, while alpha-band spectral power event-related decreases (ERD) have emerged as a putative electroencephalography (EEG) biomarker of EF in ADHD. Little is known about the roles of EF and alpha ERD and their interactions with symptoms of ADHD. We estimated network models of ADHD symptoms and integrated alpha ERD measures into the symptom network. EF emerges as a bridge network node connecting alpha ERD and the hyperactivity/impulsivity and inattention symptoms. We found that EF most closely relates to a subset of symptoms, namely the motoric symptoms, "seat" (difficulty staying seated), and "runs" (running or climbing excessively). EF functions as a bridge node connecting alpha ERD and the ADHD symptom network. Motoric-type symptoms and EF deficits may constitute important nodes in the interplay between behavior/symptoms, cognition, and neurophysiological markers of ADHD.

Unveiling the role of subjective cognitive complaints in predicting cognitive impairment in Parkinson´s Disease- A longitudinal study with 4year of follow up.

Emerging data associated subjective cognitive complaints (SCC) with a heightened risk of future cognitive decline in Parkinson´s Disease (PD). To determine whether SCC may predict the development of cognitive impairment in PD patients at baseline. Over 4years, major aspects of motor and non-motor symptoms were assessed. SCC were evaluated by non-motor symptoms scale domain-5 (NMSS5). The predictor value of SCC in cognitive change was assessed with univariate linear regression analyses, with NMSS5 at baseline as predictor. Change in cognition (ΔMoCA) was calculated by subtracting Montreal Cognitive Assessment Scale (MoCA) scores at baseline from scores obtained at reassessment and employed as the outcome. We replicated these analyses by employing alterations in MoCA subdomains as outcomes. 134 patients were evaluated at baseline, of those 73 PD patients were reassessed four years later. In our study, SCC didn´t act as a predictor for future cognitive decline. However, baseline NMSS5 was associated significantly with variation in attention, naming, and orientation domains. Our findings did not support that SCC in PD patients acts as a predictor of global cognitive decline. However, our findings enhance comprehension of how SCC correlates with performance in distinct cognitive areas, thereby providing better guidance for patients on their current complaints.

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

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

Psychological Therapy for Functional Neurological Disorder: Examining Impact on Dissociation, Psychological Distress and General Functioning

ABSTRACT Functional neurological disorder (FND) represents a broad group of motor and sensory clinical symptoms which cannot be explained by other neurological diagnoses. Dissociation is considered a key mechanism in their development and maintenance. Despite psychological therapy being the recommended choice of treatment for FND, evidence for its effectiveness is in its infancy. This study explored the dissociative profile of forty-seven patients with FND and evaluated whether individual psychological therapy improved dissociative symptoms, psychological distress and general functioning among twenty-five adults with FND. Patients completed the Multiscale Dissociation Inventory, the EuroQol five-dimensional descriptive system, the General Anxiety Disorder-7 scale and the Patient Health Questionnaire-9. Our sample showed high levels of disengagement, depersonalization and memory disturbance at baseline. Treatment was associated with significant improvements in general functioning, and symptoms of dissociation and anxiety. Improvements in dissociative experiences were found to be possibly due to reduction in anxiety. Improvements in depression were the strongest predictor of improvements in general functioning. Limitations and areas for further research are discussed.

Tango and physiotherapy interventions in Parkinson’s disease: a pilot study on efficacy outcomes on motor and cognitive skills

Pharmacological treatments in Parkinson’s disease (PD), albeit effective in alleviating many motor symptoms, have limited effects in non-motor signatures as cognitive impairment, as well as in other aspects included postural instability. Consequently, complementary interventions are nowadays a prerogative of clinical practice managing PD symptomatology. In this pilot longitudinal study, we recruited twenty-four PD patients participating in one of two interventions: adapted Argentine Tango or group-based physiotherapy. Participants underwent a motor and neuropsychological evaluation before and after four months of activities, carried out twice a week. We found a general stabilization of motor and cognitive abilities, with significant improvements in several motor skills, mainly pertaining to static and dynamic balance, similarly in both groups. At cognitive level, we measured a significant improvement in both groups in the Action Naming task. Interestingly, only PD patients in the Tango group improved their performance in the test measuring facial emotion recognition. These findings highlight the crucial role that physical activities have in the stabilization and slowdown of disease’s progression in PD. They further highlight the beneficial effects of a group-based physical intervention, which, especially in the case of Tango, could lead to behavioral ameliorations in domains other than the motor, such as emotion recognition.

Evaluation of the Parkinson's Remote Interactive Monitoring System in a Clinical Setting: Usability Study.

The fastest-growing neurological disorder is Parkinson disease (PD), a progressive neurodegenerative disease that affects 10 million people worldwide. PD is typically treated with levodopa, an oral pill taken to increase dopamine levels, and other dopaminergic agonists. As the disease advances, the efficacy of the drug diminishes, necessitating adjustments in treatment dosage according to the patient's symptoms and disease progression. Therefore, remote monitoring systems that can provide more detailed and accurate information on a patient's condition regularly are a valuable tool for clinicians and patients to manage their medication. The Parkinson's Remote Interactive Monitoring System (PRIMS), developed by PragmaClin Research Inc, was designed on the premise that it will be an easy-to-use digital system that can accurately capture motor and nonmotor symptoms of PD remotely. We performed a usability evaluation in a simulated clinical environment to assess the ease of use of the PRIMS and determine whether the product offers suitable functionality for users in a clinical setting. Participants were recruited from a user sign-up web-based database owned by PragmaClin Research Inc. A total of 11 participants were included in the study based on the following criteria: (1) being diagnosed with PD and (2) not being diagnosed with dementia or any other comorbidities that would make it difficult to complete the PRIMS assessment safely and independently. Patient users completed a questionnaire that is based on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Interviews and field notes were analyzed for underlying themes and topics. In total, 11 people with PD participated in the study (female individuals: n=5, 45%; male individuals: n=6, 55%; age: mean 66.7, SD 7.77 years). Thematic analysis of the observer's notes revealed 6 central usability issues associated with the PRIMS. These were the following: (1) the automated voice prompts are confusing, (2) the small camera is problematic, (3) the motor test exhibits excessive sensitivity to the participant's orientation and position in relation to the cameras, (4) the system poses mobility challenges, (5) navigating the system is difficult, and (6) the motor test exhibits inconsistencies and technical issues. Thematic analysis of qualitative interview responses revealed four central themes associated with participants' perspectives and opinions on the PRIMS, which were (1) admiration of purpose, (2) excessive system sensitivity, (3) video instructions preferred, and (4) written instructions disliked. The average system usability score was calculated to be 69.2 (SD 4.92), which failed to meet the acceptable system usability score of 70. Although multiple areas of improvement were identified, most of the participants showed an affinity for the overarching objective of the PRIMS. This feedback is being used to upgrade the current PRIMS so that it aligns more with patients' needs.

Lixisenatide in early parkinson's disease: efficacy, safety, and future directions: a correspondence.

Parkinson's disease (PD) presents as a complex neurodegenerative disorder characterized by motor and non-motor symptoms, resulting from dopaminergic neuron degeneration. Current treatment strategies primarily aim to alleviate symptoms through pharmacotherapy and supportive therapies. However, emerging research explores novel therapeutic avenues, including the repurposing of drugs like lixisenatide, a GLP-1 receptor agonist initially developed for type 2 diabetes. This correspondence summarizes a phase 2 clinical trial investigating lixisenatide's efficacy in early PD, demonstrating a potential for mitigating motor disability progression. Findings reveal a marginal improvement or stabilization in motor function among lixisenatide-treated individuals compared to placebo, emphasizing its therapeutic promise. Nonetheless, the emergence of gastrointestinal adverse events underscores the need for careful monitoring and management. Further extensive trials are warranted to delineate lixisenatide's efficacy and safety profile, fostering collaborative efforts towards precision treatments in PD.

Relationships between the global symptom score and electrophysiological findings after surgical release for carpal tunnel syndrome: Indications and outcomes.

Regarding surgical indications for carpal tunnel syndrome (CTS), the hypothesis that the recovery processes of subjective symptoms differ among pain, sensory, and motor symptoms and correlate with recovery in objective nerve conduction studies was examined in the present study. The global symptom score (GSS) is a method used to assess clinical outcomes and covers subjective symptoms, including pain (pain and nocturnal awakening), sensory (numbness and paresthesia), and motor (weakness/clumsiness) symptoms. The relationships between long-term changes in GSS and recovery in nerve conduction studies were investigated. Forty patients (40 hands) were included (mean age 65years; 80% female; 68% with moderate CTS: sensory nerve conduction velocity < 45m/s and motor nerve distal latency > 4.5ms). Pain and nocturnal awakening rapidly subsided within 1month after surgery and did not recur in the long term (median 5.6years). Paresthesia significantly decreased 3months after surgery and in the long term thereafter. Weakness/clumsiness significantly decreased at 1year. Sensory nerve distal latency, conduction velocity, and amplitude significantly improved 3months and 1year after surgery, and correlated with nocturnal awakening in the short term (3months) in moderate CTS cases. The patient satisfaction rate was 91%. Rapid recovery was observed in pain and nocturnal awakening, of which nocturnal awakening correlated with the recovery of sensory nerve conduction velocity. Patients with pain symptoms due to moderate CTS may benefit from surgical release.

Telerehabilitation by Videoconferencing for Balance and Gait in People with Parkinson’s Disease: A Scoping Review

Although supervised and real-time telerehabilitation by videoconferencing is now becoming common for people with Parkinson’s disease (PD), its efficacy for balance and gait is still unclear. This paper uses a scoping approach to review the current evidence on the effects of telerehabilitation by videoconferencing on balance and gait for patients with PD. We also explored whether studies have used wearable technology during telerehabilitation to assess and treat balance and gait via videoconferencing. Literature searches were conducted using PubMed, ISI’s Web of Knowledge, Cochrane’s Library, and Embase. The data were extracted for study design, treatment, and outcomes. Fourteen studies were included in this review. Of these, seven studies investigated the effects of telerehabilitation (e.g., tele-yoga and adapted physiotherapy exercises) on balance and gait measures (e.g., self-reported balance, balance scale, walking speed, mobility, and motor symptoms) using videoconferencing in both assessment and treatment. The telerehabilitation programs by videoconferencing were feasible and safe for people with PD; however, the efficacy still needs to be determined, as only four studies had a parallel group. In addition, no study used wearable technology. Robust evidence of the effects of telerehabilitation by videoconferencing on balance and gait for patients with PD was not found, suggesting that future powered, prospective, and robust clinical trials are needed.

Exploring therapeutic interventions for functional neurological disorders: a comprehensive scoping review.

Functional Neurological Disorders (FNDs) are characterized by the symptoms experienced by the individuals but also by how they express personal experiences and concerns related to the clinical condition. Access to care programs for functional neurological symptoms appears challenging and may entail circular, self-perpetuating healthcare pathways. Given the challenging and misleading interpretations around FND, in advocating for care pathways beyond medical therapies, we designed a scoping review to map recently suggested practices and interventions. We identified 31 relevant papers published between January 2018 and December 2022. Most of the literature was gathered from the US and UK healthcare experiences, with documented interventions provided by multi-professional teams or stand-alone psychotherapists. We found different care pathways addressing either motor or non-motor manifestations. Persons with Functional Motor Disorder are more likely to be referred to physical therapy first, while Persons suffering from Non-Epileptic Seizures are to mental health services. A narrow focus was given to minor components of multimodal approaches (e.g. social workers, and occupational therapists). High heterogeneity was found between assessment instruments as well, reflecting different perspectives in selecting treatment outcomes (e.g., reduction of non-epileptic events, psychological functioning, motor symptoms). Among healthcare professionals, neurologists and (neuro)psychiatrists are typically engaged in formulating and delivering diagnoses, while treatment is often administered by physiotherapists and/or psychologists. In the context of FNDs, the complex etiopathological nature of the condition, including comorbidities, suggests the recommendation of multidisciplinary treatments adopting a stepped care model progressing from standard to higher level individualized modules may better suit individual complexities.

Dynamic channelwise functional-connectivity states extracted from resting-state EEG signals of patients with Parkinson’s disease

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disease that usually happens to elderly people, with a wide range of motor and dementia symptoms. An objective and convenient biomarker for PD detection is extremely valuable, especially one that could be acquired non-invasively and low-costly. To this end, this study used resting-state scalp electroencephalography (EEG) signals to explore dynamic functional-connectivity (dFC) states between each pair of EEG recording channels, without source localization.MethodsdFC refers to synchronization patterns over time between each pair of EEG channels. First, five frequency bands were extracted from EEG signals with fourth-order Butterworth bandpass filter, including delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (8–30 Hz) and gamma (30–50 Hz). Then, after non-random joint fluctuation was measured with weighted symbolic mutual information (wSMI) algorithm, whole-brain dynamic channelwise dFC states were estimated, and classified with k-means clustering. At last, FC state occurrences were calculated, and ANOVA analyses were performed for each state. Two open-source resting-state EEG data sets (https://doi.org/10.18112/openneuro.ds002778.v1.0.4: 32 channels, 16 health controls and 15 PD subjects. https://doi.org/10.18112/openneuro.ds003490.v1.1.0: 64 channels, 25 health controls and 25 PD subjects) were used to test our methods.ResultsSignificant changes in proportions of various dFC states within beta frequency-band were consistently observed in these both data sets (p value < 0.05).ConclusionsOur findings suggest that channelwise dFC states within beta frequency-band directly extracted from resting-state scalp–EEG recordings could potentially serve as a biomarker of PD.

Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy

Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA1 mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granule cell layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, which might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we performed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dynactin Subunit 2 (Dctn2) interaction was shared across all PFF conditions, and NCK Associated Protein 1 (Nckap1) and Adaptor Related Protein Complex 3 Subunit Beta 2 (Ap3b2) were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

Subthalamic nucleus–language network connectivity predicts dopaminergic modulation of speech function in Parkinson’s disease

Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.

Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease.

This study was undertaken to investigate the effects of dietary caffeine intake on striatal dopamine function and clinical symptoms in Parkinson disease in a cross-sectional and longitudinal setting. One hundred sixty-three early Parkinson disease patients and 40 healthy controls were investigated with [123I]FP-CIT single photon emission computed tomography, and striatal dopamine transporter binding was evaluated in association with the level of daily coffee consumption and clinical measures. After a median interval of 6.1 years, 44 patients with various caffeine consumption levels underwent clinical and imaging reexamination including blood caffeine metabolite profiling. Unmedicated early Parkinson disease patients with high coffee consumption had 8.3 to 15.4% lower dopamine transporter binding in all studied striatal regions than low consumers, after accounting for age, sex, and motor symptom severity. Higher caffeine consumption was further associated with a progressive decline in striatal binding over time. No significant effects of caffeine on motor function were observed. Blood analyses demonstrated a positive correlation between caffeine metabolites after recent caffeine intake and dopamine transporter binding in the ipsilateral putamen. Chronic caffeine intake prompts compensatory and cumulative dopamine transporter downregulation, consistent with caffeine's reported risk reduction in Parkinson disease. However, this decline does not manifest in symptom changes. Transiently increased dopamine transporter binding after recent caffeine intake has implications for dopaminergic imaging guidelines. ANN NEUROL 2024.

Continuous and Unconstrained Tremor Monitoring in Parkinson's Disease Using Supervised Machine Learning and Wearable Sensors.

Accurately assessing the severity and frequency of fluctuating motor symptoms is important at all stages of Parkinson's disease management. Contrarily to time-consuming clinical testing or patient self-reporting with uncertain reliability, recordings with wearable sensors show promise as a tool for continuously and objectively assessing PD symptoms. While wearables-based clinical assessments during standardised and scripted tasks have been successfully implemented, assessments during unconstrained activity remain a challenge. We developed and implemented a supervised machine learning algorithm, trained and tested on tremor scores. We evaluated the algorithm on a 67-hour database comprising sensor data and clinical tremor scores for 24 Parkinson patients at four extremities for periods of about 3 hours. A random 25% subset of the labelled samples was used as test data, the remainder as training data. Based on features extracted from the sensor data, a Support Vector Machine was trained to predict tremor severity. Due to the inherent imbalance in tremor scores, we applied dataset rebalancing techniques. Our classifier demonstrated robust performance in detecting tremor events with a sensitivity of 0.90 on the test-portion of the resampled dataset. The overall classification accuracy was high at 0.88. We implemented an accurate classifier for tremor monitoring in free-living environments that can be trained even with modestly sized and imbalanced datasets. This advancement offers significant clinical value in continuously monitoring Parkinson's disease symptoms beyond the hospital setting, paving the way for personalized management of PD, timely therapeutic adjustments, and improved patient quality of life.