Neuroplasticity in Parkinson's disease.

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, affecting millions of people and rapidly increasing over the last decades. Even though there is no intervention yet to stop the neurodegenerative pathology, many efficient treatment methods are available, including for patients with advanced PD. Neuroplasticity is a fundamental property of the human brain to adapt both to external changes and internal insults and pathological processes. In this paper we examine the current knowledge and concepts concerning changes at network level, cellular level and molecular level as parts of the neuroplastic response to protein aggregation pathology, synapse loss and neuronal loss in PD. We analyse the beneficial, compensatory effects, such as augmentation of nigral neurons efficacy, as well as negative, maladaptive effects, such as levodopa-induced dyskinesia. Effects of physical activity and different treatments on neuroplasticity are considered and the opportunity of biomarkers identification and use is discussed.

Cortical Generators and Connections Underlying Phoneme Perception: A Mismatch Negativity and P300 Investigation.

The cortical generators of the pure tone MMN and P300 have been thoroughly studied. Their nature and interaction with respect to phoneme perception, however, is poorly understood. Accordingly, the cortical sources and functional connections that underlie the MMN and P300 in relation to passive and active speech sound perception were identified. An inattentive and attentive phonemic oddball paradigm, eliciting a MMN and P300 respectively, were administered in 60 healthy adults during simultaneous high-density EEG recording. For both the MMN and P300, eLORETA source reconstruction was performed. The maximal cross-correlation was calculated between ROI-pairs to investigate inter-regional functional connectivity specific to passive and active deviant processing. MMN activation clusters were identified in the temporal (insula, superior temporal gyrus and temporal pole), frontal (rostral middle frontal and pars opercularis) and parietal (postcentral and supramarginal gyrus) cortex. Passive discrimination of deviant phonemes was aided by a network connecting right temporoparietal cortices to left frontal areas. For the P300, clusters with significantly higher activity were found in the frontal (caudal middle frontal and precentral), parietal (precuneus) and cingulate (posterior and isthmus) cortex. Significant intra- and interhemispheric connections between parietal, cingulate and occipital regions constituted the network governing active phonemic target detection. A predominantly bilateral network was found to underly both the MMN and P300. While passive phoneme discrimination is aided by a fronto-temporo-parietal network, active categorization calls on a network entailing fronto-parieto-cingulate cortices. Neural processing of phonemic contrasts, as reflected by the MMN and P300, does not appear to show pronounced lateralization to the language-dominant hemisphere.

Towards improved access to device-aided therapies in advanced PD: the importance of cooperation of different disciplines.

Managing the many issues in advanced Parkinson's disease (PD) requires education, continuous support, and specialized outpatient care involving a variety of allied healthcare professionals. It would be greatly appreciated if general neurologists and professionals from various disciplines who work with people diagnosed with Parkinson's disease (PwP) could remain knowledgeable about the existing therapies and their respective roles within the treatment continuum. The movement disorders specialist and the PD nurse are key actors in the coordination of a targeted and patient-empowering multidisciplinary approach for advanced PD. Affordable and timely access to these therapies for the PwP who may need them is presently a challenge for health systems. Education, training, and support for all the involved stakeholders in the process of PD care may improve quality of life both for PwP and caregivers, and reduce inadequate, expensive, time-consuming, and unsuccessful prolongation of standard medical therapies.

Parkinson's disease affects the neural alpha oscillations associated with speech-in-noise processing.

Parkinson's disease (PD) has increasingly been associated with auditory dysfunction, including alterations regarding the control of auditory information processing. Although these alterations may interfere with the processing of speech in degraded listening conditions, behavioural studies have generally found preserved speech-in-noise recognition in PD. However, behavioural speech audiometry does not capture the neurophysiological mechanisms supporting speech-in-noise processing. Therefore, the aim of this study was to investigate the neural oscillatory mechanisms associated with speech-in-noise processing in PD. Twelve persons with PD and 12 age- and gender-matched healthy controls (HCs) were included in this study. Persons with PD were studied in the medication off condition. All subjects underwent an audiometric screening and performed a sentence-in-noise recognition task under simultaneous electroencephalography (EEG) recording. Behavioural speech recognition scores and self-reported ratings of effort, performance, and motivation were collected. Time-frequency analysis of EEG data revealed no significant difference between persons with PD and HCs regarding delta-theta (2-8 Hz) inter-trial phase coherence to noise and sentence onset. In contrast, significantly increased alpha (8-12 Hz) power was found in persons with PD compared with HCs during the sentence-in-noise recognition task. Behaviourally, persons with PD demonstrated significantly decreased speech recognition scores, whereas no significant differences were found regarding effort, performance, and motivation ratings. These results suggest that persons with PD allocate more cognitive resources to support speech-in-noise processing. The interpretation of this finding is discussed in the context of a top-down mediated compensation mechanism for inefficient filtering and degradation of auditory input in PD.

Evaluation of multi-feature auditory deviance detection in Parkinson's disease: a mismatch negativity study.

Behavioral studies on auditory deviance detection in patients with Parkinson's disease (PD) have reported contradictory results. The primary aim of this study was to investigate auditory deviance detection of multiple auditory features in patients with PD by means of objective and reliable electroencephalographic (EEG) measurements. Twelve patients with early-stage PD and twelve age- and gender-matched healthy controls (HCs) were included in this study. Patients with PD participated without their regular dopaminergic medication. All subjects underwent an audiometric screening and performed a passive multi-feature mismatch negativity (MMN) paradigm. Repeated-measures analysis of variance (ANOVA) demonstrated no significant differences between patients with PD and HCs regarding MMN mean amplitude and latency for frequency, duration and gap deviants. Nevertheless, a trend towards increased MMN mean amplitude and latency was found in response to intensity deviants in patients with PD compared to HCs. Increased intensity MMN amplitude may indicate that more neural resources are allocated to the processing of intensity deviances in patients with PD compared to HCs. The interpretation of this intensity-specific MMN alteration is further discussed in the context of a compensatory mechanism for auditory intensity processing and involuntary attention switching in PD.

Neurophysiological investigation of auditory intensity dependence in patients with Parkinson's disease.

There is accumulating evidence for auditory dysfunctions in patients with Parkinson's disease (PD). Moreover, a possible relationship has been suggested between altered auditory intensity processing and the hypophonic speech characteristics in PD. Nonetheless, further insight into the neurophysiological correlates of auditory intensity processing in patients with PD is needed primarily. In the present study, high-density EEG recordings were used to investigate intensity dependence of auditory evoked potentials (IDAEPs) in 14 patients with PD and 14 age- and gender-matched healthy control participants (HCs). Patients with PD were evaluated in both the on- and off-medication states. HCs were also evaluated twice. Significantly increased IDAEP of the N1/P2 was demonstrated in patients with PD evaluated in the on-medication state compared to HCs. Distinctive results were found for the N1 and P2 component. Regarding the N1 component, no differences in latency or amplitude were shown between patients with PD and HCs regardless of the medication state. In contrast, increased P2 amplitude was demonstrated in patients with PD evaluated in the on-medication state compared to the off-medication state and HCs. In addition to a dopaminergic deficiency, deficits in serotonergic neurotransmission in PD were shown based on increased IDAEP. Due to specific alterations of the N1-P2 complex, the current results suggest deficiencies in early-attentive inhibitory processing of auditory input in PD. This interpretation is consistent with the involvement of the basal ganglia and the role of dopaminergic and serotonergic neurotransmission in auditory gating.

Gastric Helicobacter suis Infection Partially Protects against Neurotoxicity in A 6-OHDA Parkinson's Disease Mouse Model.

The exact etiology of Parkinson's disease (PD) remains largely unknown, but more and more research suggests the involvement of the gut microbiota. Interestingly, idiopathic PD patients were shown to have at least a 10 times higher prevalence of Helicobacter suis (H. suis) DNA in gastric biopsies compared to control patients. H. suis is a zoonotic Helicobacter species that naturally colonizes the stomach of pigs and non-human primates but can be transmitted to humans. Here, we investigated the influence of a gastric H. suis infection on PD disease progression through a 6-hydroxydopamine (6-OHDA) mouse model. Therefore, mice with either a short- or long-term H. suis infection were stereotactically injected with 6-OHDA in the left striatum and sampled one week later. Remarkably, a reduced loss of dopaminergic neurons was seen in the H. suis/6-OHDA groups compared to the control/6-OHDA groups. Correspondingly, motor function of the H. suis-infected 6-OHDA mice was superior to that in the non-infected 6-OHDA mice. Interestingly, we also observed higher expression levels of antioxidant genes in brain tissue from H. suis-infected 6-OHDA mice, as a potential explanation for the reduced 6-OHDA-induced cell loss. Our data support an unexpected neuroprotective effect of gastric H. suis on PD pathology, mediated through changes in oxidative stress.

Multicollector Inductively Coupled Plasma-Mass Spectrometry with 1013 Ω Faraday Cup Amplifiers for Ultrasensitive Mg Isotopic Analysis of Cerebrospinal Fluid Microsamples.

Magnesium isotopic analysis of cerebrospinal fluid (CSF) is a potentially interesting approach for studies on neurodegeneration. However, this type of analysis is challenging because of the invasiveness of the sampling and small sample volume. In this work, a novel analytical method was developed for ultrasensitive Mg isotopic analysis of CSF microsamples via multicollector inductively coupled plasma-mass spectrometry (MC-ICP-MS) using high-gain 1013 Ω Faraday cup amplifiers. The intermediate and internal errors on the δ26Mg value were improved up to fourfold using 1013 Ω resistors for the monitoring of both the 24Mg and 26Mg isotopes and up to twofold using a 1011 Ω resistor for the most abundant 24Mg isotope and a 1013 Ω resistor for the 26Mg isotope. Magnesium isotope ratios measured at a concentration level of 7-10 µg L-1 were in good agreement with those obtained using the conventional method at a concentration level of 150 µg L-1. The expanded uncertainty for the quality control CSF material obtained at the ultratrace level was ±0.16‰. Ultrasensitive Mg isotopic analysis was carried out for CSF from hydrocephalus patients using only 5 µL of sample. δMg values thus obtained were not significantly different from those obtained using the conventional method using a sample volume of 400 µL instead (p ≤ 0.05). The Mg isotopic composition of the CSF from hydrocephalus patients ranged between -0.65 and 0.30‰, with a mean δ26Mg value of -0.14 ± 0.27‰.

Cognitive and Affective Theory of Mind in Healthy Aging.

BACKGROUND: Previous studies on the effect of healthy aging on Theory of Mind (ToM) have produced mixed results. A possible explanation may be that different ToM components and types of inference have not systematically been considered. This study examined the effect of aging on ToM by assessing both first and second order cognitive and affective components within a single task. METHODS: We compared performance of young (M = 18.3y) and older adults (M = 61.0y) on the Yoni task. This task allows for a within-subject assessment of both first and second order cognitive and affective ToM. RESULTS: We observed that older adults had longer reaction times than young adults across cognitive and affective first order items. For second order items, this age difference was larger for affective than cognitive items. Results showed no indications that these findings could be explained by age differences in speed/accuracy trade-offs. CONCLUSION: Our findings suggest that decision processes underlying ToM are slower in older adults on both first and second order inferences, but that age differences in these processes between cognitive and affective ToM are selective to second order inferences. We propose that the observed age differences may be associated with cortical and mental changes that occur with aging.

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel Kv4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or Kv4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.

Category specific recall in acute stroke: a case with letter speech.

Category selective recall in spontaneous speech after stroke has been reported only rarely. We recently described three cases demonstrating transient number speech in the acute stage of left hemispheric stroke and hypothesized a link with multilingualism and mathematical proficiency. In this report, we describe a similar case with a transient episode of utterances of randomly selected letters. Like in the three previous cases, this episode was preceded by a brief stage of mutism and ultimately evolved to Wernicke's aphasia over a period of days. This phenomenon is reviewed with reference to linguistic models and neuroanatomic and neurophysiological correlates.

Cognate effects and cognitive control in patients with parallel and differential bilingual aphasia.

BACKGROUND: Until today, there is no satisfying explanation for why one language may recover worse than another in differential bilingual aphasia. One potential explanation that has been largely unexplored is that differential aphasia is the consequence of a loss of language control rather than a loss of linguistic representations. Language control is part of a general control mechanism that also manages non-linguistic cognitive control. If this system is impaired, patients with differential aphasia could still show bilingual language activation, but they may be unable to manage activation in non-target languages, so that performance in another language is hindered. AIMS: To investigate whether a loss of cognitive control, rather than the loss of word representations in a particular language, might underlie differential aphasia symptoms. METHODS & PROCEDURES: We compared the performance of seven bilinguals with differential and eight bilinguals with parallel aphasia with 19 control bilinguals in a lexical decision and a flanker task to assess bilingual language co-activation and non-linguistic control respectively. OUTCOMES & RESULTS: We found similar cognate effects in the three groups, indicating similar lexical processing across groups. Additionally, we found a larger non-linguistic control congruency effect only for the patients with differential aphasia. CONCLUSIONS & IMPLICATIONS: The present data indicate preserved language co-activation for patients with parallel as well as differential aphasia. Furthermore, the results suggest a general cognitive control dysfunction, specifically for differential aphasia. Taken together, the results of the current study provide further support for the hypothesis of impaired cognitive control abilities in patients with differential aphasia, which has both theoretical and practical implications.

TBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.

The effect of vagus nerve stimulation on response inhibition.

In the current study, we explored whether vagus nerve stimulation (VNS) in patients with epilepsy, which is believed to increase norepinephrine (NE) levels via activation of the locus coeruleus, would positively affect response inhibition. Moreover, we tried to identify the dynamics of the underlying neural processes by investigating event-related potentials (ERPs) and pupil size. Patients performed a stop-signal task once when stimulation was switched on and once when it was switched off. We found a correlational pattern suggesting that patients who clinically benefit more from VNS treatment also show a larger behavioral advantage, in terms of faster response inhibition, when the vagus nerve is being stimulated. Event-related potential (ERP) results suggested more pronounced reactive inhibition when stimulation was switched on, independent of the individual amount of seizure reduction. Transient go-locked pupil size was increased from go trials to successful stop trials to unsuccessful stop trials but without displaying a clear VNS effect, which however, might relate to limited sensitivity. We conclude that VNS likely has a positive effect on response inhibition, at least in patients with epilepsy that benefit clinically from the treatment, presumably relating to enhancements of response-inhibition mechanisms and, therefore, identify enhanced response inhibition as a possible cognitive benefit of VNS.

Sex Differences in Neurophysiological Activation Patterns During Phonological Input Processing: An Influencing Factor for Normative Data.

In the context of neurophysiological normative data, it has been established that aging has a significant impact on neurophysiological correlates of auditory phonological input processes, such as phoneme discrimination (PD) and word recognition (WR). Besides age, sex is another demographic factor that influences several language processes. We aimed to disentangle whether sex has a similar effect on PD and WR. Event-related potentials (ERPs) were recorded in 20 men and 24 women. During PD, three phonemic contrasts (place and manner of articulation and voicing) were compared using the attentive P300 and pre-attentive Mismatch Negativity. To investigate WR, real words were contrasted with pseudowords in a pre-attentive oddball task. Women demonstrated a larger sensitivity to spectrotemporal differences, as evidenced by larger P300 responses to the place of articulation (PoA) contrast and larger P300 and MMN responses than men in PoA-based PD. Men did not display such sensitivity. Attention played an important role, considering that women needed more attentional resources to differentiate between PoA and the other phonemic contrasts. During WR, pseudowords evoked larger amplitudes already 100 ms post-stimulus independent of sex. However, women had decreased P200 latencies, but longer N400 latencies in response to pseudowords, whereas men showed increased N400 latencies compared to women in response to real words. The current results demonstrate significant sex-related influences on phonological input processes. Therefore, existing neurophysiological normative data for age should be complemented for the factor sex.

Task preparation processes related to reward prediction precede those related to task-difficulty expectation.

Recently, attempts have been made to disentangle the neural underpinnings of preparatory processes related to reward and attention. Functional magnetic resonance imaging (fMRI) research showed that neural activity related to the anticipation of reward and to attentional demands invokes neural activity patterns featuring large-scale overlap, along with some differences and interactions. Due to the limited temporal resolution of fMRI, however, the temporal dynamics of these processes remain unclear. Here, we report an event-related potentials (ERP) study in which cued attentional demands and reward prospect were combined in a factorial design. Results showed that reward prediction dominated early cue processing, as well as the early and later parts of the contingent negative variation (CNV) slow-wave ERP component that has been associated with task-preparation processes. Moreover these reward-related electrophysiological effects correlated across participants with response time speeding on reward-prospect trials. In contrast, cued attentional demands affected only the later part of the CNV, with the highest amplitudes following cues predicting high-difficulty potential-reward targets, thus suggesting maximal task preparation when the task requires it and entails reward prospect. Consequently, we suggest that task-preparation processes triggered by reward can arise earlier, and potentially more directly, than strategic top-down aspects of preparation based on attentional demands.

Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial.

Background: Dysregulation of the gut microbiome has been implicated in Parkinson's disease (PD). This study aimed to evaluate the clinical effects and safety of a single faecal microbiota transplantation (FMT) in patients with early-stage PD. Methods: The GUT-PARFECT trial, a single-centre randomised, double-blind, placebo-controlled trial was conducted at Ghent University Hospital between December 01, 2020 and December 12, 2022. Participants (aged 50-65 years, Hoehn and Yahr stage 2) were randomly assigned to receive nasojejunal FMT with either healthy donor stool or their own stool. Computer-generated randomisation was done in a 1:1 ratio through permutated-block scheduling. Treatment allocation was concealed for participants and investigators. The primary outcome measure at 12 months was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score obtained during off-medication evaluations. Intention-to-treat analysis was performed using a mixed model for repeated measures analysis. This completed trial is registered on ClinicalTrials.gov (NCT03808389). Findings: Between December 2020 and December 2021, FMT procedures were conducted on 46 patients with PD: 22 in the healthy donor group and 24 in the placebo group. Clinical evaluations were performed at baseline, 3, 6, and 12 months post-FMT. Full data analysis was possible for 21 participants in the healthy donor group and 22 in the placebo group. After 12 months, the MDS-UPDRS motor score significantly improved by a mean of 5.8 points (95% CI -11.4 to -0.2) in the healthy donor group and by 2.7 points (-8.3 to 2.9) in the placebo group (p = 0.0235). Adverse events were limited to temporary abdominal discomfort. Interpretation: Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages. Funding: Flemish PD patient organizations (VPL and Parkili), Research Foundation Flanders (FWO), Biocodex Microbiota Foundation.

A manic episode after bilateral subthalamic stimulation in a patient with advanced Parkinson's disease.

Deep brain stimulation (DBS) has proven to be an effective treatment for patients with refractory symptoms in the advanced stages of Parkinson's disease. However, different psychiatric and cognitive problems may occur after DBS. We report a case of a manic episode after DBS of the subthalamic nucleus in a patient with advanced Parkinson's disease. After slow and gradually restart of the neurostimulation using the lowest effective intensity, the motor symptoms remained sufficiently under control without causing any psychiatric problems.

Testing the dopamine overdose hypothesis in action control: A study in people with Parkinson's disease.

Prior work on patients with Parkinson's disease (PD) has shown that the administration of dopaminergic medication in the early to intermediate stages of PD benefits (motor) functions associated with the dopamine-depleted dorsal striatal circuitry but may 'overdose' and interfere with (cognitive) functions associated with the relatively intact ventral striatal circuitry. The present study aimed to elucidate this so-called dopamine overdose hypothesis for the action control domain. Using a within-subject design in a sample of 13 people with PD, we evaluated the effect of dopaminergic medication on two cognitive processes underlying goal-directed behaviour, namely action selection and initiation through event binding and conflict adaptation. We also investigated whether individual differences in the magnitude of medication effects were associated across these processes. Results showed no indications that dopaminergic medication affects action selection and initiation or conflict adaptation in PD patients. Additionally, we observed no correlations between both cognitive processes nor between individual differences in medication effects. Our findings do not support the notion that dopaminergic medication modulates action control processes, suggesting that the dopamine overdose hypothesis may only apply to a specific set of cognitive processes and should potentially be refined.

Effects of Oral Levodopa on Balance in People with Idiopathic Parkinson's Disease.

BACKGROUND: Balance impairment is a frequent cause of morbidity and mortality in people with Parkinson's disease (PD). As opposed to the effects of appendicular motor symptoms, the effects of Levodopa on balance impairment in idiopathic PD are less clear. OBJECTIVE: To review the literature on the effects of oral Levodopa on clinical balance test performance, posturography, step initiation, and responses to perturbation in people with idiopathic PD (PwPD). METHODS: A systematic search of three scientific databases (Pubmed, Embase, and Web of Science) was conducted in accordance with PRISMA guidelines. For the pilot meta-analysis, standardized mean differences with 95% confidence intervals were calculated using an inverse variance random effects model. Data not suitable for implementation in the meta-analysis (missing means or standard deviations, and non-independent outcomes) were analyzed narratively. RESULTS: A total of 2772 unique studies were retrieved, of which 18 met the eligibility criteria and were analyzed, including data of 710 idiopathic PwPD. Levodopa had a significant positive effect on the Berg Balance Scale, the Push and Release test, and jerk and frequency parameters during posturography. In contrast, some significant negative effects on velocity-based sway parameters were found during posturography and step initiation. However, Levodopa had no significant effect on most step initiation- and all perturbation parameters. CONCLUSION: The effects of Levodopa on balance in PwPD vary depending on the outcome parameters and patient inclusion criteria. A systematic approach with well-defined outcome parameters, and prespecified, sensitive and reliable tests is needed in future studies to unravel the effects of oral Levodopa on balance.