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.

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.

Aging and sex effects on phoneme perception: An exploratory mismatch negativity and P300 investigation.

BACKGROUND & AIMS: The mismatch negativity (MMN) and P300 event-related potentials (ERPs) have been studied in relation to phoneme discrimination and categorization, respectively. Although the effects of aging and sex on pure-tone perception have been widely investigated using these ERPs, evidence relating to phoneme perception is scarce. The current study aimed to provide insight into the effects of aging and sex on phoneme discrimination and categorization, as measured through the MMN and P300. METHOD: An inattentive and attentive oddball paradigm containing a phonemic articulation place contrast were administered during EEG registration in sixty healthy individuals (thirty males and females), of which an equal number of young (20-39 years), middle-aged (40-59 years) and elderly (60+ years) subjects were included. The amplitude, onset latency and topographical distribution of the MMN and P300 effect, as well as the amplitude of the P1-N1-P2 complex, were analyzed for age group and sex differences. RESULTS: With respect to aging, elderly subjects demonstrated a reduced MMN and P300 amplitude compared to the young group, whereas the scalp distribution of both components was unaffected. No aging effects on the P1-N1-P2 complex were found. In elderly individuals, the P300 was found to be delayed compared to the young group, while no such effect on MMN latency could be observed. No differences in MMN and P300 measures could be identified between males and females. CONCLUSION: Differential effects of aging were found on the MMN and P300, specifically in terms of latency, in relation to phoneme perception. In contrast, sex was found to scarcely affect both processes.

Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders.

Background and Objectives: Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset neurologic disorders. Methods: From January 2019 through April 2022, ES-based multigene panel testing was conducted in 1,411 patients with molecularly unexplained neurologic phenotypes at the Ghent University Hospital. Gene panels were developed for ataxia and spasticity, leukoencephalopathy, movement disorders, paroxysmal episodic disorders, neurodegeneration with brain iron accumulation, progressive myoclonic epilepsy, and amyotrophic lateral sclerosis. Single nucleotide variants, small indels, and copy number variants were analyzed. Across all panels, our analysis covered a total of 725 genes associated with Mendelian inheritance. Results: A molecular diagnosis was established in 10% of the cases (144 of 1,411) representing 71 different monogenic disorders. The diagnostic yield depended significantly on the presenting phenotype with the highest yield seen in patients with ataxia or spastic paraparesis (19%). Most of the established diagnoses comprised disorders with an autosomal dominant inheritance (62%), and the most frequently mutated genes were NOTCH3 (13 patients), SPG7 (11 patients), and RFC1 (8 patients). 34% of the disease-causing variants were novel, including a unique likely pathogenic variant in APP (Ghent mutation, p.[Asn698Asp]) in a family presenting with stroke and severe cerebral white matter disease. 7% of the pathogenic variants comprised copy number variants detected in the ES data and confirmed by an independent technique. Discussion: ES and multigene panel testing is a powerful and efficient tool to diagnose patients with unexplained, adult-onset neurologic disorders.

The underpinning of meaningful activities by brain correlates: a systematic review.

Introduction: Engaging in meaningful activities contributes to health and wellbeing. Research identifies meaningfulness by analysing retrospective and subjective data such as personal experiences in activities. Objectively measuring meaningful activities by registering the brain (fNIRS, EEG, PET, fMRI) remains poorly investigated. Methods: A systematic review using PubMed, Web of Science, CINAHL, and Cochrane Library. Findings: Thirty-one studies investigating the correlations between daily activities in adults, their degree of meaningfulness for the participant, and the brain areas involved, were identified. The activities could be classified according to the degree of meaningfulness, using the attributes of meaningfulness described in the literature. Eleven study activities contained all attributes, which means that these can be assumed to be meaningful for the participant. Brain areas involved in these activities were generally related to emotional and affective processing, motivation, and reward. Conclusion: Although it is demonstrated that neural correlates of meaningful activities can be measured objectively by neurophysiological registration techniques, "meaning" as such has not yet been investigated explicitly. Further neurophysiological research for objective monitoring of meaningful activities is recommended.

Effects of Healthy Aging and Gender on the Electrophysiological Correlates of Semantic Sentence Comprehension: The Development of Dutch Normative Data.

PURPOSE: The clinical use of event-related potentials in patients with language disorders is increasingly acknowledged. For this purpose, normative data should be available. Within this context, healthy aging and gender effects on the electrophysiological correlates of semantic sentence comprehension were investigated. METHOD: One hundred and ten healthy subjects (55 men and 55 women), divided among three age groups (young, middle aged, and elderly), performed a semantic sentence congruity task in the visual modality during electroencephalographic recording. RESULTS: The early visual complex was affected by increasing age as shown by smaller P2 amplitudes in the elderly compared to the young. Moreover, the N400 effect in the elderly was smaller than in the young and was delayed compared to latency measures in both middle-aged and young subjects. The topography of age-related amplitude changes of the N400 effect appeared to be gender specific. The late positive complex effect was increased at frontal electrode sites from middle age on, but this was not statistically significant. No gender effects were detected regarding the early P1, N1, and P2, or the late positive complex effect. CONCLUSION: Especially aging effects were found during semantic sentence comprehension, and this from the level of perceptual processing on. Normative data are now available for clinical use.

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.

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.

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.

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.

The Effect of Parkinson's Disease on Otoacoustic Emissions and Efferent Suppression of Transient Evoked Otoacoustic Emissions.

Purpose Several studies have demonstrated increased auditory thresholds in patients with Parkinson's disease (PD) based on subjective tonal audiometry. However, the pathophysiological mechanisms underlying auditory dysfunction in PD remain elusive. The primary aim of this study was to investigate cochlear and olivocochlear function in PD using objective measurements and to assess the effect of dopaminergic medication on auditory function. Method Eighteen patients with PD and 18 gender- and age-matched healthy controls (HCs) were included. Patients with PD participated in medication on and off conditions. Linear mixed models were used to determine the effect of PD on tonal audiometry, transient evoked and distortion product otoacoustic emissions (OAEs), and efferent suppression (ES). Results Tonal audiometry revealed normal auditory thresholds in patients with PD for their age across all frequencies. OAE signal amplitudes demonstrated a significant interaction effect between group (PD vs. HC) and frequency, indicating decreased OAEs at low frequencies and increased OAEs at high frequencies in patients with PD. No significant differences were found between patients with PD and HCs regarding ES. In addition, no significant effect of medication status was found on auditory measurements in patients with PD. Conclusions Altered OAEs support the hypothesis of cochlear alterations in PD. No evidence was found for the involvement of the medial olivocochlear system. Altogether, OAEs may provide an objective early indicator of auditory alterations in PD and should complement subjective tonal audiometry when assessing and monitoring auditory function in PD.

Hippocampal Sclerosis in Frontotemporal Dementia: When Vascular Pathology Meets Neurodegeneration.

Hippocampal sclerosis (HS) is a common neuropathological finding and has been associated with advanced age, TDP-43 proteinopathy, and cerebrovascular pathology. We analyzed neuropathological data of an autopsy cohort of early-onset frontotemporal dementia patients. The study aimed to determine whether in this cohort HS was related to TDP-43 proteinopathy and whether additional factors could be identified. We examined the relationship between HS, proteinopathies in frontotemporal cortices and hippocampus, Alzheimer disease, cerebrovascular changes, and age. We confirmed a strong association between HS and hippocampal TDP-43, whereas there was a weaker association between HS and frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Nearly all of the FTLD-TDP cases had TDP-43 pathology in the hippocampus. HS was present in all FTLD-TDP type D cases, in 50% of the FTLD-TDP A cohort and in 6% of the FTLD-TDP B cohort. Our data also showed a significant association between HS and vascular changes. We reviewed the literature on HS and discuss possible pathophysiological mechanisms between TDP-43 pathology, cerebrovascular disease, and HS. Additionally, we introduced a quantitative neuronal cell count in CA1 to objectify the semiquantitative visual appreciation of HS.

Evidence of rehabilitation therapy in task-specific focal dystonia: a systematic review.

INTRODUCTION: Task-specific dystonias are primary focal dystonias characterized by excessive muscle contractions producing abnormal postures during selective motor activities that often involve highly skilled, repetitive movements. Based on the idea of excessive motor excitability and aberrant sensorimotor integration in the pathophysiology of task-specific dystonia, sensorimotor retraining may hold promise. The purpose of this systematic review was to investigate the available evidence about the role of rehabilitation therapy as a treatment for task-specific dystonia. EVIDENCE ACQUISITION: A systematic review was performed of studies identified through Pubmed and Embase in a structured search strategy by independent author screening. The JBI (Joanna Briggs Institute) Critical Appraisal Checklist and RoB 2 were used to evaluate their methodological quality. EVIDENCE SYNTHESIS: Twenty-one studies were included for qualitative synthesis. Most of the reports are small single group pre-/post-test study designs with a variability in the type of task-specific dystonia and the type of evaluated outcome measures. Rehabilitation interventions were grouped into six categories based upon the underlying theoretical basis of different approaches: 1) movement practice; 2) training with constraint; 3) sensory reorganization; 4) biofeedback training; 5) neuromodulation with training; and 6) compensatory strategies. CONCLUSIONS: Although it appears that a number of task-specific dystonia patients may improve with rehabilitation therapy, no definitive conclusions can be drawn. More research in this field is needed, using standardized approaches and clearly defined outcome measures in larger cohorts of task-specific dystonia patients that are clinically and diagnostically well characterized.

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.

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‰.