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Background: Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson's disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa. Objectives: The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa. Design: Open-label randomized two-way one-period crossover trial. Methods: Nine PD patients in the 'off state' received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation (T max, C max and area under the concentration time curve (AUC) 0–3 h). Results: The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, C max and AUC 0–3 h were found to be significant higher (p = 0.028 and p = 0.028, respectively) than after pulmonary administration. T max was achieved significantly (p = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters. Conclusion: Inhaled levodopa from Cyclops® shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies. Trial registration: The study protocol was approved by the local ethics board 'Regionale toetsingscommissie patiëntgebonden onderzoek' (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as 'Overview of Medical Research in the Netherlands' (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a progressive disease, which is associated with the loss of activities of daily living independency. Several rehabilitation options have been studied during the last years, to improve mobility and independency. Objective: This systematic review will focus on inpatient multidisciplinary rehabilitation (MR) in people with Parkinson's disease (PwPD), based on recent studies from 2020 onwards. Methods: Search strategy in three databases included: multidisciplinary rehabilitation, Parkinson's Disease, inpatient rehabilitation, motor-, functional- and cognitive performance, cost-effectiveness, Quality of Life, and medication changes/Levodopa equivalent daily doses. Results: Twenty-two studies were included, consisting of 13 studies dealing with inpatient MR and 9 studies on inpatient non-MR interventions. Inpatient PD multidisciplinary rehabilitation proved to be effective, as well as non-MR rehabilitation. Conclusions: This review confirms the efficacy of inpatient MR and non-MR in PD, but is skeptical about the past and current study designs. New study designs, including new physical training methods, more attention to medication and costs, new biomarkers, artificial intelligence, and the use of wearables, will hopefully change rehabilitation trials in PwPD in the future. [ABSTRACT FROM AUTHOR]

The 5-2-1 criteria are intended to help general neurologists identify patients with advanced Parkinson's disease who may benefit from treatment optimisation, such as with a device-aided therapy. Although the 5-2-1 criteria claim to address an unmet need, we urge readers to cautiously interpret the results of this validation study. [ABSTRACT FROM AUTHOR]

Background and Objective: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. Methods: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow‐up visits were performed 3 and 5 years after baseline. We assessed the between‐group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. Results: A total of 321 patients completed the 5‐year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early‐start group and 62 of 161 patients in the delayed‐start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. Conclusions: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Facial emotion recognition (FER) is a crucial component of social cognition and is essential in social‐interpersonal behaviour regulation. Although FER impairment is well‐established in advanced PD, data about FER at the time of diagnosis and its relationship with social behavioural problems in daily life are lacking. The aim was to examine FER at the time of PD diagnosis compared to a matched healthy control (HC) group and to associate FER with indices of social behavioural problems. In total, 142 de novo, treatment‐naïve PD patients and 142 HC were included. FER was assessed by the Ekman 60 faces test (EFT). Behavioural problems in PD patients were assessed using the Dysexecutive Questionnaire (DEX‐self and DEX‐proxy) and the Apathy Evaluation Scale (AES‐self). PD patients had significantly lower EFT‐total scores (p =.001) compared to HC, with worse recognition of Disgust (p =.001) and Sadness (p =.016). Correlational analyses yielded significant correlations between AES‐self and both EFT‐total (rs =.28) and Fear (rs =.22). Significant negative correlations were found between DEX‐proxy and both EFT‐total (rs = −.28) and Anger (rs = −.26). Analyses of DEX‐subscales showed that proxy ratings were significantly higher than patient‐ratings for the Social Conventions subscale (p =.047). This DEX‐proxy subscale had the strongest correlation with EFT‐total (rs = −.29). Results show that de novo PD patients already show impaired FER compared to HC. In addition, lower FER is linked to self‐reported apathy and proxy‐reported social‐behavioural problems, especially concerning social conventions. These findings validate the importance of the inclusion of social cognition measures in the neuropsychological assessment even in early PD. [ABSTRACT FROM AUTHOR]

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non‐invasive and user‐friendly alternative. This two‐part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre‐ and post‐dose. Both study parts showed that oromucosal apomorphine was generally well‐tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration–time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) patients experience visual symptoms and retinal degeneration. Studies using optical coherence tomography (OCT) have shown reduced thickness of the retina in PD, also a key characteristic of glaucoma. Objective: To identify the presence and pattern of retinal changes in de novo, treatment-naive PD patients compared to healthy controls (HC) and early primary open angle glaucoma (POAG) patients. Methods: Macular OCT data (10×10 mm) were collected from HC, PD, and early POAG patients, at the University Medical Center Groningen. Bayesian informative hypotheses statistical analyses were carried out comparing HC, PD-, and POAG patients, within each retinal cell layer. Results: In total 100 HC, 121 PD, and 78 POAG patients were included. We showed significant reduced thickness of the inner plexiform layer and retinal pigment epithelium in PD compared to HC. POAG patients presented with a significantly thinner retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, outer plexiform layer, and outer photoreceptor and subretinal virtual space compared to PD. Only the outer segment layer and retinal pigment epithelium were significantly thinner in PD compared to POAG. Conclusions: De novo PD patients show reduced thickness of the retina compared to HC, especially of the inner plexiform layer, which differs significantly from POAG, showing a more extensive and widespread pattern of reduced thickness across layers. OCT is a useful tool to detect retinal changes in de novo PD, but its specificity versus other neurodegenerative disorders has to be established. [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is a recognized treatment for medication‐refractory dystonia. Problems in executive functions and social cognition can be part of dystonia phenotypes. The impact of pallidal DBS on cognition appears limited, but not all cognitive domains have been investigated yet. In the present study, we compare cognition before and after GPi DBS. Seventeen patients with dystonia of various aetiology completed pre‐ and post‐DBS assessment (mean age 51 years; range 20–70 years). Neuropsychological assessment covered intelligence, verbal memory, attention and processing speed, executive functioning, social cognition, language and a depression questionnaire. Pre‐DBS scores were compared with a healthy control group matched for age, gender and education, or with normative data. Patients were of average intelligence but performed significantly poorer than healthy peers on tests for planning and for information processing speed. Otherwise, they were cognitively unimpaired, including social cognition. DBS did not change the baseline neuropsychological scores. We confirmed previous reports of executive dysfunctions in adult dystonia patients with no significant influence of DBS on cognitive functioning in these patients. Pre‐DBS neuropsychological assessments appear useful as they support clinicians in counselling their patients. Decisions about post‐DBS neuropsychological evaluations should be made on a case‐by‐case basis. [ABSTRACT FROM AUTHOR]

Tremor, bradykinesia, and rigidity are incapacitating motor symptoms that can be suppressed with stereotactic neurosurgical treatment like deep brain stimulation (DBS) and ablative surgery (e.g., thalamotomy, pallidotomy). Traditionally, clinicians rely on clinical rating scales for intraoperative evaluation of these motor symptoms during awake stereotactic neurosurgery. However, these clinical scales have a relatively high inter-rater variability and rely on experienced raters. Therefore, objective registration (e.g., using movement sensors) is a reasonable extension for intraoperative assessment of tremor, bradykinesia, and rigidity. The main goal of this scoping review is to provide an overview of electronic motor measurements during awake stereotactic neurosurgery. The protocol was based on the PRISMA extension for scoping reviews. After a systematic database search (PubMed, Embase, and Web of Science), articles were screened for relevance. Hundred-and-three articles were subject to detailed screening. Key clinical and technical information was extracted. The inclusion criteria encompassed use of electronic motor measurements during stereotactic neurosurgery performed under local anesthesia. Twenty-three articles were included. These studies had various objectives, including correlating sensor-based outcome measures to clinical scores, identifying optimal DBS electrode positions, and translating clinical assessments to objective assessments. The studies were highly heterogeneous in device choice, sensor location, measurement protocol, design, outcome measures, and data analysis. This review shows that intraoperative quantification of motor symptoms is still limited by variable signal analysis techniques and lacking standardized measurement protocols. However, electronic motor measurements can complement visual evaluations and provide objective confirmation of correct placement of the DBS electrode and/or lesioning. On the long term, this might benefit patient outcomes and provide reliable outcome measures in scientific research. [ABSTRACT FROM AUTHOR]

This article provides an overview of the various screening and selection tools which have been developed over the past 25 years to identify patients with Parkinson's disease (PD) possibly eligible for device-aided therapies (DATs). For the available screening tools, we describe the target therapies (subtypes of DAT), development methods, validation data, and their use in clinical practice. In addition, the historical background and potential utility of these screening tools are discussed. The challenges in developing and validating these tools are also addressed, taking into account the differences in population, the local health care organization, and resource availability. [ABSTRACT FROM AUTHOR]

Background: People with Parkinson's disease (PD) frequently experience reading difficulties. Little is known about what functional impairments distinguish people with PD with and without reading difficulties and how these should guide rehabilitation. Objective: To provide concrete advice for an efficient stepped care model for reading difficulties in PD, based on extensive functional assessments. Methods: This study included 74 people with PD in a neurovisual rehabilitation setting who underwent assessment of visual, visuoperceptual, and cognitive functions. Outcomes were compared between those with frequent (RD+; N = 55) and infrequent reading difficulties (RD–; N = 19). Aids and advice provided during rehabilitation were registered. Results: Only a few functions appeared to distinguish RD+ and RD–. Visual functions (i.e., contrast sensitivity, g = 0.76; reading acuity, g = 0.66; visual acuity, g = 0.54) and visuoperceptual functions (i.e., visual attention, g = 0.58, visual motor speed, g = 0.56) showed significant worse scores in RD+ compared to RD–. Aids and advice applied consisted mainly of optimizing refraction, improving lighting, and optimizing text size and spacing. Conclusion: The test battery showed significant differences between RD+ and RD–on only a few tests on visual and visuoperceptual functions. The applied aids and advice matched well with these impairments. Therefore, we recommend a stepped care model, starting with a short test battery on these functions. If this battery indicates functional impairments, this can be followed by standard aids and advice to improve reading. Only in case of insufficient effect additional testing should take place. [ABSTRACT FROM AUTHOR]

Thalamotomy alleviates medication-refractory tremors in patients with movement disorders such as Parkinson's Disease (PD), Essential tremor (ET), and Holmes tremor (HT). However, limited data are available on tremor intensity during different thalamotomy stages. Also, the predictive value of the intraoperative tremor status for treatment outcomes remains unclear. Therefore, we aimed to quantify tremor status during thalamotomy and postoperatively. Data were gathered between January 2020 and June 2023 during consecutive unilateral thalamotomy procedures in patients with PD (n = 13), ET (n = 8), and HT (n = 3). MDS-UPDRS scores and tri-axial accelerometry data were obtained during rest, postural, and intention tremor tests. Measurements were performed intraoperatively (1) before lesioning-probe insertion, (2) directly after lesioning-probe insertion, (3) during coagulation, (4) directly after coagulation, and (5) 4–6 months post-surgery. Accelerometric data were recorded continuously during the coagulation process. Outcome measures included MDS-UPDRS tremor scores and accelerometric parameters (peak frequency, tremor amplitude, and area under the curve of power (AUCP)). Tremor intensity was assessed for the insertion effect (1–2), during coagulation (3), post-coagulation effect (1–4), and postoperative effect (1–5). Following insertion and coagulation, tremor intensity improved significantly compared to baseline (p < 0.001). The insertion effect clearly correlated with the postoperative effect (ρ = 0.863, p < 0.001). Both tremor amplitude and AUCP declined gradually during coagulation. Peak frequency did not change significantly intraoperatively. In conclusion, the study data show that both the intraoperative insertion effect and the post-coagulation effect are good predictors for thalamotomy outcomes. [ABSTRACT FROM AUTHOR]

A survey conducted among general neurologists in the Netherlands revealed that patient referral for device-aided therapies (DAT) in Parkinson's disease (PD) is suboptimal due to a lack of clear and objective referral criteria. Less than half of the respondents considered the eligibility criteria for DAT to be clear, and a similar minority felt they had sufficient expertise to determine eligibility. The survey also found that general neurologists ranked treatment-resistant tremor and cognitive impairment as particularly relevant factors for deep brain stimulation (DBS), which may negatively impact referrals for other DATs. The study suggests that implementing a user-friendly and validated screening tool could improve the timely referral for DAT without over-referral. [Extracted from the article]

The disease status, progression, and treatment effect of essential tremor (ET) patients are currently assessed with clinical scores, such as the Fahn–Tolosa–Marin Clinical Rating Scale for Tremor (FTM). The use of objective and rater-independent monitoring of tremors may improve clinical care for patients with ET. Therefore, the focus of this study is to develop an objective accelerometry-based method to quantify ET, based on FTM criteria. Thirteen patients with ET and thirteen matched healthy participants underwent FTM tests to rate tremor severity, paired with tri-axial accelerometric measurements at the index fingers. Analogue FTM assessments were performed by four independent raters based on video recordings. Quantitative measures were derived from the accelerometric data, e.g., the area under the curve of power in the 4–8 Hz frequency band (AUCP) and maximal tremor amplitude. As such, accelerometric tremor scores were computed, using thresholds based on healthy measurements and FTM criteria. Agreement between accelerometric and clinical FTM scores was analyzed with Cohen's kappa coefficient. It was assessed whether there was a relationship between mean FTM scores and the natural logarithm (ln) of the accelerometric outcome measures using linear regression. The agreement between accelerometric and FTM scores was substantial for resting and intention tremor tests (≥72.7%). However, the agreement between accelerometric postural tremor data and clinical FTM ratings (κ = 0.459) was low, although their logarithmic (ln) relationship was substantial (R2 ≥ 0.724). Accelerometric test–retest reliability was good to excellent (ICC ≥ 0.753). This pilot study shows that tremors can be quantified with accelerometry, using healthy thresholds and FTM criteria. The test–retest reliability of the accelerometric tremor scoring algorithm indicates that our low-cost accelerometry-based approach is a promising one. The proposed easy-to-use technology could diminish the rater dependency of FTM scores and enable physicians to monitor ET patients more objectively in clinical, intraoperative, and home settings. [ABSTRACT FROM AUTHOR]

Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools for advanced PD, and provides considerations around optimal use of infusion therapy. [ABSTRACT FROM AUTHOR]

The Movement Disorder Society Unified Parkinson's Disease Rating Scale—part III (MDS-UPDRS-III) is designed to be applied in the sitting position. However, to evaluate the clinical effect during stereotactic neurosurgery or to assess bedridden patients with Parkinson's disease (PD), the MDS-UPDRS-III is often used in a supine position. This explorative study evaluates the agreement of the MDS-UPDRS-III in the sitting and the supine positions. In 23 PD patients, the MDS-UPDRS-III was applied in both positions while accelerometric measurements were performed. Video recordings of the assessments were evaluated by two certified raters. Agreement between the sitting and supine MDS-UPDRS-III was studied using Cohen's kappa coefficient. Relationships between the MDS-UPDRS-III tremor scores and accelerometric amplitudes were calculated for both positions with linear regression. A fair to substantial agreement was found for MDS-UPDRS-III scores of individual items in the sitting and supine positions, while combining all tests resulted in a substantial agreement. The inter-rater reliability was fair to moderate for both positions. A logarithmic relationship between tremor scores and accelerometric amplitude was revealed for both the sitting and supine positions. Nevertheless, these data are insufficient to fully support the supine application of the MDS-UPDRS-III. Several recommendations are made to address the sensitivity of the scale to inter-rater variability. In conclusion, although an overall substantial agreement between sitting and supine MDS-UPDRS-III is confirmed, its application in the supine position is not endorsed for the whole range of its individual items. Caution is warranted in interpreting the supine MDS-UPDRS-III, pending additional research. [ABSTRACT FROM AUTHOR]

Introduction: Advanced Parkinson's disease (aPD) patients have a high risk on definite nursing home admission. We analyzed the effectiveness of an in-and outpatient multidisciplinary rehabilitation, focusing on activities of daily living (ADL) and delaying definite nursing home admission. Methods: This study included 24 aPD patients, who received a 6-week inpatient multidisciplinary rehabilitation program, including optimization of pharmacotherapy, which was followed by an individualized outpatient support program during 2 years (intervention group). A non-randomized matched control group (n = 19), received care as usual. Primary endpoints consisted of the Amsterdam Linear Disability Scale (ALDS) and percentage of patients being able to live independently at home after 2 years. Secondary endpoints included changes in medication (LEDD), motor performance (SCOPA-SPES), cognition (SCOPACOG), hallucinations (NPI) and depression (BDI). Results: Overall, 83% of patients were able to return home after the 6-week inpatient intervention, and 65% still lived at home at 2 years follow-up. Median ALDS scores after 2 years in the intervention group were significantly better, compared to the control group (p = 0.002). All secondary endpoints had improved significantly vs. baseline directly after the 6-week inpatient rehabilitation, which had disappeared at 2 years follow-up, with the exception of the daily dose of medication, which was significantly higher in the intervention group. Conclusion: This 2-year follow-up study showed that a combined multidisciplinary in/outpatient rehabilitation program for aPD patients, was able to stabilize ADL functions, and finally delayed definite nursing home admissions in 65% of treated patients. [ABSTRACT FROM AUTHOR]

Introduction: Visual complaints can have a vast impact on the quality of life of people with Parkinson's disease (PD). In clinical practice however, visual complaints often remain undetected. A better understanding of visual complaints is necessary to optimize care for people with PD and visual complaints. This study aims at determining the prevalence of visual complaints experienced by a large outpatient cohort of people with PD compared to a control group. In addition, relations between visual complaints and demographic and disease-related variables are investigated. Methods: The Screening Visual Complaints questionnaire (SVCq) screened for 19 visual complaints in a cohort of people with idiopathic PD (n = 581) and an age-matched control group without PD (n = 583). Results: People with PD experienced significantly more complaints than controls, and a greater impact of visual complaints on their daily lives. Complaints that were most common ('often/always') were unclear vision (21.7%), difficulty reading (21.6%), trouble focusing (17.1%), and blinded by bright light (16.8%). Largest differences with controls were found for double vision, needing more time to see and having trouble with traffic participation due to visual complaints. Age, disease duration, disease severity, and the amount of antiparkinsonian medication related positively to the prevalence and severity of visual complaints. Conclusion: Visual complaints are highly prevalent and occur in great variety in people with PD. These complaints progress with the disease and have a large impact on the daily lives of these people. Standardized questioning is advised for timely recognition and treatment of these complaints. [ABSTRACT FROM AUTHOR]

Background: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start). Objective: This paper reports the results of the economic evaluation performed alongside the LEAP-study. Methods: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up. Results: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of € 59 per patient (BCa 95% CI: –829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated. Conclusion: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa. [ABSTRACT FROM AUTHOR]

Background: Degeneration of the cholinergic system plays an important role in cognitive impairment in Parkinson's disease (PD). Positron emission tomography (PET) imaging using the presynaptic vesicular acetylcholine transporter (VAChT) tracer [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) allows for regional assessment of cholinergic innervation. The purpose of this study was to perform a data-driven analysis to identify co-varying cholinergic regions and to evaluate the relationship of these with cognitive functioning in PD. Materials and methods: A total of 87 non-demented PD patients (77% male, mean age 67.9 = 7.6 years, disease duration 5.8 = 4.6 years) and 27 healthy control (HC) subjects underwent [18F]FEOBV brain PET imaging and neuropsychological assessment. A volume-of-interest based factor analysis was performed for both groups to identify cholinergic principal components (PCs). Results: Seven main PCs were identified for the PD group: (1) bilateral posterior cortex, (2) bilateral subcortical, (3) bilateral centro-cingulate, (4) bilateral frontal, (5) right-sided fronto-temporal, (6) cerebellum, and (7) predominantly left sided temporal regions. A complementary principal component analysis (PCA) analysis in the control group showed substantially different cholinergic covarying patterns. A multivariate linear regression analyses demonstrated PC3, PC5, and PC7, together with motor impairment score, as significant predictors for cognitive functioning in PD. PC3 showed most robust correlations with cognitive functioning (p < 0.001). Conclusion: A data-driven approach identified covarying regions in the bilateral peri-central and cingulum cortex as a key determinant of cognitive impairment in PD. Cholinergic vulnerability of the centro-cingulate network appears to be disease-specific for PD rather than being age-related. The cholinergic system may be an important contributor to regional and large scale neural networks involved in cognitive functioning. [ABSTRACT FROM AUTHOR]

Background: The Screening Visual Complaints questionnaire (SVCq) is a short questionnaire to screen for visual complaints in people with Parkinson's disease (PD). Objective: The current study aims to investigate the factor structure of the SVCq to increase the usability of this measure in clinical practice and facilitate the interpretation of visual complaints in people with PD. Methods: We performed a confirmatory factor analysis using the 19 items of the SVCq of 581 people with PD, investigating the fit of three models previously found in a community sample: a one-factor model including all items, and models where items are distributed across either three or five factors. The clinical value of derived subscales was explored by comparing scores with age-matched controls (N = 583), and by investigating relationships to demographic and disease related characteristics. Results: All three models showed a good fit in people with PD, with the five-factor model outperforming the three-factor and one-factor model. Five factors were distinguished: 'Diminished visual perception–Function related' (5 items), 'Diminished visual perception–Luminance related' (3 items), 'Diminished visual perception–Task related' (3 items), 'Altered visual perception' (6 items), and 'Ocular discomfort' (2 items). On each subscale, people with PD reported more complaints than controls, even when there was no ophthalmological condition present. Furthermore, subscales were sensitive to relevant clinical characteristics, like age, disease duration, severity, and medication use. Conclusions: The five-factor model showed a good fit in people with PD and has clinical relevance. Each subscale provides a solid basis for individualized visual care. [ABSTRACT FROM AUTHOR]

Background: Scientific research increasingly focuses on visual symptoms of people with Parkinson's disease (PD). However, this mostly involves functional measures, whereas self-reported data are equally important for guiding clinical care. Objective: This review provides an overview of the nature and prevalence of self-reported visual complaints by people with PD, compared to healthy controls. Methods: A systematic literature search was performed. Studies from three databases (PubMed, PsycInfo, and Web of Science) were screened for eligibility. Only studies that reported results of visual self-reports in people with idiopathic PD were included. Results: One hundred and thirty-nine eligible articles were analyzed. Visual complaints ranged from function-related complaints (e.g., blurred vision, double vision, increased sensitivity to light or changes in contrast sensitivity) to activity-related complaints (e.g., difficulty reading, reaching, or driving). Visual complaints were more prevalent in people with PD compared to healthy controls. The presence of visual complaints leads to a reduced quality of life (QoL). Increased prevalence and severity of visual complaints in people with PD are related to longer disease duration, higher disease severity, and off-state. Conclusion: A large proportion of people with PD have visual complaints, which negatively affect QoL. Complaints are diverse in nature, and specific and active questioning by clinicians is advised to foster timely recognition, acknowledgement, and management of these complaints. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries." The authors of the original article reported that the reference details to another commentary by Antonini et al. were incorrect. The correct reference details have been provided in the correction notice. The original article has been updated accordingly. Springer Nature, the publisher, remains neutral in terms of jurisdictional claims and institutional affiliations. [Extracted from the article]

The most frequently used method for evaluating tremor in Parkinson's disease (PD) is currently the internationally standardized Movement Disorder Society—Unified PD Rating Scale (MDS-UPDRS). However, the MDS-UPDRS is associated with limitations, such as its inherent subjectivity and reliance on experienced raters. Objective motor measurements using accelerometry may overcome the shortcomings of visually scored scales. Therefore, the current study focuses on translating the MDS-UPDRS tremor tests into an objective scoring method using 3D accelerometry. An algorithm to measure and classify tremor according to MDS-UPDRS criteria is proposed. For this study, 28 PD patients undergoing neurosurgical treatment and 26 healthy control subjects were included. Both groups underwent MDS-UPDRS tests to rate tremor severity, while accelerometric measurements were performed at the index fingers. All measurements were performed in an off-medication state. Quantitative measures were calculated from the 3D acceleration data, such as tremor amplitude and area-under-the-curve of power in the 4–6 Hz range. Agreement between MDS-UPDRS tremor scores and objective accelerometric scores was investigated. The trends were consistent with the logarithmic relationship between tremor amplitude and MDS-UPDRS score reported in previous studies. The accelerometric scores showed a substantial concordance (>69.6%) with the MDS-UPDRS ratings. However, accelerometric kinetic tremor measures poorly associated with the given MDS-UPDRS scores (R2 < 0.3), mainly due to the noise between 4 and 6 Hz found in the healthy controls. This study shows that MDS-UDPRS tremor tests can be translated to objective accelerometric measurements. However, discrepancies were found between accelerometric kinetic tremor measures and MDS-UDPRS ratings. This technology has the potential to reduce rater dependency of MDS-UPDRS measurements and allow more objective intraoperative monitoring of tremor. [ABSTRACT FROM AUTHOR]

Background: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention. Objective: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment. Methods: Fifty‐seven newly diagnosed, treatment‐naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD‐NC) or mild cognitive impairment (PD‐MCI). Whole brain voxel‐based group comparisons were performed. Results: Results show bidirectional cholinergic innervation changes in PD. Both PD‐NC and PD‐MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher‐than‐normal binding was most prominent in PD‐NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala. Conclusion: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher‐than‐normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early‐stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer's disease (AD) and Lewy body dementia (LBD). However, the clinical effects are highly variable, which questions the suggested basic principles underlying these clinical trials. Therefore, preclinical and clinical data on the design of NBM stimulation experiments and its effects on behavioral and neurophysiological aspects are systematically reviewed here. Animal studies have shown that electrical stimulation of the NBM enhanced cognition, increased the release of acetylcholine, enhanced cerebral blood flow, released several neuroprotective factors, and facilitates plasticity of cortical and subcortical receptive fields. However, the translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, whereas most animals were stimulated unilaterally, with different stimulation paradigms for only restricted timeframes. Future animal research has to refine the NBM stimulation methods, using partially lesioned NBM nuclei, to better resemble the clinical situation in AD, and LBD. More preclinical data on the effect of stimulation of lesioned NBM should be present, before DBS of the NBM in human is explored further. [ABSTRACT FROM AUTHOR]

Background: The supplementary motor area (SMA) is implicated in both motor initiation and stereotypic multi-limb movements such as walking with arm swing. Gait in Parkinson's disease exhibits starting difficulties and reduced arm swing, consistent with reduced SMA activity. Objective: We tested whether enhanced arm swing could improve Parkinson gait initiation and assessed whether increased SMA activity during preparation might facilitate such improvement. Methods: Effects of instructed arm swing on cortical activity, muscle activity and kinematics were assessed by ambulant EEG, EMG, accelerometers and video in 17 Parkinson patients and 19 controls. At baseline, all participants repeatedly started walking after a simple auditory cue. Next, patients started walking at this cue, which now meant starting with enhanced arm swing. EEG changes over the putative SMA and leg motor cortex were assessed by event related spectral perturbation (ERSP) analysis of recordings at Fz and Cz. Results: Over the putative SMA location (Fz), natural PD gait initiation showed enhanced alpha/theta synchronization around the auditory cue, and reduced alpha/beta desynchronization during gait preparation and movement onset, compared to controls. Leg muscle activity in patients was reduced during preparation and movement onset, while the latter was delayed compared to controls. When starting with enhanced arm swing, these group differences virtually disappeared. Conclusion: Instructed arm swing improves Parkinson gait initiation. ERSP normalization around the cue indicates that the attributed information may serve as a semi-internal cue, recruiting an internalized motor program to overcome initiation difficulties. [ABSTRACT FROM AUTHOR]

Background: Continuous intra-duodenal infusion of levodopa-carbidopa intestinal gel (LCIG) is a well-established therapy for patients with advanced Parkinson's disease (PD) suffering from motor complications despite optimized treatment with oral dopaminomimetics. However, time to discontinuation of treatment with LCIG varies considerably between patients, ranging from a few months to more than ten years. To improve the selection of candidates for LCIG, knowledge of prognostic factors is of paramount importance. Objective: To explore baseline predictors of time to discontinuation of LCIG. Methods: In this two-center retrospective cohort study, we reviewed the medical files of 98 PD patients treated with LCIG between April 2006 and December 2015 (53% male; mean age: 66.2 years; mean disease duration: 12.3 years). Baseline patient characteristics were used as covariates in Cox regression models. Results: During follow-up (mean observation time: 2.6 years; range: 0.1–9.3) eighteen patients discontinued treatment (18.4%), while seven patients died (7.1%). Median duration of treatment with LCIG, estimated with Kaplan-Meier analysis, was 7.8 years (95% CI: 6.7–9.0). Disease duration (in years) at baseline was a statistically significant predictor of time to discontinuation of LCIG (HR: 0.85; 95% CI: 0.75–0.96, p = 0.006). All other characteristics studied, e.g. age >70 years, did not show statistically significant associations with the total duration of treatment with LCIG. Conclusion: Our findings show a low overall rate of discontinuation of LCIG infusion, with a median duration of treatment of 7.8 years. Shorter disease duration at baseline appeared to be a predictor of earlier discontinuation of LCIG. [ABSTRACT FROM AUTHOR]

Background: Parkinson's Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. To date, no disease modifying treatment for PD exists. Here, the study protocol of the Dutch Parkinson Cohort (DUPARC) is described. DUPARC is a longitudinal cohort study aimed at deeply phenotyping de novo PD patients who are treatment-naïve at baseline, to discover and validate biomarkers for PD progression, subtypes and pathophysiology.Methods/design: DUPARC is a prospective cohort study in which 150 de novo PD subjects will be recruited through a collaborative network of PD treating neurologists in the northern part of the Netherlands (Parkinson Platform Northern Netherlands, PPNN). Participants will receive follow-up assessments after 1 year and 3 years, with the intention of an extended follow-up with 3 year intervals. Subjects are extensively characterized to primarily assess objectives within three major domains of PD: cognition, gastrointestinal function and vision. This includes brain magnetic resonance imaging (MRI); brain cholinergic PET-imaging with fluoroethoxybenzovesamicol (FEOBV-PET); brain dopaminergic PET-imaging with fluorodopa (FDOPA-PET); detailed neuropsychological assessments, covering all cognitive domains; gut microbiome composition; intestinal wall permeability; optical coherence tomography (OCT); genotyping; motor and non-motor symptoms; overall clinical status and lifestyle factors, including a dietary assessment; storage of blood and feces for additional analyses of inflammation and metabolic parameters. Since the start of the inclusion, at the end of 2017, over 100 PD subjects with a confirmed dopaminergic deficit on FDOPA-PET have been included.Discussion: DUPARC is the first study to combine data within, but not limited to, the non-motor domains of cognition, gastrointestinal function and vision in PD subjects over time. As a de novo PD cohort, with treatment naïve subjects at baseline, DUPARC provides a unique opportunity for biomarker discovery and validation without the possible confounding influences of dopaminergic medication.Trial Registration: NCT04180865; registered retrospectively, November 28th 2019. [ABSTRACT FROM AUTHOR]

The increasing global burden of Parkinson's disease (PD) poses a particular challenge for developing countries, such as Thailand, when delivering care to a geographically diverse populace with limited resources, often compounded by a lack of expertise in the use of certain PD medications, such as device-aided therapies (DAT). A panel of local, regional, and international PD experts convened to review the unmet needs of PD in Thailand and share insights into effective delivery of DAT, focusing on experience with apomorphine infusion. Despite its proven efficacy and safety, implementation of apomorphine infusion as a new option was not straightforward. This has prompted a range of health-care professional and patient-focused initiatives, led by the Chulalongkorn Center of Excellence for Parkinson's Disease and Related Disorders in Bangkok, to help establish a more coordinated approach to PD management throughout the country and ensure patients have access to suitable treatments. Overcoming the challenges of education, proficiency, resource capacity and standard of care for PD patients in developing countries requires a coordinated effort both nationally and beyond. The best practices identified in Thailand following the introduction of apomorphine infusion might be helpful for other countries when implementing similar programs. [ABSTRACT FROM AUTHOR]

Background: Thalamotomy is an endorsed treatment for medication-refractory tremor. It used to be the standard, but nowadays deep brain stimulation (DBS) has become the treatment option of choice. Nevertheless, DBS has the disadvantage of hardware failure, battery replacement, and frequent setting adjustment. Radiofrequency (RF) thalamotomy lacks these issues, is relatively inexpensive, and has a broad applicability in patients with significant comorbidity. Therefore, we analyzed the long-term patient-reported outcome of RF thalamotomy in a cohort of patients with an otherwise intractable tremor. Methods: A single-center cohort of 27 consecutive patients with intractable tremor was assessed after unilateral RF thalamotomy. Over time, 4 patients had died because of non-related causes. In total, 21 patients responded to a telephone survey to assess their personal judgment on postoperative tremor severity, using a validated tremor scale, adverse events, recurrence, and patient satisfaction. The median time between surgery and telephone survey was 39 months (range 12–126). Seven patients had an additional analysis with postoperative imaging, video-assisted electromyography tremor registration, and a self-reported treatment effect (SRTE) assessment. Results: Nineteen out of 21 patients (90.5%) reported absence or significant improvement of their tremor. The rating score (WHIGET/UPDRS-III) dropped significantly from a mean of 3.57 preoperatively to 1.05 postoperatively (p < 0.001). Eleven patients (52.4%) reported adverse events, but the majority (76.2%) did not consider the adverse events to be severe. SRTE assessment showed a direct postoperative effect of 89.6 of 100 points (SD 10.8), with a gradual decrease to 75.3 (SD 23.5) during follow-up. Conclusions: RF thalamotomy is a very effective long-term treatment for medication-refractory tremor and should therefore be considered in patients with a refractory unilateral tremor. [ABSTRACT FROM AUTHOR]

Rationale: In Parkinson's disease (PD), spatial covariance analysis of 18F-FDG PET data has consistently revealed a characteristic PD-related brain pattern (PDRP). By quantifying PDRP expression on a scan-by-scan basis, this technique allows objective assessment of disease activity in individual subjects. We provide a further validation of the PDRP by applying spatial covariance analysis to PD cohorts from the Netherlands (NL), Italy (IT), and Spain (SP). Methods: The PDRPNL was previously identified (17 controls, 19 PD) and its expression was determined in 19 healthy controls and 20 PD patients from the Netherlands. The PDRPIT was identified in 20 controls and 20 "de-novo" PD patients from an Italian cohort. A further 24 controls and 18 "de-novo" Italian patients were used for validation. The PDRPSP was identified in 19 controls and 19 PD patients from a Spanish cohort with late-stage PD. Thirty Spanish PD patients were used for validation. Patterns of the three centers were visually compared and then cross-validated. Furthermore, PDRP expression was determined in 8 patients with multiple system atrophy. Results: A PDRP could be identified in each cohort. Each PDRP was characterized by relative hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex. These changes co-varied with variable degrees of hypometabolism in posterior parietal, occipital, and frontal cortices. Frontal hypometabolism was less pronounced in "de-novo" PD subjects (Italian cohort). Occipital hypometabolism was more pronounced in late-stage PD subjects (Spanish cohort). PDRPIT, PDRPNL, and PDRPSP were significantly expressed in PD patients compared with controls in validation cohorts from the same center (P < 0.0001), and maintained significance on cross-validation (P < 0.005). PDRP expression was absent in MSA. Conclusion: The PDRP is a reproducible disease characteristic across PD populations and scanning platforms globally. Further study is needed to identify the topography of specific PD subtypes, and to identify and correct for center-specific effects. [ABSTRACT FROM AUTHOR]

In this multicentre randomised controlled trial (RCT), 43 patients with Parkinson's disease (PD) were randomly allocated to either the experimental condition receiving cognitive rehabilitation including strategy training (ReSET; Strategic Executive Treatment, n = 24) or to the control condition receiving computerised repetitive practice training for attention (Cogniplus, n = 16). We expected that strategy training (ReSET) would be more effective than cognitive training (Cogniplus) in improving patients' everyday life executive functioning. Neuropsychological assessment was administered at baseline, at 2 weeks and 3-5 months post-treatment. Primary outcome measure was the Role Resumption List (RRL). Secondary outcome measures were treatment goal attainment (TGA), Dysexecutive Questionnaire (DEX), Parkinson's Disease Questionnaire (PDQ-39), Zarit Burden Interview (ZBI) and neuropsychological tests. No effects of treatment were found on the primary outcome measure and on neuropsychological tests, except for one test of attention. At 2 weeks and 3-5 months post-treatment, PD patients in both the ReSET and Cogniplus group reported a significant improvement in everyday life executive functioning, as measured with TGA and the DEX-self, with an advantage for ReSET only shortly after treatment. Given these results and that PD patients were able to adhere to these treatments despite their motor symptoms and fatigue (i.e., the drop-out rate was small), we conclude that both strategy training and cognitive training for impairments in EF might be beneficial and feasible for PD patients. [ABSTRACT FROM AUTHOR]

Abstract Faecal microbiome transplantation (FMT) is an attractive technique, because the administration is relatively simple and in general has a mild adverse effect pattern. Moreover, FMT consists of a broad mixture, which could be beneficial, because at this moment it is not known what type of changes in the microbiome are needed. However, except from a few cases no clinical data in Parkinson's disease (PD) is available yet. There is some indication that FMT might be beneficial in severe constipated PD patients, but the clinical data to support this are very scarce. So, actually there are no good data in the public domain to support FMT at this moment in PD patients. FMT at this moment is a black box with too many unanswered questions, also with respect to safety concerns. Only the administration of species of Lactobacillus and Bifidobacterium over a time period of four to twelve weeks has repeatedly proven to be effective in treating constipation in PD. Also, no solid clinical data are available about the possible effects of probiotic treatment on motor symptoms or progression of PD. Therefore, also probiotic treatments in PD should wait until better clinical data become available, in order to select the right target populations and to have good estimates of the clinical effects to be expected. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence— reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature. [ABSTRACT FROM AUTHOR]

Increasing evidence is supporting the hypothesis of α-synuclein pathology spreading from the gut to the brain although the exact etiology of Parkinson's disease (PD) is unknown. Furthermore, it has been proposed that inflammation, via the gastrointestinal tract, potentially through infections, may contribute to α-synuclein pathogenesis, and thus to the risk of developing PD. Recently, many studies have shown that PD patients have an altered microbiota composition compared to healthy controls. Inflammation in the gut might drive microbiota alterations or vice versa. Many studies focused on the detection of biomarkers of the etiology, onset, or progression of PD however also report metabolites from bacterial origin. These metabolites might reflect the bacterial composition and as well play an important role in immune homeostasis, ultimately affecting the progression of PD. Besides the bacterial metabolites, pharmacological treatment of PD might play a crucial role during the progression and thus treatment of the disease on the immune system. This review aims to establish a link between the microbial composition with the observed alterations of bacterial metabolites and their impact on the immune system, which could have influential effect in onset, progression and etiology of PD. [ABSTRACT FROM AUTHOR]

The etiology of Parkinson's disease (PD) is multifactorial, with genetics, aging, and environmental agents all a part of the PD pathogenesis. Widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites, and degeneration of substantia nigra dopamine neurons are the pathological hallmarks of PD. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. Experimental, clinical and epidemiological data suggest that intestinal inflammation contributes to the pathogenesis of PD, and the increasing number of studies suggests that the condition may start in the gastrointestinal system years before any motor symptoms develop. Patients with inflammatory bowel disease (IBD) have a higher risk of developing PD compared with non-IBD individuals. Gene association study has found a genetic link between IBD and PD, and an evidence from animal studies suggests that gut inflammation, similar to that observed in IBD, may induce loss of dopaminergic neurons. Based on preclinical models of PD, it is suggested that the enteric microbiome changes early in PD, and gut infections trigger α-synuclein release and aggregation. In this paper, the possible link between IBD and PD is reviewed based on the available literature. Given the potentially critical role of gastrointestinal pathology in PD pathogenesis, there is reason to suspect that IBD or its treatments may impact PD risk. Thus, clinicians should be aware of PD symptoms in IBD patients. [ABSTRACT FROM AUTHOR]

Gut microbiota have been studied in relation to the pathophysiology of Parkinson's disease (PD) due to the early gastrointestinal symptomatology and presence of alpha-synuclein pathology in the enteric nervous system, hypothesized to ascend via the vagal nerve to the central nervous system. Accordingly, sixteen human case-control studies have published gut microbiome composition changes in PD and reported over 100 differentially abundant taxa covering all taxonomic levels from phylum to genus or species, depending on methodology. While certain findings were replicated across several studies, various contradictory findings were reported. Here, differences in methodologies and the presence of possible confounders in the study populations are assessed for their potential to confound the results of gut microbiome studies in PD. Gut microbiome studies in PD exhibited considerable variability with respect to the study population, sample transport conditions, laboratory protocols and sequencing, bioinformatics pipelines, and biostatistical methods. To move from the current heterogeneous dataset towards clinically relevant biomarkers and the identification of putative therapeutic targets, recommendations are derived from the limitations of the available studies to increase the future comparability of microbiome studies in PD. In addition, integration of currently available data on the gut microbiome in PD is proposed to identify robust gut microbiome profiles in PD. Furthermore, expansion of the current dataset with atypical parkinsonism cohorts, prodromal and treatment-naïve de novo PD subjects, measurements of fecal microbial concentrations and multi-omics assessments are required to provide clinically relevant biomarkers and reveal therapeutic targets within the gut microbiome of PD. [ABSTRACT FROM AUTHOR]

The intestinal barrier, which primarily consists of epithelial cells stitched together with connecting proteins called tight junctions, plays a critical role in health and disease. It is in close contact with the gut microbiota on its luminal side and with the enteric neurons on the tissue side. Both microbiota and the enteric nervous system are regulatory housekeepers of the intestinal barrier. Therefore, the recently observed enteric neuropathology along with gut dysbiosis in Parkinson's disease have prompted research on intestinal permeability in this neurodegenerative disorder. In this mini-review we attempt to concisely summarize the current knowledge on intestinal barrier in Parkinson's disease. We envision future direction research that should be pursued in order to demonstrate its possible role in disease development and progression. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) has long been considered a brain disease, but studies now point to the gastrointestinal (GI) tract as a potential starting point for PD. In particular, the human vermiform appendix has been implicated in PD. The appendix is a tissue rich in immune cells, serving as part of the gut-associated lymphoid tissue and as a storehouse for the gut microbiome. The functions of the appendix converge with recent evidence demonstrating that gut inflammation and shifts in the microbiome are linked to PD. Some epidemiological studies have linked removal of the appendix to lowered PD risk, though there is controversy among these associations. What is apparent is that there is an abundance of aggregated forms of α-synuclein in the appendix relevant to PD pathology. α-Synuclein pathology is thought to propagate from gut to brain via the vagus nerve, which innervates GI tract locations, including the appendix. Remarkably, α-synuclein aggregates in the appendix occur not only in PD patients, but are also present in healthy individuals. This has led to the proposal that in the appendix α-synuclein aggregates are not unique to PD. Moreover, the molecular events leading to PD and the mechanisms by which α-synuclein aggregates transfers from gut to brain may be identifiable in the human appendix. The influence of the appendix on GI inflammation, autoimmunity, microbiome storage, and the lymphatic system may be yet unexplored mechanisms by which the appendix contributes to PD. Overall, the appendix represents a promising tissue site to advance our understanding of PD pathobiology. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease. [ABSTRACT FROM AUTHOR]