BackgroundParkinson's disease (PD) is associated with several behavioral and cognitive symptoms, the neurobiological background of which is not yet fully understood.ObjectivesThe aim was to investigate the association between monoamine function and four specific nonmotor symptoms in early PD using the Parkinson's Progression Markers Initiative data.Methods[123I]FP‐CIT SPECT imaging data of healthy controls (n = 166) and patients with PD at baseline (n = 349), 2‐year (n = 240), and 4‐year follow‐up (n = 140) were included. Depression, anxiety, rapid eye movement (REM) sleep behavior disorder (RBD) and cognition were evaluated using validated questionnaires. The associations between symptoms and subcortical monoamine transporter binding were analyzed voxel by voxel. Whole brain networks of symptom‐specific monoaminergic abnormalities were characterized using a functional connectome (n = 1000) and normative neurotransmitter receptor maps.ResultsCross‐sectionally, depression was associated with reduced ventral striatum (VS) binding at 2‐ and 4‐year and dorsal raphe (DRN) at 4‐year follow‐up (PFWE < 0.05); trait anxiety was associated with reduced DRN binding at 4‐year follow‐up (PFWE < 0.05). Longitudinally, lower baseline binding in these regions at baseline predicted more severe future depression and anxiety (PFWE < 0.05). RBD was most strongly linked to reduced VS binding at 2‐ and 4‐year follow‐up (nonsignificant after correction, PFWE < 0.1). Each of the symptom‐specific clusters was connected to distinct brain networks, corresponding to specific monoamine receptors: serotonin (5HT1F, 5HT2A, 5HT5A) and histamine (H3) for depression; histamine (H1), serotonin (5HT1E, 5HT1F, 5HT2A, 5HT3B), and adrenergic (α1D) for anxiety; and adrenergic (β2) and serotonin (5HT1F, 5HT2C, 5HT5A) receptors for RBD.ConclusionsThe findings provide novel information about the monoaminergic networks underlying depression, anxiety, and RBD in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We read with interest the systematic review on treatment options for Parkinson's disease (PD) motor fluctuations, published as an International Parkinson and Movement Disorder Society (MDS) evidence-based medicine (EBM) review article.1 We appreciate the authors' motivation to provide guidance in determining which therapeutic options are safe and efficacious to reduce patients' disease burden. The article appears intrinsically consistent, following the strict Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based methodology. Having recently evaluated the literature on the same subject while developing the German Society of Neurology Guidelines for PD,2, 3 we wish to share some comments on this article.1 First, rapid-release (dispersible/soluble) oral levodopa is still among the most frequently prescribed off-rescue medication. This option is not mentioned in the MDS review.1 In the absence of randomized controlled trials to demonstrate superiority over other therapeutic options, there is still robust clinical experience supporting this safe and efficacious option. Inhaled levodopa is not mentioned either in the MDS review,1 although the criteria set forth by the authors appear to qualify consideration of the pivotal study demonstrating its efficacy to significantly reduce motor fluctuations.4 It might have been omitted since daily off-time was not the primary readout. The drug is still approved for this indication by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Likewise, the commonly used dopamine agonist piribedil is not mentioned.1 Intermittent application of apomorphine, either subcutaneous or sublingual, has been declassified by “insufficient evidence” in the MDS review,1 although published evidence may suggest otherwise5, 6 and these treatment options are approved, reimbursed, and administered successfully in many countries. The classification of istradefylline as “likely efficacious” is interesting, since the EMA issued a negative opinion in 2021,7 refusing approval for istradefylline as an add-on treatment for motor fluctuations, considering the available evidence as inconsistent and not satisfactorily showing effectiveness to reduce ‘off’ time. A pooled analysis of eight phase IIb/III trials suggested that istradefylline reduces daily off-time by only 0.38 or 0.45 hr more than placebo at 20 or 40 mg/day, respectively.8 These discrepancies between the conclusions reached in this article1 and the current options approved and available to aid patients with motor fluctuations demonstrate the striking limitations of the GRADE methodology, when stringently applied. Obviously, there is no possibility to consider other than the specified endpoints, relative effect sizes, or clinical experience in the absence of formal data for “old” drugs, and regional availabilities. The article also does not comment on the specific medical conditions in which the different options might be advantageous for individual patients (eg, continuous vs. on-demand medications, enteral vs. parenteral administration, different half-lives, renal or hepatic elimination, and so on). These aspects, however, are very important when making treatment decisions. Furthermore, the choice of options should also consider individual patient's side effect profiles, which in reality often become decisive factors. Thus, the strict EBM methodology apparently may deliver conclusions that are strikingly distinct from the options available and meaningful in reality for patients and caring neurologists in different regions. Therefore, a reconsideration of the EBM methodology used by the MDS Task Forces to provide true guidance for clinical practice may be warranted. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. G.H.: 3A, 3B. P.L.: 3B. M.H.: 3B. C.T.: 3B. G.H. participated in industry-sponsored research projects from AbbVie, Biogen, Biohaven, Novartis, Roche, Sanofi, and UCB; has ongoing research collaborations with AbbVie, Ferrer, Roche, and UCB; serves as a consultant for AbbVie, Alzprotect, Amylyx, Bayer, Bial, Biogen, Biohaven, Ferrer, Lundbeck, Merz, Novartis, Roche, Sanofi, Takeda, TEVA, and UCB; and received honoraria for scientific presentations from AbbVie, Bayer, Bial, Biogen, Merz, Roche, TEVA, UCB, and Zambon. P.L. participated in industry-sponsored research projects from Alexion, Biogen, Blue Rock Therapeutics, Corcept Therapeutics, Mitsubishi Tanabe, Novartis, Theranexus, and Trace Neuroscience; serves as a consultant for AbbVie, Novartis, ITF Pharma, Raya Therapeutics, Stadapharm, Trace Neuroscience, Woolsey Pharmaceuticals, and Zambon; and received honoraria for scientific presentations from Bial, Desitin, ITF Pharma, and Zambon. M.H. participated in industry-sponsored research projects from AbbVie, Biogen, and Roche; serves as a consultant for AbbVie and Teitur Trophics; and received honoraria for scientific presentations from AbbVie and DESITIN. C.T. served as consultant for AbbVie, Roche, Boehringer, UCB, Bial, and Convatec; and has received honoraria for lectures from AbbVie, Bial, Esteve, and STADA. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Objective: To determine if a modified Timed Up and Go (TUG) test can be used to monitor motor improvement in patients with Parkinson's disease (PD) dependent on ambulatory assistance during a 2-week inpatient multimodal intensive neurorehabilitation and care (i-MINC) stay.Background: The TUG test is a widely used measure of functional mobility in the elderly and PD population.Its use is generally limited to patients able to walk independently.Methods: 76 PD patients (H&Y stage 3) were included.All required an assistive device and/or hands-on assistance on admission to i-MINC.They were assessed in their best ON state with a UPDRS examination and a modified TUG test allowing for ambulatory assistance at admission and prior to discharge.A paired T-test was used to analyze changes in TUG completion time and UPDRS scores, and a Wilcoxon signed-rank test for changes in TUG level of assistance (Table 1).The type of assistive device used during the test was recorded.Results: 75 out of 76 patients showed improvement in TUG completion time.76 patients improved in UPDRS total and motor scores.The average improvement in TUG completion time was 12.88 secs (p<0.0001),paralleled by a 16.84-point improvement in UPDRS total score and 6.41-point improvement in UPDRS motor score (p<0.0001).79% of patients required a reduced level of assistance at discharge (p<0.0001).Only 8 patients required a more restrictive assistive device.Conclusions: This study highlights the effectiveness of a modified TUG test as a marker for motor improvement in PD patients undergoing i-MINC.The joint reduction in TUG completion times, UPDRS total and motor scores strongly suggests that the modified test is a reliable and sensitive measure of motor function changes.Moreover, improvements in the level of assistance required during the test support the conclusion that i-MINC positively impacted functional mobility in the majority of patients.Adapting the TUG to accommodate patients dependent on ambulatory assistance creates a more inclusive assessment standard that can be used across the PD severity spectrum.Future studies may focus on formal reliability evaluation and application of the modified TUG test in other rehabilitation settings.

BackgroundThe vagus nerve (VN), the principal component of the parasympathetic branch of the autonomic nervous system (ANS), mediates bidirec communication between the central nervous system (CNS) and peripheral organs. Vagus nerve stimulation (VNS), delivered through invasive (iVNS) or non‐invasive (transcutaneous cervical [tcVNS] and transcutaneous auricular [taVNS]), exerts multimodal effects on multiple circuits and neurotransmitters, and is currently under investigation in movement disorders.ObjectivesThis systematic review evaluates the therapeutic potential of VNS in movement disorders (MDs), with a focus on Parkinson's disease (PD), parkinsonism, tremor and essential tremor (ET), cervical dystonia (CD), and Tourette's syndrome (TS).MethodsA systematic search of PubMed, Web of Science, and Scopus was conducted for studies published between 2020 and 2025, following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 guidelines.ResultsThirty‐two studies met the inclusion criteria: 22 on PD or parkinsonism (14 clinical and 8 preclinical on PD, 1 clinical on multisystem atrophy), 6 on tremor and ET (4 clinical, 2 preclinical), 2 clinical studies on CD, and 1 clinical study on TS. Across conditions, VNS was reported to improve motor and non‐motor, enhance synaptic plasticity, modulate neurotransmitter activity relevant to MDs (GABA, norepinephrine, dopamine, and acetylcholine), and reduce neuroinflammation.ConclusionsCurrent evidence supports the multimodal effect of VNS in MDs, particularly in PD, where the most consistent benefits were observed. Non‐invasive taVNS represents a promising, safer alternative to iVNS. Larger randomized controlled trials with standardized protocols are needed to validate efficacy, optimize stimulation parameters, and determine long‐term clinical and biological impact. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.