Parkinson’s disease (PD) exhibits highly heterogeneous clinical trajectories, yet “advanced PD” (aPD) lacks a standardized definition. Current reliance on clinical milestones (e.g., motor fluctuations, cognitive decline) is limited by non-linear progression and the absence of objective measures. Although biomarkers like aggregated α-synuclein, MRI, and PET are under investigation, their correlation with clinical progression remains modest. Robust, reproducible endpoints are urgently needed to evaluate disease-modifying therapies across diverse phenotypes, accounting for genetic background, age of onset, co-pathologies, and motor/autonomic/cognitive domains. Given this complexity, single-target interventions are likely insufficient. We propose a multi-domain therapeutic framework for aPD that integrates: (A) simultaneous targeting of key pathological cascades, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, proteostasis imbalance, neuroinflammation, and the gut–brain axis; (B) biology-driven patient stratification using emerging biomarkers to match subgroups with targeted interventions; and (C) systematic management of comorbidities and lifestyle factors, such as cardiovascular health and exercise, to enhance neuroresilience. Finally, advancing aPD care requires addressing systemic determinants, including global healthcare inequities, and prioritizing caregiver well-being. Mechanistically informed, patient-centered strategies that combine multi-target therapies with precision stratification and holistic support will be essential to modify disease progression and improve long-term outcomes.

Approximately 30% of patients with tremor-dominant Parkinson’s disease (PD) have rest tremor that persists despite optimal dopaminergic therapy. When deep brain stimulation and focused ultrasound are unavailable or declined, the therapeutic options narrow. Botulinum toxin (BoNT) offers a targeted, titratable, reversible approach, but whether a peripheral neuromuscular blocking agent makes sense for a centrally generated tremor is a legitimate question that deserves a direct answer. This narrative critical review appraises what is currently known across PD and non-PD tremor conditions, defines the technical requirements for safe and effective injection, and provides a practical framework for patient selection and clinical management. The PD-specific literature rests on a single positive double-blind randomized controlled trial of 30 patients; all remaining data are open-label or extrapolated from other tremor conditions, and this narrative synthesis combines heterogeneous conditions, outcome scales, and toxin protocols. A recurring technical observation is that, in the available trials, individualized, EMG-guided injection has been associated with substantially lower rates of hand weakness than fixed-dose injection (reported reductions from roughly 30–70% to below 15%) while maintaining tremor reduction, although the degree of benefit and weakness risk vary with the tremor syndrome, injected muscles, baseline impairment, dose, and guidance method. The careful patient selection this approach requires helps the individual clinician and patient achieve tremor relief, but it departs from the unselected real-world PD population and introduces selection bias that makes a large, statistically representative cohort difficult to assemble. In well-selected patients at centers with the appropriate expertise, BoNT may be a clinically useful option, but routine adoption is not yet supported.

Patients with advanced Parkinson's disease (PD) often need to continue with device-aided therapies (DAT), such as intestinal and subcutaneous infusion therapies. Recently, continuous subcutaneous administration of foslevodopa/foscarbidopa (LDp/CDp) has emerged as a new therapeutic method. Two years after its approval in Germany, a large amount of real-world experience has been collected. Based on this, we present important practical recommendations to help clinicians optimise treatment. Key topics include identifying suitable patients, approaches to initiation and dose determination as well as strategies for balancing LDp/CDp with concomitant oral dopaminergic therapies. Practical challenges, particularly infusion site reactions and neuropsychiatric vulnerability in older or cognitively impaired patients, are discussed, and recommendations are presented on how to prevent and manage these adverse effects during routine management. The review also addresses reasons for discontinuation, organisational factors relevant to real-world implementation and future directions in pump technology. Overall, LDp/CDp is effective in managing motor fluctuations and provides sustained benefits with an overall favourable tolerability profile. Dermatological reactions are common but manageable, and careful adjustment of oral medication rather than rapid pursuit of monotherapy is advisable. The rate of early discontinuation has decreased with growing clinical experience.

BACKGROUND:Cervical dystonia (CD) motor severity is typically quantified with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). An expanded version of the Motor Severity section of the TWSTRS ("TWSTRS-Delphi") has been previously evaluated for its clinimetric properties but not for inter- and intrarater reliability. OBJECTIVE:In this study we quantified inter- and intrarater reliability of the Motor Severity section of the TWSTRS-Delphi for CD. METHODS:Ten raters familiar with the TWSTRS-Delphi and ten raters unfamiliar with it independently scored standardized videos from 90 patients with CD. We computed one-way random intraclass correlation coefficient (ICC, absolute agreement) for total and item scores. We repeated assessments and calculations with a subset of raters to assess intrarater reliability. RESULTS:Interrater reliability for the Total score was good for Familiar raters (ICC = 0.697) and fair for Unfamiliar raters (ICC = 0.566). Most individual items achieved fair-excellent interrater agreement in both groups (Familiar 0.415-0.763; Unfamiliar 0.416-0.769). Sagittal Shift, Duration, and Sensory Tricks showed poor agreement. Intrarater reliability was fair-excellent for most items in both groups (Familiar 0.494-0.927; Unfamiliar 0.413-0.877), but poor for Sagittal Shift and Duration among Familiar raters. CONCLUSIONS:The TWSTRS-Delphi yields reproducible Total and item scores across movement disorder raters. The data pinpoint Sagittal Shift, Duration, and Sensory Tricks as the principal sources of between-rater variability, defining immediate priorities for scale modification and focused training.

"What's in a name?" is more than a literary question for advanced Parkinson's disease (APD). Although APD is widely used in clinical practice, what constitutes "advanced" remains poorly defined and inconsistently applied. Existing definitions have often anchored APD to motor complications, treatment complexity, or eligibility for device-aided therapies (DATs). These approaches are useful for referral and treatment planning, but they risk mistaking a treatment phenotype for the whole disease state. They also fail to capture the broader burden of progression, including non-motor symptoms, cognitive decline, functional dependence, psychosocial consequences, caregiver burden, frailty, and biological heterogeneity. We argue that APD is best understood as a multidimensional state reflecting cumulative neurodegeneration and its lived, functional, and therapeutic consequences, rather than a single stage, motor phenotype, or treatment milestone. This narrative review reframes APD through five interconnected axes: clinical symptom burden; perceived disease impact; functional consequences and participation restriction; therapeutic complexity, refractoriness, and treatment-related complications; and markers associated with disease progression. We propose that APD is a multidimensional clinical state that emerges as PD progresses, when cumulative burden across these five domains exceeds the capacity of patients and caregivers to compensate, adapt, and maintain independence, resulting in progressive disability and reduced quality of life. This framework distinguishes DAT-eligible PD, late-stage PD, and overlapping intermediate phenotypes, while accommodating emerging markers without replacing clinical judgement. By making the name APD correspond more closely to clinical reality, this framework may support earlier recognition, appropriate referral, patient-centred therapeutic planning, and more consistent research stratification.

Abstract:TDM involves measuring and interpreting drug concentrations in blood plasma or serum to optimize pharmacotherapy. In psychiatry and neurology, TDM is a well-established tool for personalized drug treatments. The AGNP-TDM task force initially published guidelines for best practice TDM in 2004, 2011, and 2017. A fundamental methodological revision has now been carried out on how to determine therapeutic reference ranges and dose-related reference ranges transparently and systematically. In the current edition, 50 experts in neuropsychopharmacology offer a complete update of both ranges for each substance following an evidence-based approach. Various types of data were considered for reference range determination, ranging from meta-analyses to drug concentrations expected under recommended doses. Therapeutic reference ranges are now listed for 160 neuropsychiatric drugs, newly included for 30 drugs and revised for 88 drugs. Expected drug concentrations can be calculated based on a revised formula for 162 drugs. Obligatory TDM (i.e. for dose titration) is strongly recommended for 15 neuropsychiatric drugs and recommended for 39 drugs. TDM is classified as useful for 49 drugs and potentially useful for 62 drugs, indicating that it is recommended in specific clinical situations, such as suspected non-adherence, insufficient clinical response despite recommended doses, relapse during maintenance treatment, and many more. The 2026 update includes practical pharmacogenetic recommendations that are directly relevant to TDM. This work integrates a combination of strategies to guide drug treatments in clinical practice using all available tools. A consistent implementation of TDM and pharmacogenetic recommendations will enhance neuropsychopharmacotherapy, improve patient outcomes, and reduce healthcare costs.

Non-pharmacological and non-surgical interventions are increasingly recognised as essential components of management of Parkinson’s disease (PD). However, as PD progresses to its advanced stages, limited mobility, cognitive impairment, treatment-refractory symptoms, and increasing dependence on care partners dominate. However, the evidence base for therapies in this stage becomes scarce. Most clinical practice guidelines and systematic reviews address PD as a whole, without highlighting specific recommendations tailored to advanced disease stage. This narrative review examines the current evidence for non-pharmacological and non-surgical therapies specifically in the context of advanced PD. This includes physiotherapy and exercise, freezing of gait management, dysphagia rehabilitation, nutrition and dietetics, neuropsychiatric care, autonomic dysfunction, pain management, and palliative care. We synthesised evidence from recent systematic reviews of clinical practice guidelines, scoping reviews of rehabilitation interventions in advanced PD, systematic reviews and meta-analyses of non-pharmacological treatments for specific symptom domains, the published literature on advanced PD management, and expert consensus. A recent systematic review identified 40 summary statements for non-pharmacological interventions in PD, yet these were developed without stage-specific differentiation. A scoping review of rehabilitation interventions specifically targeting advanced PD identified only 13 studies, predominantly focused on physical functioning. On the other hand, while interventions for freezing of gait, swallowing therapies, cognitive behavioural therapy for neuropsychiatric symptoms, non-invasive brain stimulation, non-pharmacological autonomic management, and multimodal exercise have demonstrated promise in PD, robust evidence for advanced PD remains largely absent. People with advanced PD represent a neglected population in non-pharmacological therapy research. There is a clear need for inclusion of people with advanced PD in guideline development and a holistic approach addressing factors such as demoralisation, caregiver strain, autonomic dysfunction, and spiritual wellbeing alongside physical rehabilitation.

Fewer than 15% of patients eligible for device-aided therapy (DAT) in Parkinson's disease are ever referred to a specialised centre. A central and underappreciated reason is terminological: the label "advanced Parkinson's disease" carries a powerful psychological burden that causes patients who remain functionally active to reject the very therapy that could help them most. Patients who drove themselves to the appointment, who are still working and raising families, hear "advanced" and conclude that a threshold has been crossed toward dependency and decline. This mismatch is not a communication failure that better counselling can resolve; it is structural, embedded in guidelines, referral letters, consent forms, and patient-facing materials, and it operates before any clinical conversation begins. Moreover, the field currently speaks almost exclusively of 'early' and 'advanced' Parkinson's disease, rendering invisible the prolonged intermediate phase where most patients actually live. We argue that the existing terminology is clinically imprecise, emotionally harmful, and functionally counterproductive. We propose replacing "advanced PD" with the term fluctuation-dominant Parkinson's disease (FD-PD): a functional, mechanism-based descriptor for patients in whom motor and non-motor fluctuations, including dyskinesia, are the predominant feature of the disease experience, and whose primary unmet therapeutic need is inadequate dopaminergic coverage. FD-PD reframes the conversation from disease severity to therapeutic opportunity, decouples DAT eligibility from overall disease burden, names the unnamed intermediate disease phase, and will remain fit for purpose as less-invasive continuous dopaminergic therapies enter clinical practice. We call for a structured, international evaluation of whether FD-PD or a comparable functional descriptor merits formal adoption.

Cervical dystonia (CD) is a hyperkinetic movement disorder characterized by involuntary muscle contractions leading to abnormal postures of the head and neck. The injection of botulinum neurotoxin type A (BoNT-A) into the muscles involved is the treatment of choice for CD. BoNT-A therapy of CD requires appropriate training, which has not been standardized in Germany. To address the key challenges in BoNT-A education, an expert panel developed a simplified step-by-step treatment guideline for beginners, adapted from the established Col-Cap-Concept (“Dystonia 3×3”). Based on expert consensus, recommendations were developed for the core clinical elements of BoNT-A treatment in CD—recognition of the movement pattern, identification of target muscles, development of an injection plan, ultrasound-guided injection, and dosing, taking into account the target audience of the guideline. As such, Dystonia 3×3 provides a user-friendly beginner’s guidebook, enhancing accessibility and standardization of CD treatment training. Further research is required to evaluate its clinical efficacy and suitability for training.

Foslevodopa/foscarbidopa (LDp/CDp) is a nonsurgical 24-h continuous subcutaneous infusion for patients with advanced Parkinson’s disease (aPD) and motor fluctuations uncontrolled on oral medications. We present the first multicountry real-world data from routine clinical practice. ROSSINI (NCT06107426) is an ongoing 3-year multicountry, prospective, observational study of adults with aPD who are LDp/CDp-naïve (cohort A) or transitioning from LDp/CDp open-label extension studies (NCT04379050/NCT04750226, cohort B). For this interim analysis, the primary endpoint was change from baseline to 6 months in OFF time [Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part IV (MDS-UPDRS-IV) modified item 4.3]. Safety was assessed by monitoring adverse events (AEs). Interim results for 105 cohort A patients enrolled ≥ 6 months by March 24, 2025 are presented only; cohort B results were limited (n = 5). Mixed-effects models for repeated measurements (continuous outcomes) were utilized, adjusted for country. Cohort A patients had a mean (SD) age of 68.5 (9.5) years, PD duration of 12.1 (5.3) years, and least squares mean (SE) OFF time of 5.2 (0.6) h at baseline. Patients on LDp/CDp showed statistically significant reductions (95

INTRODUCTION:Our aim was to identify Parkinson's disease (PD) patients with overflow incontinence and to observe trends between pre- and post-void residual volume (PVR) and urinary urgency, incontinence or nocturia in our sample. MATERIAL AND METHODS:As part of our diagnostic evaluation, we measured PVR using a portable bladder scanner in patients with PD at our inpatient facility. The initial measurement was conducted upon admission, and, if increased (PVR > 50 mL), a control measurement was carried out on the same or following day. If the PVR was ≥ 150 mL at follow-up, further control measurements were made immediately before and after micturition. Data on urinary urgency, urinary incontinence and nocturia were retrieved from the non-motor symptoms (NMS) part of the standardized medical history taken at admission. RESULTS:We identified 117 PD patients with increased PVR (≥ 150 mL) during the 8-month period. Due to limited mobility, cognitive impairment, lack of compliance, or early discharge, we were able to carry out the measurements in only 23 out of 117 patients. The investigated population consisted of these 23 PD patients. Further control measurements were carried out to exclude overflow incontinence. We identified no patients with overflow incontinence in our sample. We found that the voiding volume and the volume before voiding were the highest in the urinary urgency group (234.1 mL and 148.3 mL, respectively), while the PVR was the highest among patients with nocturia (91.9 mL vs. 85.8 mL in urgency and 86.6 mL in incontinence). Notable differences in pre-void, post-void, and voiding volumes were observed between men and women in all subgroups, in favor of male patients in our male-dominant sample. Urinary urgency was the most prevalent (78.3%) lower urinary tract symptom (LUTS), followed by nocturia (65.2%) and urinary incontinence (34.8%). We initially hypothesized a possible association between high PVR and urinary urgency in PD patients, but this could not be confirmed. Although the initial PVR was ≥ 150 mL, repeated controls showed lower values, underlining the importance of PVR controls in PD patients. The average age of the patients with nocturia was somewhat higher and they had higher UPDRS III scores than patients in the other subgroups. We only observed slight differences across the subgroups with regard to pre-void, post-void, and voiding volumes. CONCLUSION:The strength of the evaluation is limited by the relatively small sample size. Further studies are needed to clarify the characteristics and possible associations of LUTS subgroups (urgency, incontinence, and nocturia) in PD patients with high PVR.

In addition to response fluctuations caused by the pharmacokinetics of dopamine replacement medication, temporal variation in the expression and severity of motor and non-motor symptoms, which is not or only partially attributable to the effects of the medication, are also common in Parkinson's disease (PD). The spectrum of transient changes of motor symptom expression unrelated to the classical ON-OFF fluctuations ranges from brief episodes of gait freezing or tremor breakthroughs to severe akinetic crisis and non-motor phenomena include discontinuous changes in cognition and vigilance. Disease-related factors such as dementia or orthostatic dysregulation or disturbances of the circadian rhythm may also contribute to these non-pharmacological symptom fluctuations. Additionally, external factors including infections or surgery and general anaesthesia can lead to transient changes of PD symptom severity and drug responsiveness. Accurately classifying these symptom oscillations and distinguishing them from drug-induced ON-OFF fluctuations is essential for their appropriate management.

Parkinson's disease (PD) is now recognized as a multisystem, heterogeneous neurodegenerative disease with fluctuating trajectories and complex symptom profiles. Despite therapeutic advances, many patients (particularly women and those in late stages) and their caregivers face substantial unmet needs across physical, psychological, social, and spiritual domains, which highlight the need for a more integrative care model. Palliative care, defined as holistic, person-centered care for individuals with life-limiting illnesses, is increasingly recognized as particularly relevant in PD, from early to terminal stages. However, its implementation in neurology remains limited, notably due to persistent misconceptions, and delayed or absent referrals. This narrative review therefore aims to equip PD care teams with a clearer understanding of palliative care principles and their applicability to PD, by synthesizing emerging evidence in neuropalliative care, and providing practical recommendations for integration into routine neurological practice. Building on the specificities of quality of care for chronic conditions, optimal neuropalliative care in PD involves regular (re)assessment of symptoms and priorities, effective management of the chronic-palliative interface, good communication, continuity of care (including neurological care until the end of life), and a multidisciplinary network of professionals working both in the community and in specialized clinics, while leaving room for the involvement of caregivers. Far from being "the end of the road", neuropalliative care is a strategic and compassionate response to the evolving complexity of PD, which ultimately enhances quality of life, supports families, and reinforces the neurologist's pivotal role in longitudinal, person-centered care.

BACKGROUND:Two distinct patterns of alpha-synuclein spread in Parkinson's disease were proposed with a body-first and a brain-first subtype. The body-first subtype originates in the periphery, while the brain-first subtype initiates in the central nervous system, notably affecting the amygdala. OBJECTIVES:This retrospective cross-sectional study compared the integrity of the substantia nigra and amygdala between body-first and brain-first Parkinson's disease subtypes. METHODS:We analyzed data from 30 Parkinson's disease patients, classified into body-first (n = 21) and brain-first (n = 9) subtypes based on REM sleep behavior disorder history. Microstructural integrity was assessed using diffusion microstructure MRI. RESULTS:No significant differences were found in the substantia nigra between subtypes. However, amygdala degeneration was significantly pronounced in the "brain-first" compared to the "body-first" group reflected by increased free interstitial fluid (p = 0.02, Cohen's d = -1.22). CONCLUSIONS:The degeneration of amygdala is distinctively pronounced in "brain-first" Parkinson's disease, supporting differential disease progression patterns between subtypes.

Background: Cognitive impairment significantly contributes to the disease burden of progressive supranuclear palsy (PSP), however, the underlying pathophysiologiy is not well understood. Objectives: To gain a better understanding of the pathophysiology, we identified the brain regions associated with individual domains of impaired cognition. Methods: We analyzed MRI data from a cohort of 31 patients with PSP (age 71.0 +-7.0 years, range 58–87; 15 females; disease duration 2.9 +- 1.8 years). Cerebral microstructure was approximated with Diffusion Microstructure Imaging and cognitive performance was measured using the Frontal Assessment Battery (FAB) and Montreal Cognitive Assessment (MoCA). To reveal the underlying affected brain regions, whole-brain voxel-wise associations were employed to test the microstructural metrics regarding their correlation with the FAB as well as the individual cognitive domains ‚Attention‘, ‚Execution‘, ‚Language‘, ‚Memory‘, ‚Orientation‘, and ‚Visuoconstruction‘ derived from MoCA. Results: MoCA performance was impaired in 87.5% of patients (20.2 +- 5.4 points, range 8–28; cut-off value: <26/30). In the voxel-wise analyses, we noted significant associations of cerebral microstructure and FAB in the right-sided frontal and temporopolar white matter, deficits in ‚Memory‘ with hippocampal and temporomesial regions, in reduced ‚Orientation‘ with wide spread white-matter areas with a parietal accentuation, whereas deficits in ‚Attention‘ correlated with frontal and prefrontal structures. Conclusions: Diffusion Microstructure Imaging revealed domain-specific regions of neurodegenerative alterations in PSP. The regions identified in this approach integrate well in existing disease concepts. They might therefore be a possible biomarker for cognitive impairment, as well as amonitoring parameter for future disease modifying therapeutics.