Foslevodopa/foscarbidopa (LDp/CDp) in advanced Parkinson's Disease (aPD): demonstration of savings from a societal perspective in the UK.

AIMS: In advanced Parkinson's disease (aPD), adequate 24-hour control of OFF-time may not be achievable using oral/transdermal therapies. Clinical trials of foslevodopa/foscarbidopa (LDp/CDP) demonstrate meaningful reductions in OFF-time and OFF-related sleep disturbance in aPD. Previous analyses have only considered direct medical costs: this analysis considers a broader societal perspective (direct non-medical costs, informal care, loss of earnings, productivity and tax). METHODS: Inputs for the societal impact model were taken from a cost-utility model comparing LDp/CDp with best medical treatment (BMT), accepted by the UK National Institute of Health and Care Excellence (NICE). Quintiles of normalized OFF-time across a 16-hour waking day in each treatment group were applied to literature-based estimates for direct medical, non-medical and indirect costs. The resulting state-specific cost estimates were applied to the modelled aPD patient population. RESULTS: The model estimates the potential UK population for LDp/CDp at 17,505. Continuous 24-hour delivery of LDp/CDp results in greater time spent in in OFF-time states 0-1 (0-4 hours of OFF-time/16-hour waking day) vs BMT alone. Net savings if all eligible patients receive LDp/CDp are £79.1M in year 1, £235.4M in year 2, rising to £262.2M in year 3, declining to £222.9M in year 4 and £153.7M in year 5 as disease progresses and efficacy of LDp/CDp declines, Estimated total net savings are £953M after 5 years. Results are robust in scenario analyses (excluding costs of excessive sleepiness, earnings loss, productivity and tax loss). LIMITATIONS: A NICE-accepted model was used as the economic modelling basis for the societal impact model, however, much of the data was derived from Adelphi datasets, with the potential for inconsistent definitions. CONCLUSION: When considered from a societal perspective, the use of LDp/CDp in aPD patients inadequately controlled on oral therapy, is associated with net healthcare and societal annual savings of over £79.1M vs BMT.

Response to letter to the editor regarding "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 5-2-1 criteria was developed to facilitate the identification and referral of patients with Parkinson's Disease (PD) inadequately controlled by oral medications. The criterion was not developed to screen patients with PD for device-aided therapy eligibility. The robust design and validation of the 5-2-1 criteria minimizes over or inappropriate referrals, and supports physicians in the timely identification of patients with PD who may warrant further evaluation for treatment optimization. This response letter clarifies concerns raised by Moes et al.

Parkinson's disease psychosis associated with accelerated multidomain cognitive decline.

BACKGROUND: Cognitive deficits are associated with poor quality of life and increased risk of development of dementia in patients with Parkinson's disease (PD) psychosis. The trajectory of cognitive decline in PD psychosis remains however unclear. OBJECTIVE: We examined this using data from the Parkinson's Progression Markers Initiative study. METHODS: We analysed data from patients with drug-naïve PD (n=676) and healthy controls (HC, n=187) over 5 years, and examined all cognitive measures assessed at each time point. We classified patients with PD into those who developed psychosis over the course of the study (PDP) and those without psychosis throughout (PDnP) using the Movement Disorders Society Unified Parkinson's Disease Rating Scale part I hallucinations/psychosis item. We used linear mixed-effect models with restricted maximum likelihood. Age, sex, ethnicity, education and neuropsychiatric and PD-specific symptoms were entered as covariates of interest. FINDINGS: There were no baseline cognitive differences between PD patient groups. There were differences in cognitive performance between PD and HC across the majority of the assessments.Patients with PDP exhibited greater cognitive decline over 5 years compared with PDnP across most domains even after controlling for sociodemographics, depression, sleepiness, rapid eye movement sleep behaviour disorder and motor symptom severity (immediate recall, b=-0.288, p=0.003; delayed recall, b=-0.146, p=0.003; global cognition, Montreal Cognitive Assessment, b=-0.206, p<0.001; visuospatial, b=-0.178, p=0.012; semantic fluency, b=-0.704, p=0.002; processing speed, b=-0.337, p=0.029). CONCLUSIONS: Patients with PD psychosis exhibited decline in semantic aspects of language, processing speed, global cognition, visuospatial abilities and memory, regardless of sociodemographic characteristics, neuropsychiatric and motor symptoms. These cognitive domains, particularly semantic aspects of language may therefore play an important role in PD psychosis and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT01141023.

Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review.

PURPOSE OF REVIEW: Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson's Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as "Alpha-synucleinopathies" AND "Orexin" AND "Sleep Disturbances". RECENT FINDINGS: 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

Pain characteristics of Parkinson's disease using validated Arabic versions of the King's Parkinson's Disease Pain Scale and Questionnaire: A Multicenter Egyptian Study.

Objective: Pain is one of the most common non-motor symptoms in Parkinson's disease (PD), with variable characteristics among populations. This multicenter Egyptian study aimed to translate and validate the King's Parkinson's Disease Pain Scale (KPPS) and questionnaire (KPPQ) into Arabic versions and to investigate the pain characteristics in Egyptian people with PD (PWP). Methods: 192 PWP and 100 sex and age-matched controls were evaluated by KPPS-Arabic and KPPQ-Arabic. Both tools were assessed for test-retest reliability, floor or ceiling effects, construct validity and convert validity. PWP were assessed also by MDS-UPDRS, Hoehn and Yahr, NMSS, PD Questionnaire-39, and the Non-Motor Fluctuation Assessment (NoMoFA). Results: KPPS-Arabic and KPPQ-Arabic showed inter and intra-rater consistency and high validity, with an acceptable ceiling effect. 188 PWP (97.9%) reported at least 1 type of pain, (p<0.001). The severity and prevalence of KPPS-Arabic domains were significantly higher in all pain domains among PWP compared to controls (p < 0.001). Fluctuation-related and musculoskeletal pains were the most common (81.3% and 80.7%, respectively). In the PD group, the total and domains of KPPS-Arabic were significantly correlated to the MDS-UPDRS total, parts I, II, III, PIGD, axial, and H &Y scores, but not age or age of onset. Predictors of KPPS-Arabic included the total MDS-UPDRS, part III-Off, disease duration, total NMSS, and NoMoFA. Conclusion: The current multicentre study provided a validated Arabic versions of KPPS and KPPQ, with high reliability and validity, and demonstrated a high prevalence and severity of pain within Egyptian PWP and characterized its determinants.

Predictors of short-term anxiety outcome in subthalamic stimulation for Parkinson's disease.

The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson's disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD.

Subcutaneous Levodopa: A New Engine for the Vintage Molecule.

The management of Parkinson's disease (PD) continues to evolve with advancements in non-oral levodopa-based therapies aiming to provide continuous drug delivery (CDD). Such therapies address the challenges posed by the emergence of motor fluctuations, dyskinesias, and non-motor fluctuations (NMF) associated with oral levodopa administration and contributing to define the advanced stage of PD. The key focus of this review is placed on subcutaneous foslevodopa/foscarbidopa (Foslevodopa/foscarbidopa) infusion, showcasing its recent clinical availability and efficacy in providing continuous levodopa delivery. While providing an overview of the other non-oral levodopa-based CDD systems, such as intrajejunal levodopa-carbidopa infusion and levodopa-entacapone-carbidopa infusion, we highlight the current promising evidence for Foslevodopa/foscarbidopa to improve, for example, "on time" without troublesome dyskinesia and reducing "off time" in people with advanced PD. Additionally, Foslevodopa/foscarbidopa demonstrates potential in managing early morning off periods, sleep quality and other motor and non-motor symptoms. Moreover, other non-oral CDD options such as ND0612 and DIZ102/DIZ101 are discussed, with focus on their pharmacokinetics/pharmacodynamics, efficacy, and safety profiles. While these advancements present new therapeutic avenues, long-term observational studies are warranted to elucidate their impact on existing PD therapies. Overall, this review provides insights into the evolving landscape of non-oral CDD therapies and offers a pragmatic approach for their integration into clinical practice.

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study.

BACKGROUND: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. METHODS: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. RESULTS: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres' catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. CONCLUSIONS: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.

No evidence for an association of voxel-based morphometry with short-term non-motor outcomes in deep brain stimulation for Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established therapy in advanced Parkinson's disease (PD). Motor and non-motor outcomes, however, show considerable inter-individual variability. Preoperative morphometry-based metrics have recently received increasing attention to explain treatment effects. As evidence for the prediction of non-motor outcomes is limited, we sought to investigate the association between metrics of voxel-based morphometry and short-term non-motor outcomes following STN-DBS in this prospective open-label study. Forty-nine PD patients underwent structural MRI and a comprehensive clinical assessment at preoperative baseline and 6-month follow-up. Voxel-based morphometry was used to assess associations between cerebral volume and non-motor outcomes corrected for multiple comparisons using a permutation-based approach. We replicated existing results associating volume loss of the superior frontal cortex with subpar motor outcomes. Overall non-motor burden, however, was not significantly associated with morphometric features, limiting its use as a marker to inform patient selection and holistic preoperative counselling.

The Impact of Fatigue on Sleep and Other Non-Motor Symptoms in Parkinson's Disease.

Fatigue is a common non-motor symptom in Parkinson's disease (PD), but even so, it may still be underdiagnosed or misdiagnosed in current practice due to its non-specific manifestations. The aims of this study were to investigate the prevalence of fatigue in PD patients compared to healthy controls and to identify the main characteristics and associations of fatigue with other non-motor symptoms and the impact of fatigue on sleep disturbances in Parkinson's disease. MATERIALS AND METHODS: case-control study in which 131 PD patients and 131 age- and sex-matched controls were enrolled. Main characteristics of fatigue, sleep, and other non-motor symptoms were assessed using specific validated questionnaires. RESULTS: According to the Chalder fatigue scale, fatigue is more prevalent in PD patients (38.16%) compared to healthy controls (26.71%). Fatigue was identified in 46.54% of the PD patients using the Parkinson's Fatigue Scale (PFS-16). PD patients with fatigue presented a worse motor status, more sleep disturbances (insomnia, daytime sleepiness), a broader spectrum of non-motor symptoms (pain, anxiety, urinary disturbances), worse cognitive performances, a lower level of happiness, and worse quality of life compared to PD patients without fatigue. CONCLUSION: Fatigue is a common symptom of PD and needs to be assessed, considering its consequences on quality of life. Sleep disturbances have a great influence over fatigue in PD patients.

Diplopia in Movement Disorders: A Systematic Review of the Literature.

INTRODUCTION: Although the reported frequency of diplopia is between 10 to 40% of patients with Parkinson's disease (PD) and other movement disorders, it remains one of the most undiagnosed non-motor symptoms. Furthermore, it has a major impact on the quality of life of these patients. The aim of this study is to systematically review the literature regarding the frequency, causes, and implications of diplopia in movement disorders. METHODOLOGY: An electronic search was conducted in March and June 2023 using the PubMed database in order to identify appropriate studies. Studies that were written in English, that represented observational, analytical studies, and case reports, and that provided information regarding diplopia in movement disorders were included in the systematic review. RESULTS: A total of 686 articles were identified out of which 43 met the inclusion criteria. The studies included in the systematic review ranged from descriptive studies (case reports and case series) to analytical-observational studies (cross-sectional studies, prospective and retrospective cohort studies, and case-control studies). In Parkinson's disease, the incidence of diplopia ranged from 10 to 38%. In these patients, diplopia was linked to the presence of visual hallucinations and cognitive decline but also to convergence insufficiency and the presence of motor fluctuations. Cases of diplopia secondary to deep brain stimulation were also reported. Diplopia was associated with longer disease duration and worse motor and non-motor scores. Diplopia was also reported in other movement disorders such as multiple system atrophy (frequency as high as 18%) and progressive supranuclear palsy (frequency as high as 39%) and was associated with increased mortality and shorter duration in life span. CONCLUSIONS: Diplopia occurs in up to 38% of patients with movement disorders and has a negative impact on their health-related quality of life. Treating physicians should actively ask about diplopia and other ophthalmological symptoms, as many patients do not spontaneously report them. The pathophysiology of diplopia is complex, and it involves heterogeneous peripheral and central mechanisms. The management of these patients should involve a multidisciplinary team of health professionals in order to provide appropriate, tailored management.

TDCS for parkinson's disease disease-related pain: A randomized trial.

OBJECTIVE: To evaluate the effects of transcranial direct current stimulation (tDCS) on Parkinson's disease (PD)-related pain. METHODS: This triple-blind randomized controlled trial included twenty-two patients (age range 38-85, 10 male) with PD-related pain. Eleven subjects received ten sessions of 20 minutes tDCS over the primary motor cortex contralateral to pain at 2 mA intensity. Eleven subjects received sham stimulation. Outcome measures included changes in the Kinǵs Parkinsons Pain Scale (KPPS), Brief Pain Inventory (BPI), widespread mechanical hyperalgesia (WMH), temporal summation of pain (TS), and conditioned pain modulation (CPM). RESULTS: Significant differences were found in KPPS between groups favoring the active-tDCS group compared to the sham-tDCS group at 15-days follow-up (p = 0.014) but not at 2 days post-intervention (p = 0.059). The active-group showed significant improvements over the sham-group after 15 days (p = 0.017). Significant changes were found in CPM between groups in favor of active-tDCS group at 2 days post-intervention (p = 0.002) and at 15 days (p = 0.017). No meaningful differences were observed in BPI or TS. CONCLUSIONS: tDCS of the primary motor cortex alleviates perceived PD-related pain, reduces pain sensitization, and enhances descending pain inhibition. SIGNIFICANCE: This is the first study to test and demonstrate the use of tDCS for improving PD-related pain.

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson's disease complicated by OFF episodes: a phase 3, open-label study.

BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.

Improved Sleep Correlates with Improved Quality of Life and Motor Symptoms with Foslevodopa/Foscarbidopa.

BACKGROUND: Foslevodopa/foscarbidopa is a subcutaneous infusion of levodopa/carbidopa prodrugs. OBJECTIVES: Assess correlations between sleep and efficacy from interim data of a phase 3 trial of foslevodopa/foscarbidopa (NCT03781167). METHODS: Pearson correlations between sleep (Parkinson's Disease Sleep Scale-2 [PDSS-2]) and quality of life (QoL; Parkinson's Disease Questionnaire-39), motor experiences of daily living (m-EDL; Movement Disorder Society-Unified Parkinson's Disease Scale Part II), and "Off"/"On" times were calculated for baseline and week 26 improvements. Regression analyses were adjusted for baseline PDSS-2 score. RESULTS: Baseline sleep correlated moderately with QoL (r = 0.44, P < 0.001) and weakly with m-EDL (r = 0.28; P < 0.001). Sleep improvement weakly correlated with improved "Off" time (r = 0.37; P < 0.001) and QoL (r = 0.36; P < 0.001). Regression analyses demonstrated significant positive associations for improved sleep, "Off" time, QoL, and m-EDL. CONCLUSIONS: Improved sleep with foslevodopa/foscarbidopa was associated with improved QoL and "Off" time.

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences.

Background: Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physiologic processes is not new, such studies in patients with sleep disorders remain exceptionally scarce. Here, using SGA and other dream content analyses, we set to investigate structural and thematic differences in morning dream recalls of patients diagnosed with Non-Rapid Eye Movement Parasomnia (NREMP) and Idiopathic REM Sleep Behavior Disorder (iRBD). Methods: A retrospective cross-sectional study of morning dream recalls of iRBD and NREMP patients was undertaken. Traditional dream content analyses, such as Orlinsky and Hall and Van de Castle analyses, were initially conducted. Subsequently, SGA was performed in order to objectively quantify structural speech differences between the dream recalls of the two patient groups. Results: Comparable rate of morning recall of dreams in the sleep laboratory was recorded; 25% of iRBD and 18.35% of NREMP patients. Aggression in dreams was recorded by 28.57% iRBD versus 20.00% in NREMP group. iRBD patients were more likely to recall dreams (iRBD vs NREMP; P = 0.007), but they also had more white dreams, ie having a feeling of having dreamt, but with no memory of it. Visual and quantitative graph speech analyses of iRBD dreams suggested stable sequential structure, reflecting the linearity of the chronological narrative. Conversely, NREMP dream reports displayed more recursive, less stable systems, with significantly higher scores of graph connectivity measures. Conclusion: The findings of our exploratory study suggest that iRBD and NREMP patients may not only differ on what is recalled in their dreams but also, perhaps more strikingly, on how dreams are recalled. It is hoped that future SGA-led dream investigations of larger groups of patients will help discern distinct mechanistic underpinnings and any associated clinical implications.

A general clinical overview of the non-motor symptoms in Parkinson's disease: Neuropsychiatric symptoms.

The heterogeneity of non-motor features observed in people with Parkinson's disease (PD) is often dominated by one or more symptoms belonging to the neuropsychiatric spectrum, such as cognitive impairment, psychosis, depression, anxiety, and apathy. Due to their high prevalence in people with PD (PwP) and their occurrence in every stage of the disease, from the prodromal to the advanced stage, it is not surprising that PD can be conceptualised as a complex neuropsychiatric disorder. Despite progress in understanding the pathophysiological mechanisms underlying the neuropsychiatric signs and symptoms in PD, and better identification and diagnosis of these symptoms, effective treatments are still a major unmet need. The impact of these symptoms on the quality of life of PwP and caregivers, as well as their contribution to the overall non-motor symptom burden can be greater than that of motor symptoms and require a personalised, holistic approach. In this chapter, we provide a general clinical overview of the major neuropsychiatric symptoms of PD.

Setting the clinical context to non-motor symptoms reflected by Park-pain, Park-sleep, and Park-autonomic subtypes of Parkinson's disease.

Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments.