Late-stage Parkinson's Disease Research Articles

Single-cell transcriptomic and proteomic analysis of Parkinson's disease brains.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer's disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.

The treatment gap for deep brain stimulation in Parkinson's disease: a comparative analysis of cost and utilisation in high-income countries.

ObjectiveParkinson's disease (PD) is one of the most prevalent neurodegenerative disorders, globally affecting approximately 120 per 100,000 people by age 70. Deep brain stimulation (DBS) is a US Federal Drug Administration (FDA)-approved and highly effective treatment for late-stage PD. However, country-specific reimbursement regulations and health policies may affect access to PD-DBS. We aimed to evaluate the uptake rate and 'treatment gap' for DBS across high-income countries.MethodsWe reviewed previous literature to investigate the cost and utilisation of PD-DBS in high-income countries across Asia, Europe, Oceania, and North America (Australia, Canada, France, Germany, Hong Kong, Japan, Korea, the Netherlands, New Zealand, Norway, Spain, Switzerland, UK, and USA). Using previous estimates of DBS candidate eligibility rates, we calculated theoretical DBS uptake rates and treatment gaps nationally.ResultsPD-DBS utilisation was highest in Australia and the USA and lowest in Korea and New Zealand. The total cost of PD-DBS in the first 12months was highest in the USA and France and lowest in the UK and Germany. The utilisation rate (i.e. uptake rate) of PD-DBS (% DBS surgeries per PD case) was highest in Australia and the USA, and lowest in New Zealand and the UK, where the treatment gap reflected these trends.ConclusionsOur results highlight differences in access to DBS for PD patients among high-income countries, which we discuss in the context of health systems. Better access to effective PD treatments such as DBS is critical given the increasing prevalence of PD in an ageing world and the associated, avoidable morbidity.

Prevalence of Late-Stage Parkinson's Disease in the US Healthcare System: Insights from TriNetX.

Patients in late-stage Parkinson's disease (PDLS) are caregiver-dependent, have low quality of life, and higher healthcare costs. To estimate the prevalence of PDLS patients in the current US healthcare system. We downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 US healthcare sites. PD was identified using standard diagnosis codes, and PDLS was identified by the usage of wheelchair dependence, personal care assistance, and/or presence of diagnoses of dementia. Age of PDLS identification and survival information were obtained and stratified by demographic and the disability subgroups. We identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fitted our definition of PDLS (n = 194,297), and 10.2% met two or more late-stage criteria. Among all PDLS, the mean age of PDLS identification was 78.1 (±7.7) years, and 49% were already reported as deceased. PDLS patients were predominantly male (58.5%) with similar distribution across PDLS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information >90% (n = 53,162) were White, 8.2% (n = 5121) Hispanic/Latino, 7.8% (n = 4557) Black, and <0.01% (n = 408) Asian. Of the PDLS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair-bound. Late-stage patients are a significant part of the PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Factors associated with self-rated health in people with late-stage parkinson’s and cognitive impairment

PurposeTo investigate the contributors to self-rated health in people with late-stage Parkinson’s disease (PD) and cognitive impairment.MethodsA secondary analysis of baseline data from the international Care of Late-Stage Parkinsonism (CLaSP) cohort study was conducted. Participants with PD and either dementia or mild cognitive impairment or MMSE < 24/30 in the absence of major depression were included if they had completed the EQ-5D-3L assessment (n = 277). Factors associated with self-rated health (EQ-5D-3L Index and Visual Analogue Scale) were investigated through multivariable linear regression.ResultsMore severe PD (motor and non-motor) was associated with worse self-rated health. The EQ-5D-3L dimensions of Mobility, Self-Care and Usual Activities were almost universally affected; the latter two particularly severely. Being unable to perform usual activities or having moderate to extreme anxiety or depression were significantly associated with EQ-5D-3L Visual Analogue Scale, suggesting these are particularly valued. Worse motor impairment and function and the non-motor symptom domains of mood, perception, sexual function, and miscellaneous (e.g., pain) were associated with worse self-rated health, whereas greater burden of gastrointestinal symptoms was associated with better self-rated health in multivariate analysis. Better self-rated health was associated with recent PD nurse consultation, and higher doses of dopaminergic medication.ConclusionImprovement of activities of daily living, mood and anxiety should be prioritised in clinical practice, with consideration of perception and sexual function in this population. Recent nurse consultations and higher antiparkinsonian doses are associated with better self-rated health, suggesting there is no room for a therapeutic nihilism in this population of people within a complex phase of PD.

Another Step Forward for Freezing of Gait in Parkinson's Disease.

The study "A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease" by Milekovic et al. introduces a novel neuroprosthesis for treating locomotor deficits in late-stage Parkinson's disease (PD). This approach employs an epidural spinal array targeting dorsal roots and electromyography to create a spatiotemporal map of muscle activation, aiming to restore natural gait patterns. Significant improvements in gait freezing and balance were observed in both non-human primate models and a human patient, resulting in improved mobility and quality of life. This innovative method, integrating real-time feedback and non-invasive motor intention decoding, marks a significant advancement in PD treatment.

Effect of Deep Brain Stimulation on Parkinson Disease Dementia: A Systematic Review and Meta-analysis.

Patients in the early stages of Parkinson disease (PD) may have subtle cognitive deficits, while overt cognitive deficits are usually manifestations of late-stage PD. There is still a debate on the outcome of deep brain stimulation (DBS) on the cognitive function of PD patients. This study aimed to investigate the effect of subthalamic nucleus (STN)-DBS on the dementia of PD patients after surgery compared to medical therapy and other procedures. We searched PubMed, Scopus, Cochrane Library, and Web of Science database on October 2020, with keywords: "Deep brain stimulation," "Parkinson disease," "dementia," and "memory." Reviews, abstracts, case presentations, and letters were excluded. In total, 491 studies were screened after removing the duplicates. The screening results yielded 81 articles to be screened for eligibility. Finally, 6 studies were included in this meta-analysis for synthesis. Overall, 800 patients were included in this meta-analysis, using the Mattis dementia rating scale (MDRS) and descriptive data from the articles extracted to assess global dementia. Our results suggest that the STN-DBS group showed a larger cognitive decline than the patients receiving the best medical treatment (BMT). However, comparing STN-DBS with globus pallidus interna stimulation and pallidotomy could not demonstrate a significant statistical effect on the global dementia of patients. More long-term studies with larger sample sizes are needed to validate current findings.

Care of Late-Stage Parkinsonism: Resource Utilization of the Disease in Five European Countries.

Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Terminal Care in Parkinson's Disease: Real-Life Use of Continuous Subcutaneous Apomorphine Infusion to Improve Patient Comfort.

There are currently no recommendations on the therapeutic management of Parkinson's disease (PD) patients at the end of life. To describe a cohort of patients with PD who benefited from continuous subcutaneous apomorphine infusion (CSAI) initiation at the end of their life as comfort care. This real-life cohort includes 14 PD patients, who benefited from 24-h, low-dose CSAI (0.5-3 mg/h) in the context of terminal care. Patient's comfort (pain, rigidity, and/or ability to communicate) and occurrence of CSAI-related side-effects (nausea/vomiting, cutaneous and behavioral manifestations) were evaluated based on medical records. All patients (age 62-94 years, disease duration 2-32 years) presented with late-stage PD and a compromised oral route. Treatment lasted from a few hours to 39 days. CSAI led to substantial functional improvement, with a good safety profile. Overall clinical comfort was deemed improved by the medical team, the patient, and/or caregivers. CSAI might be a promising approach in PD terminal care, as it reduces motor symptoms and overall discomfort, with an apparent good safety profile. Use of the apomorphine pen, sublingual film or a classic syringe pump might be considered when apomorphine pumps are not available. Larger observational cohorts and randomized controlled trials are needed to establish the efficacy and tolerability of apomorphine in the context of terminal care and more broadly, in an advance care planning perspective.

The Care Needs of Patients With Cognitive Impairment in Late-Stage Parkinson's Disease.

Cognitive impairment is common in Parkinson's disease (PD), but care needs and resource use for those with significant cognitive impairment are not well established. 675 participants with PD from the international Care of Late-Stage Parkinsonism (CLaSP) study were grouped into those without (n = 333, 49%) and with cognitive impairment (MMSE < 24/30 or diagnosis of dementia or Mild Cognitive Impairment; n = 342, 51%) and their clinical features, care needs and healthcare utilisation compared. The relationship between cognition and healthcare consultations was investigated through logistic regression. Cognitive impairment was associated with more motor and non-motor symptoms, less antiparkinsonian but higher rates of dementia and antipsychotic medication, worse subjective health status and greater caregiver burden. A considerable proportion did not have a pre-established cognitive diagnosis. Care needs were high across the whole sample but higher in the cognitive impairment group. Home care and care home use was higher in the cognitive impairment group. However, use of healthcare consultations was similar between the groups and significantly fewer participants with cognitive impairment had had recent PD Nurse consultations. Worse cognitive impairment was associated with lower frequency of recent PD nurse and multidisciplinary therapy consultation (physiotherapy, massage, occupational therapy, speech training and general nursing). Those with cognitive impairment have more severe PD, higher care needs and greater social care utilisation than those with normal cognition, yet use of health care services is similar or less. Cognitive impairment appears to be a barrier to PD nurse and multidisciplinary therapy consultations. This challenges current models of care: alternative models of care may be required to serve this population. Parkinson's disease is a long-term progressive health condition. Over time, many people with Parkinson's develop problems with thinking and memory, called cognitive impairment. This can negatively impact the daily lives of the person with Parkinson's and their caregiver. It is also thought to be a barrier to accessing healthcare. How people with Parkinson's who have cognitive impairment use healthcare and detail of their care needs is not well known.We analysed data from a large sample of people with advanced Parkinson's from six European countries to investigate their symptoms, care needs and healthcare use. We compared those with cognitive impairment to (342 people) to those without cognitive impairment (333 people).We found that those with cognitive impairment had more severe Parkinson's across a range of symptoms compared to those without cognitive impairment. They also had more care needs, reported their health status to be worse, and their caregivers experienced greater strain from caring. Whilst use of other healthcare services was similar between the two groups, those with cognitive impairment were less likely to have recently seen a Parkinson's nurse than those without cognitive impairment. Further analysis showed an association between cognitive impairment and not having seen a Parkinson's nurse or therapist recently, taking psychiatric symptoms, functional disability and care home residence into account. Therapists included were physiotherapy, massage, occupational therapy, speech training and general nursing. These findings highlight unmet need. We suggest that healthcare should be more targeted to help this group of people, given their higher care needs.

The effect of rasagiline on swallowing function in Parkinson's disease

Dysphagia, a potentially fatal symptom of Parkinson's disease, is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with Parkinson's disease and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation during swallowing. Rasagiline is a monoamine oxidase B (MAOB) inhibitor that facilitates continuous dopaminergic stimulation. We hypothesized that MAOB inhibition by rasagiline would be effective in improving swallowing function in patients with early- and mid-to late-stage Parkinson's disease. To this end, we performed an analytical observational study to determine the effects of rasagiline (1 mg/day) on swallowing function using videofluoroscopic swallowing study. This open-label, evaluator-blinded study enrolled 32 patients with Parkinson's disease, among whom 19 were drug-naïve and 13 were receiving add-on therapy. Our results showed that rasagiline significantly improved all swallowing measures during the oral and pharyngeal phases, including oral transit time and pharyngeal transit time, in all enrolled patients. Similar results were found in drug-naïve and mid-to late-stage patients, with no intergroup differences. In conclusion, drugs capable of continuous dopaminergic stimulation may effectively improve swallowing function in patients with Parkinson's disease, with similar effects in early- and mid-to late-stage Parkinson's disease. This study has been the first to show that rasagiline significantly improves swallowing function in mid-to late-stage patients receiving add-on therapy.

Development and internal validation of a prognostic model for loss of balance and falls in mid- to late-stage Parkinson's disease.

Mid- to late-stage Parkinson's disease (PD) is often linked with worsened and significant impairment of motor activities, but existing prognostic markers do not adequately capture the risk of loss of balance in PD patients. This study aims to develop a risk prognostic model for mid- to late-stage PD and identify prognostic factors that are indicative of impending loss of balance and falls. The study included 307 participants of which 75 were diagnosed with idiopathic PD and 232 were neurological or non-neurological controls. Among the PD group, 46 were early-stage (Hoehn and Yahr [H&Y] = 1,2) with no significant loss of balance while 29 were mid- to late-stage (H&Y = 3,4,5) which is characterized by loss of balance and falls. Multivariable logistic regression (MLR) was used to develop a prognostic model for mid- to late-stage PD. Model discrimination was assessed by ROC curves. The model was internally validated through bootstrapping and calibration plots. The relevant factors identified and included in the final MLR model were shortness of breath, age, swollen joints, heme oxygenase-1 (HO-1) protein, and total salivary protein. The model had an AUC of 0.82 (95% CI = 0.71-0.92) and was well calibrated (calibration slope = 0.77, intercept = 0.03). The likelihood of shortness of breath (OR = 7.91, 95% CI = 1.63-45.12) was significantly higher among mid- to late-stage PD than early-stage. Age and total salivary protein were also significantly higher among mid- to late-stage PD. The MLR prognostic model for mid- to late-stage PD may assist physicians in identifying patients at high risk for loss of balance and falls.

Meaning in Life in Late-Stage Parkinson's Disease: Results from the Care of Late-Stage Parkinsonism Study (CLaSP) in Six European Countries.

The Care of Late-Stage Parkinsonism (CLaSP) study is a longitudinal, multicentre, prospective cohort study to assess the needs and provision of care for people with late-stage Parkinson's disease and their caregivers in six European countries. As a cross-sectional study within the CLaSP study, 509 people with Parkinson's disease completed the "Schedule-for-Meaning-in-Life-Evaluation" (SMiLE) questionnaire. We compared the results to those of a representative sample of healthy participants (n = 856). People with late-stage Parkinson's disease reported family, partnership and spirituality as the greatest areas of importance. Overall, they had lower SMiLE indices compared to healthy participants. People with late-stage Parkinson's disease rated the importance of core meaning in life areas (namely family, social relations and health) as significantly lower than the representative cohort and they also rated satisfaction as significantly lower in most areas. In conclusion, people with late-stage Parkinson's disease do have areas where they can find meaning, such as family, partnership and spirituality. However, they indicate a lack of fulfilment of their individual MiL, reflected by low satisfaction rates in the majority of meaning in life categories. The need for spiritual support for people with Parkinson's disease indicates the important role of chaplains to help people with Parkinson's disease maintain meaning in life.

Compliance with National and International Guidelines in the Treatment of Nonmotor Symptoms in Late-Stage Parkinson's Disease.

National as well as international Parkinson's disease (PD) treatment guidelines are available to guide clinicians. Previous research has shown that nonmotor symptoms (NMS) are pronounced in late-stage PD and has suggested that current treatment is insufficient and could be improved. The aim of this study was to investigate to which degree the national and international treatment guidelines are followed in the treatment of NMS in late-stage PD. This Swedish cohort was part of the Care of Late-Stage Parkinsonism (CLaSP) study. Late-stage PD was defined as Hoehn and Yahr stages IV-V in "on" and/or ≤50% on the Schwab and England Activities of Daily Living (ADL) scale. NMS were assessed with the NMS scale (NMSS), cognition with the Mini-Mental State Examination (MMSE), and depressive symptoms with the Geriatric Depression Scale (GDS-30). Symptomatic individuals were defined as ≥ 6 on an item of the NMSS; for dementia, a cutoff of ≤18 on the MMSE; for depression, a cutoff of ≥10 on the GDS. All 107 participants exhibited NMS to various degrees and severities; the median NMSS score was 91. Among symptomatic individuals, for depressive symptoms, 37/63 (59%) were treated with antidepressants; for hallucinations and delusions, 9/18 (50%) and 5/13 (38%) were treated with antipsychotics; and for dementia, 9/27 (33%) were treated with rivastigmine and 1 (4%) was treated with donepezil. For orthostatic hypotension, 11/19 (58%) with lightheadedness and 7/8 (88%) with fainting were treated with antihypotensives; for sialorrhea, 2/42 (5%) were treated with botulinum toxin; and for constipation, 19/35 (54%) were treated with laxatives. For insomnia, 4/16 (25%) were treated with hypnotics, and for daytime sleepiness, 1/29 (3%) was treated with psychostimulants. The present analyses suggest a need for clinicians to further screen for and treat NMS. Optimizing treatment of NMS according to the national and international treatment guidelines may improve symptomatology and enhance quality of life in late-stage PD.

Proteomic analysis of the human hippocampus identifies neuronal pentraxin 1 (NPTX1) as synapto-axonal target in late-stage Parkinson's disease.

Parkinson's disease (PD) affects a significant proportion of the population over the age of 60 years, and its prevalence is increasing. While symptomatic treatment is available for motor symptoms of PD, non-motor complications such as dementia result in diminished life quality for patients and are far more difficult to treat. In this study, we analyzed PD-associated alterations in the hippocampus of PD patients, since this brain region is strongly affected by PD dementia. We focused on synapses, analyzing the proteome of post-mortal hippocampal tissue from 16 PD cases and 14 control subjects by mass spectrometry. Whole tissue lysates and synaptosomal fractions were analyzed in parallel. Differential analysis combined with bioinformatic network analyses identified neuronal pentraxin 1 (NPTX1) to be significantly dysregulated in PD and interacting with proteins of the synaptic compartment. Modulation of NPTX1 protein levels in primary hippocampal neuron cultures validated its role in synapse morphology. Our analysis suggests that NPTX1 contributes to synaptic pathology in late-stage PD and represents a putative target for novel therapeutic strategies.

Handicap as a Measure of Perceived-Health Status in Parkinson's Disease.

Handicap is a patient-centered measure of health status that encompasses the impact of social and physical environment on daily living, having been assessed in advanced and late-stage Parkinson's Disease (PD). To characterize the handicap of a broader sample of patients. A cross-sectional study of 405 PD patients during the MDS-UPDRS Portuguese validation study, using the MDS-UPDRS, Unified Dyskinesias Rating Scale, Nonmotor symptoms questionnaire, PDQ-8 and EQ-5D-3L. Handicap was measured using the London Handicap Scale (LHS). Mean age was 64.42 (±10.3) years, mean disease duration 11.30 (±6.5) years and median HY 2 (IQR, 2-3). Mean LHS was 0.652 (±0.204); "Mobility," "Occupation" and "Physical Independence" were the most affected domains. LHS was significantly worse in patients with longer disease duration, older age and increased disability. In contrast, PDQ-8 did not differentiate age groups. Handicap was significantly correlated with disease duration (r = -0.35), nonmotor experiences of daily living (EDL) (MDS-UPDRS-I) (r = -0.51), motor EDL (MDS-UPDRS-II) (r = -0.69), motor disability (MDS-UPDRS-III) (r = -0.49), axial signs of MDS-UPDRS-III (r = -0.55), HY (r = -0.44), presence of nonmotor symptoms (r = -0.51) and PDQ-8 index (r = -0.64) (all P < 0.05). Motor EDL, MDS-UPDRS-III and PDQ-8 independently predicted Handicap (adjusted R 2 = 0.582; P = 0.007). The LHS was easily completed by patients and caregivers. Patients were mild-moderately handicapped, which was strongly determined by motor disability and its impact on EDL, and poor QoL. Despite correlated, handicap and QoL seem to differ in what they measure, and handicap may have an added value to QoL. Handicap seems to be a good measure of perceived-health status in a broad sample of PD.

Altered Trunk Position Sense and Its Relationship With Spinal Posture and Spinal Mobility in Patients With Parkinson's Disease.

Proprioception is significantly affected by dysfunction of the basal ganglia, which play an important role in sensorimotor integration. Parkinson's disease (PD), which is characterized by progressive loss of the dopaminergic neurons of the substantia nigra, leads to a variety of motor and nonmotor symptoms throughout the course of the disease. The aim of this study was to determine trunk position sense and to investigate its relationship with spinal posture and spinal mobility in patients with PD. The study included 35 patients with PD and 35 age-matched control subjects. Trunk position sense was determined with "trunk reposition errors." A spinal mouse was used to assess spinal posture and spinal mobility. According to the Hoehn-Yahr rating scale, the majority of the patients were in Stage 1 (68.6%). Trunk position sense was found to be significantly decreased in patients with PD compared with the control group (p < .001) but was not correlated with spinal posture and spinal mobility in patients with PD (p > .05). This study revealed that trunk position sense was impaired in PD from the early stages of the disease. However, neither spinal posture nor spinal mobility was associated with decreased trunk proprioception. Further research into these relationships in the late stages of PD is needed.

The Assessment of the Diagnostic Delay in Japanese People with Parkinson's Disease Using a Web-based Survey of Patients and Physicians.

Objective Although diagnostic criteria of Parkinson's disease (PD) have been established, the details of the process by which patients notice symptoms, visit a physician, and receive a diagnosis of PD is unclear. We therefore explored factors influencing latency in diagnosing PD. Methods We performed an internet-based survey of patients with PD and their families as well as physicians treating patients with PD to identify any diagnostic latency and its determinants. Evaluated factors included motor and non-motor symptoms, the diagnosis history and symptoms, patients' feelings toward PD prior to the diagnosis, and physician-determined reasons for the diagnostic delay. Results Among the 186 eligible patient respondents (including 87 responses from family members of patients), 24% received a PD diagnosis >1 year after the onset of PD-related symptoms, 58.6% had mid- or late-stage PD at the diagnosis, and 29% of patients had initially thought their symptoms were common age-related phenomena. Tremor (42%) was the most frequent symptom that led patients to visit a medical institution, whereas gait disturbance (14%) was the least frequent. More patients diagnosed with early-stage PD than those diagnosed with mid- or late-stage PD consulted a neurologist at their first visit. Among the 331 eligible physicians, patients' misinterpretation of their symptoms as being age-related was deemed one of or the most common cause (s) of a diagnostic delay by 67% and 36%, respectively. Conclusion Patients' insufficient or misinterpreted information about PD may cause delays in accessing healthcare services, leading to diagnostic delay.

The Lived Experience of Caregiving and Perception of Service Provision among Family-Caregivers of People with Late-Stage Parkinson's: A Qualitative Study.

The complex nature of late-stage Parkinson's requires multiagency support and leads to an increased burden on family members who assume a multiplicity of responsibilities. The aim of this study is to further understand the lived experiences of family-caregivers and their perception of, and satisfaction with, service provision. This qualitative substudy was a part of the European multicentre Care of Late-Stage Parkinsonism (CLaSP) project. Purposive sampling resulted in a sample of eleven family-caregivers of people with late-stage Parkinson's, who were interviewed using semistructured open-ended questions. Thematic analysis followed. Findings. Three overarching themes were developed from the data: ensuring continuous support is vital to providing care at home, perceiving unmet service provision needs, and advocating and co-ordinating all aspects of care take their toll. These themes include not only experience of services that caregivers find supportive in order to deliver care but also of disjointed care between multiple agencies, a perceived lack of Parkinson's expertise, and there was a lack of anticipatory future planning. The constancy and scope of the family-caregiver role is described, including the need to project manage multiple aspects of care with multiple agencies, to be an advocate, and to assume new roles such as managing finances. Multiple losses were reported, which in part was mitigated by gaining expertise through information and support from professionals and organised and informal support. The intricacies and consequences of the family-caregivers' role and their experience of service provision indicate the need to acknowledge and consider their role and needs, fully involve them in consultations and provide information and joined-up support to improve their well-being, and ensure their continuous significant contribution to the ongoing care of the person with Parkinson's.

How and why the adenosine A2A receptor became a target for Parkinson's disease therapy.

Dopaminergic therapy for Parkinson's disease has revolutionised the treatment of the motor symptoms of the illness. However, it does not alleviate all components of the motor deficits and has only limited effects on non-motor symptoms. For this reason, alternative non-dopaminergic approaches to treatment have been sought and the adenosine A2A receptor provided a novel target for symptomatic therapy both within the basal ganglia and elsewhere in the brain. Despite an impressive preclinical profile that would indicate a clear role for adenosine A2A antagonists in the treatment of Parkinson's disease, the road to clinical use has been long and full of difficulties. Some aspects of the drugs preclinical profile have not translated into clinical effectiveness and not all the clinical studies undertaken have had a positive outcome. The reasons for this will be explored and suggestions made for the further development of this drug class in the treatment of Parkinson's disease. However, one adenosine A2A antagonist, namely istradefylline has been introduced successfully for the treatment of late-stage Parkinson's disease in two major areas of the world and has become a commercial success through offering the first non-dopaminergic approach to the treatment of unmet need to be introduced in several decades.

Total synthesis of atropisomeric indolosesquiterpenoids via N-N bond formation: dixiamycins A and B.

N-N dimeric indolosesquiterpene alkaloids constitute a class of under-investigated architecturally intriguing natural products. Herein, we report the first chemical oxidation approach to the asymmetric total syntheses of these atropisomeric indolosesquiterpenoids through N-N bond formation. Specifically, dixiamycins A (1a) and B (1b) were prepared through a Cu(i)-mediated aerobic dehydrogenative dimerization from the naturally occurring monomer xiamycin A methyl ester (2b); this preparation also represents the first total synthesis of dixiamycin A (1a). The monomer xiamycin A methyl ester (2b) was synthesized via a late-stage Buchwald Pd(ii)-mediated aerobic dehydrogenative C-N bond formation.