Late-stage Parkinson's Disease Research Articles

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.

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.

Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson's disease

Parkinson's disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients' and caregivers' quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson's disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT1A) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD's effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID.

Conformational change of α-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson’s disease

α-Synuclein (α-syn) has been shown to form various conformational fibrils associated with different synucleinopathies. But whether the conformation of α-syn fibrils changes during disease progression is unclear. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) staged in preclinical PD (pre-PD), middle- to late-stage PD (mid-PD), and late-stage PD (late-PD). Our results show that α-syn fibrils derived from the late-PD patient are most potent in inducing endogenous α-syn aggregation in primary neurons, followed by the mid-PD and pre-PD fibrils. By using cryo-electron microscopy, we further determined the high-resolution structures of the CSF-amplified fibrils. The structures exhibit remarkable differences in a minor but significant population of conformational species in different staged samples. Our work demonstrates structural and pathological differences between α-syn fibrils derived from PD patients at a spectrum of clinical stages, which suggests potential conformational transition of α-syn fibrils during the progression of PD.

Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders.

Neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD) and Parkinson's Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NMDs) are a group of diseases in which patients show primary progressive muscle weaknesses, including Duchenne Muscular Dystrophy (DMD), Pompe disease, and Spinal Muscular Atrophy (SMA). NDDs and NMDs typically have a genetic component, which affects the physiological functioning of critical cellular processes, leading to pathogenesis. Currently, there is no cure or efficient treatment for most of these diseases. More than 200 clinical trials have been completed or are currently underway in order to establish safety, tolerability, and efficacy of promising gene therapy approaches. Thus, gene therapy-based therapeutics, including viral or non-viral delivery, are very appealing for the treatment of NDDs and NMDs. In particular, adeno-associated viral vectors (AAV) are an attractive option for gene therapy for NDDs and NMDs. However, limitations have been identified after systemic delivery, including the suboptimal capacity of these therapies to traverse the blood-brain barrier (BBB), degradation of the particles during the delivery, high reactivity of the patient's immune system during the treatment, and the potential need for redosing. To circumvent these limitations, several preclinical and clinical studies have suggested intrathecal (IT) delivery to target the CNS and peripheral organs via cerebrospinal fluid (CSF). CSF administration can vastly improve the delivery of small molecules and drugs to the brain and spinal cord as compared to systemic delivery. Here, we review AAV biology and vector design elements, different therapeutic routes of administration, and highlight CSF delivery as an attractive route of administration. We discuss the different aspects of neuromuscular and neurodegenerative diseases, such as pathogenesis, the landscape of mutations, and the biological processes associated with the disease. We also describe the hallmarks of NDDs and NMDs as well as discuss current therapeutic approaches and clinical progress in viral and non-viral gene therapy and enzyme replacement strategies for those diseases.

Dysregulation of miR-543 in Parkinson's disease: Impact on the neuroprotective gene SIRT1.

Parkinson's disease (PD) is a progressive and age-dependent neurodegenerative disease characterised clinically by a variety of motor symptoms and cognitive impairment. PD was initially considered to be a grey matter disease; however, recently, evidence has emerged that white matter changes in PD precede the neuronal loss seen in the grey matter. The cause of these initial white matter changes is yet to be elucidated. Here, we explored whether dysregulated miRNAs and their target mRNA could provide insight into the underlying mechanisms of early white matter changes in PD. We analysed the expression of miRNAs in three different stages of PD through RNA-sequencing and validated the differential expression of miRNAs through quantitative reverse transcription polymerase chain reaction. With bioinformatic analyses, we predicted target genes of dysregulated miRNAs and investigated their biomarker potential. Finally, in vitro, we confirmed the targetting of thegene SIRT1 by miR-543. We identified 12 dysregulated miRNAs in PD and found that miR-543 holds potential as a biomarker for late-stage PD with dementia. We report upregulation of miR-543 in early PD white matter tissue and downregulation of SIRT1. In vitro experiments showed that the upregulation of miR-543 results in the downregulation of SIRT1 in the white matter, but not in the grey matter. We validated SIRT1 as a target of miR-543 in the brain and showed its function as a potential biomarker. Our results highlight the idea that dysregulation of miR-543 in early PD white matter, resulting in the dysregulation of SIRT1, potentially influencing the early white matter changes observed in PD.

The Validity of Health-Related Quality of Life Instruments in Patients With Late-Stage Parkinson's Disease.

To examine the validity of health-related quality of life (Hr-QoL) measures in patients with late-stage Parkinson's disease (PD). We analysed data from patients with late-stage PD and their carers who were assessed with a range of clinical measures and the EQ-5D-3L. The DEMQOL-Proxy was completed for 157 patients with a diagnosis of dementia and the PDQ-8 by 401 patients without dementia. Convergent validity was assessed using correlations with measures of Parkinson's severity, independence and cognitive function, and construct validity using correlations with patients' own EQ-5D-3L scores. In addition, we assessed divergent validity using correlations with carers' own EQ-5D index, EQ-VAS and Zarit caregiver burden scores. In patients without dementia, both the PDQ-8 and EQ-5D-3L correlated with measures of disease severity, dependence and carer burden scores, and PDQ-8 scores moderately with EQ-5D-3L and EQ-5D-3L VAS scores. In patients with dementia, EQ-5D-3L scores correlated with disease severity, cognition and dependence scores, but DEMQOL-Proxy scores were moderately associated only with patients' dependence and carers' own EQ-5D-3L scores but not patients' disease severity, EQ-5D-3L or cognitive scores. The PDQ-8 and EQ-5D-3L have adequate validity in late stage PD without dementia, but in those with PD and dementia the EQ-5D-3L may be preferable to the DEMQOL-Proxy.