Current Nondopaminergic Therapeutic Options for Motor Symptoms of Parkinson's Disease.
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ABSTRACT:
SUBMITTER: Du JJ
PROVIDER: S-EPMC5547839 | biostudies-other | 2017 Aug
REPOSITORIES: biostudies-other
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Project description:Despite being classified as a movement disorder, Parkinson's disease (PD) is characterized by a wide range of non-motor symptoms that significantly affect the patients' quality of life. However, clear evidence-based therapy recommendations for non-motor symptoms of PD are uncommon. Animal models of PD have previously been shown to be useful for advancing the knowledge and treatment of motor symptoms. However, these models may provide insight into and assess therapies for non-motor symptoms in PD. This paper highlights non-motor symptoms in preclinical models of PD and the current position regarding preclinical therapeutic approaches for these non-motor symptoms. This information may be relevant for designing future preclinical investigations of therapies for nonmotor symptoms in PD.
| S-EPMC10207906 | biostudies-literature
Project description:Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that is clinically manifested by a triad of cardinal motor symptoms - rigidity, bradykinesia and tremor - due to loss of dopaminergic neurons. The motor symptoms of PD become progressively worse as the disease advances. PD is also a heterogeneous disease since rigidity and bradykinesia are the major complaints in some patients whereas tremor is predominant in others. In recent years, many studies have investigated the progression of the hallmark symptoms over time, and the cardinal motor symptoms have different rates of progression, with the disease usually progressing faster in patients with rigidity and bradykinesia than in those with predominant tremor. The current treatment regime of dopamine-replacement therapy improves motor symptoms and alleviates disability. Increasing the dosage of dopaminergic medication is commonly used to combat the worsening symptoms. However, the drug-induced involuntary body movements and motor complications can significantly contribute to overall disability. Further, none of the currently-available therapies can slow or halt the disease progression. Significant research efforts have been directed towards developing neuroprotective or disease-modifying agents that are intended to slow the progression. In this article, the most recent clinical studies investigating disease progression and current progress on the development of disease-modifying drug trials are reviewed.
| S-EPMC5560285 | biostudies-other
Project description:BackgroundParkinson's disease (PD) causes movement disorders [called motor symptoms (MS)], and motor dysfunction poses a great barrier to the quality of life. Although pharmacological therapy like levodopa can relieve the symptoms, it can also cause complications, such as psychosis, nausea, and dyskinesia. A therapy with more minor side effects is needed for PD. Therapeutic massages are the most commonly used forms of complementary and alternative medicine (CAM), but no systematic review and meta-analysis have focused on the efficacy of massage on PD.ObjectiveTo evaluate the quality of evidence and efficacy of therapeutic massage for improving MS in PD.MethodsWe independently searched four electronic databases, including Chinese National Knowledge Infrastructure (CNKI), MEDLINE/PubMed, Embase, and Cochrane Library, for randomized controlled trials (RCTs) about therapeutic massage and other available manual therapies improving MS in PD from January 1, 2012, to December 31, 2021 (recent 10 years). The main outcome measures were total effectiveness and the Unified Parkinson's Disease Rating Scale (UPDRS), including UPDRS total, II, and III. For the statistical analysis, the risk ratio, standard mean difference, and 95% confidence interval (CI) were used to calculate effect sizes between groups. To determine heterogeneity, statistical index I 2 was used.ResultsA total of 363 PD participants in seven RCTs and one randomized pilot-control study were included in this meta-analysis. The total effectiveness showed that therapeutic massage was more effective than the intervention of the control group for improving MS [ratio risk (RR): 1.33, 95% CI (1.14-1.55), p = 0.0002]. The UPDRS-III scores showed that massage improves motor function more than the control group [SMD = -0.46, 95% CI (-0.67, -0.24), p < 0.00001]. But we found that massage performed no better than the control group in improving daily life activities [SMD = -0.15, 95% CI (-0.40, 0.10), p = 0.23].ConclusionTherapeutic massage was effective in improving MS in PD. It is suggested to be an appropriate form of CAM in treating PD.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=323182, identifier: CRD42022323182.
| S-EPMC9483027 | biostudies-literature
Project description:Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale (n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study (n = 540). k-means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages.
| S-EPMC5611404 | biostudies-literature
Project description:BackgroundsSleep disorders are the most common and disabling symptoms in patients with Parkinson's disease (PD). Understanding the associations between sleep characteristics and motor and non-motor symptoms (NMSs) in PD can provide evidence to guide therapeutic interventions and nursing strategies. We aimed to investigate the association between sleep characteristics and motor function and NMSs in PD using multiple approaches.MethodsA total of 328 participants were included, and all participants underwent Pittsburgh Sleep Quality Index (PSQI) evaluation and clinical assessments of PD symptoms. We conducted Spearman's correlation to evaluate the associations between sleep and PD symptoms, nonlinear regression to assess the relationships between sleep habits and PD, and mediated analyses to test the effects of NMSs on global PSQI and PD severity, quality of life, and motor symptoms.ResultsPoor sleep was associated with more severe PD symptoms. In addition, the reflection point for bedtime was around 21:52, associated with motor symptoms, and insufficient and excessive total time spent in bed and nocturnal sleep duration were correlated with higher NMS burdens. The optimal points were 8-9.2 and 6.2-6.9 h, respectively. It was also discovered that NMSs played the mediating roles in global sleep with the quality of life, PD stages, and motor symptoms to a varying range of 6.8-95.4%.ConclusionsSleep disorders have a significant effect on the burden of PD symptoms. The current findings provide new insights into the monitoring and management of sleep and PD and need to be further explored in the future studies.
| S-EPMC9226540 | biostudies-literature
Project description:OBJECTIVE:The objective of this study was to assess the efficacy and safety of nabilone, a synthetic tetrahydrocannabinol analogue, as a treatment for non-motor symptoms (NMS) in Parkinson's disease (PD). METHODS:This was a phase II placebo-controlled, double-blind, parallel-group, enriched enrollment randomized withdrawal trial conducted at the Medical University Innsbruck. A random sample of 47 patients with PD with stable motor disease and disturbing NMS defined by a score of ?4 points on the Movement Disorder Society - Unified PD Rating Scale-I (MDS-UPDRS-I) underwent open-label nabilone titration (0.25 mg once daily to 1 mg twice daily, phase I). Responders were randomized 1:1 to continue with nabilone or switch to placebo for 4?weeks (phase II). The primary efficacy criterion was the change of the MDS-UPDRS-I between randomization and week 4. Safety was analyzed in all patients who received at least one nabilone dose. RESULTS:Between October 2017 and July 2019, 19 patients received either nabilone (median dose = 0.75 mg) or placebo. At week 4, mean change of the MDS-UPDRS-I was 2.63 (95% confidence interval [CI] 1.53 to 3.74, p =?0.002, effect size = 1.15) in the placebo versus 1.00 (95% CI -0.16 to 2.16, p =?0.280, effect size = 0.42) in the nabilone-group (difference: 1.63, 95% CI 0.09 to 3.18, p =?0.030, effect size = 0.66). Seventy-seven percent of patients had adverse events (AEs) during open-label titration, most of them were transient. In the double-blind phase, similar proportions of patients in each group had AEs (42% in the placebo group and 32% in the nabilone group). There were no serious AEs. INTERPRETATION:Our results highlight the potential efficacy of nabilone for patients with PD with disturbing NMS, which appears to be driven by positive effects on anxious mood and night-time sleep problems. TRIAL REGISTRY:ClinicalTrials.gov (NCT03769896) and EudraCT (2017-000192-86). ANN NEUROL 2020;88:712-722.
| S-EPMC7540547 | biostudies-literature
Project description:Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson´s disease. For this, we developed a knock-in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV-based strategy carrying intein-split-dCas9 in combination with activators (AAV-dCAS). Both approaches were successful in reprogramming striatal astrocytes into induced GABAergic neurons confirmed by single cell transcriptome analysis of reprogrammed neurons in vivo. These GABAergic neurons functionally integrate into striatal circuits, alleviating voluntary motor behavior aspects in a 6-OHDA Parkinson's disease model. Our results suggest a novel intervention strategy beyond the restoration of dopamine levels. Thus, the AAV-dCAS approach might enable an alternative route for clinical therapies of Parkinson´s disease.
| S-SCDT-EMM-2021-14797 | biostudies-other
Project description:Sturge-Weber syndrome is a vascular malformation syndrome consisting of a facial port-wine birthmark associated with malformed leptomeningeal blood vessels and a choroid "angioma" of the eye. It is a rare neurocutaneous disorder that occurs sporadically, is not inherited, and is caused by a somatic mosaic mutation in GNAQ. In patients with Sturge-Weber syndrome, brain involvement typically presents in infancy with seizures, strokes, and stroke-like episodes, and a range of neurologic impairments. Standard treatment includes laser therapy for the birthmark, control of glaucoma through eyedrops or surgery, and the use of anticonvulsants. Increasingly low-dose aspirin is offered. Treatment with propranolol has been tried generally without the dramatic results seen in hemangiomas. Treatment with an anticonvulsant or low-dose aspirin or both before the onset of seizures is an option. Surgical resection may be offered to those whose seizures are medically refractory. Endocrine, medical rehabilitation and cognitive comorbidities are important to manage. In the future, new therapeutic options are likely to be offered stemming from preclinical studies and small pilot clinical trials currently ongoing. Discovery of the causative somatic mosaic mutation suggests new insights into the pathophysiology of this vascular malformation disorder, and potential novel treatment strategies for future study. The mutation results in constitutive overactivation of the Ras-Raf-MEK-ERK and the HIPPO-YAP pathways and inhibitors of these pathways may in the future prove useful in the treatment of Sturge-Weber syndrome.
| S-EPMC4943027 | biostudies-literature
Project description:Background and purposeThe prevalence and duration of non-motor symptoms (NMS) in prodromal Parkinson's disease (PD) has not been extensively studied. The aim of this study was to determine the prevalence and duration of prodromal NMS (pNMS) in a cohort of patients with recently diagnosed PD.MethodsWe evaluated the prevalence and duration of pNMS in patients with early PD (n = 154). NMS were screened for using the Non-Motor Symptom Questionnaire (NMSQuest). We subtracted the duration of the presence of each individual NMS reported from the duration of the earliest motor symptom. NMS whose duration preceded the duration of motor symptoms were considered a pNMS. Individual pNMS were then grouped into relevant pNMS clusters based on the NMSQuest domains. Motor subtypes were defined as tremor dominant, postural instability gait difficulty (PIGD) and indeterminate type according to the Movement Disorder Society Unified Parkinson's Disease Rating Scale revision.ResultsProdromal NMS were experienced by 90.3% of patients with PD and the median number experienced was 4 (interquartile range, 2-7). A gender difference existed in the pNMS experienced, with males reporting more sexual dysfunction, forgetfulness and dream re-enactment, whereas females reported more unexplained weight change and anxiety. There was a significant association between any prodromal gastrointestinal symptoms [odds ratio (OR), 2.30; 95% confidence interval (CI), 1.08-4.89, P = 0.03] and urinary symptoms (OR, 2.54; 95% CI, 1.19-5.35, P = 0.016) and the PIGD phenotype. Further analysis revealed that total pNMS were not significantly associated with the PIGD phenotype (OR, 1.10; 95% CI, 0.99-1.21, P = 0.068).ConclusionsProdromal NMS are common and a gender difference in pNMS experienced in prodromal PD may exist. The PIGD phenotype had a higher prevalence of prodromal gastrointestinal and urinary tract symptoms.
| S-EPMC6563450 | biostudies-literature
Project description:BackgroundMany of the motor symptoms of Parkinson's disease (PD) impact quality of life and are not fully ameliorated by current pharmacological and surgical treatments. A better understanding of the pathophysiology underlying these symptoms is needed. Previous research has suggested that inflammation may play a significant role in PD pathophysiology and progression, but there is limited research exploring how inflammation directly relates to motor symptoms in PD. Thus, the purpose of this study was to evaluate associations between peripheral immune inflammatory markers and motor symptoms of PD, specifically, tremor, bradykinesia, and postural and gait instability. We hypothesized that peripheral inflammatory cytokines would predict the severity of motor symptoms in persons with PD, and that there will be higher levels of peripheral inflammatory cytokine markers in persons with PD when compared to age-matched healthy older adults.MethodsTwenty-six participants with PD and fourteen healthy older adults completed the study. For participants with PD, the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) was recorded and scored by two Movement Disorders Neurologists masked to the study. A blood sample was collected from both participants with PD and the healthy older adults. Through the MILLIPLEX® map High Sensitivity Human Cytokine Kit, key inflammation-related markers were analyzed (TNF-α, IFN-γ, IL-1β, IL-8, IL-2, IL-7, IL-5, IL-13, IL, 4, IL-10 IL-12p70, GM-CSF, and IL-6).ResultsResults revealed significantly higher levels of IL-6 in persons with PD when compared to healthy older adults (p = 0.005). Moreover, results revealed that higher levels of IL-4 (p = 0.011) and lower levels of IFNγ (p = 0.003) significantly predicted more severe tremor in persons with PD. No other associations between the peripheral inflammation markers and other motor symptoms were observed.ConclusionsOverall, these results are consistent with a growing body of literature that implicates inflammatory cytokines in the PD, and further suggests that inflammatory cytokines, or lack thereof, may be associated with tremor in persons with PD.
| S-EPMC8927904 | biostudies-literature