Adult Parkinson's Disease Research Articles

Characterizing the adult zebrafish model of Parkinson's disease: a systematic review of dynamic changes in behavior and physiology post-MPTP administration.

Adult zebrafish are increasingly used in Parkinson's disease (PD) research due to their well-characterized dopaminergic system. Among the toxin-based models, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is widely utilized to induce parkinsonism in adult zebrafish. Therefore, this review presents an overview of the procedures and the dynamic changes in behavior and physiology observed in the adult zebrafish PD model following a single intraperitoneal injection of MPTP. A systematic literature search in the PubMed and Google Scholar databases was conducted to identify relevant articles. Of the 165 articles identified, 9 were included in this review. These chosen articles are original works published before March 2024, all of which utilized adult zebrafish induced with MPTP as the model for PD. Other articles were excluded based on factors such as limited relevance, utilization of zebrafish embryos or larvae instead of adults, and variations in MPTP deliveries. Studies indicated that the ideal model entails the utilization of mixed gender zebrafish aged between 4 and 6 months from the wild-type strain. The acceptable MPTP doses ranges between 20 μg/g (lowest) and 225 μg/g (highest) and doses above 292 μg/g are lethal. Furthermore, noticeable parkinsonian symptoms appear 1 day after administration and persist for more than 1 week. Mitochondrial dysfunction precedes dopaminergic neurodegeneration within this experimental regime. A single administration of MPTP effectively induces PD in adult zebrafish. This study aids in crafting the adult zebrafish PD model, outlining the progressive behavioral and physiological changes ensuing from MPTP administration.

Assessing Uptake of the Core Outcome Set in Randomized Controlled Trials for Parkinson's Disease: A Systematic Review.

Parkinson's Disease (PD) affects more than 10 million individuals, with increasing incidence worldwide. As PD's incidence rises, research funding is increasing substantially. PD's core outcome set (COS) provides standardization for PD clinical trial outcomes, improves research quality, and study comparability. Our study aimed to analyze COS uptake rate before and after the PD COS publication. We searched ClinicalTrials.gov to retrieve phase III/IV adult PD trials published between 2013-2023. Screening for inclusion and data extraction occurred in a masked, duplicate fashion. Trial characteristics and COS uptake rate were extracted from this sample. In our 111 included trials, the COS uptake rate was highest for the 'Walking and Balance' outcome and lowest for the 'Hospital Admissions' outcome. Overall, there was a non-significant monthly increase of 0.26% (P = 0.266, CI = [-0.20, 0.72]) in "COS-defined outcome" measurement when comparing pre- and post-COS publication. Our study found no significant increase in COS uptake in PD clinical trials. We found multiple outcomes to be vastly unmeasured and heterogeneity among the measurement instruments used. These findings complicate standardizing and comparing RCT outcomes. Overcoming these barriers is vital to improving the usefulness of PD research.

Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

KW-6356 is a novel adenosine A2A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A2A receptor but also inhibits the constitutive activity of adenosine A2A receptor. The efficacy of KW-6356 as both monotherapy and an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor in Parkinson's disease (PD) patients has been reported. However, the first-generation A2A antagonist istradefylline, which is approved for use as an adjunct treatment to L-DOPA/decarboxylase inhibitor in adult PD patients experiencing OFF episodes, has not shown statistically significant efficacy as monotherapy. In vitro pharmacological studies have shown that the pharmacological properties of KW-6356 and istradefylline at adenosine A2A receptor are markedly different. However, the anti-parkinsonian activity and effects on dyskinesia of KW-6356 in PD animal models and the differences in the efficacy between KW-6356 and istradefylline are unknown. The present study investigated the anti-parkinsonian activity of KW-6356 as monotherapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, and its efficacy was directly compared with that of istradefylline. In addition, we investigated whether or not repeated administration of KW-6356 induced dyskinesia. Oral administration of KW-6356 reversed motor disability in a dose-dependent manner up to 1 mg/kg in MPTP-treated common marmosets. The magnitude of anti-parkinsonian activity induced by KW-6356 was significantly greater than that of istradefylline. Repeated administration of KW-6356 induced little dyskinesia in MPTP-treated common marmosets primed to exhibit dyskinesia by prior exposure to L-DOPA. These results indicate that KW-6356 can be a novel non-dopaminergic therapy as monotherapy without inducing dyskinesia in PD patients.

Locomotor Assessment of 6-Hydroxydopamine-induced Adult Zebrafish-based Parkinson's Disease Model.

The limitations of current treatments in delaying dopaminergic neuronal loss in Parkinson's disease (PD) raise the need for alternative therapies that can restore these neurons. Much effort is currently directed toward a better understanding of neuroregeneration using preclinical in vivo models. This regenerative capability for self-repair is, however, inefficient in mammals. Non-mammalian animals like zebrafish have thus emerged as an excellent neuroregenerative model due to its capability to continuously self-renew and have a close brain homology to humans. As part of the effort in elucidating cellular events involved in neuroregeneration in vivo, we have established the 6-hydroxydopamine (6-OHDA)-induced adult zebrafish-based PD model. This was achieved through the optimized intracerebroventricular (ICV) microinjection of 99.96mM 6-OHDA to specifically ablate dopaminergic neurons (DpN) in the ventral diencephalon (Dn) of zebrafish brain. Immunofluorescence indicated more than 85% of DpN ablation at day three postlesion and full restoration of DpN at lesioned site 30 days postlesion. The present study determined the impairment and subsequent recovery of zebrafish swimming behavior following lesion by using the open field test through which two parameters, distance traveled (cm) and mean speed (cm/s), were quantified. The locomotion was assessed by analyzing the recordings of individual fish of each group (n = 6) using video tracking software. The findings showed a significant (p < 0.0001) reduction in speed (cm/s) and distance traveled (cm) of lesioned zebrafish 3 days postlesion when compared to sham. The lesioned zebrafish exhibited full recovery of swimming behavior 30 days postlesion. The present findings suggest that 6-OHDA lesioned adult zebrafish is an excellent model with reproducible quality to facilitate the study of neuroregeneration in PD. Future studies on the mechanisms underlying neuroregeneration as well as intrinsic and extrinsic factors that modulate the process may provide important insight into new cell replacement treatment strategies against PD.

Degradation of alpha-synuclein by dendritic cell factor 1 delays neurodegeneration and extends lifespan in Drosophila

Parkinson's disease (PD) is a common neurodegenerative disease associated with the progressive loss of dopaminergic neurons in the substantia nigra. Proteinaceous depositions of alpha-synuclein (α-syn) and its mutations, A30P and A53T, are one important characteristic of PD. However, little is known about their aggregation and degradation mechanisms. Dendritic cell factor 1 (DCF1) is a membrane protein that plays important roles in nerve development in mouse. In this study, we aimed to show that DCF1 overexpression in a PD Drosophila model significantly ameliorates impaired locomotor behavior in third instar larvae and normalizes neuromuscular junction growth. Furthermore, climbing ability also significantly increased in adult PD Drosophila. More importantly, the lifespan dramatically extended by an average of approximately 23%, and surprisingly, DCF1 could prevent α-syn-induced dopaminergic neuron loss by aggregating α-syn in the dorsomedial region of Drosophila. Mechanistically, we confirmed that DCF1 could degrade α-syn both invivo and invitro. Our findings revealed an important role of DCF1 in PD process and may provide new potential strategies for developing drugs to treat neurodegenerative diseases.

Spotlight on opicapone as an adjunct to levodopa in Parkinson's disease: design, development and potential place in therapy.

Parkinson’s disease (PD) is a progressive, chronic, neurodegenerative disease characterized by rigidity, tremor, bradykinesia and postural instability secondary to dopaminergic deficit in the nigrostriatal system. Currently, disease-modifying therapies are not available, and levodopa (LD) treatment remains the gold standard for controlling motor and nonmotor symptoms of the disease. LD is extensively and rapidly metabolized by peripheral enzymes, namely, aromatic amino acid decarboxylase and catechol-O-methyltransferase (COMT). To increase the bioavailability of LD, COMT inhibitors are frequently used in clinical settings. Opicapone is a novel COMT inhibitor that has been recently approved by the European Medicines Agency as an adjunctive therapy to combinations of LD and aromatic amino acid decarboxylase inhibitor in adult PD patients with end-of-dose motor fluctuations. We aimed to review the biochemical properties of opicapone, summarize its preclinical and clinical trials and discuss its future potential role in the treatment of PD.

A Systematic Review on the Use of Oral Therapeutic Agents in the Management of Constipation in Adult Patients With Parkinsonʼs Disease

Introduction: Constipation is common in patients with Parkinson's disease (PD) and has been postulated as an early non-motor symptom that precedes the diagnosis of PD. Although constipation significantly affects PD patients' quality of life, the efficacy of oral therapeutic agents that treat constipation in PD is unclear. We aim to conduct a systematic review of the literature to evaluate the effect of oral agents on constipation in adult PD patients. Methods: A comprehensive literature search in Ovid MEDLINE, Embase, Cochrane Central Register of CT, Cochrane Database of SR and CINAHL was performed up to 13 April 2015 using various root words of Parkinson and constipation alone and in combination. Two authors (AA, YT) independently reviewed all abstracts. Disagreements were resolved with the third author (LL). Exclusion criteria include: no abstract, non-English papers, non-human studies, not prospective clinical studies, non-adult patients, not Parkinson's disease, and not a study on oral therapeutic agent. Methodological quality was assessed using Cochrane's Risk of Bias. Results: The search identified 3069 studies. After removing duplications and applying the exclusion criteria, 9 studies (Figure 1, involving 237 patients, mean age = 68.1 years) were included in the analysis. In general, study designs were heterogeneous and assessment of constipation outcomes varied significantly between studies. There were 3 double-blind randomized controlled trials (RCT): 1 on Macrogol, 1 on lubiprostone and 1 on tegaserod. Although 2 small open label non-RCT (n=39) on prokinetics showed improvement in constipation, the one small RCT (n=15) showed no benefit. Osmotic laxative using Macrogol (1 RCT, n=57; 1 open label, n=8), fibre supplementation with psyllium (single-blind RCT, n=7) and secretagogue using lubiprostone (RCT, n= 52) demonstrated beneficial effects on constipation. The one open label study on levodopa (n=19) and the other one on probiotics (n=40) showed no effect.Figure 1Conclusion: This systematic review illustrates that studies assessing the effect of treatment agents on constipation in PD patients are lacking. Well-designed prospective RCT evaluating treatment options of constipation in PD patients are needed to optimize the symptomatic management in this challenging population.

Subjective sleep dysfunction and insomnia symptoms in Parkinson's disease: Insights from a cross-sectional evaluation of the French CoPark cohort.

Twenty-seven to 80% of patients with Parkinson's Disease (PD) complain of subjective sleep dysfunction and insomnia symptoms. Our aim is to describe the prevalence and features of subjective sleep dysfunction and insomnia symptoms in patients with PD compared to other patients. Cross-sectional analysis of 636 adult PD patients compared to 143 age and sex-matched non-PD control patients consulting their general practitioners. Insomnia symptoms and other sleep features were assessed by the Pittsburgh Sleep Quality Index (PSQI), a global score>5 defining impaired sleep. The Chi-square test or the Student's t-test were used to assess the potential clinical and demographic differences between groups and between PD patients with vs. without sleep dysfunction. Logistic regression analysis was employed to test multivariate effects. Sleep dysfunction and insomnia symptoms were more frequent in PD patients compared to control patients (63 vs. 45%, p=0.001). Female gender, PD duration, presence of depression and anxiety were associated with the presence of insomnia in PD. Subjective sleep efficiency, habitual sleep quality, sleep disturbance and daytime dysfunction, but not sleep latency, were reduced in PD patients compared to controls. The prevalence of sleep dysfunction is higher in PD than in other general medical conditions. Insomnia in PD seems to affect sleep maintenance and consolidation, but not sleep onset.

Comparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson's disease

Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD), and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years. Here, we use a statistical meta-analysis of human brain transcriptomics data to investigate potential mechanistic relationships between adult brain aging and PD pathogenesis at the pathway and network level. The analyses identify statistically significant shared pathway and network alterations in aging and PD and an enrichment in PD-associated sequence variants from genome-wide association studies among the jointly deregulated genes. We find robust discriminative patterns for groups of functionally related genes with potential applications as combined risk biomarkers to detect aging- and PD-linked oxidative stress, e.g., a consistent over-expression of metallothioneins matching with findings in previous independent studies. Interestingly, analyzing the regulatory network and mouse knockout expression data for NR4A2, a transcription factor previously associated with rare mutations in PD and here found as the most significantly under-expressed gene in PD among the jointly altered genes, suggests that aging-related NR4A2 expression changes may increase PD risk via downstream effects similar to disease-linked mutations and to expression changes in sporadic PD. Overall, the analyses suggest mechanistic explanations for the age-dependence of PD risk and reveal significant and robust shared process alterations with potential applications in biomarker development for pre-symptomatic risk assessment or early stage diagnosis.

Factors associated with fall-related fractures in Parkinson's disease

PurposeFall-related fracture is one of the most disabling features of idiopathic Parkinson's disease (PD). A better understanding of the associated factors is needed to predict PD patients who will require treatment. MethodsThis prospective study enrolled 100 adult idiopathic PD patients. Stepwise logistic regressions were used to evaluate the relationships between clinical factors and fall-related fracture. ResultsFalls occurred in 56 PD patients, including 32 with fall-related fractures. The rate of falls in the study period was 2.2 ± 1.4 per 18 months. The percentage of osteoporosis was 34% (19/56) and 11% in PD patients with and without falls, respectively. Risk factors associated with fall-related fracture were sex, underlying knee osteoarthritis, mean Unified Parkinson's Disease Rating Scale score, mean Morse fall scale, mean Hoehn and Yahr stage, and exercise habit. By stepwise logistic regression, sex and mean Morse fall scale were independently associated with fall-related fracture. Females had an odds ratio of 3.8 compared to males and the cut-off value of the Morse fall scale for predicting fall-related fracture was 72.5 (sensitivity 72% and specificity 70%). DiscussionHigher mean Morse fall scales (>72.5) and female sex are associated with higher risk of fall-related fractures. Preventing falls in the high-risk PD group is an important safety issue and highly relevant for their quality of life.

Functioning and disability in Parkinson's disease

Objective. To describe functioning and disability of patients with Parkinson's Disease (PD) according to the model endorsed by the International Classification of Functioning Disability and Health (ICF).Design. Adult PD patients were consecutively enrolled. The ICF checklist and the WHO Disability Assessment Schedule II (WHO-DAS II) were administered in individual sessions. Hoehn and Yahr Staging (HY) was used to define PD severity. Descriptive analyses have been performed to report on HY and WHO-DAS II scores. ICF categories reported as a problem by more than 20% of patients are described in detail.Results. Ninety-six patients with PD (mean age 64.1, 33.3% females) were enrolled, 48.4% of them were in HY class 2. WHO-DAS II mean score was 18.1 and the most severe limitations are reported in getting around and in participation to social situations. A total of 71 ICF categories reached the threshold of 20%, mostly derived from Activities and Participation domain.Conclusions. We reported information on a broad set of domains, expanding those PD-specific, such as reduced mobility. Our results are useful to define what dimensions have to be considered to expand disability assessment in patients with PD, considering both symptoms, activities and the role of environmental factors.

Comparación del desempeño neuropsicológico según la edad de inicio en sujetos con enfermedad de Parkinson y parkinsonismo

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, and it is characterised by tremor, bradykinesia, rigidity and postural instability. The most frequent cognitive disorder is executive dysfunction, although global deficits associated to late onset of the disease have also been reported. To describe and to compare cognitive performance in three groups with PD and one with Parkinsonism. A neurological and neuropsychological evaluation was carried out on 175 patients with idiopathic PD and Parkinsonism. The data analysis was performed by comparing the results of the tests carried out on the four groups: three with PD (age of onset: juvenile, adult and late) and one with Parkinsonism, while controlling for age, schooling and time of progression. In the juvenile PD group, alterations were observed in the number of intrusions in verbal memory; in the adult PD and late PD groups, there were alterations in time in continuous visual execution. These differences disappeared when the groups were compared to each other while also controlling for age. The Parkinsonism group obtained results that were lower than those of all the groups with PD for most of the cognitive and functional variables. Idiopathic PD would not be the cause of multiple cognitive impairment, but of a specific alteration, mainly involving the speed of processing and information recall. Age of onset would not be a decisive factor in the degree of impairment of cognitive functioning; important cognitive impairment was only present in the group with Parkinsonism.

Dopamine agonists and sleepiness in PD: review of the literature and personal findings

Background and purpose This study is aimed at evaluating daytime sleepiness in a series of Parkinson's disease (PD) patients chronically treated with dopamine agonists (DAs) alone or in combination with l-Dopa. Patients and methods A preliminary series of 22 non-demented, adult PD patients (mean age 68.9, 13 men and 9 women) were evaluated by means of structured sleep interview, Epworth sleepiness scale (ESS) and 24-h ambulatory polysomnography (A-PSG). Results Sleep attacks (SAs) were reported by 32% of the patients, in three of them (43%) after DA treatment was initiated (alone or in addition to l-Dopa). In two patients, both with chronic use of ropinirole, we documented NREM SAs during a continuous ambulatory polysomnography (A-PSG) performed in the patients' real-life settings. The subjects experiencing SAs showed a higher degree of daytime sleep propensity than those without SA, having higher ESS scores and a higher proportion of microsleeps and intentional naps on A-PSG. Interestingly, we found that nocturnal total sleep time is higher in PD patients with SAs than in the others. Conclusions All in all, our data indicate that SAs are an extreme manifestation of increased daytime sleepiness. The occurrence of SAs in our series of PD patients is unlikely to depend simply on the demands of homeostatic mechanisms.

Fixed-ratio discrimination training as replacement therapy in Parkinson's disease: studies in a 6-hydroxydopamine-treated rat model

Severe 6-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) depletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson's disease (PD) and Lesch–Nyhan syndrome (LNS). Prior studies in our laboratory indicate that prolonged training on incrementally more difficult fixed-ratio (FR) discriminations can reverse `irreversible' 6-OHDA-induced neostriatal DA depletion in adult LNS rats. The present study evaluated the effects of such training on neostriatal DA depletion and its functional consequences in adult PD and control (vehicle-injected) rats. After recovery from 6-OHDA-induced hypophagia, rats were sacrificed to assess neostriatal DA depletion magnitude, or were food-deprived and either subjected to food-maintained operant FR discrimination training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behavior and locomotor activity in 3-month-old PD rats prior to training, and reduced operant response rates throughout training without affecting learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP-increased behavioral frequencies was essentially eliminated. Cumulative apomorphine (APO) dose–effect curve (0.1–3.2 mg/kg) construction 3 weeks post-training revealed that 6-OHDA treatment abolished APO-induced intense licking behavior. However, training eliminated the hyperresponsiveness of 6-OHDA-treated rats to the locomotor- and brief-rearing stimulant effects of APO but did not affect the depletion of neostriatal DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA and HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the functional responsiveness of at least some central DA receptors, FR discrimination training could be a useful adjunct to PD replacement therapy and that the neostriatal DA-repleting action of training in 6-OHDA-treated rats depend on the age at which 6-OHDA is administered.

Health maintenance behaviors in advanced Parkinson's disease.

Co-morbidity in the older adult Parkinson's disease patient decreases functional status and quality of life, and increases the risk of permanent disability. Although many chronic conditions in the adult population can be prevented, or at least influenced by early detection and treatment many progressive neurologic disorders such as Parkinson's disease cannot. This pilot study describes the health maintenance and disease prevention behaviors of a group of patients with Parkinson's disease. Findings demonstrate that parkinsonians attend in a way similar to their peers without Parkinson's disease to most parameters of general health maintenance as established by the United States Preventive Task Force. In fact, in 11 out of 12 selective parameters, parkinsonians exhibit increased frequency of participation in the recommended behaviors. However, achievement of our national goals for health promotion and disease prevention will require additional efforts in this population. Emphasis should include the participation in Pap smears, mammograms, exercise, seat belt usage and adult immunizations, especially the pneumococcal vaccination. Neuroscience nurses can play an important role in reaching health promotion and disease prevention goals in persons with Parkinson's disease through patient education, advocacy, case management, anticipatory guidance and referrals to primary care providers.

Motor Control in Childhood Onset Dopa-Responsive Dystonia (Segawa Syndrome)*

To elucidate the pathophysiological features of childhood onset dopa-responsive dystonia (DRD) we used a variety of quantitative analysis techniques to evaluate aspects of reflex- and voluntary motor control in two brothers with this disorder. The observed patterns were compared with those obtained in patients with adult onset Parkinson's disease (PD) and Huntington's disease (HD). In both brothers onset of the disease was in the first decade. Both responded either to treatment with L-Dopa or a combination of L-Dopa with trihexiphenidyl. Neurophysiological studies revealed slowing of different upper extremity voluntary motor activities and a low frequency postural tremor similar to results in other basal ganglia disorders including PD. In contrast to adult onset PD, fastest isometric voluntary index finger contractions did not show the typical kinetic tremor oscillations superimposed on the force trajectories. Also, different to adult PD, no impairment of stance regulating reflexes or saccadic and smooth pursuit eye movements was found in DRD. Magnetoelectrical stimulation of motor cortex showed normal efferent cortical spinal activity. Data indicate that like in other basal ganglia diseases slowing of voluntary motor activity is also a constant feature in DRD. DRD patients show, however, a clear difference to the pattern of motor abnormalities obtainable in PD. Both the pattern of motor control abnormalities is different, and the longlasting effect. In contrast to PD the pathophysiological mechanism in DRD possibly involves a lack of maturation of dopaminergic substantia nigra neurons rather than a degenerative process.