rs10501087, rs1491850 and rs11030094 polymorphisms associated with delayed progression in early-stage Parkinson's disease.

Parkinson's disease (PD) is heterogenous in its presentation, progression and response to therapies. Genetic polymorphisms may account for some of this variability. Several single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor gene have been associated with differing clinical outcomes from different dopaminergic replacement strategies, and one of these, the rs6265 SNP, has been associated with a milder clinical phenotype in the unmedicated, early-stage of PD.

Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures.

Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA.

BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease.

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659).

Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction.

Background: Pituitary pars intermedia dysfunction (PPID) develops slowly in aged horses as degeneration of hypothalamic dopaminergic neurons leads to proliferation of pars intermedia (PI) melanotropes through hyperplasia and adenoma formation. Dopamine (DA) concentrations and tyrosine hydroxylase (TH) immunoreactivity are markedly reduced in PI tissue of PPID-affected equids and treatment with the DA receptor agonist pergolide results in notable clinical improvement. Thus, we hypothesized that pergolide treatment of PPID-affected horses would result in greater DA and TH levels in PI tissue collected from PPID-affected horses versus untreated PPID-affected horses.

Sex differences by design and outcome in the Safety of Urate Elevation in PD (SURE-PD) trial.

Objective: To investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.

Methods: The Safety of Urate Elevation in Parkinson's Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1-7.

Critical appraisal of the recent US FDA approval for earlier DBS intervention.

In November 2015, Medtronic announced the US Food and Drug Administration (FDA) approval for the use of deep brain stimulation (DBS) therapy in people with Parkinson disease (PD) "of at least 4 years duration and with recent onset motor complications, or motor complications of longer-standing duration that are not adequately controlled with medication." The approval was based on data from the EARLYSTIM clinical trial, a randomized, prospective, multicenter, parallel-group clinical trial in Germany and France involving 251 patients with PD. While others have reviewed the application of DBS earlier in the disease course and the results from EARLYSTIM, we focus on the conceptual, scientific, clinical, ethical, and policy issues that arise regarding the recent FDA approval.

Bdnf variant is associated with milder motor symptom severity in early-stage Parkinson's disease.

Introduction: Parkinson's disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene Bdnf alters clinical phenotype in early-stage, unmedicated PD.

Metabolism of Dopamine in Nucleus Accumbens Astrocytes Is Preserved in Aged Mice Exposed to MPTP.

Parkinson disease (PD) is prevalent in elderly individuals and is characterized by selective degeneration of igrotriatal opmine (NSDA) neurons. Interestingly, not all dopamine (DA) neurons are affected equally by PD and aging, particularly esoimbic (ML) DA neurons. Here, effects of aging were examined on presynaptic DA synthesis, reuptake, metabolism and neurotoxicant susceptibility of NSDA and mesolimbic dopamine (MLDA) neurons and astrocyte DA metabolism.

Autonomic and electrocardiographic findings in Parkinson's disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10-second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression.

Longer Duration of MAO-B Inhibitor Exposure is Associated with Less Clinical Decline in Parkinson's Disease: An Analysis of NET-PD LS1.

Background: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients.

Objective: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline.

Methods: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson's Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most recent Modified Rankin Scale.

FosB and ΔFosB expression in brain regions containing differentially susceptible dopamine neurons following acute neurotoxicant exposure.

Parkinson disease (PD) is characterized by progressive neuronal degeneration, in particular nigrostriatal dopamine (NSDA) neurons and consequent deficits in movement. In mice and non-human primates, NSDA neurons preferentially degenerate following exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tuberoinfundibular (TI) DA neurons, in contrast, appear to be unaffected in PD and recover following acute MPTP exposure-induced injury (Behrouz et al.

Choice of dopaminergic therapy among early, mild Parkinson disease subjects in North America.

The choice of dopaminergic therapy in early Parkinson disease (PD) is an important clinical decision, yet factors influencing this decision have not been extensively studied. We sought to investigate the factors that may be associated with the choice of dopaminergic therapy at the NINDS Exploratory Trials in PD (NET-PD) Long-Term Study-1 (LS1). NET-PD LS1 was a clinical trial of creatine versus placebo in participants with early, mild PD on stable doses of dopaminergic therapy.

Reduced Noradrenergic Signaling in the Spleen Capsule in the Absence of CB and CB Cannabinoid Receptors.

The spleen is a visceral organ that contracts during hypoxia to expel erythrocytes and immune cells into the circulation. Spleen contraction is under the control of noradrenergic sympathetic innervation. The activity of noradrenergic neurons terminating in the spleen capsule is regulated by α2-adrenergic receptors (AR).

Comparison of the structure, function and autophagic maintenance of mitochondria in nigrostriatal and tuberoinfundibular dopamine neurons.

A pathological hallmark of Parkinson׳s disease (PD) is progressive degeneration of nigrostriatal dopamine (NSDA) neurons, which underlies the motor symptoms of PD. While there is severe loss of midbrain NSDA neurons, tuberoinfundibular (TI) DA neurons in the mediobasal hypothalamus (MBH) remain intact. In the present study, confocal microscopic analysis revealed that mitochondrial content and numbers of mitophagosomes were lower in NSDA neuronal cell bodies in the substantia nigra pars compacta (SNpc) compared to TIDA neuronal cell bodies in the arcuate nucleus (ARC) of C57BL/6J male mice.

Methylmercury impairs canonical dopamine metabolism in rat undifferentiated pheochromocytoma (PC12) cells by indirect inhibition of aldehyde dehydrogenase.

The environmental neurotoxicant methylmercury (MeHg) disrupts dopamine (DA) neurochemical homeostasis by stimulating DA synthesis and release. Evidence also suggests that DA metabolism is independently impaired. The present investigation was designed to characterize the DA metabolomic profile induced by MeHg, and examine potential mechanisms by which MeHg inhibits the DA metabolic enzyme aldehyde dehydrogenase (ALDH) in rat undifferentiated PC12 cells.

Parkinson's disease severity and use of dopaminergic medications.

Background: The effects of dopaminergic therapy in parkinson's disease (PD) can vary depending on the class of medication selected.

Objective: The aim of this post hoc study was to determine if the class of dopaminergic therapy correlated with disease severity in persons with early, treated PD.

Methods: A non-parametric global statistical test (GST) was used to assess the status of participants treated with dopamine agonist (DA) monotherapy, levodopa (LD) monotherapy or combined LD and DA therapy on multiple PD outcomes encompassing motor, cognitive, psychiatric and autonomic function, as well as disability and quality of life.

The role of parkin in the differential susceptibility of tuberoinfundibular and nigrostriatal dopamine neurons to acute toxicant exposure.

Parkinson disease causes degeneration of nigrostriatal dopamine (DA) neurons, while tuberoinfundibular DA neurons remain unaffected. A similar pattern is observed following exposure to 1-methy-4-phenyl-1,2,3,6-tetrahydropyradine (MPTP). The mechanism of tuberoinfundibular neuronal recovery from MPTP is associated with up-regulation of parkin protein.

Enhanced humoral immunity in mice lacking CB1 and CB2 receptors (Cnr1-/-/Cnr2-/- mice) is not due to increased splenic noradrenergic neuronal activity.

Peripheral sympathetic noradrenergic neurons originating in the celiac mesenteric plexus have axons that terminate in close proximity to antibody-producing B cells in the spleen. Norepinephrine (NE) released from these neurons is reported to augment antibody production in response to an immune challenge via an action at the β2-adrenergic receptor (β2AR). Cannabinoids are immunosuppressive, and mice lacking CB1 and CB2 receptors (Cnr1(-/-)/Cnr2(-/-) mice) have augmented cell-mediated immune responses.

Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein.

Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined.

The role of de novo catecholamine synthesis in mediating methylmercury-induced vesicular dopamine release from rat pheochromocytoma (PC12) cells.

The purpose of this study was to characterize methylmercury (MeHg)-induced dopamine (DA) release from undifferentiated pheochromocytoma (PC12) cells and to examine the potential role for DA synthesis in this process. MeHg caused a significant increase in DA release that was both concentration- and time-dependent. DA release was significantly increased by 2µM MeHg at 60min and by 5µM MeHg at 30min; 1µM MeHg was without effect.

A call for transparent reporting to optimize the predictive value of preclinical research.

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors.

Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice.

Motor dysfunctions of Parkinson Disease (PD) are due to the progressive loss of midbrain nigrostriatal dopamine (NSDA) neurons. Evidence suggests a role for cannabinoid receptors in the neurodegeneration of these neurons following neurotoxicant-induced injury. This work evaluates NSDA neurons in CB1/CB2 knockout (KO) mice and tests the hypothesis that CB1/CB2 KO mice are more susceptible to neurotoxicant exposure.