Substantia nigra hyperechogenicity and Parkinson's disease risk in patients with essential tremor.

BACKGROUND: Several studies have reported an increased risk for patients with essential tremor to develop Parkinson's disease. In addition, hyperechogenicity in the area of the substantia nigra has been associated with a markedly increased risk for Parkinson's disease. The objective of this study was to evaluate the validity of substantia nigra hyperechogenicity in patients with essential tremor as a risk marker for Parkinson's disease. METHODS: Transcranial sonography was performed in 70 patients suffering from essential tremor. Fifty-four of these patients were available for follow-up after a mean of 6.16 ± 2.05 years and were assessed for the incidence of new-onset Parkinson's disease. RESULTS: The relative risk for developing Parkinson's disease in patients with essential tremor who had hyperechogenicity at baseline versus those without this hyperechogenicity was 7.00 (95% confidence interval, 1.62-30.34; sensitivity, 77.8%; specificity, 75.6%). CONCLUSIONS: Substantia nigra hyperechogenicity is also associated with an increased risk for Parkinson's disease in patients with essential tremor. These findings further support the potential role of this echofeature as a risk marker for Parkinson's disease.

Nonmotor symptoms in subjects without evidence of dopaminergic deficits.

BACKGROUND: A subgroup of patients initially diagnosed with Parkinson's disease (PD) turn out to have normal dopamine transporter single-photon emission computed tomography imaging and have been labeled as subjects without evidence of dopaminergic deficit (SWEDDs). In this study, we sought to further characterize these patients and have analyzed the frequency of nonmotor symptoms (NMS) in SWEDDs, PD patients, and healthy controls. METHODS: We analyzed the baseline clinical data of 412 PD patients, 184 controls, and 62 SWEDDs included in the Parkinson's Progression Marker Initiative study on a variety of different NMS questionnaires. RESULTS: Both PD patients and SWEDDs had greater frequency of NMS than healthy controls. Furthermore, some NMS, such as orthostatic hypotension as well as cardiovascular and thermoregulatory dysfunction were even more commonly reported in SWEDDs than in PD patients, whereas hyposmia was more common in PD, compared to SWEDDs. CONCLUSION: NMS are more frequent in SWEDDs than in controls, and autonomic dysfunction and orthostatic hypotension were even more common than in PD patients. These findings support the notion that SWEDDS represent a group of patients with still poorly understood pathophysiology. © 2015 International Parkinson and Movement Disorder Society.

Diffusion imaging of nigral alterations in early Parkinson's disease with dopaminergic deficits.

BACKGROUND: This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. METHODS: Two hundred twenty subjects (PD = 153; control = 67) from 10 imaging sites were included. All subjects had a full neurological exam, a ((123) I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. RESULTS: A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P = 0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P = 0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. CONCLUSIONS: Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality.

An antibody microarray analysis of serum cytokines in neurodegenerative Parkinsonian syndromes.

BACKGROUND: Microarray technology may offer a new opportunity to gain insight into disease-specific global protein expression profiles. The present study was performed to apply a serum antibody microarray to screen for differentially regulated cytokines in Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). RESULTS: Serum samples were obtained from patients with clinical diagnoses of PD (n = 117), MSA (n = 31) and PSP/CBS (n = 38) and 99 controls. Cytokine profiles of sera from patients and controls were analyzed with a semiquantitative human antibody array for 174 cytokines and the expression of 12 cytokines was found to be significantly altered. In a next step, results from the microarray experiment were individually validated by different immunoassays. Immunoassay validation confirmed a significant increase of median PDGF-BB levels in patients with PSP/CBS, MSA and PD and a decrease of median prolactin levels in PD. However, neither PDGF-BB nor prolactin were specific biomarkers to discriminate PSP/CBS, MSA, PD and controls. CONCLUSIONS: In our unbiased cytokine array based screening approach and validation by a different immunoassay only two of 174 cytokines were significantly altered between patients and controls.

Elastic Abdominal Binders Attenuate Orthostatic Hypotension in Parkinson's Disease.

BACKGROUND AND METHODS: To investigate the possible efficacy of an elastic abdominal binder to control orthostatic hypotension (OH) associated with Parkinson's disease (PD), 15 patients with PD and OH were enrolled in a single-blind crossover study with elastic abdominal versus placebo binder on two different days, separated by a 1-day interval, followed by a 4-week open-label follow-up. RESULTS: Intervention significantly reduced blood pressure fall upon tilting. The mean difference (standard deviation; 95% confidence intervals) between abdominal binder versus placebo was +10 mm Hg (10.2; +3.5, +16.5; P = 0.006). No significant effect on supine mean blood pressure values was observed compared to placebo (P = 0.3). Symptoms of OH decreased significantly during follow-up (P = 0.003), as assessed by means of the Orthostatic Hypotension Questionnaire. CONCLUSIONS: Our findings suggest that elastic abdominal binders may be a simple complementary tool to alleviate OH in PD.

Alpha-synuclein immunoreactivity patterns in the enteric nervous system.

We aimed to compare immunoreactivity patterns of four different anti-α-syn antibodies in surgical specimens of the gastrointestinal tract of Parkinson disease and control cases. Surgical specimens from stomach, small and large bowel of 6 PD cases and 12 controls were studied. Primary antibodies: anti-α-syn clone KM51, anti-phosphorylated α-syn Ser129, anti-α-syn clone 15G7 and anti-nitrated α-syn505. We found different immunoreactivity patterns: (a) coarse, Lewy-body-like aggregates labelled by the 4 antibodies and detected in 4/6 PD cases and in 1/12 controls; (b) distinct punctate cytoplasmic staining of ganglion cells labelled by anti-phosphorylated-α-syn and detected in 3/6 PD cases and 3/12 controls; (c) fine diffuse, synaptic-type staining of neural structures labelled by anti-α-syn-15G7 and anti-nitrated-α-syn505 and detected in all subjects. We conclude that different specific and non-specific immunoreactivity patterns are detected in surgical specimens of gastrointestinal tract when using different anti-α-syn antibodies, as they recognize different epitopes and states of alpha-synuclein protein. Coarse aggregates in neural structures seem to be the most promising marker for the diagnosis of Lewy-body parkinsonism when evaluating abnormal α-syn in the gastrointestinal tract.

Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder.

OBJECTIVE: To investigate the expression of α-synuclein in colonic biopsies of patients with idiopathic REM sleep behavior disorder (iRBD) and address if α-synuclein immunostaining of tissue obtained via colonic biopsies holds promise as a diagnostic biomarker for prodromal Parkinson disease (PD). METHODS: Patients with iRBD, patients with PD, and healthy controls were prospectively recruited to undergo colonic biopsies for comparison of α-synuclein immunoreactivity patterns between the groups by using 2 different antibodies. RESULTS: There was no difference in colonic mucosal and submucosal immunostaining between groups using the 15G7 α-synuclein antibody, which was found in almost all participants enrolled in this study. By contrast, immunostaining for serine 129-phosphorylated α-synuclein (pSyn) in submucosal nerve fibers or ganglia was found in none of 14 controls but was observed in 4 of 17 participants with iRBD and 1 out of 19 patients with PD. CONCLUSIONS: The present findings of pSyn immunostaining of colonic biopsies in a substantial proportion of iRBD participants raise the possibility that this tissue marker may be a suitable candidate to study further as a prodromal PD marker in at-risk cohorts.

Management of motor and non-motor symptoms in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects approximately 1 % of people over the age of 60 years. Accurate diagnosis and individualized assessment of the risks and benefits of available antiparkinsonian medications as well as specific clinical features and the phase of disease should guide treatment for patients with PD. Levodopa still remains the gold standard for the treatment of motor symptoms of PD but dopamine agonists (DAs), catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes and decrease the risk of levodopa-induced motor complications. Deep-brain stimulation as well as other invasive therapies can be used for the treatment of drug-refractory levodopa-induced motor complications. Despite all of the therapeutic advances achieved within the last 20 years, PD continues to be a progressive disorder leading to severe disability caused by motor and non-motor symptoms. To date, neuroprotective interventions able to modify PD progression are not available. This review focuses on medical and invasive treatment strategies for early and advanced stages of PD as well as on the treatment of PD non-motor symptoms such as mood and behavioural disorders, cognitive and autonomic dysfunction, and sleep disorders, which can antedate PD motor symptoms for years.

Drug safety evaluation of rotigotine.

INTRODUCTION: Rotigotine, a non-ergolinic dopamine-receptor agonist, is currently approved as monotherapy in early idiopathic Parkinson's disease (IPD), in moderate to severe idiopathic restless legs syndrome (RLS) and as adjunct therapy to levodopa in advanced IPD. Randomized, double-blind, placebo-controlled, as well as open-label studies were conducted in IPD and RLS patients to evaluate the efficacy, tolerability and safety of rotigotine in dosages up to 16 mg/24 h. Overall, these trials have shown that rotigotine has a similar adverse event (AE) profile as other non-ergolinic dopamine agonists such as pramipexole or ropinirole, inducing typical dopaminergic effects like nausea, daytime somnolence, peripheral edema or impulse control disorders. In addition, the most common AE seen with transdermal delivery of rotigotine are local skin reactions, which may lead to a treatment discontinuation in approximately 8% of patients. AREAS COVERED: This review outlines Phase II and III trials that were published between 2003 and 2011. The focus of this review is on the safety profile of rotigotine but it also goes into detail about clinical trial data, pharmacokinetics and pharmacodynamics. EXPERT OPINION: The emergent safety profile is similar to other non-ergolinic dopamine agonists. In addition, transdermal delivery is associated with local skin reactions, which are usually mild but may lead to a treatment discontinuation in a minority of patients.