Parkinson's disease and other neurodegenerative disorders among welders: A Danish cohort study

It has been hypothesized that welders are at increased risk for neurological disorders, including Parkinson's disease, but few well-designed cohort studies have been conducted. The risk for Parkinson's disease and other neurodegenerative disorders was examined in an updated follow-up study based on a previous cohort of 5867 Danish welders and 1735 nonwelding metal workers exposed to welding fume. Occupational history and information on smoking were obtained from questionnaires, supplemented by information from the compulsory Danish Supplementary Pension Fund. Hospital contacts, including outpatient data from 1994, for Parkinson's disease and other neurological disorders were ascertained from the Danish National Hospital Register. Based on first-time hospital contacts, standardized hospitalization ratios (SHRs) were calculated for the entire cohort and for welders, metal workers, and nonresponders separately and for the general Danish population in 1987-2008. In an internal analysis of welders, Cox proportional hazard models were used to estimate hospitalization rate ratios (HRRs) for Parkinson's disease associated with lifelong exposure to welding. Overall, 45 cohort members had a hospital contact for Parkinson's disease (SHR, 1.12; 95% confidence interval [CI], 0.82-1.50), of whom 25 were welders (standardized incidence rate ratio, 1.05; 95% CI, 0.68-1.55). When duration of welding was compared among 5736 welders, the HRR was 0.83 (95% CI, 0.59-1.16) per 10 years' welding, after adjustment for smoking. The results of this study do not support the hypothesis that welders are at increased risk for Parkinson's disease; these findings are consistent with those of our previously published analysis. ? 2012 Movement Disorder Society.     

Prevalence of Restless Legs Syndrome in a Georgian Primary Healthcare Setting: A Pilot Study

Background: The prevalence of restless legs syndrome (RLS) is approximately 10% in Western Europe, but unknown in Georgia. This pilot study aimed to assess RLS prevalence in a focused Georgian population. Methods: An RLS epidemiological questionnaire [Allen et al.: Sleep Med 2003;4:101-119] was filled out by patients in five primary healthcare centers in two Georgian cities between March and September 2006. Additionally, questions related to RLS symptom onset, family history, treatment, sleep disturbance and history of iron deficiency were included. RLS diagnosis was based on an expert interview and an epidemiological questionnaire for RLS. Results: The total number of respondents was 115 (75% women/25% men); mean age was 47 years (range 18-85). Thirteen subjects (11.3%) reported RLS symptoms (9 women/4 men); mean age was 52 years (range 32-83). Eleven (85%) had a positive family history of RLS. All subjects had sleep disturbance and none had a history of known iron deficiency. Conclusion: The prevalence of RLS in a focused Georgian population is in line with other RLS epidemiologic studies performed in clinical settings. However, the prevalence rate of RLS in a studied group might not be representative for the general Georgian population. Further population-based epidemiological studies are required.     

Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies

The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can be occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of QUIN concentration or decrease of KYNA concentration could enhance the symptoms of several diseases. According to numerous studies, lowered KYNA level was found in patients with Parkinson's disease. It can be also noticeable that KYNA-treatment prevents against the QUIN-induced lesion of rat striatum in animal experiments. Administrating of KYNA can be appear a promising therapeutic approach, but its use is limited because of its poorly transport across the blood-brain barrier. The solution may be the development of KYNA analogues (e.g. glucoseamine-kynurenic acid) which can pass across this barrier and disengaging in the brain, then KYNA can exert its neuroprotective effects binding at the excitatory glutamate receptors, in particular the NMDA receptors. Furthermore, it seems hopeful to use kynurenine derivatives (e.g. 4-chloro-kynurenine) or enzyme inhibitors (e.g. Ro-61-8048) to ensure an increased kynurenic acid concentration in the central nervous system.     

The role of the ubiquitin-proteasomal pathway in Parkinson's disease and other neurodegenerative disorders

A unifying feature of neurodegenerative diseases is the abnormal accumulation and processing of mutant or damaged intra- and extracellular proteins; this leads to selective neuronal vulnerability and dysfunction. The ubiquitin-proteasomal pathway (UPP) is poised to play a central role in the processing of damaged and toxic proteins by ubiquitin-dependent proteolysis. The UPP can be overwhelmed in several neurodegenerative diseases. This results in the accumulation of toxic proteins and the formation of inclusions, and ultimately to neuronal dysfunction and cell death. Further analysis of the cellular and molecular mechanisms by which the UPP influences the detoxification of damaged and toxic proteins in neurodegenerative diseases could provide novel concepts and targets for the treatment and understanding of the pathogenesis of these devastating disorders.     

Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study.

We studied the association between preceding psychiatric disorders and Parkinson's disease (PD) using a case-control design. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, Minnesota, during the years 1976-1995. Each case was matched by age (+/-1 yr) and sex to a general population control. We reviewed the complete medical records of cases and control subjects to detect preceding psychiatric disorders. The frequency of psychiatric disorders was higher in cases than in control subjects; the odds ratio was 2.2 for anxiety disorders (95% confidence interval [95% CI] = 1.4-3.4; p = 0.0003), 1.9 for depressive disorders (95% CI = 1.1-3.2; p = 0.02), and 2.4 for both anxiety disorders and depressive disorders occurring in the same individual (95% CI = 1.2-4.8; p = 0.02). When we restricted analyses to disorders present 5 years or more before the onset of motor symptoms of PD, the association with depressive disorders lost statistical significance. However, the association with anxiety disorders remained significant for disorders present 5, 10, or 20 years before onset of motor symptoms. Our results suggest that anxiety disorders and depressive disorders are associated with PD and that the causative process or the risk factors underlying PD are present many years before the appearance of motor symptoms.     

Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia

Reduced glutathione (GSH) and oxidized glutathione (GSSG) levels were measured in various brain areas (substantia nigra, putamen, caudate nucleus, globus pallidus, and cerebral cortex) from patients dying with Parkinson's disease, progressive supranuclear palsy, multiple-system atrophy, and Huntington's disease and from control subjects with no neuropathological changes in substantia nigra. GSH levels were reduced in substantia nigra in Parkinson's disease patients (40% compared to control subjects) and GSSG levels were marginally (29%) but insignificantly elevated; there were no changes in other brain areas. The only significant change in multiple-system atrophy was an increase of GSH (196%) coupled with a reduction of GSSG (60%) in the globus pallidus. The only change in progressive supranuclear palsy was a reduced level of GSH in the caudate nucleus (51%). The only change in Huntington's disease was a reduction of GSSG in the caudate nucleus (50%). Despite profound nigral cell loss in the substantia nigra in Parkinson's disease, multiple-system atrophy, and progressive supranuclear palsy, the level of GSH in the substantia nigra was significantly reduced only in Parkinson's disease. This suggests that the change in GSH in Parkinson's disease is not solely due to nigral cell death, or entirely explained by drug therapy, for multiple-system atrophy patients were also treated with levodopa. The altered GSH/GSSG ratio in the substantia nigra in Parkinson's disease is consistent with the concept of oxidative stress as a major component in the pathogenesis of nigral cell death in Parkinson's disease.     

医学史话:不宁腿综合征的认识史

正不宁腿综合征(restless legs syndrome,RLS)似乎是一个颇具神秘色彩的疾病,其症状常难以形容和表述,呈昼夜规律性发作。RLS曾是难治性疾病,目前治疗已有突破。然而,还有许多未知的发病机制、病理和最佳治疗方案仍需探讨,回顾RLS的认识史对攻克这一疾病或有裨益。1类似不宁腿综合征的早期描述不宁腿综合征的第一次描述要追溯到法     

Hemochromatosis and iron therapy of Restless Legs Syndrome

Restless legs syndrome (RLS) occurs in some persons with iron deficiency, and some persons with RLS benefit from oral iron therapy. Approximately one in 200 persons of northern European ancestry have hemochromatosis attributable to inheritance of two common mutations of the hemochromatosis-associated HFE gene on chromosome 6. We evaluated and treated a 46-year-old man with RLS who was diagnosed as having hemochromatosis after he developed new symptoms associated with taking iron therapy for RLS. He had transferrin saturation 88%, serum ferritin 658 ng/ml, and C282Y homozygosity. Therapeutic phlebotomy of one unit of blood (450-500 ml) weekly (total 24 units) relieved his non-RLS symptoms, caused RLS symptoms to occur more frequently, and was associated with transient fatigue and mild dependent edema. His sister, who also has RLS, was subsequently diagnosed as having hemochromatosis. We conclude that serum transferrin saturation and ferritin levels should be measured before initiation of iron therapy of RLS. Patients with a history of iron deficiency or low serum iron parameters should undergo evaluation for iron deficiency; patients who have histories suggestive of hemochromatosis or iron overload or elevated pre-treatment transferrin saturation or serum ferritin levels should undergo evaluation to determine the cause of these abnormalities before they are treated with iron. In all persons with RLS treated with oral iron, serum iron parameters should be re-measured once or twice yearly during therapy.     

Melatonin in Alzheimer's disease and other neurodegenerative disorders

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.     

A phase II,open-label,non-comparative study of Botulinum toxin in Restless Legs Syndrome

ObjectiveTo assess the efficacy of intradermally injected botulinum neurotoxin type A (BoNT/A) in patients with Restless Legs Syndrome (RLS).MethodsWe conducted an optimal two-stage, phase II exploratory, open label, non-comparative clinical trial. The primary outcome measure was the efficacy of BoNT/A defined by the proportion of patients (responders) with ?50% improvement of their RLS severity score at week 2 following injections compared to baseline score at inclusion. Twenty-seven patients were to be included in the first stage of the trial, which was to be stopped if less than nine responders were documented. Selected patients had a minimum score of 21 on the International RLS Rating Scale. They all received a series of 20 intradermal injections of 0.05 ml of BoNT/A in symptomatic areas in their lower limbs. Change of RLS severity was evaluated over a 6 months period.ResultsOf the 27 selected patients, only six achieved the primary endpoint at week 2. In these six patients, the median duration (Inter-Quartile Range) of the IRLSRS score improvement of at least 50% was 46 days (42–126).ConclusionsConsidering the proportion of responders as the primary endpoint of this trial, BoNT/A showed no efficacy in alleviating RLS sensory symptoms.     

Increased Frequency of Restless Legs Syndrome in Myasthenia Gravis

Background/Aims: The objective of this study was to assess the prevalence of restless legs syndrome (RLS) in patients with myasthenia gravis (MG). Methods: We interviewed 73 MG patients and 65 healthy controls by using a structured diagnostic questionnaire based on the International Restless Legs Syndrome Study Group diagnostic criteria. We also collected data about the course of MG therapy, the presence of other comorbidities, sleep complaints, and demographic characteristics. All of the MG patients underwent neurological assessment. Results: RLS was present in 43.2% of the MG patients and in 20% of the controls (p = 0.0029). We failed to identify a relationship between the prevalence of RLS and the duration and type of MG therapy, other comorbidities, age or sex of the patients. Patients with MG more frequently reported daytime sleepiness. For 9.4% of the RLS-positive MG patients, RLS symptoms represented the most disturbing health problem; for 46.9% of them, RLS was as problematic as other diseases. Conclusions: RLS is common in MG patients. MG patients consider RLS symptoms as a troublesome health problem.     

Validation of an algorithm for the diagnosis of Restless Legs Syndrome: The Restless Legs Syndrome-Diagnostic Index (RLS-DI)

BackgroundThere is a need for structured methods to improve sensitivity and specificity of diagnostic decision making in Restless Legs Syndrome (RLS). We present the RLS-Diagnostic Index (RLS-DI), a diagnostic algorithm which combines essential and supportive diagnostic criteria from patient interviews, polysomnography and neurological examination in an adaptive procedure.MethodThe RLS-DI consists of 10 items which are related to the essential diagnostic criteria established by the International RLS Study Group (five items) as well as their supportive criteria (3 items) and features associated with RLS (2 items). Items have to be completed using three categories per item that address frequency of occurrence of symptoms or certainty of presence or absence of other diagnostic information. Negative weights were given when the clinically most relevant items were not present. The RLS-DI was administered in a telephone interview to 179 patients (86 with RLS, 93 with other sleep disorders) of the 21 month cohort of one sleep center in Germany.ResultsWith receiver-operating characteristics, a cut-off of ?11 points on a scale ranging from ?22 (no RLS) to 20 (definite RLS) was identified by comparing the RLS-DI total score to the diagnosis of two independent sleep experts. Sensitivity was 93.0%, specificity was 98.9%, and 96.1% of the patients could be correctly diagnosed. Specificity was higher in items related to supportive or associated diagnostic information (95.7%) than in those related to the essential diagnostic criteria (81.7%). Patients with RLS scored a higher RLS-DI than those with primary insomnia or other neurological or psychiatric disorders (p < .001).ConclusionThe RLS-DI demonstrated the ability to validly diagnose an actual and persistently present Restless Legs Syndrome in patients of a sleep lab population and to exclude those patients whose sleep disturbances have other causes.     

Imaging Brain Functional and Metabolic Changes in Restless Legs Syndrome

Even though the pathophysiology of restless legs syndrome is not completely understood, several imaging studies have contributed to our understanding of the disease. Functional and metabolic impairment seems to be the pathophysiological core, tied to a single brain network or multiple connected brain networks, via neurotransmitter modifications. Positron emission tomography and single photon emission computed tomography studies support a dysfunction of dopaminergic pathways, involving not only the nigrostriatal pathway but also the mesolimbic pathway. Furthermore, a possible role of serotonergic neurotransmission has been suggested. Functional magnetic resonance imaging studies have demonstrated in restless legs syndrome patients a pathologic activation of cerebral areas belonging to both the sensorimotor and the limbic networks. Proton magnetic resonance spectroscopy has confirmed abnormality of the limbic system and suggested the presence of a glutamatergic disorder. Finally magnetic resonance studies using iron-sensitive sequences have demonstrated reduced iron content in several regions of the brain of restless legs syndrome patients. In this review we attempt to integrate all current imaging study results into a convergent pathophysiological interpretation.