Restless legs syndrome in Parkinson disease: Clinical characteristics, abnormal iron metabolism and altered neurotransmitters.

Relationships among clinical characteristics, iron metabolism and neurotransmitters in Parkinson disease (PD) patients with restless legs syndrome (RLS) remains unclear. We divided 218 patients into PD with and with no RLS (PD-RLS and PD-NRLS) groups by RLS-rating scale (RLS-RS) score. Motor and non-motor symptoms were rated by related scales. Iron and related proteins, and neurotransmitters in cerebrospinal fluid (CSF) and serum were measured. PD-RLS frequency was 40.37%. PD-RLS group had longer duration, higher stage and scores of motor symptoms, depression, anxiety, sleep disorders, fatigue and apathy, and increased transferrin and decreased iron, ferritin, dopamine (DA) and 5-hydroxytryptamine (5-HT) in CSF. In CSF of PD-RLS group, RLS-RS score was positively correlated with transferrin level and negatively correlated with iron and ferritin levels; RLS-RS score was negatively correlated with DA and 5-HT levels; transferrin level was negatively correlated with DA and 5-HT levels, and ferritin level was positively correlated with DA level. In serum, PD-RLS group had decreased iron and transferrin levels, which were negatively correlated with RLS-RS score. PD-RLS was common and severer in motor and some non-motor symptoms. Iron deficiency induced by its metabolism dysfunctions in peripheral and central systems might cause PD-RLS through decreasing brain DA and 5-HT.

Sleep disorders in Parkinson's disease: clinical features, iron metabolism and related mechanism.

OBJECTIVE: To investigate clinical features, iron metabolism and neuroinflammation in Parkinson's disease (PD) patients with sleep disorders (SD). METHODS: 211 PD patients were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a body of scales for motor symptoms and non-motor symptoms. 94 blood and 38 cerebral spinal fluid (CSF) samples were collected and iron and its metabolism-relating proteins, neuroinflammatory factors were detected and analyzed. RESULTS: 136 cases (64.5%) of PD patients were accompanied by SD. Factor with the highest score in PSQI was daytime dysfunction. Depression, restless leg syndrome, autonomic symptoms and fatigue contributed 68.6% of the variance of PSQI score. Transferrin level in serum and tumor necrosis factor-α level in CSF decreased, and the levels of iron, transferrin, lactoferrin and prostaglandin E2 in CSF increased in PD patients with SD compared with those without SD. In CSF, prostaglandin E2 level was positively correlated with the levels of transferrin and lactoferrin, and tumor necrosis factor-α level was negatively correlated with the levels of iron, transferrin and lactoferrin in CSF. CONCLUSIONS: Depression, restless leg syndrome, autonomic disorders and fatigue are the important contributors for the poor sleep in PD patients. Abnormal iron metabolism may cause excessive iron deposition in brain and be related to SD in PD patients through dual potential mechanisms, including neuroinflammation by activating microglia and neurotoxicity by targeting neurons. Hence, inhibition of iron deposition-related neuroinflammation and neurotoxicity may cast a new light for drug development for SD in PD patients.

Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency.

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of L-Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals.

Circadian rhythm of CSF monoamines and hypocretin-1 in restless legs syndrome and Parkinson's disease.

The symptoms of restless legs syndrome (RLS) have a circadian pattern and central nervous system dopamine has been implicated in the pathogenesis of the condition. We sought to characterize circadian variation in dopamine and related compounds in human cerebro-spinal fluid (CSF). CSF was continuously withdrawn for 22 h from an implanted lumbar intradural catheter and sampled from three patients with RLS, three patients with Parkinson's disease (PD) and three healthy volunteers. Patients had moderate disease severity and took no medications. We assayed CSF dopamine (DA), homovanillic acid (HVA), dihydroxy-phenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) from samples every 30 min by reversed-phase HPLC coupled with electrochemical detection. We also measured CSF levels of hypocretin-1 every hour by RIA. The procedure was well-tolerated. One patient ended the study early due to lumbar radicular pain and was not included in the analysis. There were no changes in CSF cell counts or protein levels from the first to the last samples. There was no difference in any of the compounds between groups, so we fit 24-h cosines to examine if the entire group had significant phase consistency. There was a peak for dopamine at 10 a.m. (p<0.025) and for HVA at 2 p.m. (p<0.01), but no evidence of a significant 24-h rhythm for DOPAC, 5-HIAA, the HVA/5-HIAA ratio, or hypocretin-1. These results demonstrate a circadian rhythm for CSF dopamine and HVA concentrations in humans, with higher levels in the daytime than at nighttime. This circadian variation could underlie the symptoms of RLS and sleep-related variation in motor function in PD.

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis.

BACKGROUND: Abnormally high CSF 3-OMD occurs frequently for RLS patients indicating either increased l-dopa synthesis, limitations in l-dopa decarboxylation or increased MAT/COMT activity, or some combination of these. Increased tyrosine hydroxylase activity was found on both the RLS autopsy and the rodent iron-deprivation model of RLS, suggesting increased DA synthesis in RLS. We, therefore, hypothesized elevated 3-OMD in RLS results from increased DA synthesis and that this should occur accordingly with increased HVA. It would then also reflect both the more severe iron insufficiency pathology of RLS and greater clinical severity, shown by the objective measure of PLMS/hr. METHODS: Patients off RLS medications and matched controls had lumbar punctures at either 10 a.m. or 10 p.m.; RLS patients were grouped by normal or abnormally high 3-OMD (>10 nmol/l). RESULTS: Forty-nine RLS patients (30 high, 19 normal 3-OMD) and 36 age- and gender-matched controls, analyzed separately by time of CSF collection, did not significantly differ in age or gender. RLS patients with high 3-OMD had significantly higher CSF HVA, while those with normal 3-OMD had consistently lower CSF HVA than controls. CSF ferritin was consistently lower compared to controls for the high 3-OMD but not the normal 3-OMD RLS patients. The PLMS/hr was significantly higher for RLS patients with high compared to normal 3-OMD, indicating high 3-OMD patients had more severe RLS. CONCLUSIONS: Abnormal elevation in 3-OMD for RLS patients may reflect increased dopamine synthesis for more severe but perhaps not mild RLS. These differences in the putative dopamine pathology of RLS may indicate different phases or expression of RLS biology or different underlying disease processes.

Circadian changes in CSF dopaminergic measures in restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) has a circadian component with symptoms being prominent at night. The dopaminergic (DAergic) system, which plays a role in RLS, entails circadian changes that parallel RLS symptom changes. The aim of this study was to look for relative and diurnal differences in DAergic activity. PATIENTS AND METHODS: All RLS subjects were treated prior to their enrollment in the study but were all drug-free for at least 2 weeks prior to evaluation. Cerebrospinal fluid (CSF) collected at 10 p.m. was used to determine DA-related co-factors and metabolites. These were compared to CSF values collected in a previous study at 10 a.m. RESULTS: The only significant finding from the 10 p.m. samples (30 RLS; 22 control) was increased 3-ortho-methyldopa (3OMD) for RLS compared to controls. A comparison of the 10 p.m. to 10 a.m. values (16 RLS; 9 controls) showed small, non-significant diurnal changes for controls but large diurnal changes in tetrahydrobiopterin (BH4), HVA:5HIAA ratio and 3OMD for RLS, with the 10 a.m. sample showing increases in all three CSF factors compared to the 10 p.m. sample. CONCLUSIONS: The greater diurnal changes in RLS suggest greater fluctuations than normal in DAergic circadian dynamics. The increased 3OMD concentration in the absence of concurrent exogenous levodopa (l-dopa) suggests changes in synthesis or metabolism of l-dopa in RLS.

Ferritin subunits in CSF are decreased in restless legs syndrome.

Restless legs syndrome (RLS) is a neurological disorder that may be related to iron misregulation at the level of the central nervous system. Evidence that iron is involved in RLS comes from magnetic resonance imaging data, autopsy studies, analyses of cerebrospinal fluid (CSF), and correlations of symptoms with serum ferritin. To further examine the possibility that brain iron status is insufficient in RLS, we determined ferritin levels in the CSF. Specifically, we differentiated between the H- and L-subunits of ferritin, because these peptides are expressed from different chromosomes and have different functions. We measured H- and L-ferritin subunit levels in control and RLS human CSF using immunoblot analysis and found that both H- and L-ferritin are significantly decreased in early but not late-onset RLS. Additionally, we quantified total protein in each CSF sample to establish that the decrease in ferritin subunits in RLS did not reflect a decrease in total protein in CSF. Furthermore, we used equal amounts of total CSF protein in the immunoblot analyses, in contrast to previously published studies that provided only volumetric data, to determine which approach was more accurate for quantifying the amount of ferritin relative to other proteins in CSF. Our results establish a protein standard in RLS, provide a comparative analysis of protein-controlled versus volumetric immunoblot techniques, and argue for a profound loss of iron storage capacity in the brain in RLS, specifically in the early onset RLS phenotype. These data suggest that CSF ferritin levels may provide a biomarker for assisting in the diagnosis of RLS.

CSF iron, ferritin and transferrin levels in restless legs syndrome.

The aim of this study is evaluating iron, ferritin, and transferrin in both serum and CSF in patients of restless legs syndrome (RLS), based on the hypothesis that iron deficiency in the central nervous system (CNS) causes the symptoms as a result of the dysfunction of dopaminergic systems. These parameters, polysomnographic sleep measures, and subjective evaluation of the sleep quality were compared in 10 patients of idiopathic RLS (RLS group) and 10 age-matched patients of psychophysiological insomnia without RLS symptoms (non-RLS group). With sleep patterns, sleep latency was longer and sleep efficiency was lower in the RLS group than those in the non-RLS group. Periodic leg movement index in the RLS group was higher than that of the non-RLS group. With serum examination, there were no significant differences for the iron, ferritin, and transferrin values between the both groups. With CSF examination, the iron and ferritin values were lower and the transferrin values were higher in the RLS group than those in the non-RLS group. There was positive correlation between the serum and CSF ferritin levels in the both groups, but the slope of the regression lines for the RLS group was lower than that for the non-RLS group. These results indicate low brain iron concentration caused by the dysfunction of iron transportation from serum to CNS in patients with idiopathic RLS.

Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients.

Cerebrospinal fluid (CSF) and blood obtained from 22 untreated or scarcely treated patients with moderate to severe restless legs syndrome (RLS; mean age, 58.6 +/- 13 years) and 11 control subjects (mean age, 56.6 +/- 12.9 years) were investigated for biogenic amines between 6:00 and 8:00 PM. We did not find any significant differences in the CSF concentrations of homovanillic acid, 3-ortho- methyl-dopa, levodopa, 5-hydroxytryptophan, 5-hydroxyindoleacetic acid, tetrahydrobiopterin, dihydrobiopterin, 5-methyltetrahydrofolate, and neopterin. In addition, serotonin in whole blood and plasma activity of aromatic amino acid decarboxylase were all normal. Our results suggest that dopaminergic and serotonergic release is not substantially affected in RLS.

CSF hypocretin-1 levels in restless legs syndrome.

CSF hypocretin-1 levels at 6 PM did not significantly differ between patients with restless legs syndrome (RLS) and control subjects as measured by direct radioimmunoassay and after acid extraction. The authors did not observe significant differences between early onset and late onset RLS. Hypocretin-1 levels did not correlate with RLS severity or polysomnographic measures. These results contrast with previous findings reporting significantly increased CSF hypocretin-1 in the late evening and mostly in early onset RLS.

Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome.

Hypocretin-1 levels were increased in evening CSF samples from subjects with restless legs syndrome, indicating altered hypocretin transmission in this sleep disorder. Increases in CSF hypocretin-1 levels were most striking in patients with early-onset restless legs syndrome.

CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome.

PURPOSE: To evaluate the role of CNS dopaminergic systems in Restless Legs Syndrome (RLS), homovanillic acid (HVA), tetrahydrobiopterin (BH4), and neopterin (NEOP), were assayed in CSF from RLS patients. The serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), was also measured. METHODS: CSF was taken from 16 RLS patients after 2 weeks off medication and from 14 control subjects. The CSF metabolites were determined using HPLC techniques. RESULTS: There was no significant difference in HVA or 5-HIAA, but NEOP and BH4 were higher in RLS patients. The RLS group was significantly older than the control group (64.2 +/- 9.2 years vs. 51.4 +/- 6.3 years; P < 0.001). A multiple regression analysis showed a strong correlation between age and 5-HIAA (r = 0.46, P = 0.04) and between age and NEOP (r = 0.61, P < 0.01). To eliminate the potential error created by the age difference between groups, an age-adjusted subgroup of RLS and control subjects were compared. There was still no difference found for HVA; however, 5-HIAA was now significantly lower (P < 0.01) in the RLS subgroup. Age-adjustment eliminated the differences previously found for NEOP, (P = 0.12), but BH4 continued to remain higher in the RLS group (P < 0.01). CONCLUSION: Differences in CSF HVA concentrations were not found. The changes in 5-HIAA and BH4 are of unclear clinical significance and require further assessment with appropriate age-matched controls.

Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome.

CSF and serum were obtained from 16 patients with idiopathic restless legs syndrome (RLS) and 8 age-matched healthy control subjects. Patients with RLS had lower CSF ferritin levels (1. 11 +/- 0.25 ng/mL versus 3.50 +/- 0.55 ng/mL; p = 0.0002) and higher CSF transferrin levels (26.4 +/- 5.1 mg/L versus 6.71 +/- 1.6 mg/L; p = 0.018) compared with control subjects. There was no difference in serum ferritin and transferrin levels between groups. The presence of reduced ferritin and elevated transferrin levels in CSF is indicative of low brain iron in patients with idiopathic RLS.