Levodopa increases oxidative stress and repulsive guidance molecule A levels: a pilot study in patients with Parkinson's disease.

Exposure to free radicals influences synthesis, degradation and function of proteins, such as repulsive guidance molecule A. Decay of this protein is essential for neuronal maintenance and recovery. Levodopa elevates oxidative stress. Therefore levodopa may impact repulsive guidance molecule A metabolism. Objectives were to investigate plasma concentrations of repulsive guidance molecule A, levodopa, cysteine and cysteinyl-glycine before and 1 h after levodopa application in patients with Parkinson's disease. Cysteine and cysteinyl-glycine as biomarkers for oxidative stress exposure decreased, repulsive guidance molecule A and levodopa rose. Repulsive guidance molecule A remained unchanged in levodopa naïve patients, but particularly went up in patients on a prior chronic levodopa regimen. Decay of cysteine specifically cysteinyl-glycine results from an elevated glutathione generation with rising cysteine consumption respectively from the alternative glutathione transformation to its oxidized form glutathione disulfide after free radical scavenging. Repulsive guidance molecule A rise may inhibit physiologic mechanisms for neuronal survival.

Levodopa-related cysteinyl-glycine and cysteine reduction with and without catechol-O-methyltransferase inhibition in Parkinson's disease patients.

Oxidative stress is influenced by the thiol homeostasis, which regulates the redox milieu via glutathione. Components of glutathione metabolism are cysteine and cysteinyl-glycine. Both substrates decay following levodopa application or dopamine-related oxidative stress. Objective was to investigate the impact of an acute levodopa application with and without catechol-O-methyltransferase inhibitor on cysteine- and cysteinyl-glycine plasma levels. On two investigation days, 13 patients with Parkinson's disease took one retarded release 200-mg levodopa/50 mg carbidopa-containing tablet or one 150-mg levodopa/50-mg carbidopa/200-mg entacapone formulation under standardized conditions. Levodopa, 3-O-methyldopa, cysteine and cysteinyl-glycine were measured at baseline, 80 and 140 min following levodopa administration. Cysteine and cysteinyl-glycine similarly decreased, levodopa was nearly equal during both conditions. Entacapone lowered 3-O-methyldopa. Cysteine decay may be due to an elevated glutathione generation, which consumes cysteine. Cysteinyl-glycine decrease results from the alternative glutathione transformation to its oxidized form glutathione dissulfide after free radical scavenging.

Fewer fluctuations, higher maximum concentration and better motor response of levodopa with catechol-O-methyltransferase inhibition.

Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.

Longitudinal evaluation of polyneuropathy in Parkinson's disease.

BACKGROUND: Increasing evidence indicates a higher prevalence of polyneuropathy (PNP) in Parkinson's disease (PD). However, the involvement of large fiber neuropathy in PD still remains poorly understood. Given the lack of longitudinal data, we investigated the course of PNP associated with PD. METHODS: In total, 41 PD patients underwent comprehensive clinical evaluation including motor and non-motor assessments as well as nerve conduction studies at baseline and at 2 years of follow-up. The definition of PNP was based on electrophysiological standard criteria. Common causes of PNP were excluded. RESULTS: At baseline, PNP was diagnosed in 65.85% of PD patients via electroneurography. Patients with PNP presented with higher age (p = 0.019) and PD motor symptom severity (UPDRS III; p < 0.001). Over the course of 2 years, PNP deteriorated in 21.95% of cases, and 26.83% remained without PNP. Deterioration of nerve amplitude was most prevalent in the median sensory nerve affecting 57.58% of all PD cases with an overall reduction of median sensory nerve amplitude of 45.0%. With regard to PD phenotype, PNP progression was observed in 33.33% of the tremor dominant and 23.81% of the postural instability/gait difficulties subtype. Decrease of sural nerve amplitude correlated with lower quality of life (PDQ-39, p = 0.037) and worse cognitive status at baseline (MoCA, p = 0.042). CONCLUSION: The study confirms the high PNP rate in PD, and demonstrates a significant electrophysiological progression also involving nerves of the upper extremities. Longitudinal studies with larger cohorts are urgently needed and should elucidate the link between PD and PNP with the underlying pathomechanisms.

COVID-19 outcomes in hospitalized Parkinson's disease patients in two pandemic waves in 2020: a nationwide cross-sectional study from Germany.

BACKGROUND: The individualized clinical and public health management of the COVID-19 pandemic have changed over time, including care of people with PD. The objective was to investigate whether in-hospital COVID-19 outcomes and hospital care utilization of people with PD differed between the first two pandemic waves (W) 2020 in Germany. METHODS: We conducted a nationwide cross-sectional study of inpatients with confirmed COVID-19 and PD between March 1 and May 31 (W1), and October 1 and December 31 (W2), 2020 and 2019, using an administrative database. Outcomes were in-hospital mortality, ICU admission rate, change in hospital care utilization, demographical data, PD clinical characteristics, and selected comorbidities. Differences were assessed between waves, PD/non-PD groups, and years. RESULTS: We identified 2600 PD COVID-19 inpatients in W2 who in total showed higher in-hospital mortality rates and lower ICU admission rates, compared to both W1 (n = 775) and W1/W2 non-PD COVID-19 inpatients (n = 144,355). Compared to W1, W2 inpatients were more long-term care-dependent, older, more of female sex, and had less advanced disease. During both waves, PD inpatients were older, more frequently male and long-term care-dependent, and showed more risk comorbidities than non-PD COVID-19 inpatients. Decreases in hospital care utilization were stronger than average for PD inpatients but relatively weaker during W2. Non-COVID-19 PD inpatients showed poorer in-hospital outcomes in 2020 than in 2019 with better outcomes during W2. CONCLUSIONS: In-hospital COVID-19 outcomes and hospital care utilization of PD patients in Germany differed between the two pandemic waves in 2020 with increased in-hospital mortality for PD COVID-19. Overall hospital care utilization for PD was increased during W2. TRIAL REGISTRATION: No trial registration or ethical approval was required because data were publicly available, anonymized, and complied with the German data protection regulations.

Cysteinyl-glycine reduction as marker for levodopa-induced oxidative stress in Parkinson's disease patients.

Oxidative stress is influenced by the thiol homeostasis, which determines the redox milieu. One of its components is Cysteinyl-glycine (Cys-Gly) generation, as its metabolic precursor is the free radicals scavenging glutathione. Levodopa is under suspicion to promote oxidative stress via the turnover of its metabolite dopamine in abundant mitochondria. Objective was to investigate the impact of levodopa on Cys-Gly plasma metabolism. Fifteen patients with Parkinson's disease orally took one 200-mg levodopa/50-mg carbidopa (CD) containing tablet. Levodopa, its derivative 3-O-methyldopa (3-OMD), and free Cys-Gly were measured at baseline, 60 and 120 min following levodopa/CD administration. Cys-gly concentrations decreased, levodopa and 3-OMD levels increased. Inverse relationships appeared between computed differences of Cys-gly and 3-OMD bioavailability. We conclude that Cys-Gly decline is related to levodopa metabolism to 3-OMD. Cys-Gly decay may result from the alternative transformation of glutathione to its oxidized form glutathione dissulfide as consequence of free radical scavenging.

Pain perception, pain drug therapy and health status in patients with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is traditionally characterized as a movement disorder; however, sensory perception problems including pain syndromes are also frequent. We performed a survey to analyze the relations between health status, pain perception and gender in 4,086 PD patients. Moreover, the participants should tick whether they took pain medications or not. SUBJECTS AND METHODS: The questionnaire included the EQ-5D and visual analogue scales (VAS) on pain, which asked for mean (VAS A), most (VAS B), and minimal (VAS C) intensity of pain during an interval of 4 weeks prior to the completion of the survey. RESULTS: PD patients were divided into three groups according to their EQ-5D total score (I: <8; II: 8-9; III: 10-15). An impairment of health status occurred in relation to the increase in pain syndromes in PD patients. There was a significant increase in VAS scores in relation to the EQ-5D group membership. Female patients reported more on pain and more frequently received a pain drug treatment than male patients. Significant associations were found between the VAS and the EQ-5D scores, and the correlation coefficients were higher in men than in women. CONCLUSIONS: Pain is associated with the health status of PD patients and worsens it. More female than male PD patients have to deal with handling of pain and pain drug treatment.

Elevation of total homocysteine levels in patients with Parkinson's disease treated with duodenal levodopa/carbidopa gel.

Levodopa/carbidopa (LD/CD) application elevates total plasma homocysteine (thcys). We determined thcys-, LD- and 3-O-methyldopa (3-OMD) concentrations in 28 patients with Parkinson's disease (PD) on a LD/CD duodenal gel treatment. We found a distinct thcys increase (29.52 ± 28.98 µmol/l [median ± SD]) above the 15 µmol/l threshold and a significant (R = 0.7) correlation between LD and 3-OMD. thcys ascent was observed in relation with the onset of atherosclerosis, non-motor symptoms and polyneuropathy in PD patients in the long term.

Effect of exercise on reactivity and motor behaviour in patients with Parkinson's disease.

BACKGROUND: Following cued levodopa (LD) intake, endurance exercise showed a beneficial effect on scored motor performance in patients with Parkinson's disease (PD) in comparison with rest. This may result from an exercise induced increase in endogenous dopamine synthesis. As a result, beneficial effects on movement and reactivity may occur. OBJECTIVES: To measure reactivity and motor performance in a repeated fashion with instrumental tasks after cued administration of soluble 200 mg of LD/50 mg of benserazide. DESIGN: PD patients consecutively performed paradigms, which assess reactivity and movement performance, after a standardised period of rest or of age-related, heart rate adapted endurance exercise on two consecutive days in a random order. RESULTS: Reactivity and execution of simple and complex motion series were significantly better following exercise than after rest. DISCUSSION: Endurance exercise has a beneficial effect on reactivity and movement behaviour in PD patients following cued application of LD probably due to an augmented synthesis and release of dopamine and other catecholamines and release in the prefrontal cortex, the nucleus accumbens and the basal ganglia. Small changes in catecholamine modulation of prefrontal cortex cells can have profound effects on the ability of the prefrontal cortex to guide behaviour. Previous exercise may also improve pedunculopontine nucleus function, which is involved in motor-related attention processes.

Parkinson's Disease Multimodal Complex Treatment improves motor symptoms, depression and quality of life.

Parkinson's disease (PD) is the world's fastest growing neurological disorder disabling patients through a broad range of motor and non-motor symptoms. For the clinical management, a multidisciplinary approach has increasingly been shown to be beneficial. In Germany, inpatient Parkinson's Disease Multimodal Complex Treatment (PD-MCT) is a well-established and frequent approach, although data on its effectiveness are rare. We conducted a prospective real-world observational study in 47 subjects [age (M ± SD): 68.5 ± 9.0 years, disease duration: 8.5 ± 5.3 years, modified Hoehn and Yahr stage (median, IQR): 3, 2.5-3] aiming at evaluating the effectiveness of 14-day PD-MCT in terms of quality of life (Parkinson's Disease Questionnaire, EuroQol), motor [Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III], Timed Up and Go Test, Purdue Pegboard Test) and non-motor symptoms (revised Beck Depression Inventory). Six weeks after hospital discharge, a follow-up examination was performed. PD patients with a predominantly moderate disability level benefited from PD-MCT in terms of health-related quality of life, motor symptoms and non-motor symptoms (depression). Significant improvements were found for social support, emotional well-being and bodily discomfort domains of health-related quality of life. Sustainable improvement occurred for motor symptoms and the subjective evaluation of health state. We found a higher probability of motor response especially for patients with moderate motor impairment (MDS-UPDRS III ≥ 33). In conclusion, Parkinson's Disease Multimodal Complex Treatment improves motor symptoms, depression and quality of life. A more detailed selection of patients who will benefit best from this intervention should be examined in future studies.

Parkinson's Disease Multimodal Complex Treatment (PD-MCT): Analysis of Therapeutic Effects and Predictors for Improvement.

Parkinson's disease Multimodal Complex Treatment (PD-MCT) is a multidisciplinary inpatient treatment approach that has been demonstrated to improve motor function and quality of life in patients with Parkinson's disease (PD). In this study, we assessed the efficacy of PD-MCT and calculated predictors for improvement. We performed a prospective analysis in a non-randomized, open-label observational patient cohort. Study examinations were done at baseline (BL), at discharge after two-weeks of inpatient treatment (DC) and at a six-week follow-up examination (FU). Besides Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III as a primary outcome, motor performance was measured by the Timed Up-and-Go (TUG), the Berg Balance Scale (BBS) and the Perdue Pegboard Test (PPT). Until DC, motor performance improved significantly in several parameters and was largely maintained until FU (MDS-UPDRS III BL-to-DC: -4.7 ± 1.2 (SE) p = 0.0012, BL-to-FU: -6.1 ± 1.3 p = 0.0001; TUG BL-to-DC: -2.5 ± 0.9 p = 0.015, BL-to-FU: 2.4 ± 0.9 p = 0.027; BBS BL-to-DC: 2.4 ± 0.7 p = 0.003, BL-to-FU: 1.3 ± 0.7 p = 0.176, PPT BL-to-DC: 3.0 ± 0.5 p = 0.000004, BL-to-FU: 1.7 ± 0.7 p = 0.059). Overall, nontremor items were more therapy responsive than tremor items. Motor complications evaluated with MDS-UPDRS IV occurred significantly less frequent at DC (-1.8 ± 0.5 p = 0.002). Predictor analyses revealed an influence of initial motor impairment and disease severity on the treatment response in different motor aspects. In summary, we demonstrate a significant positive treatment effect of PD-MCT on motor function of PD patients which can be maintained in several parameters for an extended time period of six weeks and identify predictors for an improvement of motor function.

Peripheral COMT inhibition prevents levodopa associated homocysteine increase.

Chronic levodopa (LD)/dopadecarboxylase inhibitor (DDI) increases homocysteine generation as side reaction of O-methylation. Aim was to investigate the impact of the peripheral COMT inhibitor entacapone (EN) on plasma concentrations of homocysteine, LD and 3-O-methyl-dopa (3-OMD). Patients with Parkinson's disease (PD) received on two consecutive days in a standardised fashion one single dose of 200 mg retarded release LD/carbidopa (CD) or of 150 mg LD/CD/EN, since both were shown to have simultaneous pharmacokinetic LD behaviour. Homocysteine increased after retarded release LD/CD application, but not following LD/CD/EN intake. Homocysteine was lower during the LD/CD/EN condition 80 min after baseline when compared with its levels after LD/CD administration. LD levels simultaneously rose on both days. 3-OMD concentrations did not change. Acute LD/CD application caused a rise of homocysteine levels, which was prevented by LD/CD/EN intake. Therefore, peripheral COMT inhibition may have a beneficial effect on putative, controversially debated components of homocysteine-related progression of PD.

Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson's Disease.

The etiology of Parkinson's disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

Emerging Immunotherapies for Parkinson Disease.

Symptomatic treatment options for Parkinson disease have steadily improved, and individualized therapeutic approaches are becoming established for every stage of the disease. However, disease-modifying therapy with a causal approach is still unavailable. The central causative role of alpha-synuclein pathology, including its progressive spread to most areas of the CNS, has been widely recognized, and a strong involvement of immune responses has recently been discovered. New immunologic technologies have been shown to effectively prevent the progression of alpha-synuclein pathology in animal models. These approaches have recently been translated into the first human clinical trials, representing a novel starting point for the causal therapy of Parkinson disease. In this review, the pathomechanistic role of alpha-synuclein and its influence on the surrounding cellular environment are analyzed with a strong focus on immune responses and neuroinflammation. The potential of novel immunotherapeutic approaches that reduce the burden of alpha-synuclein pathology in the CNS is critically evaluated, and currently ongoing human clinical trials are presented. The clinical development of these new immunotherapies is progressing rapidly and gives reason to hope that a causal therapy of Parkinson disease could be possible in the foreseeable future.

Dynamics of Parkinson's Disease Multimodal Complex Treatment in Germany from 2010⁻2016: Patient Characteristics, Access to Treatment, and Formation of Regional Centers.

Parkinson's disease (PD) is currently the world's fastest-growing neurological disorder. It is characterized by motor and non-motor symptoms which progressively lead to significant clinical impairment, causing a high burden of disease. In addition to pharmacological therapies, various non-pharmacological treatment options are available. A well established and frequently used multiprofessional inpatient treatment concept in Germany is "Parkinson's disease multimodal complex treatment" (PD-MCT) which involves physiotherapists, occupational therapists, speech therapists, and other specializations for the optimization of treatment in PD (ICD G20) and other Parkinsonian syndromes (ICD G21 and G23). In this study we analyze the PD-MCT characteristics of 55,141 PD inpatients who have been integrated into this therapy concept in Germany in the years 2010⁻2016. We demonstrate that PD-MCT is increasingly applied over this time period. Predominately, PD patients with advanced disease stage and motor fluctuations in age groups between 45 and 69 years were hospitalized. In terms of gender, more male than female patients were treated. PD-MCT is provided primarily in specialized hospitals with high patient numbers but a minor part of all therapies is performed in a rather large number of hospitals with each one treating only a few patients. Access to PD-MCT differs widely across regions, leading to significant migration of patients from underserved areas to PD-MCT centers ⁻ a development that should be considered when implementing such therapies in other countries. Furthermore, our data imply that despite the overall increase in PD-MCT treatments during the observational period, the restricted treatment accessibility may not adequately satisfy current patient´s need.

Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson's Disease.

We took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson's disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites.

Brainstem Raphe Alterations in TCS: A Biomarker for Depression and Apathy in Parkinson's Disease Patients.

Depression and apathy can both be present in patients with Parkinson's disease (PD) while e. g., essential tremor (ET) patients mostly only report depressive symptoms. In PD, depression has been linked with brainstem raphe (BR) signal alterations in transcranial sonography (TCS) but apathy has not been evaluated in such terms as a putative biomarker. Furthermore, the BR has only been investigated using a singular axial TCS examination plane, although coronal TCS examination allows a much more accurate evaluation of the craniocaudal formation of serotonergic raphe structures in the midbrain area. The objective of this study was to investigate the value of coronal TCS examination for the detection of BR signal alterations and clinically correlate it to apathy in patients with PD, ET and healthy controls (HC). We prospectively included PD patients (n = 31), ET patients (n = 16), and HC (n = 16). All were examined by TCS in the axial and coronal plane with focus on BR signal alterations. LARS and BDI-II scores were conducted to assess apathic and depressive symptoms in the study population. In a detailed analysis we found that the correlation of coronal and axial TCS alterations of BR was very high (rho = 0.950, p < 0.001). BR signal alterations were more frequent in PD patients than in ET patients and HC, while it was not different between ET patients and HC. In the PD patient group, BDI-II and LARS scores were negatively correlated to BR signal changes in TCS in a significant manner (BDI-II and axial BR: p = 0.019; BDI-II and coronal BR: p = 0.011; LARS and axial BR: p = 0.017; LARS and coronal BR: p = 0.023). Together in this brainstem ultrasound study we find a significant association of BR signal alterations with clinically evident apathy and depression in patients with PD. Therefore, TCS might enable the identification of a subgroup of PD patients which are at higher risk to suffer from or to develop depression or apathy.

Association of exposure to manganese and iron with relaxation rates R1 and R2*- magnetic resonance imaging results from the WELDOX II study.

OBJECTIVE: Magnetic resonance imaging is a non-invasive method that allows the indirect quantification of manganese (Mn) and iron (Fe) accumulation in the brain due to their paramagnetic features. The WELDOX II study aimed to explore the influence of airborne and systemic exposure to Mn and Fe on the brain deposition using the relaxation rates R1 and R2* as biomarkers of metal accumulation in regions of interest in 161 men, including active and former welders. MATERIAL AND METHODS: We obtained data on the relaxation rates R1 and R2* in regions that included structures within the globus pallidus (GP), substantia nigra (SN), and white matter of the frontal lobe (FL) of both hemispheres, as well as Mn in whole blood (MnB), and serum ferritin (SF). The study subjects, all male, included 48 active and 20 former welders, 41 patients with Parkinson's disease (PD), 13 patients with hemochromatosis (HC), and 39 controls. Respirable Mn and Fe were measured during a working shift for welders. Mixed regression models were applied to estimate the effects of MnB and SF on R1 and R2*. Furthermore, we estimated the influence of airborne Mn and Fe on the relaxation rates in active welders. RESULTS: MnB and SF were significant predictors of R1 but not of R2* in the GP, and were marginally associated with R1 in the SN (SF) and FL (MnB). Being a welder or suffering from PD or HC elicited no additional group effect on R1 or R2* beyond the effects of MnB and SF. In active welders, shift concentrations of respirable Mn>100µg/m3 were associated with stronger R1 signals in the GP. In addition to the effects of MnB and SF, the welding technique had no further influence on R1. CONCLUSIONS: MnB and SF were significant predictors of R1 but not of R2*, indicative of metal accumulation, especially in the GP. Also, high airborne Mn concentration was associated with higher R1 signals in this brain region. The negative results obtained for being a welder or for the techniques with higher exposure to ultrafine particles when the blood-borne concentration was included into the models indicate that airborne exposure to Mn may act mainly through MnB.

Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study.

OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23µg/m3 and 110µg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(ß)=0.87, p<0.01) and choline (exp(ß)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations.

Endurance exercise modulates levodopa induced growth hormone release in patients with Parkinson's disease.

Acute levodopa (LD) application and exercise release human growth hormone (GH). An earlier trial showed, that combined stimulus of exercise and LD administration is the best provocative test for GH response in healthy participants. Objective was to show this combined effect of LD application and exercise on GH response and to investigate the impact on LD metabolism in 20 previously treated patients with Parkinson's disease (PD). We measured GH- and LD plasma concentrations following soluble 200 mg LD/50 mg benserazide administration during endurance exercise and rest on two separate consecutive days. GH concentrations significantly increased on both days, but GH release was significantly delayed during rest. LD metabolism was not altered due to exercise in a clinical relevant manner. Exercise induced a significant faster LD stimulated GH release in comparison with the rest condition. We did not find the supposed increase of LD induced GH release by endurance exercise. We assume, that only a limited amount of GH is available for GH release in the anterior pituitary following an acute 200 mg LD administration. GH disposal also depends on growth hormone releasing hormone (GHRH), which is secreted into hypothalamic portal capillaries. During the exercise condition, the resulting higher blood pressure supports blood flow and thus GHRH transport towards the GH producing cells in the pituitary. This might additionally have caused the significant faster GH release during exercise.