Mental stress induces endothelial dysfunction by AT1R-mediated redox imbalance in overweight/obese men.

The main goal of this study was to determine whether oxidative imbalance mediated by AT1 receptor (AT1R) is responsible for deleterious endothelial responses to mental stress (MS) in overweight/obese class I men. Fifteen overweight/obese men (27±7 years old; 29.8±2.6 kg/m2) participated in three randomized experimental sessions with oral administration of the AT1R blocker olmesartan (40 mg; AT1R blockade) or ascorbic acid (AA; 3g) infusion or placebo [both intravenously (0.9% NaCl) and orally]. After two hours, endothelial function was determined by flow-mediated dilation (FMD) before (baseline), 30 min (30MS), and 60 min (60MS) after a five-minute acute MS session (Stroop Color Word Test). Blood was collected before (baseline), during MS, and 60 min after MS for redox homeostasis profiling: lipid peroxidation (TBARS; thiobarbituric acid reactive species), protein carbonylation, and catalase activity by colorimetry and superoxide dismutase (SOD) activity by an ELISA kit. At the placebo session, FMD significantly decreased 30MS (P=0.05). When compared to baseline, TBARS (P<0.02), protein carbonylation (P<0.01), catalase (P<0.01), and SOD (P<0.01) increased during the placebo session. During AT1R blockade, FMD increased 30 min after MS (P=0.01 vs baseline; P<0.01 vs placebo), while AA infusion increased FMD only 60 min after MS. No differences were observed during MS with the AT1R blockade and AA regarding TBARS, protein carbonylation, catalase, and SOD. AT1R-mediated redox imbalances played an important role in endothelial dysfunction to mental stress.

Mental stress induces endothelial dysfunction by AT1R-mediated redox imbalance in overweight/obese men

The main goal of this study was to determine whether oxidative imbalance mediated by AT1 receptor (AT1R) is responsible for deleterious endothelial responses to mental stress (MS) in overweight/obese class I men. Fifteen overweight/obese men (27±7 years old; 29.8±2.6 kg/m2) participated in three randomized experimental sessions with oral administration of the AT1R blocker olmesartan (40 mg; AT1R blockade) or ascorbic acid (AA; 3g) infusion or placebo [both intravenously (0.9% NaCl) and orally]. After two hours, endothelial function was determined by flow-mediated dilation (FMD) before (baseline), 30 min (30MS), and 60 min (60MS) after a five-minute acute MS session (Stroop Color Word Test). Blood was collected before (baseline), during MS, and 60 min after MS for redox homeostasis profiling: lipid peroxidation (TBARS; thiobarbituric acid reactive species), protein carbonylation, and catalase activity by colorimetry and superoxide dismutase (SOD) activity by an ELISA kit. At the placebo session, FMD significantly decreased 30MS (P=0.05). When compared to baseline, TBARS (P<0.02), protein carbonylation (P<0.01), catalase (P<0.01), and SOD (P<0.01) increased during the placebo session. During AT1R blockade, FMD increased 30 min after MS (P=0.01 vs baseline; P<0.01 vs placebo), while AA infusion increased FMD only 60 min after MS. No differences were observed during MS with the AT1R blockade and AA regarding TBARS, protein carbonylation, catalase, and SOD. AT1R-mediated redox imbalances played an important role in endothelial dysfunction to mental stress.

Disruption of NREM sleep and sleep-related spatial memory consolidation in mice lacking adult hippocampal neurogenesis.

Cellular plasticity at the structural level and sleep at the behavioural level are both essential for memory formation. The link between the two is not well understood. A functional connection between adult neurogenesis and hippocampus-dependent memory consolidation during NREM sleep has been hypothesized but not experimentally shown. Here, we present evidence that during a three-day learning session in the Morris water maze task a genetic knockout model of adult neurogenesis (Cyclin D2-/-) showed changes in sleep macro- and microstructure. Sleep EEG analyses revealed a lower total sleep time and NREM fraction in Cyclin D2-/- mice as well as an impairment of sleep specific neuronal oscillations that are associated with memory consolidation. Better performance in the memory task was associated with specific sleep parameters in wild-type, but not in Cyclin D2-/- mice. In wild-type animals the number of proliferating cells correlated with the amount of NREM sleep. The lack of adult neurogenesis led to changes in sleep architecture and oscillations that represent the dialog between hippocampus and neocortex during sleep. We suggest that adult neurogenesis-as a key event of hippocampal plasticity-might play an important role for sleep-dependent memory consolidation and modulates learning-induced changes of sleep macro- and microstructure.

[Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) for assessment of non-motor symptoms in dystonia : Intercultural adaptation in the German language]. / Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) zur Erhebung nichtmotorischer Symptome bei Dystonie : Interkulturelle Adaptation in deutscher Sprache.

BACKGROUND: Non-motor symptoms (NMS) in patients with dystonia have a relevant impact on health-related quality of life; however, a comprehensive easy to use NMS assessment tool for clinical bedside use is currently not available. OBJECTIVE: The validated German version of the dystonia non-motor symptoms questionnaire (DNMSQuest) for assessing NMS in craniocervical dystonia is presented. METHODS: The DNMSQuest in the German language was developed based on internationally recognized standards for intercultural adaptation of self-completed patient questionnaires. Translation of the original English questionnaire into the German language as well as back translation to English was carried out independently by four bilingual specialists in neurological movement disorders. In each case a consensus version accepted by each translator was created by another neurologist. The back translated English version was compared with the original English questionnaire for relevant linguistic and content discrepancies by a neurologist who was significantly involved in the development of the original questionnaire. The final German version was used in 130 patients with cervical dystonia and 48 healthy controls in an international, multicenter validation study. RESULTS: An interculturally adapted validated version of the DNMSQuest in the German and English languages was developed for rapid bedside assessment and evaluation of NMS in cervical dystonia. CONCLUSION: The DNMSQuest successfully bridges the current gap of a validated disease-specific, patient self-administered, short, comprehensive questionnaire for NMS assessment in routine clinical practice in craniocervical dystonia. It is envisaged that this tool will be useful for the clinical practice and trials.

Ascorbic acid inhibits vascular remodeling induced by mental stress in overweight/obese men.

BACKGROUND: Mental stress (MS) is related to endothelial dysfunction in overweight/obese men. It is believed that the pro-oxidant profile, associated with an imbalance in the vascular remodeling process, may contribute to deleterious effects of MS on endothelial function. However, it is unknown whether administration of ascorbic acid (AA), a potent antioxidant, can prevent oxidative and remodeling dysfunction during MS in these subjects. METHODS: Fourteen overweight/obese grade I men (27 ± 7 years; 29.7 ± 2.6 kg·m-2) underwent the Stroop Color Word Test for 5 min to induce MS after AA (3 g) or placebo (PL, 0.9% NaCl) intravenous infusions. Venous blood samples were collected at baseline and the last minute of MS to measure nitrite concentration (chemiluminescence), protein carbonylation, thiobarbituric acid reactive substances (TBARS) and catalase activity (colorimetric assays), superoxide dismutase (SOD; immunoenzymatic assay), activities of active/inactive (pro) forms of metalloproteinases-9 and -2 (MMP; zymography) and its respective tissue inhibitors concentration (TIMP-1 and TIMP-2; immunoenzymatic assays). RESULTS: At baseline, MMP-9 activity (p < 0.01), the MMP-9/proMMP-9 ratio (p = 0.02) and TIMP-1 concentration (p = 0.05) were reduced, whereas proMPP-9 activity was increased (p = 0.02) after AA compared to PL infusion. After PL infusion, MS increased protein carbonylation (p < 0.01), catalase (p < 0.01), and the MMP-9/proMMP-9 ratio (p = 0.04) when compared to baseline. AA infusion reduced protein carbonylation (p = 0.02), MMP-9 activity (p < 0.01), and MMP-9/pro-MMP-9 ratio (p < 0.01), while SOD (p = 0.04 vs baseline), proMPP-9 (p < 0.01 vs PL), MMP-2 (p < 0.01 vs PL) and TIMP-2 (p = 0.02 vs baseline) remained elevated during MS. CONCLUSIONS: AA appears to minimize the oxidative imbalance and vascular remodeling induced by MS.

Age-dependent neurodegeneration and organelle transport deficiencies in mutant TDP43 patient-derived neurons are independent of TDP43 aggregation.

TAR DNA-binding protein 43 (TDP43) plays a significant role in familiar and sporadic amyotrophic lateral sclerosis (ALS). The diverse postulated mechanisms by which TDP43 mutations cause the disease are not fully understood. Human wildtype and TDP43 S393L and G294V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs. Mutant hTDP43 and wildtype motor neuron cultures did not differ in neuron differentiation capacity during early maturation stage. During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only in TDP43 mutant cultures. Additionally mitochondria and lysosomes of aging spinal motor neurons revealed robust TDP43 mutation dependent abnormal phenotypes in size, shape, speed and motility which all appeared without TDP43 mislocalization or aggregation formation. Furthermore, D-sorbitol - known to induce stress granules and cytoplasmic mislocalization of TDP43 - rescued axonal trafficking phenotypes without signs of TDP43 mislocalization or aggregation formation. Our data indicate TDP43 mutation-dependent but cytosolic aggregation-independent mechanisms of motor neuron degeneration in TDP43 ALS.

Rasagiline improves polysomnographic sleep parameters in patients with Parkinson's disease: a double-blind, baseline-controlled trial.

BACKGROUND AND PURPOSE: The aim was to study the effects of rasagiline on sleep quality in patients with Parkinson's disease (PD) with sleep disturbances. Sleep disorders are common in PD. Rasagiline is widely used in patients with PD, but double-blind polysomnographic trials on its effects on sleep disturbances are missing. METHODS: This was a single-center, double-blind, baseline-controlled investigator-initiated clinical trial of rasagiline (1 mg/day) over 8 weeks in patients with PD with sleep disturbances. Blinding was achieved by running a strategic matched placebo parallel group. Co-primary outcome measures were the changes between baseline and end of the treatment period in sleep maintenance/efficiency as assessed by polysomnography and the Parkinson's Disease Sleep Scale Version 2 (PDSS-2) score. RESULTS: A total of 20 of 30 patients were randomized to rasagiline (mean ± SD age, 69.9 ± 6.9 years; 10 male; Hoehn-Yahr stage, 1.9 ± 0.8). Compared with baseline, sleep maintenance was significantly increased at the end of the treatment period (relative change normalized to baseline, +16.3 ± 27.9%; P = 0.024, paired two-sided t-test) and a positive trend for sleep efficiency was detected (+12.1 ± 28.6%; P = 0.097). Treatment with rasagiline led to significantly decreased wake time after sleep onset, number of arousals, percentage of light sleep and improved daytime sleepiness as measured by the Epworth Sleepiness Scale. We did not observe changes in the co-primary endpoint PDSS-2 score, and no correlations of polysomnographic sleep parameters or PDSS-2 score with motor function (Unified Parkinson's Disease Rating Scale motor score). Rasagiline was well tolerated with no unexpected adverse events. CONCLUSIONS: In patients with PD with sleep disturbances, rasagiline showed beneficial effects on sleep quality as measured by polysomnography. These effects were probably not related to motor improvement or translated into improved overall sleep quality perception by patients.

[King's Parkinson's disease pain scale : Intercultural adaptation in the German language]. / King's Parkinson's Disease Pain Scale : Interkulturelle Adaption in deutscher Sprache.

BACKGROUND: Pain is a frequent symptom of idiopathic Parkinson's disease and has a substantial impact on quality of life. The King's Parkinson's disease pain scale (KPPS) has become internationally established and is an English-language, standardized, reliable and valid scale for evaluation of pain in idiopathic Parkinson's disease. This article presents a validated version in German. METHOD: The German translation was adapted interculturally and developed using an internationally recognized procedure in consultation with the authors of the original publication. The primary text was first translated by two bilingual neuroscientists independently of one another. Thereafter, the two versions were collated to generate a consensus version, which was accepted by the translators and preliminarily trialled with 10 patients. Hereafter, the German version was re-translated back into English by two other neurologists, again independently of one another, and a final consensus was agreed on using these versions. This English version was then compared with the original text by all of the translators, a process which entailed as many linguistic modifications to the German version as the translators considered necessary to generate a linguistically acceptable German version that was as similar as possible to the original English version. After this test text had been subsequently approved by the authors, the German text was applied to 50 patients in two hospitals, and reviewed as to its practicability and comprehensibility. RESULTS: This work led to the successful creation of an inter-culturally adapted and linguistically validated German version of the KPPS. DISCUSSION: The German version presented here is a useful scare for recording and quantifying pain in empirical studies, as well as in clinical practice.

[Cellular replacement strategies and adult neurogenesis in idiopathic Parkinson's disease]. / Zellersatz und adulte Neurogenese beim idiopathischen Parkinson-Syndrom.

Parkinson's disease (PD) is the most common age-related movement disorder and characterized by slowly progressive neurodegeneration resulting in motor symptoms, such as bradykinesia, rigidity, tremor and postural instability. Moreover, non-motor symptoms, such as hyposmia, anxiety and depression reduce the quality of life in PD. Motor symptoms are associated with a distinct striatal dopaminergic deficit resulting from axonal dysfunction and neuronal loss in the substantia nigra (SN). Recent progress in stem cell technology allows the optimization of cellular transplantation strategies in order to alleviate the motor deficit, which potentially leads to a reactivation of this therapeutic strategy. Besides neurodegenerative processes impaired adult neurogenesis and consequentially reduced endogenous cellular plasticity may play an important role in PD. This article discusses the notion that non-motor symptoms in PD may partly be explained by reduced adult neurogenesis in the olfactory bulb and hippocampus.

Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.

BACKGROUND: Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered. METHOD: The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates. RESULTS: Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis. CONCLUSIONS: Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

Novel frameshift mutation in the CACNA1A gene causing a mixed phenotype of episodic ataxia and familiar hemiplegic migraine.

Episodic ataxia type 2 (EA2, MIM#108500) is the most common form of EA and an autosomal-dominant inherited disorder characterized by paroxysmal episodes of ataxia. The disease causative gene CACNA1A encodes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel. We report on a family with a novel mutation in the CACNA1A gene. The clinical symptoms within the family varied from the typical clinical presentation of EA2 with dysarthria, gait ataxia and oculomotor symptoms to migraine and dystonia. A novel nonsense mutation of the CACNA1A gene was identified in all affected family members and is most likely the disease causing molecular defect. The pharmacological treatment with acetazolamide (AAA) was successful in three family members so far. Treatment with AAA led to a reduction of migraine attacks and an improvement of the dystonia. This relationship confirmed the hypothesis that this novel mutation results in a heterogeneous phenotype and confutes the coincidence with common migraine. Dystonia is potentially included as a further part of the phenotype spectrum of CACNA1A gene mutations.

Short- and long-term treatment with modafinil differentially affects adult hippocampal neurogenesis.

The generation of new neurons in the dentate gyrus of the adult brain has been demonstrated in many species including humans and is suggested to have functional relevance for learning and memory. The wake promoting drug modafinil has popularly been categorized as a so-called neuroenhancer due to its positive effects on cognition. We here show that short- and long-term treatment with modafinil differentially effects hippocampal neurogenesis. We used different thymidine analogs (5-bromo-2-deoxyuridine (BrdU), chlorodeoxyuridine (CldU), iododeoxyuridine (IdU)) and labeling protocols to investigate distinct regulative events during hippocampal neurogenesis, namely cell proliferation and survival. Eight-week-old mice that were treated with modafinil (64mg/kg, i.p.) every 24h for 4days show increased proliferation in the dentate gyrus indicated by BrdU-labeling and more newborn granule cells 3weeks after treatment. Short-term treatment for 4days also enhanced the number of postmitotic calretinin-expressing progenitor cells that were labeled with BrdU 1week prior to treatment indicating an increased survival of new born immature granule cells. Interestingly, long-term treatment for 14days resulted in an increased number of newborn Prox1(+) granule cells, but we could not detect an additive effect of the prolonged treatment on proliferation and survival of newborn cells. Moreover, daily administration for 14days did not influence the number of proliferating cells in the dentate gyrus. Together, modafinil has an acute impact on precursor cell proliferation as well as survival but loses this ability during longer treatment durations.

[Executive task performance under deep brain stimulation of the subthalamic nucleus in Parkinson's disease revisited: the modulating influence of apathy, depression and mood]. / Einfluss der Tiefen Hirnstimulation des Nucleus subthalamicus auf exekutive Funktionen bei Patienten mit idiopathischem Parkinson-Syndrom unter Berücksichtigung von Apathie, Depressivität und Stimmung.

We investigated the moderating influence of apathy, depression and transient mood changes on executive functions under best medical treatment and under postoperative stimulation-on and -off conditions in a sample of 33 patients with Parkinson's disease (PD) after deep brain stimulation of the subthalamic nucleus (STN), 33 PD patients with pharmacological treatment only and 34 healthy controls. In comparison to clinical and healthy control groups, DBS patients showed worse executive task performance and also more severe symptoms of depression and apathy. Apathy accounted for differences in stroop interference between groups. The effects of DBS on stroop interference were explained by increased state anxiety in the -off, so that DBS STN had no significant influence on test performance. Consideration of neuropsychiatric symptoms and acute mood changes is an important aspect when evaluating neuropsychological deficits in DBS patients.

[Impulsive-compulsive behaviours in a German Parkinson's disease outpatient sample]. / Impulsiv-zwanghafte verhaltensstörungen in einer deutschen stichprobe ambulant versorgter Parkinson-patienten.

BACKGROUND: Impulsive-compulsive behaviours (ICBs) are frequent complications of Parkinson's disease (PD), associated with treatment by dopamine agonists (DAs). These include impulse control disorders (ICDs), repetitive behaviour (RB) and the dopamine-dysregulation syndrome (DDS). METHODS: A subsample of 72 patients of a large longitudinal study (n = 739) was screened with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP). Results were associated with socio-demographic, clinical and neuropsychological parameters. RESULTS: A large proportion of the sample reported ICBs (60%), RBs were most frequent (47 %). Patients with ICBs consumed higher doses of DAs (343 ± 177 mg vs. 390 ± 153 mg; p < 0.01). Pramipexole was associated with RB but not ICDs (273 ± 225 mg and 53 ± 106 mg vs. 151 ± 209 mg in patients without ICB). Patients with ICDs reported more dyskinesias (UPDRS IV: 1.78 ± 1.6 vs. 0.55 ± 1.1 points; p = 0.012) and patients with multiple ICBs a longer duration of PD (9.3 ± 5.0 vs. 6.2 ± 4.0 years; p = 0.026) and worse quality of life (PDQ39: 29.9 ± 13.8 vs. 20.3 ± 13.4 points; p = 0.036) compared to patients without any ICB. CONCLUSIONS: ICBs are frequent even in outpatients with moderate duration and severity of PD and associated with DA dose. Because of possible serious psychosocial consequences, detecting and managing them is of high importance.

[Early recognition of Parkinson's disease. Objectifiable non-motor symptoms and biomarkers]. / Früherkennung der Parkinson-Krankheit. Objektivierbare nichtmotorische Symptome und Biomarker.

The clinical diagnosis of Parkinson's disease (PD) according to the UK Brain Bank criteria is based on the presence of motor symptoms and the response to dopaminergic medication. According to these criteria the clinical diagnosis is delineated too late when more than 50 % of the dopaminergic neurons are already degenerated. In recent years interest has shifted increasingly more towards non-motor symptoms (NMS), such as rapid eye movement (REM) sleep behavior disorder (RBD), constipation, hyposmia and neuropsychiatric as well as cognitive symptoms. It was shown that NMS can precede the motor symptoms by some years and may thus possibly enable support of an earlier clinical diagnosis. Furthermore, cerebrospinal fluid or blood biomarkers as well as brain imaging techniques can objectively support an earlier diagnosis of PD. This article reviews important NMSs (e.g. RBD, hyposmia and neuropsychiatric/cognitive symptoms) as well as the current status on biomarkers and brain imaging in early (premotor) phases of PD and their relevance for the early diagnosis.

[Possible applications of new stem cell sources in neurology]. / Anwendungsmöglichkeiten neuer Stammzellquellen in der Neurologie.

Stem cells provide broad possibilities in modern science and medicine. This counts not only for investigations of developmental aspects but also for cell-based therapies, pharmacotoxicological testing and improvements in personalized medicine. The recent described techniques of induced pluripotent stem cells, directly induced neural stem cells and directly induced neurons are a major step forward by providing new possibilities for research on neurological diseases. Nevertheless, a variety of questions remain open regarding stem cell-based therapeutic strategies including tumorigenicity and phenotypical stability in the receptor brain. The major hope is that the new stem cell-based neural cell systems will help to understand the pathophysiology of neurodegenerative diseases. The future will show whether and how stem cells will lead to successful restorative therapies and/or to suitable cell models for neurological diseases.

[The prevalence of Parkinson's disease, associated dementia, and depression in Dresden]. / Die epidemiologie des idiopathischen Parkinson-syndroms und assoziierter demenz und depression in Dresden.

BACKGROUND: Parkinson's disease (PD) is frequently compounded by dementia and depression. Yet local total estimates on the prevalence of PD with dementia/depression are still lacking. These are socioeconomically important, especially for the eastern federal states in Germany due to the demographic structures. METHODS: We conducted a two-staged total estimation in the area of Dresden. First, all local office-based neurologists, hospitals and retirement homes were asked to list their patients/residents with PD on a single study day. Then a random sample of patients/home residents was neuropsycholoigcally examined, including the Mini-mental-state exam and the Montgomery-Asberg Depression rating scale. Dementia was diagnosed according to DSM-IV criteria. RESULTS: Overall, 886 PD cases (95 % CI: 809 - 926) were estimated, of which 252 (95 % CI: 226 - 279) suffered from dementia and 216 (95 % CI: 191 - 242) from depression. Dementia rates increased by age with 13.8 % (≤ 65 years) to 40.2 % (≥ 76 years). Depression rates ranged from 23.3 % to 28.0 %. Overall, 20.6 % of all ambulatory treated PD patients and 85.7 % of all home residents with PD had dementia. CONCLUSION: The prevalence of PD in Dresden dovetails with previous reported estimates. Dementia and depression are frequent complications in outpatients as well as home residents with PD.

[Avoidance, diagnostics and therapy of nerve lesions after total hip arthroplasty]. / Vermeidung, Diagnostik und Therapie von Nervenläsionen nach Hüftendoprothesenimplantation.

Nerve palsy following total hip arthroplasty is a rare complication. Developmental dysplasia of the hip, previous fracture treatment and medical comorbidities are characteristic risk factors. By accurate preparation of the patient and a careful operative technique nerve palsy can be avoided in most cases. Nerve palsy following poor patient positioning during the perioperative period should be avoided by close cooperation with anesthesiologists.In cases of postoperative nerve palsy correct diagnostics should be carried out immediately. Further treatment options should be considered to minimize the damage. For patients with definite nerve palsy, devices such as a foot drop splint are often necessary and should be carried out as soon as possible.