Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism.

Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.

Interventional Influence of the Intestinal Microbiome Through Dietary Intervention and Bowel Cleansing Might Improve Motor Symptoms in Parkinson's Disease.

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson's disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae. Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients.

Impact of Oral Fast Release Amantadine on Movement Performance in Patients with Parkinson's Disease.

Application of oral fast release amantadine and levodopa may induce an improvement of motor symptoms in patients with Parkinson's disease (PD). The objective of this trial was to investigate the clinical efficacy of a fast release amantadine sulfate formulation on simple and complex movement performance and putative relations to the pharmacokinetic behavior in PD patients. We challenged two cohorts of 12 PD patients, who were taken off their regular antiparkinsonian treatment for at least 12 hours, with oral 300 mg amantadine sulfate. We scored motor symptoms and performed instrumental tasks, which ask for performance of simple or complex motion series under cued conditions. Motor symptoms and performance of complex movements significantly improved in contrast to the carrying-out of simple motions. N-methyl-D-aspartic acid antagonistic and dopaminomimetic amantadine also influences altered higher predominant prefrontal cognitive functions. Therefore, performance of complex motion series improved, whereas carrying-out of simple repetitive movements is more associated to the striatal dopamine dependent basal ganglia function.

Selegiline reduces cisplatin-induced neuronal death in neuroblastoma cells.

Long-term administration of the monoamine oxidase (MAO)-B inhibitor selegiline may reduce neuronal death based on preclinical findings and reduce progression of chronic neurodegeneration due to outcomes of long-term clinical trials in patients with Parkinson's disease. Additional modes of action of this compound are immune system modulating and neurotrophic properties. We investigated the impact of simultaneous selegiline and cisplatin administration on the degree of cisplatin-induced cell death in SH-SY 5Y human neuroblastoma cells. We found a significantly reduced cell death rate after 50 and 74 hours after 2 hours lasting cisplatin exposure of SH-SY 5Y cells with additional selegiline treatment in comparison with cultures without selegiline. No previous incubation of cell cultures with selegiline was necessary to achieve this neuroprotective effect. We suggest that the neuroprotective effect of selegiline is predominantly associated with neurotrophic actions but not MAO-B inhibition, because SH-SY 5Y human neuroblastoma cells only contain MAO-A. Clinically, our findings support an early start of long-term treatment with selegiline in view of the various neurotoxin hypotheses and mechanisms of neuronal death in chronic neurodegenerative disorders.

Riluzole in Huntington's disease: a 3-year, randomized controlled study.

OBJECTIVE: We conducted a randomized double-blind trial of riluzole in Huntington's disease to investigate the efficacy of this antiexcitotoxic drug in slowing disease progression. METHODS: The study included 537 adult patients with a clinical diagnosis of Huntington's disease confirmed by genotyping. Patients were randomized (2:1) to treatment with riluzole (50mg twice daily) or placebo for 3 years. Concomitant use of antichoreic medication was forbidden, and introduction of such medication was a predefined end point. The primary outcome measure was change in a combined score derived from the motor and total functional capacity subscores of the Unified Huntington's Disease Rating Scale. Safety was also evaluated. RESULTS: A total of 379 patients completed the study (mean age, 47 [standard deviation, 9.5] years; 50% female patients). The principal reason for discontinuation was introduction of antichoreic medication. The median change from baseline in the combined score (primary outcome) for the "per protocol" population was 13.7 (95% confidence interval, 11.1-17.2) in the placebo group and 14.3 (95% confidence interval, 11.7-16.6) in the riluzole group. No intergroup difference in outcome could thus be demonstrated (p = 0.93, Mann-Whitney U test). No differences in secondary efficacy outcome variables were observed except for more frequent recourse to antichoreic medication in the placebo group. No unexpected adverse events were reported, and tolerability was acceptable. INTERPRETATION: No neuroprotective or beneficial symptomatic effects of riluzole in Huntington's disease were demonstrated.

Cardiomyopathy in Friedreich's ataxia-assessment by cardiac MRI.

Cardiomyopathy is an important and frequently life limiting manifestation of Friedreich's ataxia (FA), the most prevalent form of autosomal recessive ataxia. Left ventricular mass is used as primary outcome measure in recent intervention studies but systematic analyses of FA cardiomyopathy are sparse. To assess cardiac hypertrophy by cardiac magnetic resonance imaging (MRI) in vivo, we assessed 41 adult patients with genetically confirmed FA and 33 age- and sex-matched healthy controls by cardiac MRI and echocardiogarphy. Septal hypertrophy and left ventricular mass index were determined by two independent raters. MRI revealed hypertrophy of the interventricular septum in 40% and increased left ventricular mass index in 29% of patients. Interobserver variability was less than 5% for both measures. GAA repeat length had only minor influence on interventricular septum thickness. Left ventricular mass index decreased with age. Severity of ataxia did not correlate with cardiac disease. In echocardiography wall diameter was assessable only in 31 of 41 FA patients with 32% of patients presenting septal hypertrophy and 6% increased left ventricular mass index. We conclude that cardiac hypertrophy is present only in a minority of adult FA patients. If despite this limitation intervention studies use left ventricular mass as outcome measure, MRI is recommended as the most accurate assessment of cardiac anatomy in vivo.

Entacapone improves complex movement performance in patients with Parkinson's disease.

BACKGROUND: A possible strategy to prolong plasma metabolism of Levodopa/Carbidopa (LD/CD) is Entacapone addition (EN), which improves impaired motor behaviour in patients with Parkinson's disease (PD). AIMS OF THE STUDY: Objectives were to evaluate the clinical response to an increased dopaminergic substitution with EN by clinical rating and assessment of complex motions and to investigate the change of movement in PD patients during repeat drug administration during an eight hour interval. METHODS: We used peg insertion with a computer based device and clinical rating for assessment of motor function in 20 treated PD patients. They received LD/CD and then the same LD/CD dosage plus EN in a standardised, open label fashion. RESULTS: Motor scores and performance of the instrumental task were significantly better and the fluctuation of movement was less intense during the LD/CD/EN condition according to the motor test outcomes. CONCLUSION: EN supplementation improves motor symptoms and provides a more continuous movement behaviour in PD patients.

Dissociation of grey and white matter reduction in spinocerebellar ataxia type 3 and 6: a voxel-based morphometry study.

The aim of this study was to examine the different patterns of cerebellar and/or brainstem atrophy in spinocerebellar ataxia (SCA) type 3 and 6. Eighteen patients (SCA3 n=9, SCA6 n=9) and 15 healthy volunteers were studied. Voxel-based morphometry (VBM) was applied to segmented grey matter (GM) and white matter (WM) of high-resolution T1-weighted brain volumes of each group. We found reduction of grey matter in the pons as well as in the vermis in SCA3 as compared to control subjects. In SCA6 significant grey matter loss was found in hemispheric lobules bilaterally as well as in the vermis. White matter analysis revealed significant changes in SCA3, especially in the pons, in the white matter surrounding the dentate nucleus (DN) and in the cerebellar peduncles, whereas no significant white matter reduction was found in SCA6 patients. Our results demonstrate different patterns of grey and white matter affection detected by magnetic resonance imaging (MRI) in SCA3 and SCA6 patients, confirming the pathological concept of cortical cerebellar atrophy in SCA6. In contrast, SCA3 represents a form of ponto-cerebellar atrophy with predominant affection of pontine nuclei and fibre tracts.

Efficacy of mitoxantrone and intrathecal triamcinolone acetonide treatment in chronic progressive multiple sclerosis patients.

Treatment approaches are rare for chronic progressive patients with multiple sclerosis (MS). Objective was to evaluate the clinical benefit of repeated intrathecal application of the sustained release steroid triamcinolone acetonide or the administration of mitoxantrone (MIX) in 2 similar cohorts of chronic progressive patients with MS in an open-label fashion. Expanded Disability Status Scale scores significantly decreased after the first 6 intraspinal triamcinolone acetonide injections, which were performed every third day, and then remained stable. Walking distance significantly increased and did not reduce until the end of the 1-year-long trial period. Mitoxantrone treatment did not improve the Expanded Disability Status Scale score; however, no further significant deterioration appeared. Walking distance did not significantly decrease. Both treatment regimens were safe; the patients experienced nearly no adverse effects. Triamcinolone acetonide application provided a clinical benefit, whereas MIX administration prevented further worsening of MS symptoms. We stress that only specialists with a broad experience in intraspinal triamcinolone acetonide application and MIX administration should perform both kinds of therapy only after a careful information and risk-benefit evaluation in cooperation with the patient. Future trials will show the efficacy of combination of both treatment approaches in chronic progressive patients with MS.

Assessment of simple movements reflects impairment in Huntington's disease.

Clinical rating, caudate atrophy, disturbed movement performance, neuropsychological testing, and age-related genetic disease load (CAG index) are tools that reflect impairment after onset of Huntington's disease (HD). Objectives were to compare scored HD symptoms, results of neuropsychological testing and of instrumental measurement of simple motion sequences, assess caudate atrophy and CAG index, and investigate their relation to each other in 131 subjects of various HD stages. Caudate atrophy and CAG index significantly increased in advanced HD patients. Motor test results significantly differed between HD patients and 49 controls, but not between HD gene carriers and controls. Instrumental test outcomes, scored HD intensity, caudate atrophy, and CAG index significantly correlated to each other. Neuropsychological testing, which we only performed in the HD gene carriers and the previously untreated HD patients, reflected the early appearance of HD symptoms and correlated with the motor test results. Results of our applied instrumental tool measure impaired movement performance, which is not specific for HD, but reflects the various methods assessed and the slowly evolving symptoms of the degenerative process in HD.

Levodopa availability improves with progression of Parkinson's disease.

BACKGROUND: Previous pharmacokinetic trials with standard levodopa formulations showed a different behaviour of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various stages. OBJECTIVES: To investigate associations between levodopa plasma levels in relation to the scored intensity of PD. SUBJECTS AND METHODS: We administered water soluble 100 mg levodopa and 25 mg benserazide to 50 PD patients, taken off medication for at least 12 hours, and assessed the levodopa plasma concentrations during an 180 minutes period under standardised conditions. RESULTS: The computed area under the curve (AUC) values of levodopa plasma levels were significant higher in advanced PD patients. PD rating scores significantly correlated to the AUC outcomes and the maximum levodopa plasma concentration. CONCLUSIONS: Levodopa availability improves with progression of PD. This may result from deteriorated peripheral activity of levodopa metabolising enzymes or an increasing enteric dysfunction with subsequent better duodenal levodopa absorption or both.

Repeat intrathecal triamcinolone acetonide application reduces acute occurring painful dysesthesia in patients with relapsing remitting multiple sclerosis.

We describe four patients with relapsing remitting multiple sclerosis (RRMS) who experienced a relapse with acute onset of painful sensations. Pain sensations disappeared in two of them and markedly reduced in the other ones after repeat application of intrathecal triamcinolone acetonide (TCA) following a prior unsuccessful treatment with intravenous steroids. TCA administration was well tolerated and no serious side effects occurred. Repeated intrathecal TCA injection may provide a substantial benefit in RRMS patients with acute onset of pain due to an inflammatory lesion within the spinal cord.

Dose-dependent improvement of myoclonic hyperkinesia due to Valproic acid in eight Huntington's Disease patients: a case series.

BACKGROUND: Chorea in Huntington's Disease (HD) is usually treated with antidopaminergic neuroleptics like haloperidol, olanzapine and tiaprid or dopamine depleting drugs like tetrabenazine. Some patients with hyperkinesia, however, react to treatment with antidopaminergic drugs by developing extrapyramidal side effects. In earlier studies valproic acid showed no beneficial effect on involuntary choreatic movements. Myoclonus is rare in HD and is often overseen or misdiagnosed as chorea. METHODS: In this report, we present eight patients whose main symptom is myoclonic hyperkinesia. All patients were treated with valproic acid and scored by using the Unified Huntington's Disease Rating Scale (UHDRS) motor score before and after treatment. In addition to this, two patients agreed to be videotaped. RESULTS: In seven patients myoclonus and, therefore the UHDRS motor score improved in a dose dependent manner. In three of these patients antidopaminergic medication could be reduced. CONCLUSION: In the rare subgroup of HD patients suffering from myoclonic hyperkinesia, valproic acid is a possible alternative treatment.

Contrast-enhanced ultrasonic parametric perfusion imaging detects dysfunctional tissue at risk in acute MCA stroke.

Ultrasonic perfusion imaging predicts size and localization of acute stroke. It is unclear whether irreversibly damaged tissue can be differentiated from tissue at risk. Thirty-four patients (ischemic stroke <12 h) were included (Phase Inversion Harmonic Perfusion Imaging; bolus kinetic; fitted model function). Three patterns of perfusion were defined in 14 prespecified regions of interest (ROI): 'normal', 'hypoperfusion', and 'no perfusion'. Clinical status was assessed using the National Institutes of Health Stroke Scale (NIHSS) (at baseline and at days 2 to 4). Cranial Computed Tomography (CCT) (days 2 to 4) displayed final infarction. The pattern 'hypoperfusion' (ROIs presumably representing tissue at risk) was tested twofold: (i) Functional impairment by correlating their number with baseline NIHSS. (ii) Viability by correlating their recruitment rate to infarction with clinical course (DeltaNIHSS days 2 to 4). In addition, various predictive values were assessed. Twenty-seven patients were eligible for analysis. The sum of ROIs with 'no perfusion' and 'hypoperfusion' correlated highest with baseline NIHSS (rho=0.78, P<0.001). Recruitment of hypoperfused ROIs to infarction highly correlated with clinical course (rho=0.79, P<0.001). Clinical course dichotomized the patients into subgroups A ('stable', DeltaNIHSS>or=-3) and B ('improved', DeltaNIHSS

Inhibition of catechol-O-methyltransferase contributes to more stable levodopa plasma levels.

The short plasma half-life limits the antiparkinsonian efficacy of levodopa/carbidopa (LD/CD). Administration of LD/CD with the catechol-O-methyltransferase inhibitor entacapone in one tablet (LCE) may extend plasma half-life of LD and thus its effect on motor symptoms in patients with Parkinson's disease (PD). The objectives of this study were to monitor the motor response to a switch from LD/CD to LCE by a simultaneous performance of an instrumental motor test and rating of motor symptoms and to compare the LD plasma behavior between both conditions in terms of stability. Twenty-one treated PD patients received LD/CD and then the identical oral LD dosage of LCE within a standardized setting on 2 consecutive days. Rating better reflected the motor improvement after LD application than the instrumental test. Motor symptoms of PD patients decreased significantly more during the LCE than the LD/CD condition, probably due to significantly higher LD plasma levels and a significantly less pronounced fall of the LD concentrations following the second LD intake. Our study shows a more stable LD plasma behavior during LCE intake and accordingly a better effect on motor symptoms according to rating outcomes and motor test results to a lesser extent.

[Amisulpride in Huntington's disease]. / Der Einsatz von Amisulprid bei Patienten mit Morbus Huntington.

OBJECTIVES: Amisulpride is a substituted benzamide derivative with atypical antipsychotic properties and low side effects. METHOD: We report four cases of patients with clinically and genetically established Huntington's disease and signs of psychosis who were treated with Amisulpride. RESULTS: Two patients developed extrapyramidal side effects due to the treatment. The antipsychotic therapy of all patients was effective. DISCUSSION: Due to degeneration of striatal neurons patients suffering from Huntington's disease react early with development of extrapyramidal side effects after therapy with amisulpride.

Transcranial ultrasound brain perfusion assessment with a contrast agent-specific imaging mode: results of a two-center trial.

BACKGROUND AND PURPOSE: The purpose of this study was to assess brain perfusion with an ultrasound contrast-specific imaging mode and to prove if the results are comparable between 2 centers using a standardized study protocol. METHODS: A total of 32 individuals without known cerebrovascular disease were included in the study. Perfusion studies were performed ipsilaterally in an axial diencephalic plane after intravenous administration of 0.75 mL of Optison. Offline time intensity curves (TIC) were generated in different anatomic regions. Both centers used identical study protocols, ultrasound machines, and contrast agent. RESULTS: In both centers, the comparison of the parameter time to peak intensity (TPI) revealed significantly shorter TPIs in the main vessel structures compared with any parenchymal region of interest (ROI), whereas no significant differences were seen between the parenchymal ROIs. The parameter peak intensity (PI) varied widely interindividually in both centers, whereas the inter-ROI comparison revealed statistical significance (P < 0.05) in most of the cases according to the following pattern: (1) lentiforme nucleus > thalamus and white matter region, (2) thalamus > white matter region, and (3) main vessel > any parenchymal structure. Similar results were achieved in both centers independently. CONCLUSIONS: The study demonstrates that brain perfusion assessment with an ultrasound contrast-specific imaging mode is comparable between different centers using the same study protocol.

Semiquantitative analysis of ultrasonic cerebral perfusion imaging.

The bolus kinetic in ultrasonic cerebral perfusion imaging is the most favored data acquisition and processing technique. However, there has not yet been convincing evidence for the potential to (semi-) quantitatively describe perfusion. Aim of this study was to determine the intraindividual range of relevant perfusion parameters to describe individual physiological cutoff scores. In 20 healthy volunteers, cerebral perfusion was evaluated using the bilateral approach with phase inversion harmonic imaging and the bolus kinetic. Relevant parameters (time-to-peak intensity, TPI; peak width, PW) were derived in 14 regions-of-interest in both hemispheres. The median and quartile deviation (QD) of these values were individually calculated. Within the 20 individuals, the mean QD of TPI was 0.68 s, and there was no case in which any TPI exceeded the mean more than 2 s. With PW, the mean QD was 1.2 s, and the mean was not exceeded by more than 6 s. Intraindividual perfusion parameters, especially TPI, show a considerable small range. Thus, the bolus kinetic derives reliable semiquantitative information once intraindividual comparison can be accomplished. We therefore propose that bilateral examination with the unaffected hemisphere as referential region should be performed in acute stroke. Future studies have to evaluate the potential of this approach of discriminating ischemia and hypoperfusion in the affected hemisphere.

Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT-15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age- and gender-matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.

Impaired gastric emptying of a solid test meal in patients with Parkinson's disease using 13C-sodium octanoate breath test.

Up to now gastric emptying in patients with Parkinson's disease was determined by radioscintigraphy. The 13C-sodium octanoate breath test (OBT) has been established for the non-invasive evaluation of gastric emptying with a solid test meal. The aim of the study was to evaluate the OBT in patients with Parkinson's disease and to investigate the prevalence of delayed gastric emptying for solids in PD and the relationship to clinical staging patterns. Twenty-two healthy subjects and 36 patients with different clinical stages of PD classified using Hoehn and Yahr (H&Y) and Unified Parkinson's Disease Rating Scale (UPDRS) were studied. Each fasting control and patient received a solid test meal (241 kcal) labelled with 100 mg of 13C-sodium octanoate. Breath samples were obtained before substrate administration and then in 15-min intervals over 4 h. The 13CO2/12CO2 ratio was determined in each breath sample as delta over baseline. Time to peak (t(peak)), gastric half emptying time (t1/2b), lag phase (t(lagb)) and gastric emptying coefficient (GEC) were calculated. Significant differences in t(peak), t1/2b, t(lagb) and GEC were found between patients and healthy volunteers (p<0.0001), with a 60% delay in gastric half emptying time in the patient group. Gastric half emptying time was different between clinical disease groups (H&Y 0-2 versus H&Y 2.5-5, p=0.001; UPDRS 0-30 versus UPDRS 61-92, p<0.05). The OBT detects a significant delay in gastric emptying of a solid test meal in patients with PD. Delayed gastric emptying for solids is associated with disease severity.