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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Contrast burst depletion imaging (CODIM): a new imaging procedure and analysis method for semiquantitative ultrasonic perfusion imaging.

BACKGROUND AND PURPOSE: Established methods of ultrasonic perfusion imaging using a bolus application of echo contrast agent provide only qualitative data because of various physical phenomena. This study was intended to investigate whether a new ultrasound perfusion imaging method termed contrast burst depletion imaging (CODIM) may provide semiquantitative measures of parenchymal perfusion independent of examination depth and acoustic energy distribution. METHODS: In a system with a constant concentration of contrast agent, analyzing the decrease in image intensity that occurs with microbubble-destructive imaging modes yields parameters that are considered to correlate with tissue perfusion. This method was first evaluated with a perfusion model that showed that the main resulting parameter "perfusion coefficient" (PC) is a monotonic nonlinear function of flow velocity. Seventeen human volunteers were then scanned according to this method with the use of 2 different contrast agents. Results were correlated with those from perfusion-weighted MRI examinations. RESULTS: The PC did not show significant differences in gray matter areas (ranging from 1.466x10(-2) x s(-1) to 1.641x10(-2) x s(-1)) of the brain despite different insonation depths (eg, ipsilateral and contralateral thalamus). In contrast, white matter exhibited significantly lower perfusion values in both imaging modes (PC: 0.604x10(-2) x s(-1) to 0.745x10(-2) x s(-1); P<0.05). CONCLUSIONS: CODIM is a promising new tool of imaging parenchymal (brain) perfusion in healthy persons. The method provides semiquantitative and depth-independent perfusion parameters and in this way overcomes the limitations of the perfusion methods using a bolus kinetic. Further investigations must be done to evaluate the potential of the method in patients with perfusion deficits.

Budipine provides additional benefit in patients with Parkinson disease receiving a stable optimum dopaminergic drug regimen.

BACKGROUND: The complex pharmacological profile of the antiparkinsonian drug budipine influences neurotransmission beyond the dopaminergic system. Previous studies have demonstrated the therapeutic efficacy of budipine on motor symptoms in insufficiently treated patients with Parkinson disease. OBJECTIVE: To demonstrate the efficacy of 20 mg of budipine, 3 times daily, in addition to a stable, prior, optimum-titrated dopaminergic substitution consisting of a combination of levodopa and a dopa decarboxylase inhibitor, bromocriptine mesylate, and optional selegiline hydrochloride in 99 patients with idiopathic Parkinson disease in a multicenter, double-blind, placebo-controlled trial. RESULTS: Budipine significantly (P<.001) decreased the Columbia University Rating Scale sum score (median, 15.0; 95% confidence interval, 11.3-17.0) compared with placebo (median, 4.3; 95% confidence interval, 3.0-7.5) at study end point. Budipine reduced Columbia University Rating Scale subscores for tremor, rigidity, and akinesia. CONCLUSION: The additional application of budipine provides further therapeutic benefit in subjects with Parkinson disease receiving a stable, prior, optimum-titrated dopaminergic drug regimen because of the hypothetical positive impact of budipine on altered nondopaminergic neurotransmission in patients with Parkinson disease.

Apomorphine reduces BOLD signal in fMRI during voluntary movement in Parkinsonian patients.

Our group investigated modulatory effects of apomorphine on cerebral activation patterns during finger tapping movements in seven Parkinson's disease (PD) patients off medication. Cerebral activation was measured according to an established fMRI protocol. Apomorphine application disclosed a reduction of cerebral activation patterns to the contralateral precentral gyrus affecting both clinically affected and unaffected sides; tapping with the unaffected hand additionally revealed activation in the contralateral postcentral gyrus. These findings contradict those of similar functional imaging studies performed in PD to date, which variously found augmentation of cerebral activation patterns in Parkinsonian patients after dopaminergic stimulation. One conceivable explanation for our singular results would be preferred binding of apomorphine to presynaptic dopaminergic receptors, leading to inhibition of endogenous dopamine release and resultant diminished dopaminergic stimulation, reflected in diminished cerebral activation patterns. These findings warrant future consideration and further investigation of possible central inhibitory effects of dopaminergic therapy in functional imaging studies in PD.

Treatment benefit and daily drug costs associated with treating Parkinson's disease in a Parkinson's disease clinic.

OBJECTIVE: In some countries, such as Germany, there has been a move towards the treatment of patients with Parkinson's disease in specialised inpatient units. However, data on patient outcome and the daily costs of antiparkinsonian drugs in these settings are rare. This study was conducted to determine the effect of an inpatient setting (a specialised Parkinson's disease clinic) on drug therapy costs and patient symptoms. PATIENTS AND METHODS: This study involved 63 consecutively referred inpatients of a Parkinson's disease clinic. On entry to the clinic, the patients' antiparkinsonian drug regimen was titrated in order to improve their motor function. The daily costs of drug therapy per patient (in 2002 values) were calculated, and the severity of Parkinson's disease symptoms scored via scores on the Unified Parkinson's Disease Rating Scale (UPDRS) and standardised instrumental procedures (peg insertion and tapping), both initially and at the end of the patients' stay in the clinic. The variables between the two evaluation timepoints were compared. RESULTS: The titration of antiparkinsonian drugs was associated with a significant decrease in the symptoms of Parkinson's disease at discharge from the clinic compared with admission (as measured by UPDRS total and subscale scores [all p < 0.001], and, to a lesser extent, by peg insertion and tapping [both p < 0.05]). A significant increase in daily drug costs (an increase of euro14.11 per patient for all drugs and euro12.36 per patient for antiparkinsonian drugs [both p <0.001]) was also observed. CONCLUSION: The results demonstrate that the symptoms experienced by patients with Parkinson's disease improve after performance of antiparkinsonian drug titration within the setting of a specialised Parkinson's disease clinic. The effect on symptoms was seen most clearly with the UPDRS, although both peg insertion and tapping reflected this improvement to a certain extent. Drug titration resulted in, on average, a doubling of daily drug costs. Future trials are needed to investigate the long-term effects of such a hospital stay on indirect costs associated with treating Parkinson's disease, and on caregiver burden, and also to compare the efficacy of a Parkinson's disease clinic with an outpatient setting.

Assessment of complex movements reflects dysfunction in Huntington's disease.

Results of various complex instrumental tools, rating scales, caudate atrophy and CAG repeat length may reflect the severity of Huntington's disease (HD). A simple assessment task for dysfunction due to disease is the standardized, computer based performance of peg insertion. The objectives of our study were to compare scored HD symptoms, computed bicaudate diameter ratio (BDR), age related genetic disease load (CAG index = [CAG-35.5 x age]) and peg insertion scores between asymptomatic 34 HD gene carriers, 89 previously untreated HD patients with psychiatric or motor symptoms, or both, and 51 treated HD patients. We measured the period of the total time taken to insert 25 pegs from a rack into a series of appropriate holes, calculated the CAG index, estimated the bicaudate diameter ratio (BDR) of a current brain CT and scored the HD patients under blind conditions. Times for the peg insertion task significantly differed between HD patients and controls, but not between HD gene carriers and controls. BDR and CAG index reflected the increase of symptoms in HD. Peg insertion results and scored severity of HD, BDR and CAG index significantly correlated with each other. Peg insertion scores are not specific diagnostic markers for HD, but they reflect clinical symptoms of neurodegeneration. The performance of peg insertion involves visuospatial cognition, self-elaboration of internal strategies, sorting and planning of movement. Therefore peg insertion particularly reflects executive dysfunction in early HD and additionally motor impairment in advanced HD.

Intravenous amantadine sulphate application improves the performance of complex but not simple motor tasks in patients with Parkinson's disease.

Intravenous application of amantadine sulphate induces a rapid improvement of motor symptoms in Parkinson's disease (PD), but there are no trials on the efficacy of this compound on bradykinesia, rigidity and tremor in detail in combination with standardized instrumental measurement of tapping and peg insertion abilities. We treated 31 stable non fluctuating PD patients with amantadine, scored motor symptoms of both arms and performed peg insertion and tapping under cued conditions before and after 3 days. Motor symptoms and peg insertion significantly improved in contrast to tapping. Tapping asks for repetitive performance of simple standardized movements, therefore it needs low cognitive efforts. Since peg insertion depends on more complex movements and thus more dopamine dependent cognitive processes, it improved after application of the indirect dopaminomimetic substance amantadine.

Chronic levodopa intake increases levodopa plasma bioavailability in patients with Parkinson's disease.

Previous pharmacokinetic trials with standard levodopa formulations showed a different behavior of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various advanced stages. The objective of this trial was to compare levodopa plasma metabolism in PD patients with and without previous long-term levodopa intake after oral intake of a dispensable levodopa/benserazide formulation (DLB). The over a 150 min interval computed area under the curve values of levodopa plasma levels after DLB administration were significantly (ANCOVA: F(1,19) = 7.88, P = 0.01) higher in PD patients with chronic levodopa treatment compared to patients without prior levodopa treatment. The maximum plasma levodopa concentration did not differ (ANCOVA: F(1.19) = 1.17, P = 0.29). Long-term levodopa administration results in an increased levodopa plasma bioavailability in PD patients.