Boura E.,University of Marburg |
Stamelou M.,University of Marburg |
Stamelou M.,National and Kapodistrian University of Athens |
Vadasz D.,University of Marburg |
And 9 more authors.
Journal of Neurology | Year: 2017
Augmented spinal nociception during the “off” phase has been observed early in Parkinson’s disease further increasing with disease duration. To find out whether increased spinal nociception represents a premotor feature, experimental pain sensitivity was assessed in idiopathic REM-sleep behavior disorder (IRBD) patients with or without signs of a neurodegenerative disorder compared to early Parkinson’s disease (ePD) patients and healthy controls (HC). Spinal nociception as measured by the nociceptive flexion reflex (NFR) and experimental pain sensitivity as measured by heat and electrical pain thresholds were determined in 14 IRBD, 15 ePD patients in the medication-defined “off” state and 27 HC in an explorative cohort study. No significant differences between IRBD and HC were found with regard to spinal nociception (NFR) and experimental pain sensitivity. However, IRBD patient with anosmia and/or abnormal DaTSCAN tended to increased experimental pain sensitivity. In contrast, early PD patients exhibited increased NFR responses compared to HC, and a tendency for increased spinal nociception compared to IRBD patients. Increased spinal nociception may represent an early but not a premotor, non-motor feature of PD. Whether increased pain sensitivity already presents a premotor feature should be assessed in further studies. © 2017 Springer-Verlag Berlin Heidelberg
D'Angelo V.,University of Rome Tor Vergata |
Di Giovanni G.,University of Malta |
Tinkhauser G.,University of Bern |
Sancesario G.,University of Rome Tor Vergata |
And 2 more authors.
Experimental Neurology | Year: 2016
Enhanced β band (βB) activity, which is suppressed by levodopa (LD) treatment, has been demonstrated within the basal ganglia (BG) of Parkinson's disease (PD) patients. However, some data suggest that Parkinsonian symptoms are not directly related to this brain frequency and therefore, its causative role remains questionable. A less explored phenomenon is the link between the γ band (γB) and PD phenomenology. Here, we monitored the development of the oscillatory activity during chronic LD depletion and LD treatment in Parkinsonian and levodopa-induced dyskinesia (LID) in rats. We found a significant and bilateral power increase in the high βB frequencies (20-30. Hz) within the first 10. days after 6-hydroxydopamine (6-OHDA) lesion, which was in accordance with a significant depletion of dopaminergic fibers in the striatum. We also observed a clear-cut γB increase during LD treatment. The development of LID was characterized by a slight increase in the cumulative power of βB accompanied by a large augmentation in the γB frequency (60-80. Hz). This latter effect reached a plateau in the frontal cortex bilaterally and the left globus pallidus after the second week of LD treatment. Our data suggest that the βB parallels the emergence of Parkinsonian signs and can be taken as a predictive sign of DA depletion, matching TH-staining reduction. On the other hand, the γB is strictly correlated to the development of LID. LD treatment had an opposite effect on βB and γB, respectively. © 2015 Elsevier Inc.
Giordano R.,Cell Factory |
Canesi M.,Parkinson Center |
Isalberti M.,Interventional Neuroradiology Unit |
Isaias I.U.,Parkinson Center |
And 10 more authors.
Journal of Translational Medicine | Year: 2014
Background: Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available.Methods/design: Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors.Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection.Discussion: To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this " first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect.Trial registration: NCT01824121. © 2014 Giordano et al.; licensee BioMed Central Ltd.
Csoti I.,Parkinson Center |
Storch A.,TU Dresden |
Storch A.,German Center for Neurodegenerative Diseases |
Muller W.,Goethe University Frankfurt |
Jost W.H.,Deutsche Klinik fur. Diagnostik
Basal Ganglia | Year: 2012
In patients with Parkinson's disease (PD), long-term, successful use of a medication is not only determined by its efficacy, but also by its therapeutic safety and tolerability. This is especially relevant when two effective medications from the same class of active substances are available, in our case two monoamine oxidase B inhibitors (MAO-BI): Rasagiline and selegiline. The monitoring, collection, analysis and reporting of information for drug safety (" pharmacovigilance" ) are receiving increasing attention. Ever increasing demands are placed on the establishment of faster lines of communication between physicians, the pharmaceutical industry and the supervising authorities for reporting and investigating adverse events. Neglect or delay in the communication of serious side effects can also - even after introduction onto the market - entail immediate sanctions, extending to authorisation restrictions or revocation of the authorisation. Hence the broad application of budipine was considerably restricted due to its possible prolongation effect on the QT interval, cisapride was removed from the market and cabergoline and pergolide may only now be used as second-line dopamine agonists. It is not generally known to the physicians that adverse effects of a medication are frequently caused by interactions with other drugs. As a chronic progressive neurodegenerative illness, PD necessitates lifelong continual treatment with a highly complex combination of active substances. Adding to this are concomitant diseases requiring treatment and the generally advanced age of the patients. The main focus of the present work is to demonstrate possible drug interactions described in the literature when using rasagiline and selegiline, which could lead either to limitation in efficacy or to potential harm to the patient through an unforeseen alteration of efficacy. In addition, differences in the interaction potential of both MAO inhibitors are addressed. © 2012 Elsevier GmbH.
Herbert M.K.,Donders Institute for Brain |
Herbert M.K.,Radboud University Nijmegen |
Aerts M.B.,Donders Institute for Brain |
Aerts M.B.,Parkinson Center |
And 12 more authors.
Frontiers in Neurology | Year: 2015
The differentiation between multiple system atrophy (MSA) and Parkinson's disease (PD) is difficult, particularly in early disease stages. Therefore, we aimed to evaluate the diagnostic value of neurofilament light chain (NFL), fms-like tyrosine kinase ligand (FLT3L), and total tau protein (t-tau) in cerebrospinal fluid (CSF) as biomarkers to discriminate MSA from PD. Using commercially available enzyme-linked immunosorbent assays, we measured CSF levels of NFL, FLT3L, and t-tau in a discovery cohort of 36 PD patients, 27 MSA patients, and 57 non-neurological controls and in a validation cohort of 32 PD patients, 25 MSA patients, 15 PSP patients, 5 CBS patients, and 56 non-neurological controls. Cut-offs obtained from individual assays and binary logistic regression models developed from combinations of biomarkers were assessed. CSF levels of NFL were substantially increased in MSA and discriminated between MSA and PD with a sensitivity of 74% and specificity of 92% (AUC = 0.85) in the discovery cohort and with 80% sensitivity and 97% specificity (AUC = 0.94) in the validation cohort. FLT3L levels in CSF were significantly lower in both PD and MSA compared to controls in the discovery cohort, but not in the validation cohort. t-tau levels were significantly higher in MSA than PD and controls. Addition of either FLT3L or t-tau to NFL did not improve discrimination of PD from MSA above NFL alone. Our findings show that increased levels of NFL in CSF offer clinically relevant, high accuracy discrimination between PD and MSA. © 2015 Herbert, Aerts, Beenes, Norgren, Esselink, Bloem, Kuiperij and Verbeek.
Brockmann K.,University of Tübingen |
Brockmann K.,German Center for Neurodegenerative Diseases |
Srulijes K.,University of Tübingen |
Srulijes K.,German Center for Neurodegenerative Diseases |
And 8 more authors.
Neurology | Year: 2011
Objective: To evaluate whether there exists distinct characteristics in glucocerebrosidase (GBA)- associated Parkinson disease (PD) with regard to motor and nonmotor symptoms as well as imaging characteristics assessed by transcranial sonography (TCS). Methods: Twenty patients with PD with heterozygous GBA mutations (N370S, L444P) (GBA-PD) in comparison to 20 patients with sporadic PD negative for GBA mutations (sPD) were included. We assessed motor impairment with the Unified Parkinson's Disease Rating Scale-III. Nonmotor symptoms were evaluated using the Montreal Cognitive Assessment, Neuropsychiatric Inventory, revised form of the Beck Depression Inventory, Parkinson Disease Sleep Scale, Sniffin' Sticks, and Unified Multiple System Atrophy Rating Scale items 9-12. TCS imaging was used to detect morphologic characteristics. Results: Patients with GBA-PD more often had a variety of nonmotor symptoms, namely dementia, neuropsychiatric disturbances, and autonomic dysfunction, and had more severe cases, than patients with sPD. They also demonstrated a higher prevalence of a reduced echogenicity of the brainstem raphe assessed by TCS. Conclusions: Especially nonmotor symptoms seem to be very common in GBA-PD. Further studies are needed to validate these observations in order to better understand the pathogenesis of GBA-PD and develop specific therapeutic concepts. © 2011 by AAN Enterprises, Inc.
Gan-Or Z.,Genetic Institute |
Gan-Or Z.,Tel Aviv University |
Bar-Shira A.,Genetic Institute |
Gurevich T.,Parkinson Center |
And 5 more authors.
Neurogenetics | Year: 2011
A strong association was established between the GBA gene and Parkinson's disease (PD) worldwide. The most frequent GBA mutation among the Ashkenazi population (p.N370S) was previously associated with the c.1051T>C (p.F351L) alteration in the closely located MTX1 gene. We further studied the association between these two genes and its possible effect on PD. The entire coding region and exon-intron boundaries of MTX1 were analyzed in 81 PD patient carriers of GBA mutations, 15 healthy controls that carry GBA mutations, and in 25 non-carrier patients. Among them, the MTX1 c.184T>A (p.S63T) variation was detected in 93% of GBA mutation carriers (both patients and healthy controls) and in 64% of non-carrier patients (p=0.0008). This alteration was analyzed in 600 consecutively recruited Ashkenazi PD patients and in 353 controls, all genotyped for the LRRK2 p.G2019S and GBA founder mutations. A significantly higher frequency of the MTX1 c.184A allele was found in carriers of GBA mutations compared to non-carriers (0.67 and 0.45, respectively, p<0.0001). The homozygous MTX1 c.184A/A genotype was associated with a significantly earlier age of motor symptoms onset in patients with GBA mutations compared to other groups of patients tested (5.1-5.9 years younger, p= 0.002-0.01). A significantly higher frequency of early-onset PD (<50 years) was detected among patients carrying both GBA mutation and the homozygous MTX1 c.184A/A genotype (35.9%, compared to 13.6-17.5%, p=0.028). Our results raise the possibility that alteration on the opposite allele, which is in trans to the GBA mutant allele, may affect the clinical course of GBA-associated PD. © Springer-Verlag 2011.
Brockmann K.,University of Tübingen |
Brockmann K.,German Center for Neurodegenerative Diseases |
Hilker R.,Goethe University Frankfurt |
Pilatus U.,Goethe University Frankfurt |
And 15 more authors.
Neurology | Year: 2012
Objective: To elucidate possible mechanisms leading to neurodegeneration in patients with gluco-cerebrosidase (GBA)-associated Parkinson disease (PD) using combined proton ( 1H) and phosphorus ( 31P) magnetic resonance spectroscopic imaging (MRSI) in vivo. Methods: 1H and 1H-decoupled 31P MRSI was performed in 13 patients with PD with heterozygous GBA mutations (GBA-PD) and 19 age- and sex-matched healthy controls to investigate metabolite concentrations in the mesostriatal target regions of PD pathology. NAA as marker of neuronal integrity, choline and ethanolamine containing compounds as markers of membrane phospholipid metabolism, and energy metabolites (notably high-energy phosphates) were quantified. Results: Compared to controls, NAA was significantly reduced in the putamen (p = 0.012) and in the midbrain of GBA-PD (p = 0.05). The choline concentration obtained from 1H MRSI wassignif-cantly decreased in the midbrain of GBA-PD (p = 0.010). The phospholipid degradation product glycerophosphoethalonamine was increased in the putamen of GBA-PD (p = 0.05). Changes of energy metabolism were not detected in any region of interest. Conclusion: The pattern of neurodegeneration in GBA-associated PD is more pronounced in the putamen than in the midbrain. Our MRSI findings suggest that the neurodegenerative process in GBA-PD is associated with alterations of membrane phospholipid metabolism which might be also nvolved in abnormal α-synuclein aggregation. Copyright © 2012 by AAN Enterprises, Inc.
Moller J.C.,Parkinson Center |
Oechsner M.,Parkinson Center
Basal Ganglia | Year: 2015
Levodopa-associated motor fluctuations and dyskinesia in patients with Parkinson's disease (PD) are often difficult to control by the oral administration of levodopa. Continuous infusion of a levodopa/carbidopa intestinal gel (LCIG) may represent a feasible treatment option for this patient population. To start LCIG infusion, a temporary nasoduodenal/nasojejunal tube should be considered to show that the patient responds favorably, before a permanent percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) is placed. The present review focuses on recently published key studies on the efficacy and safety of LCIG treatment in advanced PD. The results provide robust evidence of a marked reduction of OFF-fluctuations and dyskinesia, thereby also improving the quality of life of these severely disabled patients. LCIG treatment is therefore a promising alternative to continuous subcutaneous apomorphine infusion or deep brain stimulation in advanced PD patients with severe motor fluctuations. © 2015 Elsevier GmbH.