References of "Krüger, Rejko 50002143"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailGuidelines for the use and interpretation of assays for monitoring autophagy.
Klionsky, Daniel J.; Abdalla, Fabio C.; Abeliovich, Hagai et al

in Autophagy (2012), 8(4), 445-544

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field ... [more ▼]

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field. [less ▲]

Detailed reference viewed: 602 (51 UL)
Full Text
Peer Reviewed
See detailDeep-brain-stimulation does not impair deglutition in Parkinson's disease.
Lengerer, Sabrina; Kipping, Judy; Rommel, Natalie et al

in Parkinsonism & related disorders (2012), 18(7), 847-53

OBJECTIVE: A large proportion of patients with Parkinson's disease develop dysphagia during the course of the disease. Dysphagia in Parkinson's disease affects different phases of deglutition, has a ... [more ▼]

OBJECTIVE: A large proportion of patients with Parkinson's disease develop dysphagia during the course of the disease. Dysphagia in Parkinson's disease affects different phases of deglutition, has a strong impact on quality of life and may cause severe complications, i.e., aspirational pneumonia. So far, little is known on how deep-brain-stimulation of the subthalamic nucleus influences deglutition in PD. METHODS: Videofluoroscopic swallowing studies on 18 patients with Parkinson's disease, which had been performed preoperatively, and postoperatively with deep-brain-stimulation-on and deep-brain-stimulation-off, were analyzed retrospectively. The patients were examined in each condition with three consistencies (viscous, fluid and solid). The 'New Zealand index for multidisciplinary evaluation of swallowing (NZIMES) Subscale One' for qualitative and 'Logemann-MBS-Parameters' for quantitative evaluation were assessed. RESULTS: Preoperatively, none of the patients presented with clinically relevant signs of dysphagia. While postoperatively, the mean daily levodopa equivalent dosage was reduced by 50% and deep-brain-stimulation led to a 50% improvement in motor symptoms measured by the UPDRS III, no clinically relevant influence of deep-brain-stimulation-on swallowing was observed using qualitative parameters (NZIMES). However quantitative parameters (Logemann scale) found significant changes of pharyngeal parameters with deep-brain-stimulation-on as compared to preoperative condition and deep-brain-stimulation-off mostly with fluid consistency. CONCLUSION: In Parkinson patients without dysphagia deep-brain-stimulation of the subthalamic nucleus modulates the pharyngeal deglutition phase but has no clinically relevant influence on deglutition. Further studies are needed to test if deep-brain-stimulation is a therapeutic option for patients with swallowing disorders. [less ▲]

Detailed reference viewed: 128 (0 UL)
Full Text
Peer Reviewed
See detailLRRK2: Understanding the role of common and rare variants in Parkinson's disease.
Sharma, Manu; Krüger, Rejko UL; Gasser, Thomas

in Movement disorders : official journal of the Movement Disorder Society (2012), 27(4), 475

Detailed reference viewed: 110 (1 UL)
Full Text
Peer Reviewed
See detailSubthalamic nucleus stimulation restores the efferent cortical drive to muscle in parallel to functional motor improvement.
Weiss, Daniel; Breit, Sorin; Hoppe, Julia et al

in The European journal of neuroscience (2012), 35(6), 896-908

Pathological synchronization in large-scale motor networks constitutes a pathophysiological hallmark of Parkinson's disease (PD). Corticomuscular synchronization in PD is pronounced in lower frequency ... [more ▼]

Pathological synchronization in large-scale motor networks constitutes a pathophysiological hallmark of Parkinson's disease (PD). Corticomuscular synchronization in PD is pronounced in lower frequency bands (< 10 Hz), whereas efficient cortical motor integration in healthy persons is driven in the beta frequency range. Electroencephalogram and electromyogram recordings at rest and during an isometric precision grip task were performed in four perioperative sessions in 10 patients with PD undergoing subthalamic nucleus deep-brain stimulation: (i) 1 day before (D0); (ii) 1 day after (D1); (iii) 8 days after implantation of macroelectrodes with stimulation off (D8StimOff); and (iv) on (D8StimOn). Analyses of coherence and phase delays were performed in order to challenge the effects of microlesion and stimulation on corticomuscular coherence (CMC). Additionally, local field potentials recorded from the subthalamic nucleus on D1 allowed comprehensive mapping of motor-related synchronization in subthalamocortical and cerebromuscular networks. Motor performance improved at D8StimOn compared with D0 and D8StimOff paralleled by a reduction of muscular activity and CMC in the theta band (3.9-7.8 Hz) and by an increase of CMC in the low-beta band (13.7-19.5 Hz). Efferent motor cortical drives to muscle presented mainly below 10 Hz on D8StimOff that were suppressed on D8StimOn and occurred on higher frequencies from 13 to 45 Hz. On D1, coherence of the high-beta band (20.5-30.2 Hz) increased during movement compared with rest in subthalamomuscular and corticomuscular projections, whereas it was attenuated in subcorticocortical projections. The present findings lend further support to the concept of pathological network synchronization in PD that is beneficially modulated by stimulation. [less ▲]

Detailed reference viewed: 103 (0 UL)
Full Text
Peer Reviewed
See detailThe use of primary human fibroblasts for monitoring mitochondrial phenotypes in the field of Parkinson's disease.
Burbulla, Lena F.; Krüger, Rejko UL

in Journal of visualized experiments : JoVE (2012), (68),

Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 (1). Because ageing is the most important risk factor, cases of PD will increase during the ... [more ▼]

Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 (1). Because ageing is the most important risk factor, cases of PD will increase during the next decades (2). Next to pathological protein folding and impaired protein degradation pathways, alterations of mitochondrial function and morphology were pointed out as further hallmark of neurodegeneration in PD (3-11). After years of research in murine and human cancer cells as in vitro models to dissect molecular pathways of Parkinsonism, the use of human fibroblasts from patients and appropriate controls as ex vivo models has become a valuable research tool, if potential caveats are considered. Other than immortalized, rather artificial cell models, primary fibroblasts from patients carrying disease-associated mutations apparently reflect important pathological features of the human disease. Here we delineate the procedure of taking skin biopsies, culturing human fibroblasts and using detailed protocols for essential microscopic techniques to define mitochondrial phenotypes. These were used to investigate different features associated with PD that are relevant to mitochondrial function and dynamics. Ex vivo, mitochondria can be analyzed in terms of their function, morphology, colocalization with lysosomes (the organelles degrading dysfunctional mitochondria) and degradation via the lysosomal pathway. These phenotypes are highly relevant for the identification of early signs of PD and may precede clinical motor symptoms in human disease-gene carriers. Hence, the assays presented here can be utilized as valuable tools to identify pathological features of neurodegeneration and help to define new therapeutic strategies in PD. [less ▲]

Detailed reference viewed: 126 (2 UL)
Full Text
Peer Reviewed
See detailConverging environmental and genetic pathways in the pathogenesis of Parkinson's disease.
Burbulla, Lena F.; Krüger, Rejko UL

in Journal of the neurological sciences (2011), 306(1-2), 1-8

As a prototypic neurodegenerative disorder Parkinson's disease (PD) is characterized by the progressive loss of specific neuronal subpopulations leading to a late-onset movement disorder. Based on ... [more ▼]

As a prototypic neurodegenerative disorder Parkinson's disease (PD) is characterized by the progressive loss of specific neuronal subpopulations leading to a late-onset movement disorder. Based on familial forms of PD, to date a significant number of genes were identified that allowed first insight into the molecular pathogenesis of this common movement disorder. These pathways include impaired protein degradation and subsequent aggregation within neuronal cells and impaired mitochondrial function followed by energy depletion due to oxidative stress leading to cell death. The respective disease models were supported by pathoanatomical and biochemical findings in brains of sporadic PD patients without apparent genetic contribution to pathogenesis. Indeed recent genetic and epidemiological studies hint to a complex interplay of genetic susceptibility factors and environmental risk factors to converge to processes of pathological protein accumulation and mitochondrial damage that trigger neurodegeneration in PD. Therefore large-scale geneticoepidemiological studies combining genetic whole genome approaches with a detailed ascertainment of environmental exposures are expected to provide important clues to decipher the complexity of neurodegeneration of this most frequent neurodegenerative movement disorder. [less ▲]

Detailed reference viewed: 125 (1 UL)
Full Text
Peer Reviewed
See detailIndependent and joint effects of the MAPT and SNCA genes in Parkinson disease.
Elbaz, Alexis; Ross, Owen A.; Ioannidis, John P. A. et al

in Annals of neurology (2011), 69(5), 778-92

OBJECTIVE: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta ... [more ▼]

OBJECTIVE: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. METHODS: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. RESULTS: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. INTERPRETATION: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. [less ▲]

Detailed reference viewed: 123 (0 UL)
Full Text
Peer Reviewed
See detailAssociation of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study.
Ross, Owen A.; Soto-Ortolaza, Alexandra I.; Heckman, Michael G. et al

in Lancet neurology (2011), 10(10), 898-908

BACKGROUND: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in ... [more ▼]

BACKGROUND: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS: LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS: 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 1.33-15.09; p=0.012). INTERPRETATION: The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING: Michael J Fox Foundation and National Institutes of Health. [less ▲]

Detailed reference viewed: 118 (0 UL)
Full Text
Peer Reviewed
See detailSlowly progressive Parkinson syndrome due to thalamic butterfly astrocytoma.
Wachter, T.; Engeholm, M.; Bisdas, S. et al

in Neurology (2011), 77(4), 404-5

Detailed reference viewed: 84 (0 UL)
Full Text
Peer Reviewed
See detailA large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease.
Krüger, Rejko UL; Sharma, Manu; Riess, Olaf et al

in Neurobiology of aging (2011), 32(3), 5489-18

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the ... [more ▼]

High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide. [less ▲]

Detailed reference viewed: 115 (1 UL)
Full Text
Peer Reviewed
See detailRole of sepiapterin reductase gene at the PARK3 locus in Parkinson's disease.
Sharma, Manu; Maraganore, Demetrius M.; Ioannidis, John P. A. et al

in Neurobiology of aging (2011), 32(11), 21081-5

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for ... [more ▼]

Sepiapterin reductase (SPR) gene is an enzyme which catalyses the final step of tetrahydrobiopterin synthesis (BH4) and was implicated in Parkinson's disease (PD) pathogenesis as a candidate gene for PARK3 locus. A number of studies yielded association of the PARK3 locus with PD, and SPR knockout mice were shown to display parkinsonian features. To evaluate the role of SPR gene polymorphisms in diverse populations in PD, we performed collaborative analyses in the Genetic Epidemiology of Parkinson Disease (GEO-PD) Consortium. A total of 5 single nucleotide polymorphisms (3 in the promoter region and 2 in the 3' untranslated region [UTR]) were genotyped. Fixed as well as random effect models were used to provide summary risk estimates of SPR variants. A total of 19 sites provided data for 6547 cases and 9321 controls. Overall odds ratio estimates varied from 0.92 to 1.01. No overall association with the SPR gene using either fixed effect or random effect model was observed in the studied population. I(2) Metric varied from 0% to 36.2%. There was some evidence for an association for participants of North European/Scandinavian descent with the strongest signal for rs1876487 (odds ratio = 0.82; p value = 0.003). Interestingly, families which were used to map the PARK3 locus, have Scandinavian ancestry suggesting a founder effect. In conclusion, this large association study for the SPR gene revealed no association for PD worldwide. However, taking the initial mapping of the PARK3 into account, the role of a population-specific effect warrants consideration in future studies. [less ▲]

Detailed reference viewed: 133 (0 UL)
Full Text
Peer Reviewed
See detailCentral oscillators in a patient with neuropathic tremor: evidence from intraoperative local field potential recordings.
Weiss, Daniel; Govindan, Rathinaswamy B.; Rilk, Albrecht et al

in Movement disorders : official journal of the Movement Disorder Society (2011), 26(2), 323-7

Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello-thalamo-cortical motor networks. Here, we provide direct ... [more ▼]

Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello-thalamo-cortical motor networks. Here, we provide direct evidence of central tremor processing in a 76-year-old female who underwent bilateral deep brain stimulation of the ventral intermedial nucleus of the thalamus (Vim-DBS) because of neuropathic tremor associated with IgM paraproteinemia. Electrophysiological recordings of EEG and EMG were performed in three perioperative sessions: (1) preoperatively, (2) intraoperatively, and (3) 4 days after surgery in both rest and postural tremor conditions. Tremor-related synchronization (coherence) between motor cortex (M1) and muscles (M. extensor digitorum, M. flexor digitorum) was assessed, and additional intraoperative local field potential (LFP) recordings from Vim allowed comprehensive coherence mapping in thalamo-cortico-muscular networks. Directionality of information flow was determined by directed transfer function (DTF) and phase analyses. Stimulation effects on tremor and corticomuscular coherence were assessed and the patient was followed for 12 months on clinical outcome measures (Tremor Rating Scale, CADET-Score). Vim-DBS reduced tremor (59%) and improved motor functionality in daily activities (31%, CADET-A) after 12 months. Intraoperative recordings demonstrated significant coherence in the tremor frequency (4 Hz) between M1 and contralateral muscle, Vim and ipsilateral M1, Vim and contralateral muscle, but not between Vim and contralateral M1. Information flow was directed from M1 to Vim and bidirectional between M1 and muscle and between Vim and muscle, respectively. Corticomuscular coherence at tremor frequency was completely suppressed by Vim-DBS. Our case study demonstrates central oscillators underlying neuropathic tremor and implies a strong pathophysiological rationale for Vim-DBS. [less ▲]

Detailed reference viewed: 135 (1 UL)
Full Text
Peer Reviewed
See detailRapid emergence of temporal and pulvinar lesions in MELAS mimicking Creutzfeldt-Jakob disease.
Weiss, D.; Brockmann, K.; Nagele, T. et al

in Neurology (2011), 77(9), 914

Detailed reference viewed: 107 (1 UL)
Full Text
Peer Reviewed
See detailCombined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson's disease.
Weiss, Daniel; Breit, Sorin; Wachter, Tobias et al

in Journal of neurology (2011), 258(6), 1183-5

Detailed reference viewed: 132 (1 UL)
Full Text
Peer Reviewed
See detailOlfactory neuron-specific expression of A30P alpha-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages.
Nuber, Silke; Petrasch-Parwez, Elisabeth; Arias-Carrion, Oscar et al

in Neurobiology of disease (2011), 44(2), 192-204

Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop ... [more ▼]

Mutations in the N-terminus of the gene encoding alpha-synuclein (alpha-syn) are linked to autosomal dominantly inherited Parkinson's disease (PD). The vast majority of PD patients develop neuropsychiatric symptoms preceding motor impairments. During this premotor stage, synucleinopathy is first detectable in the olfactory bulb (OB) and brain stem nuclei; however its impact on interconnected brain regions and related symptoms is still less far understood. Using a novel conditional transgenic mouse model, displaying region-specific expression of human mutant alpha-syn, we evaluated effect and reversibility of olfactory synucleinopathy. Our data showed that induction of mutant A30P alpha-syn expression increased transgenic deposition into somatodendritic compartment of dopaminergic neurons, without generating fibrillar inclusions. We found reversibly reduced levels of dopamine and metabolites in the OB, suggesting an impact of A30P alpha-syn on olfactory neurotransmitter content. We further showed that mutant A30P expression led to neurodegenerative changes on an ultrastructural level and a behaviorally hyperactive response correlated with novelty, odor processing and stress associated with an increased dopaminergic tone in midbrain regions. Our present data indicate that mutant (A30P) alpha-syn is directly implicated in reduction of dopamine signaling in OB interneurons, which mediates further alterations in brain regions without transgenic expression leading functionally to a hyperactive response. These modulations of neurotransmission may underlie in part some of the early neuropsychiatric symptoms in PD preceding dysfunction of the nigrostriatal dopaminergic system. [less ▲]

Detailed reference viewed: 110 (0 UL)
Full Text
Peer Reviewed
See detailCombined STN/SNr-DBS for the treatment of refractory gait disturbances in Parkinson's disease: study protocol for a randomized controlled trial.
Weiss, Daniel; Wachter, Tobias; Meisner, Christoph et al

in Trials (2011), 12

BACKGROUND: Severe gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages with important impact on quality of life. There is an unmet ... [more ▼]

BACKGROUND: Severe gait disturbances in idiopathic Parkinson's disease (PD) are observed in up to 80% of all patients in advanced disease stages with important impact on quality of life. There is an unmet need for further symptomatic therapeutic strategies, particularly as gait disturbances generally respond unfavourably to dopaminergic medication and conventional deep brain stimulation of the subthalamic nucleus in advanced disease stages. Recent pathophysiological research pointed to nigro-pontine networks entrained to locomotor integration. Stimulation of the pedunculopontine nucleus is currently under investigation, however, hitherto remains controversial. The substantia nigra pars reticulata (SNr)--entrained into integrative locomotor networks--is pathologically overactive in PD. High-frequent stimulation of the substantia nigra pars reticulata preferentially modulated axial symptoms and therefore is suggested as a novel therapeutic candidate target for neuromodulation of refractory gait disturbances in PD. METHODS: 12 patients with idiopathic Parkinson's disease and refractory gait disturbances under best individual subthalamic nucleus stimulation and dopaminergic medication will be enroled into this double-blind 2 x 2 cross-over clinical trial. The treatment consists of two different stimulation settings using (i) conventional stimulation of the subthalamic nucleus [STNmono] and (ii) combined stimulation of distant electrode contacts located in the subthalamic nucleus and caudal border zone of STN and substantia nigra pars reticulata [STN+SNr]. The primary outcome measure is the change of the cumulative 'axial score' (UPDRS II items '13-15' and UPRDS III items '27-31') at three weeks of constant stimulation in either condition. Secondary outcome measures include specific scores on freezing of gait, balance function, quality of life, non-motor symptoms, and neuropsychiatric symptoms. The aim of the present trial is to investigate the efficacy and safety of a three week constant combined stimulation on [STN+SNr] compared to [STNmono]. The results will clarify, whether stimulation on nigral contacts additional to subthalamic stimulation will improve therapeutic response of otherwise refractory gait disturbances in PD. TRIAL REGISTRATION: The trial was registered with the clinical trials register of http://www.clinicaltrials.gov (NCT01355835). [less ▲]

Detailed reference viewed: 113 (1 UL)
Full Text
Peer Reviewed
See detailSuppression of extrapyramidal side effects of doxepin by thalamic deep brain stimulation for Tourette syndrome.
Rzesnitzek, L.; Wachter, T.; Krüger, Rejko UL et al

in Neurology (2011), 77(18), 1708-9

Detailed reference viewed: 112 (0 UL)
Full Text
Peer Reviewed
See detailEffects of subthalamic nucleus stimulation on emotional prosody comprehension in Parkinson's disease.
Bruck, Carolin; Wildgruber, Dirk; Kreifelts, Benjamin et al

in PloS one (2011), 6(4), 19140

BACKGROUND: Although impaired decoding of emotional prosody has frequently been associated with Parkinson's disease (PD), to date only few reports have sought to explore the effect of Parkinson's ... [more ▼]

BACKGROUND: Although impaired decoding of emotional prosody has frequently been associated with Parkinson's disease (PD), to date only few reports have sought to explore the effect of Parkinson's treatment on disturbances of prosody decoding. In particular, little is known about how surgical treatment approaches such as high frequency deep brain stimulation (DBS) affect emotional speech perception in patients with PD. Accordingly, the objective of this study was to evaluate the effect of subthalamic nucleus (STN) stimulation on prosody processing. METHODOLOGY/PRINCIPAL FINDINGS: To this end the performance of 13 PD patients on three tasks requiring the decoding of emotional speech was assessed and subsequently compared to the performance of healthy control individuals. To delineate the effect of STN-DBS, all patients were tested with stimulators turned on as well as with stimulators turned off. Results revealed that irrespective of whether assessments were made "on" or "off" stimulation, patients' performance was less accurate as compared to healthy control participants on all tasks employed in this study. However, while accuracy appeared to be unaffected by stimulator status, a facilitation of reactions specific to highly conflicting emotional stimulus material (i.e. stimulus material presenting contradicting emotional messages on a verbal and non-verbal prosodic level) was observed during "on" stimulation assessments. CONCLUSION: In sum, presented results suggest that the processing of emotional speech is indeed modulated by STN-DBS. Observed alterations might, on the one hand, reflect a more efficient processing of highly conflicting stimulus material following DBS. However, on the other hand, given the lack of an improvement in accuracy, increased impulsivity associated with STN stimulation needs to be taken into consideration. [less ▲]

Detailed reference viewed: 127 (2 UL)
Full Text
Peer Reviewed
See detailReduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1.
Krebiehl, Guido; Ruckerbauer, Sabine; Burbulla, Lena F. et al

in PloS one (2010), 5(2), 9367

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD ... [more ▼]

BACKGROUND: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. CONCLUSIONS/SIGNIFICANCE: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease. [less ▲]

Detailed reference viewed: 169 (7 UL)
Full Text
Peer Reviewed
See detailEffective long-term subthalamic stimulation in PARK8 positive Parkinson's disease.
Breit, Sorin; Wachter, T.; Schmid-Bielenberg, D. et al

in Journal of neurology (2010), 257(7), 1205-7

Whether patients with genetically defined Parkinson's disease (PD) may be particularly eligible to benefit from deep brain stimulation of the nucleus subthalamicus (STN-DBS) is currently the subject of ... [more ▼]

Whether patients with genetically defined Parkinson's disease (PD) may be particularly eligible to benefit from deep brain stimulation of the nucleus subthalamicus (STN-DBS) is currently the subject of debate. We report on a patient with advanced PD due to R793M missense mutation in the LRRK2 gene successfully treated by STN-DBS. Disease onset was at age 42 with bradykinesia, rigidity and rest tremor. During the course of the disease he developed severe motor fluctuations, dyskinesias, postural instability with falls, but preserved levodopa responsiveness. At age 60 the patient was treated by bilateral DBS of the STN. At one year after surgery a 66% improvement of the UPDRS motor score in the off-medication state was determined. During the long-term follow-up there was sustained benefit with 56% improvement of motor score after 8 years. Our report adds evidence that patients with LRRK2 monogenetic Parkinsonism are well suited candidates for DBS treatment and may indicate a potential genetic predictor for positive long-term effect of STN-DBS treatment. [less ▲]

Detailed reference viewed: 109 (0 UL)