Steffen Paschen

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET. Methods: Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET. Results: We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10−5, odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10−3, OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10−10, OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087. Conclusions: We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.

Clinical outcome of deep brain stimulation for Parkinson’s disease

Deep brain stimulation is one of the most effective treatments of Parkinsons disease (PD). This report summarizes the state of the art as at January 2013. Stimulation of the subthalamic nucleus is the most commonly used approach. It improves the core motor symptoms better than medication in patients with advanced disease. It also improves the majority of nonmotor symptoms, such as mood, impulse control disorders, sleep, and some autonomic dysfunctions. Quality of life (QoL) is improved significantly more than with medication. Long-term data show that the treatment is effective for up to 10 years, but the late appearance of l-dopa-resistant symptoms is seemingly not influenced. Internal globus pallidus (GPi) stimulation is less well studied but seems to have similar short-term efficacy. Importantly l-dopa use cannot be reduced with GPi DBS, which is a major disadvantage for patients suffering from medication side-effects, although gait may be influenced more positively. Although short-term QoL improvement seems to be similar to that for subthalamic nucleus (STN) DBS - gait and speech may be better improved - long-term data are rare for GPi DBS. Thalamic stimulation in the ventral intermediate nucleus (VIM) is applied only in tremor-dominant elderly patients. The treatment improves the dopa-sensitive symptoms and effectively reduces fluctuations leading to an overall QoL improvement. Although most of the controlled studies have been on advanced PD, the recently published EARLYSTIM study suggests that even patients with a very short duration of their fluctuations and dyskinesia are doing significantly better with neurostimulation in terms of QoL and all major motor outcome parameters.

The central oscillatory network of orthostatic tremor

Orthostatic tremor (OT) is a movement disorder of the legs and trunk that is present in the standing position but typically absent when sitting. The pathological central network involved in orthostatic tremor is still unknown. In this study we analyzed 15 patients with simultaneous high‐resolution electroencephalography and electromyography recording to assess corticomuscular coherence. In 1 patient we were able to simultaneously record the local field potential in the ventrolateral thalamus and electroencephalography. Dynamic imaging of coherent source analysis was used to find the sources in the brain that are coherent with the peripheral tremor signal. When standing, the network for the tremor frequency consisted of unilateral activation in the primary motor leg area, supplementary motor area, primary sensory cortex, two prefrontal/premotor sources, thalamus, and cerebellum for the whole 30‐second segment recorded. The source coherence dynamics for the primary leg area and the thalamic source signals with the tibialis anterior muscle showed that they were highly coherent for the whole 30 seconds for the contralateral side but markedly decreased after 15 seconds for the ipsilateral side. The source signal and the recorded thalamus signal followed the same time frequency dynamics of coherence in 1 patient. The corticomuscular interaction in OT follows a consistent pattern with an initially bilateral pattern and then a segregated unilateral pattern after 15 seconds. This may add to the feeling of unsteadiness. It also makes the thalamus unlikely as the main source of orthostatic tremor.

No evidence for differential methylation of α-synuclein in leukocyte DNA of Parkinson's disease patients†‡§

Alpha-synuclein (a-Syn) is central to the pathogenesis of Parkinson’s disease (PD). Overexpression of a-Syn caused by genomic duplications/triplications is sufficient to cause monogenic PD. Moreover, association studies have identified potentially regulatory polymorphisms in the a-Syn gene (SNCA, Acc. No. NM_000345.3) associated with an increased risk for sporadic PD. These observations demonstrate that the regulation of a-Syn expression is pivotal in the pathogenesis of PD. It has recently been shown that a CpG island in a putative promoter region of intron 1 of SNCA is hypomethylated in brain tissue of PD patients compared with in neurologically healthy controls. Hypomethylation was associated with increased a-Syn expression in cell lines as well as with increased transcriptional activity in a luciferase reporter assay in both studies. In an attempt to identify a biomarker for PD, we analyzed the methylation status of SNCA in bisulfite converted genomic DNA of peripheral white blood cells of 43 patients with idiopathic PD (49% female; average age, 64.8 years; average age at onset, 61 years), 3 patients with monogenic PD because of duplication of the SNCA gene, and 37 neurologically normal controls (50% female; average age, 64.6 years). All patients were diagnosed and recruited in 2 centers that specialize in movement disorders (Kiel and Lübeck). The study was approved by the local ethics committees, and written informed consent was obtained from all participants. The groups with idiopathic PD and controls did not differ significantly regarding sex (P 1⁄4 .36, chi-square test), age (P 1⁄4 1.00, ANOVA), or ethnic origin (all German). White blood cell DNA was prepared after erythrocyte lysis by the same standard salting-out procedure for all patients. Bisulfite conversion, PCR amplification, and pyrosequencing were performed as described previously, except that a PyroMark PCR kit (Qiagen, Hilden, Germany) was used for PCR amplifications. The 2 PCR amplicons (SNCA_a, SNCA_c) allowed for analysis of 2 CpG stretches (Fig. 1). One stretch encompassed CpGs also analyzed in the 2 previous studies on brain tissue by Jowaed et al and Matsumoto et al (Fig. 1 SNCA_c). The second amplicon covered 8 additional CpGs of a CpG island shore in the untranslated first exon of SNCA (Fig. 1, SNCA_a). Figure 1 shows the distribution of the mean CpG methylation per region for each individual in the 3 groups. Comparisons using the Mann– Whitney test did not reveal any significant methylation differences between the groups with idiopathic PD and controls (P > .1), neither using mean methylation per individual across each of the 2 amplicons (Fig. 1) nor comparing single CpG positions (results not shown). The group with monogenic PD caused by duplication of the SNCA gene was too small for a meaningful statistical comparison. Nevertheless, we did not identify any sample with a grossly different methylation pattern in this group (Fig. 1). Taken together, we demonstrate in a sizable group that the analyzed cytosins are not differentially methylated between idiopathic PD patients and neurologically normal controls using DNA derived from peripheral white blood cells. To serve as a biomarker, a laboratory measure needs to be able to discriminate between patients and controls on an individual basis, which is clearly not the case. Peripheral blood leukocytes were chosen because they are easily attainable, which is essential for diagnostic application. It has previously been shown that methylation profiles are often but not always highly correlated between different tissues. However, SNCA has not been specifically investigated in this regard. Methylation differences between blood leukocyte DNA and brain DNA might explain the difference between our results and the ones obtained in brain tissue. A limitation of our study is that not all CpGs analyzed by Jowaed and Matsumoto in brain tissue were amenable to analysis by pyrosequencing because a number of them were located in long poly-T stretches after bisulfite conversion. On the other hand, we analyzed an additional region (SNCA_a), and our pyrosequencing approach has the advantage of allowing fairly accurate quantification of the percentage of methylated versus unmethylated CpGs.

Resistance versus balance training to improve postural control in Parkinson's disease: a randomized rater blinded controlled study

Background Reduced muscle strength is an independent risk factor for falls and related to postural instability in individuals with Parkinson’s disease. The ability of resistance training to improve postural control still remains unclear. Objective To compare resistance training with balance training to improve postural control in people with Parkinson’s disease. Methods 40 patients with idiopathic Parkinson’s disease (Hoehn&Yahr: 2.5–3.0) were randomly assigned into resistance or balance training (2x/week for 7 weeks). Assessments were performed at baseline, 8- and 12-weeks follow-up: primary outcome: Fullerton Advanced Balance (FAB) scale; secondary outcomes: center of mass analysis during surface perturbations, Timed-up-and-go-test, Unified Parkinson’s Disease Rating Scale, Clinical Global Impression, gait analysis, maximal isometric leg strength, PDQ-39, Beck Depression Inventory. Clinical tests were videotaped and analysed by a second rater, blind to group allocation and assessment time. Results 32 participants (resistance training: n = 17, balance training: n = 15; 8 drop-outs) were analyzed at 8-weeks follow-up. No significant difference was found in the FAB scale when comparing the effects of the two training types (p = 0.14; effect size (Cohen’s d) = -0.59). Participants from the resistance training group, but not from the balance training group significantly improved on the FAB scale (resistance training: +2.4 points, Cohen’s d = -0.46; balance training: +0.3 points, Cohen’s d = -0.08). Within the resistance training group, improvements of the FAB scale were significantly correlated with improvements of rate of force development and stride time variability. No significant differences were found in the secondary outcome measures when comparing the training effects of both training types. Conclusions The difference between resistance and balance training to improve postural control in people with Parkinson’s disease was small and not significant with this sample size. There was weak evidence that freely coordinated resistance training might be more effective than balance training. Our results indicate a relationship between the enhancement of rate of force development and the improvement of postural control. Trial Registration ClinicalTrials.gov ID: NCT02253563

Orthostatic myoclonus associated with Caspr2 antibodies

Orthostatic myoclonus (OM) is a clinical phenomenon in which myoclonus of the lower limbs appears or becomes worse upon standing.1 OM usually affects patients older than 65 years and may be a frequent cause of unsteadiness upon standing in the elderly.2 Although the underlying etiology remains unclear, OM has predominantly been described in association with neurodegenerative diseases.1 We describe a patient with OM in association with antibodies against contactin-associated protein-2 (Caspr2) whose symptoms markedly improved with immunotherapy.

Locating the STN-DBS electrodes and resolving their subsequent networks using coherent source analysis on EEG

The deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most effective surgical therapy for Parkinsons disease (PD). The first aim of the study was to locate the STN-DBS electrode by applying source analysis on EEG. Secondly, to identify tremor related areas which are associated with the STN. The Dynamic imaging of coherent sources (DICS) was used to find the coherent sources in the brain. The capability of the source analysis to detect deep sources like STN in the brain using EEG data was tested with two model dipole simulations. The simulations were concentrated on two aspects, the angle of the dipole orientation and the disturbance of the cortical areas on locating subcortical regions. In all the DBS treated Parkinsonian tremor patients the power spectrum showed a clear peak at the stimulated frequency and followed by there harmonics. The DBS stimulated frequency constituted a network of primary sensory motor cortex, supplementary motor area, prefrontal cortex, diencephalon, cerebellum and brainstem. Thus the STN was located in the region of the diencephalon. The resolved network may give better understanding to the pathophysiology of the effected tremor network in PD patients with STN-DBS.

Patient Evaluation and Selection for Movement Disorders Surgery: The Changing Spectrum of Indications

This report summarizes the state-of-the-art and controversies around patient selection for deep brain stimulation (DBS) for various conditions. Parkinsons disease (PD): several class I studies have shown superiority of DBS over best medical treatment for advanced PD with fluctuations and further inclusion criteria. One class I study suggests that PD patients with early motor complications might gain more quality of life if operated within 3 years after the onset of fluctuations. The subthalamic nucleus (STN) is still the standard target. STN DBS has an impact on impulse control disorders though the exact mechanism is unclear. Tremor: essential tremor (ET) patients found to be eligible for DBS surgery should first be treated with primidone, propranolol, and with a combined therapy preoperatively. Second-line drugs (i.e., topiramate and gabapentin) may be useful. No class I studies exist for DBS treatment of ET. The optimal target of DBS in ET might be the posterior subthalamic area. Dystonia: there is class I evidence for primary generalized and segmental dystonia and for some botulinum-resistant focal dystonias. The impact of age, symptom duration, and DYT-mutation status in primary dystonia on the outcome of DBS surgery clearly demands more studies. DBS has a role in SCGE-mutation positive myoclonus dystonia and tardive dystonia. Finally, neurostimulation in secondary dystonia might be considered in selected patients based on an individual patients approach.

Ergotherapie macht Parkinson-Patienten aktiver

Bisher liegt keine ausreichende Evidenz zur Wirksamkeit der Ergotherapie in der Behandlung der Parkinson-Erkrankung vor. Eine große Studie aus den Niederlanden liefert nun Pro-Argumente.

SSRI und SNRI sind wirksam und sicher

Patienten und Methodik: In die multizentrische Studie wurden 115 Patienten mit einem M. Parkinson und begleitender Depression eingeschlossen und zu einer Therapie mit Paroxetin (n = 42), Venlafaxin extended release (XR; n = 34) oder Placebo (n = 39) randomisiert. Haupteinschlusskriterium war das Vorliegen einer Depression (nach den DSM-IV-Kriterien) oder einer subsyndromalen Depression mit > 12 Punkten der ersten 17 Items in der Hamilton Depressionsskala (HAM-D) bei Patienten mit einem M. Parkinson. Nach einer jeweils sechswöchigen Eindosierungsund Erhaltungsphase