Polypharmacy in Parkinson's disease: risks and benefits with little evidence.

Polypharmacy is common practice in Parkinson's disease. Medical treatment targeting the dopaminergic system alone may include up to five different compounds: L-DOPA (in combination with a DOPA decarboxylase inhibitor), a catechol-O-methyltransferase (COMT) and a monoamine oxidase (MAO-B) inhibitor and a dopamine agonist. Particular motor and non-motor symptoms may require additional specific therapeutics, such as drugs aimed at tremor control and to treat depression, dementia and orthostatic and autonomic dysfunction. No prospective studies have yet been performed with regard to the efficacy or the long-term benefit of combining such different treatments in Parkinson's disease and retrospective analyses are sparse. We thus tried to compile the available evidence for polypharmacy strategies in Parkinson's disease and devised an expert opinion statement.

[The gut microbiome in Parkinson's disease]. / Das Darmmikrobiom bei der Parkinson-Krankheit.

The vast majority of Parkinson's disease (PD) cases are of sporadic origin and despite extensive research in recent years, the etiology still remains unclear. Several current case control studies are aiming to characterize a putative PD-specific composition of the gut microbiome, reflecting the potential relevance of microbiota in the pathogenesis of PD. Although methodologies and cohort sizes differed, the currently available studies showed reproducible or consistent results in terms of PD-specific alterations to the intestinal bacteria. By applying metagenomic sequencing procedures, it is even possible to distinguish PD cases from healthy individuals at a very early disease stage by means of individually modified microbiota. Among others, microbiota that are associated with an altered intestinal barrier or immune function, such as Akkermansia, Lactobacillus, Faecalibacterium and Prevotella were significantly over-represented or under-represented. There may even be a prodromal microbiome, as a comparable microbial shift is also found in patients with rapid eye movement (REM) sleep behavior disorder (RBD), a risk factor for the later development of synucleinopathies, such as PD.

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson's disease patients.

BACKGROUND: Parkinson's disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker. METHODS: We performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls. RESULTS: We found increased Verrucomicrobiaceae (Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae (Prevotella copri) and Erysipelotrichaceae (Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions. CONCLUSIONS: Our data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts.

[Epigenetics in Parkinson's Disease]. / Epigenetik und die Parkinson'sche Krankheit.

The genetic information encoded in the DNA sequence provides a blueprint of the entire organism. The epigenetic modifications, in particular DNA methylation and histone modifications, determine how and when this information is made available and define the specific gene transcription pattern of a given cell. Epigenetic modifications determine the functional differences of genetically identical cells in multicellular organisms and are important factors in various processes from embryonic development to learning and memory consolidation. DNA methylation patterns are altered by environmental conditions and some alterations are preserved through mitosis and meiosis. Thus, DNA methylation can mediate environmental impact on health and disease, contributes to the severity of diseases and probably contributes to the effects and side effects of drugs. In addition to the classical monogenic epigenetic diseases such as Prader-Willi syndrome and Rett syndrome, recent data point to an epigenetic component also in sporadic neuro-psychiatric disorders.

A randomized pilot study of stochastic vibration therapy in spinocerebellar ataxia.

Whole body vibration (WBV) is a biomechanical treatment used widely in professional sports and rehabilitation. We examined the effect of stochastic WBV on ataxia in spinocerebellar ataxia types 1, 2, 3, and 6 (SCA 1, 2, 3 and 6) in a single-center double-blind sham-controlled study. Stochastic WBV was applied on four sequent days, each treatment consisting of five stimulus trains of 60-s duration at a frequency of 6.5 Hz and 60-s resting time between stimuli (n = 17). Patients allocated to the sham group received the same treatment with 1 Hz (n = 15). All patients were rated at baseline and after the last treatment using clinical scores (SARA, SCAFI, and INAS). After treatment, we found significant improvements of gait, posture, and speed of speech in the verum group while limb kinetics and ataxia of speech did not respond. Stochastic WBV might act on proprioceptive mechanisms and could also stimulate non-cerebellar/compensatory mechanisms. But at present, the involved cellular mechanism and the presumed neuronal loops cannot be deciphered. Thus, future work is needed to understand the mechanisms of whole body vibration. Finally, the use of stochastic WBV could provide a supplementation to treat ataxia in SCA and can be combined with physiotherapeutical motor training.

Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.

Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 µg) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 µg), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 µg VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated.

Patient selection for mechanical thrombectomy.

PURPOSE: To evaluate the influence of tissue parameters as assessed by multimodal computed tomography and procedural parameters on clinical outcome after mechanical thrombectomy. METHODS: A total of 301 consecutive patients with acute onset ischemic stroke were included in this study. Of these, 65 had thromboembolic occlusions of the carotid T or middle cerebral artery (MCA) and underwent mechanical thrombectomy. Tissue parameters were given by unenhanced CT and perfusion CT (PCT) parameter maps of total hypoperfused tissue, infarct core, and tissue at risk. Procedural parameters comprised time from symptom onset (SO) to PCT, from SO to the first angiographic series, and from SO to vessel recanalization (occlusion time). In a subset of 22 fully recanalized occlusions, infarcted tissue and "tissue at risk" as defined by PCT were coregistered to final infarcts on follow-up imaging. RESULTS: Thrombolysis in cerebral infarction score (TICI) 2b/3 recanalization was achieved in 58/65 patients (89%). Only the infarct core size (p = 0.007) and the ratio of the infarct core relative to the tissue at risk (p = 0.001) yielded significant differences regarding the clinical outcome. Small infarct cores and low ratios of core size relative to the tissue at risk were correlated with a favorable outcome after mechanical thrombectomy. In the PCT coregistration subset, the congruency between predicted infarct cores and final infarcts was 68%, and between tissue at risk and final infarcts 7%, respectively. CONCLUSIONS: The size of the infarct core and the ratio relative to the tissue at risk are more relevant parameters for clinical outcome after mechanical thrombectomy than time related factors.

[Parkinson's disease. Perioperative management and anesthesia]. / Morbus Parkinson. Perioperatives Management und Anästhesie.

Approximately 10,000-15,000 Parkinson's disease (PD) patients per year undergo surgery in Germany. The demographic developments along with further surgical progress and procedural refinements will lead to increasing numbers of PD patients in the operating theatre (OR). There are several perioperative risk factors for PD patients, they more often require prolonged intensive care treatment and warrant particular anesthesiological attention with regard to the choice of drugs and equipment. Careful evaluation of concomitant diseases, maintenance of oral Parkinson therapeutic drugs up to the time of surgery and continuous perioperative dopaminergic therapy are key factors for reducing postoperative morbidity in PD patients undergoing surgery.

Mechanical thrombectomy compared to local-intraarterial thrombolysis in carotid T and middle cerebral artery occlusions: a single center experience.

PURPOSE: The aim of the study was to examine the effects of mechanical thrombectomy using the Solitaire stent in patients with thromboembolic occlusions of the intracranial carotid artery bifurcation (carotid T) or middle cerebral artery (MCA) and to compare the results with a historical cohort treated with local intraarterial thrombolysis using urokinase. METHODS: The time intervals from stroke onset to treatment, recanalization rates, occlusion sites, recanalization times and functional outcomes on the modified Rankin scale at 3 months in 25 patients treated with the Solitaire stent between 2010 and 2011 were evaluated. The data were compared with those of a historical cohort of 62 patients treated with local intraarterial thrombolysis between 1992 and 2001. RESULTS: A total of 15 out of 25 (60%) patients treated with mechanical thrombectomy and 25 out of 62 (40%) treated with local intraarterial thrombolysis achieved a modified Rankin score of ≤2 (p = 0.07). Occlusion sites, intervals from stroke onset to treatment and rates of parenchymal hematomas, 3 out of 25 (12%) versus 8 out of 62 (13%), were similar in both cohorts while the recanalization rate was significantly higher, 22 out of 25 (88%) versus 33 of 62 (53%), in the mechanical thrombectomy group (p ≤ 0.01). CONCLUSION: The data show that mechanical thrombectomy is superior to local intraarterial thrombolysis with respect to the recanalization rate in patients with thrombeoembolic carotid T or MCA occlusions.

Depression in Parkinson's disease.

Among the recently well appreciated non-motor symptoms in Parkinson's disease (PD), depression plays a prominent role due to its frequency and impact on quality of life. However, depression may be confounded by motor symptoms, especially akinesia and other non-motor symptoms such as apathy, anxiety and dementia. Data on specific diagnostic tools or treatment for depressive symptoms in PD patients are still sparse. Here we summarize an expert opinion based on available data and clinical experience.

Tremor in Parkinson's disease is not associated with the DRD3 Ser9Gly polymorphism.

A common subset of genetic risk factors for Parkinson's disease (PD) and essential tremor (ET) has been postulated. Recently, an association between the dopamine D(3) receptor (DRD3) Ser9Gly polymorphism and ET has been reported. We studied whether PD tremor is influenced by Ser9Gly in a genetic association study based on the gene bank of the German Competence Network on Parkinson's disease. The study included analyses of motor predominance (mixed, hypokinetic, and tremor), and tremor type (resting, postural, and action). We did not identify any effect of DRD3 Ser9Gly on tremor in PD, even when regarding various symptom combinations to avoid missing a weak effect on the phenotype. Additional studies incorporating symptoms at disease onset, and grading of tremor response to dopaminergic therapy, are warranted.

[On the role of MAO B inhibitors and NMDA antagonists in the therapy of Parkinson's disease]. / Stellenwert von MAO-B-Inhibitoren und NMDA-Antagonisten in der Therapie des Morbus Parkinson.

In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy.

Combined 3T diffusion tensor tractography and 1H-MR spectroscopy in motor neuron disease.

BACKGROUND AND PURPOSE: Diagnostic confidence in motor neuron disease may be improved by the use of advanced MR imaging techniques. Our aim was to assess the accuracy (sensitivity/specificity) and agreement of combined (1)H-MR spectroscopy (proton MR spectroscopy) and diffusion tensor imaging (DTI) at 3T in patients with suspected motor neuron disease regarding detection of upper motor neuron (UMN) dysfunction. MATERIALS AND METHODS: Eighteen patients with suspected motor neuron disease were studied with MR spectroscopy/DTI and clinically rated according to the El-Escorial and ALSFRS-R scales. For MR spectroscopy, absolute N-acetylaspartate (NAA), choline (Cho), and phosphocreatine (PCr) concentrations and relative NAA/Cho and NAA/PCr ratios of corresponding volumes of interest within the primary motor cortex were calculated. For DTI, fractional anisotropy (FA) and mean diffusivity (MD) were measured bilaterally at the level of the precentral gyrus, corona radiata, internal capsule, cerebral peduncles, pons, and pyramid. FA and MD statistics were averaged on the corticospinal tracts (CSTs) as a whole to account for a region-independent analysis. RESULTS: MR spectroscopy indicated NAA reduction beyond the double SD of controls in 6 of 8 patients with clinical evidence for UMN involvement. Congruently, the mean FA of these patients was significantly lower in the upper 3 regions of measurements (P < .01). Overall, MR spectroscopy and DTI were concordant in all except 3 cases: 1 was correctly excluded from motor neuron disease by DTI (genetically proved Kennedy syndrome), whereas MR spectroscopy indicated CST involvement. MR spectroscopy and DTI each were false-positive for CST affection in 1 patient with lower motor neuron involvement only. CONCLUSION: Combined MR spectroscopy/DTI at 3T effectively adds to the detection of motor neuron disease with a high degree of accordance.

[Parkinson's disease influences the perioperative risk profile in trauma patients]. / Der Einfluss des Morbus Parkinson auf das perioperative Risikoprofil unfallchirurgischer Patienten.

AIM: Parkinson's disease (PD) is one of the most common degenerative diseases of the central nervous system affecting elderly patients with increasing demographic prevalence. The aim of this study was to define the perioperative risk profile in trauma patients suffering from Parkinson's disease in order to improve treatment options in these patients. METHOD: Over a period of 13 years, 16 patients suffering from Parkinson's disease treated in the department of trauma surgery were retrospectively compared using matched-pair analysis with 16 controls not affected by PD. Both groups of patients were assessed regarding morbidity, length of treatment and rehabilitation. RESULTS: Trauma patients suffering from Parkinson's disease showed an increase in morbidity risk. Postoperative falls occurred significantly, infections of the urinary tract and pneumonia tendentiously more often in PD patients. Postoperative stay and length of treatment were significantly longer in patients with PD. These patients also tended to stay longer preoperatively and remained longer in intensive care. PD patients required on-ward rehabilitation significantly more often. CONCLUSION: Concomitant Parkinson's disease is a significant factor of perioperative morbidity in trauma patients. Perioperative morbidity in PD patients may be influenced by early diagnostic and therapeutic measures.

Autonomic dysfunction in 3414 Parkinson's disease patients enrolled in the German Network on Parkinson's disease (KNP e.V.): the effect of ageing.

We analysed non-motor symptoms (NMS) related to autonomic dysfunction in 3414 patients with Parkinson's disease (PD) enrolled in the multicentre registry of the German Competence Network on PD. Orthostatic hypotension (> 20 mmHg systolic or > 10 mmHg diastolic) was reported for 10% of women and 11% of men, urinary incontinence for 22% of women and 21% of men, sexual dysfunction for 8% of women and 30% of men (50% of whom reported erectile dysfunction) and sleep disturbances for 43% of women and 35% of men. Autonomic symptoms occurred in a frequency similar to severe disabling dyskinesia which was reported for 16% of women and 11% of men. A logistic regression analyses with age, sex and disease duration as covariates revealed a significant correlation of orthostatic hypotension and urinary incontinence with age and disease duration whilst sexual dysfunction was related to age only. These observations suggests that the effects of the PD process and ageing contribute to non-levodopa responsive NMS. Sleep disturbances were more common in women and a correlation was found with disease duration only supporting the notion that sleep is specifically affected in PD.

Synthetic approaches and bio-distribution studies of [11C]methyl-phenidate.

PURPOSE: The purpose of this study was a) to present a facilitated method for the preparation and workup of [11C]d-threo-methylphenidate ([11C]d-threo-MP) (a ligand that was shown to bind selectively to the presynaptic dopaminergic transporters) from [11C]methyliodide ([11C]CH3I), b) to demonstrate that the ligand can as well be produced by an alternative labeling method employing [11C]diazomethane as the labeling agent and c) to present biodistribution data for this tracer obtained in rats. METHODS: 11C-labeling with [11C]CH3I was performed using either [d-threo-1-(2-nitrophenylsulfanyl)piperidin-2-yl]phenyl-acetic acid (d-threo-N-NPS-ritalinic acid) under addition of sodium hydroxide as base or the previously prepared sodium salt of d-threo-N-NPS-ritalinic acid. The two approaches were compared with regard to radiochemical yield and purification procedures needed in order to obtain a sufficiently pure tracer solution for human use. For the alternative reaction pathway using [11C]diazo-methane as the labeling agent the reaction was performed with d-threo-N-NPS-ritalinic acid. The biodistribution of [11C]d-threo-MP was determined in rats at 5, 10 and 30 min post injection of the tracer. RESULTS: The application of the sodium salt of d-threo-N-NPS-ritalinic acid as precursor resulted in higher radiochemical yields than the use of the free acid under basic conditions, the yields were 20 +/- 8% and 6 +/- 3%, respectively for the final isolated product (based on [11C]CH3I starting activity). The alternative labeling approach by means of [11C]diazomethane as the labeling agent was demonstrated to give radiochemical yields of 76 +/- 8% (based on [11C]diazomethane starting activity, determined by HPLC analysis of the crude reaction mixture before final work-up) within shorter process times. Based on [11C]methane starting activity both approaches result in similar yields (17% and 15%, respectively) Biodistribution studies in rats revealed a low blood activity (0.09% injected dose/g (% ID/g)) at 5 min post injection (p.i.), as well as a relatively high liver uptake (15.9% ID at 30 min) compared to a lower kidney uptake (3.2% ID at 30 min). Brain uptake was 0.9% ID/g already 5 and 10 min p.i.. CONCLUSIONS: The application of the sodium salt of d-threo-N-NPS-ritalinic acid as precursor for the radiosynthesis of [11C]d-threo-MP reduces the amount of [11C]methanol formed from the reaction of [11C]CH3I with sodium hydroxide, that is added to generate the carboxylic anion of d-threo-N-NPS-ritalinic acid needed for labeling with [11C]CH3I. The purification process could be simplified (omission of one solid phase extraction step), resulting in an easily automated process for the production of the tracer. The preparation of [11C]d-threo-MP by means of [11C]diazomethane as the labeling agent appears to be an interesting alternative to the [11C]CH3I methods because of shorter overall process times and high labeling yields. Biodistribution data show a rapid extraction of the tracer from the blood pool. Tracer excretion seems to take place predominantly via the hepatic pathway since liver uptake at 30 min was considerably higher than kidney uptake. [11C]d-threo-MP exhibits a rapid and sufficiently high brain uptake in rats.