Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The ...arsenal of pharmacotherapies includes L‐Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)‐B and catechol‐o‐methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L‐Dopa or dopamine agonists with long half‐life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L‐Dopa, dopamine agonists, and amantadine as well as new MAO‐B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non‐dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 ‐ mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV‐mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α‐synuclein and inhibitors or modulators of α‐synuclein‐aggregation are currently studied in clinical trials. However, to date, no disease‐modifying treatment is available. We here review the current status of treatment options for motor and non‐motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non‐specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease‐modifying therapies has been unsuccessful so far.
The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L‐Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)‐B and catechol‐o‐methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L‐Dopa, dopamine agonists, and amantadine as well as new MAO‐B and COMT inhibitors are currently tested in clinical trials. Non‐dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV‐mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine – a dihydropyridine calcium channel blocker – as well as active and passive immunization against α‐synuclein and inhibitors of α‐synuclein‐aggregation are currently studied in clinical trials. However, to date, no disease‐modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non‐motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease‐modifying therapies has been unsuccessful so far.
This article is part of a special issue on Parkinson disease.
The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L‐Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)‐B and catechol‐o‐methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L‐Dopa, dopamine agonists, and amantadine as well as new MAO‐B and COMT inhibitors are currently tested in clinical trials. Non‐dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV‐mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine – a dihydropyridine calcium channel blocker – as well as active and passive immunization against α‐synuclein and inhibitors of α‐synuclein‐aggregation are currently studied in clinical trials. However, to date, no disease‐modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non‐motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease‐modifying therapies has been unsuccessful so far.
This article is part of a special issue on Parkinson disease.
There are two competing hypotheses for the origin of megaliths in Europe. The conventional view from the late 19th and early 20th centuries was of a single-source diffusion of megaliths in Europe ...from the Near East through the Mediterranean and along the Atlantic coast. Following early radiocarbon dating in the 1970s, an alternative hypothesis arose of regional independent developments in Europe. This model has dominated megalith research until today. We applied a Bayesian statistical approach to 2,410 currently available radiocarbon results from megalithic, partly premegalithic, and contemporaneous nonmegalithic contexts in Europe to resolve this long-standing debate. The radiocarbon results suggest that megalithic graves emerged within a brief time interval of 200 y to 300 y in the second half of the fifth millennium calibrated years BC in northwest France, the Mediterranean, and the Atlantic coast of Iberia. We found decisive support for the spread of megaliths along the sea route in three main phases. Thus, a maritime diffusion model is the most likely explanation of their expansion.
ABSTRACT
Polymetamorphic garnet micaschists from the Austroalpine Saualpe Eclogite Unit (Kärnten, Austria, Eastern Alps) display complex microstructural and mineral–chemical relationships. Automated ...scanning electron microscopy routines with energy dispersive X‐ray (EDX) spectral mapping were applied for monazite detection and garnet mineral–chemical characterization. When the Fe, Mg, Mn and Ca element wt% compositions are used as generic labels for garnet EDX spectra, complex zonations and porphyroblast generations can be resolved in complete thin sections for selective electron‐microprobe analyses. Two garnet porphyroblast generations and diverse monazite age populations have been revealed in low‐Ca and high‐Al‐metapelites. Garnet 1 has decreasing Mn, constant Ca and significantly increasing Mg from cores to rims. Geothermobarometry of garnet 1 assemblages signals a crystallization along a M1 prograde metamorphism at ~650 °C/6–8 kbar. Sporadic monazite 1 crystallization started at c. 320 Ma. Subsequent pervasive 300–250 Ma high‐Y and high‐Gd monazite 1 formation during decompression coincided with the intrusion of Permian and Early Triassic pegmatites. Monazite 1 crystallized along the margin of garnet 1. Coronas of apatite and allanite around the large 320–250 Ma monazite signal a retrogressive stage. These microstructures suggest a Carboniferous‐to‐Early‐Permian age for the prograde M1 event with garnet 1. Such a M1 event at an intermediate‐P/T gradient has not yet been described from the Saualpe, and preceded a Permo‐Triassic low‐P stage. The M2 event with garnet 2 postdates the corona formation around Permian monazite. Garnet 2 displays first increasing XCa at decreasing XMg, then increasing XCa and XMg, and finally decreasing XCa with increasing XMg, always at high Ca and Mg, and low Mn. This records a P–T evolution which passed through eclogite facies conditions and reached maximum temperatures at ~750 °C/14 kbar during decompression‐heating. A monazite 2 population (94–86 Ma) with lower Y and Gd contents crystallized at decreasing pressure during the Cretaceous (Eo‐Alpine) metamorphism M2 at a high‐P/T gradient. The Saualpe Eclogite Unit underwent two distinct clockwise metamorphic cycles at different P–T conditions, related to continental collisions under different thermal regimes. This led to a characteristic distribution pattern of monazite ages in this unit which is different from other Austroalpine basement areas.
In recent years, an increasing number of neuroimaging studies have sought to identify the brain anomalies associated with mood and anxiety disorders. The results of such studies could have ...significant implications for the development of novel treatments for these disorders. A challenge currently facing the field is to assimilate the large and growing corpus of imaging data to inform a systems-level model of the neural circuitry underlying the disorders. One prominent theoretical perspective highlights the top-down inhibition of amygdala by ventromedial prefrontal cortex (vmPFC) as a crucial neural mechanism that may be defective in certain mood and anxiety disorders, such as major depression and post-traumatic stress disorder. In this article, we provide a critical review of animal and human data related to this model. In particular, we emphasize the considerable body of research that challenges the veracity (or at least completeness) of the predominant model. We propose a framework for constructing a more comprehensive model of vmPFC function, with the goal of fostering further progress in understanding the neuropathophysiological basis of mood and anxiety disorders.
Drosophila melanogaster provides an important resource for in vivo modifier screens of neurodegenerative diseases. To study the underlying pathogenesis of Alzheimer's disease, fly models that address ...Tau or amyloid toxicity have been developed. Overexpression of human wild-type or mutant Tau causes age-dependent neurodegeneration, axonal transport defects and early death. Large-scale screens utilizing a neurodegenerative phenotype induced by eye-specific overexpression of human Tau have identified several kinases and phosphatases, apoptotic regulators and cytoskeleton proteins as determinants of Tau toxicity in vivo. The APP ortholog of Drosophila (dAPPl) shares the characteristic domains with vertebrate APP family members, but does not contain the human Aβ42 domain. To circumvent this drawback, researches have developed strategies by either direct secretion of human Aβ42 or triple transgenic flies expressing human APP, β-secretase and Drosophila γ-secretase presenilin (dPsn). Here, we provide a brief overview of how fly models of AD have contributed to our knowledge of the pathomechanisms of disease.
Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) therapy have an increased risk of developing cognitive impairment and dementia, which are known relevant factors in disease ...prognosis and therapeutic success, but still lack adequate screening in clinical routine. We evaluated the Montreal Cognitive Assessment (MoCA) for suitability in assessing cognitive performance in HD patients in comparison to the commonly used Mini-Mental State Examination (MMSE) and a detailed neuropsychological test battery, used as gold standard.
43 HD patients and 42 healthy controls with an average age of 58 years, were assessed with the MoCA, the MMSE and a detailed neuropsychological test battery, covering the domains of memory, attention, language, visuospatial and executive functions. Composite scores were created for comparison of cognitive domains and test results were analyzed using Spearman's correlation and linear regression. Cognitive dysfunction was defined using z-score values and predictive values were calculated. Sensitivity and specificity of the MoCA were determined using receiver operating characteristic (ROC) analysis.
HD patients performed worse in all cognitive domains, especially in memory recall and executive functions. The MoCA correlated well with the detailed test battery and identified patients with cognitive impairment with a sensitivity of 76.7% and specificity of 78.6% for a cut-off value of ≤24 out of 30 points. In the detailed assessment executive functions accounted significantly for performance in the MoCA. The MMSE only discriminated weakly between groups.
The MoCA represents a suitable cognitive screening tool for hemodialysis patients, demonstrating good sensitivity and specificity levels, and covering executive functions, which appear to play an important role in cognitive performance of HD patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar ...degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear--a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity in vivo. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function--but not ALS/FTLD-linked mutation, mislocalization, or truncation--for TDP-43-mediated neurotoxicity in vivo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the ...existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: ...SCA1, SCA2, SCA3, and SCA6. Methods Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18–50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35–70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov , number NCT01037777. Findings 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was −9 years (IQR −13 to −6) in 50 carriers of the SCA1 mutation, −12 years (–15 to −9) in 31 SCA2 mutation carriers, −8 years (–11 to −6) in 26 SCA3 mutation carriers, and −18 years (–22 to −16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 IQR 0–1·0 vs 0 0–0; p=0·0052), as did SCA2 mutation carriers (0·5 0–2·0 vs 0 0–0·5; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (–0·43 –0·91 to −0·07 vs 0·09 –0·30 to 0·56; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 0·861–0·959 vs 0·849 0·764–0·886; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r =0·36, p=0·0112; SCA2: r =0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012–0·016) than in non-carriers (0·019, 0·017–0·021; p=0·0107). Interpretation Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. Funding ERA-Net E-Rare and Polish Ministry of Science and Higher Education.
PML in a Patient Treated with Fumaric Acid Ermis, Ummehan; Weis, Joachim; Schulz, Jörg B
The New England journal of medicine,
04/2013, Letnik:
368, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Two cases of progressive multifocal leukoencephalopathy (PML) are reported in patients with psoriasis who were treated with fumarates, one with Fumaderm and the other with a compound containing ...dimethyl fumarate. The manufacturer of Fumaderm comments on the reports.
To the Editor:
Fumaric acid is considered effective and safe in the treatment of psoriasis vulgaris
1
and is licensed for this use in Germany. We diagnosed progressive multifocal leukoencephalopathy (PML) in a 74-year-old man who had received monotherapy for psoriasis with oral fumaric acid for 3 years (2007 through 2010) in doses of up to 120 mg of dimethyl fumarate and 95 mg of monoethyl fumarate, each taken two times a day. The patient had had psoriasis for more than 5 years and had been treated topically with glucocorticoids (January through May 2005) and orally with acitretin (maximum dose of . . .
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