bluuebunny/crossref_metadata_2025_split huggingface dataset:
The natural history of parkinson's disease
Authors: Poewe W. H. , Wenning G. K. 
Published: February 2014

AbstractThere are still insufficient data on the natural course of Parkinson's disease (PD) owing to lack of standardized longitudinal follow‐up studies. Reported progression rates in early PD vary considerably by a factor of 2 to 3. Similarly, data from sequential [18F]dopa PET studies in PD patients have produced variable decline rates of PET indices ranging between 7 and 70% per decade. Risk factors for rapid progression include old age at onset, concomitant major depression, dementia, and akinetic‐rigid symptom presentation. The introduction of levodopa into the routine treatment of PD patients had a dramatic impact on symptomatic control without affecting the underlying rate of disease progression. By contrast, monoamine oxidase (MAO) B inhibition by deprenyl monotherapy in early PD was shown to delay the need for levodopa by around 9 months. However, the neuroprotective action disappeared after 2 years of follow‐up. Furthermore, deprenyl also failed to influence the subsequent development of levodopa‐induced motor complications. Available studies on mortality in PD provide heterogeneous mortality rates, probably because of discrepancies between patient populations with respect to co‐morbidity, disease stage at study entry, and diagnostic accuracy. However, the most recent follow‐up from the DATATOP cohort suggests normal life expectancy in carefully selected patients without significant co‐morbidity and with adequate treatment and expert follow‐up.
The early diagnosis of parkinson's disease
Authors: Brooks David J. 
Published: February 2014

AbstractCurrent accepted clinical criteria for the diagnosis of Parkinson's disease (PD) provide high sensitivity for detecting parkinsonism but generally show poor specificity for identifying brainstem Lewy body disease. Biochemical markers that can be used to reliably diagnose clinical and preclinical PD have thus far been sought unsuccessfully. It is now known that some PD kindreds have a mutation of the α‐synuclein gene, but this cannot be used as a genetic marker for most familial and sporadic cases. Functional imaging provides a means of discriminating typical from atypical PD, revealing characteristic patterns of loss of dopaminergic function. In addition, PET and SPECT show preserved levels of striatal metabolism and dopamine receptor binding in PD, whereas levels are reduced in the atypical variants. [18F]Dopa PET can also detect preclinical PD. In one series there was a reported 40% prevalence of preclinical dopaminergic dysfunction in asymptomatic adult relatives of familial PD patients. Finally, PET and SPECT can both be used to follow PD progression objectively. Such studies suggest an annual 4 to 12% loss of dopamine terminal function in early PD and a preclinical disease window of only a few years. In the future, functional imaging is likely to play an increasingly important role in assessing the efficacy of putative neuroprotective agents.
Genetics of parkinson's disease
Authors: Gasser Thomas 
Published: February 2014

AbstractA genetic contribution to the etiology of Lewy body Parkinson's disease (PD) is now well established, based on the demonstration of a familial aggregation of the disease by case‐control and twin studies and on the description of large multigenerational families in whom clinically and pathologically typical PD is inherited in an autosomal dominant fashion. In the largest of these families, a gene locus has been mapped to the long arm of chromosome 4 and a putative disease‐causing mutation has been identified in the gene for α‐synuclein. However, analysis of a large number of individuals with sporadic and familial PD suggests that a mutation in this gene is a very rare cause of the disorder, either familial or sporadic. Another locus for autosomal dominantly inherited Lewy body PD has recently been mapped to chromosome 2p13. Possible strategies for the identification of further PD genes are discussed.
Genetic risk factors in parkinson's disease
Authors: Wood Nicholas W. 
Published: February 2014

AbstractThere is now overwhelming evidence for a role of genetic factors in susceptibility to Parkinson's disease. This review concentrates only on the evidence from candidate association studies because the role of linkage analysis and the successes of positional cloning are dealt with by others in this supplement. Candidate gene studies are a useful and powerful adjunct to the armamentarium of the researcher, but the robustness of the data is difficult to achieve. This is illustrated by the large literature on this subject, only a relatively small proportion of which has been reproduced. A recent study by our group is used to illustrate some of these difficulties, and the possible ways around some of the inherent biases in most of the studies are also discussed.
Autosomal dominant parkinson's disease and α‐synuclein
Authors: Polymeropoulos Mihael H. 
Published: February 2014

AbstractMultiple factors have been hypothesized over the years to be contributory and/or causative for Parkinson's disease (PD). Hereditary factors, although originally discounted, have recently emerged in the focus of PD research. The study of a large Italian family with PD using a genome scan approach led to the mapping of a PD susceptibility gene to the 4q21–q23 genomic region, where the gene for α‐synuclein was previously mapped. Mutation analysis of the α‐synuclein in four unrelated families with PD revealed a missense mutation segregating with the illness. α‐Synuclein is an abundant presynaptic protein in the human brain with unknown function. It is conceivable that the mutation identified in the PD families may result in self‐aggregation and/or decreased degradation of the protein, leading to the development of intracytoplasmic inclusion bodies and eventually to neuronal cell death. Moreover, the discovery of a mutation in the synuclein gene may offer us new insights in the understanding of the pathways that lead to neuronal degeneration.
Structure/function in neuroprotection and apoptosis
Authors: Borden Katherine L.B. 
Published: February 2014

AbstractThe three‐dimensional conformation of proteins influences their potential to function correctly within the cell. Protein conformational issues are particularly important in neurodegeneration, as has been shown by misfolded protein forming the basis of plaques in Alzheimer's disease and prion diseases. This article focuses on protein structure/function specifically for proteins important in the pathogenesis of neurodegenerative conditions and those involved in apoptosis. The proteins used as examples in this review include α‐synuclein, the promyelocytic leukemia protein, and glyceraldehyde 3‐phosphate dehydrogenase.
Advanced glycation end products in neurodegeneration: More than early markers of oxidative stress?
Authors: Münch G. , Gerlach M. , Sian J. , Wong A. , Riederer P. 
Published: February 2014

AbstractOxidative stress is believed to play a decisive role in the pathogenesis of Parkinson's disease (PD). In addition, Lewy bodies, densely crosslinked intracellular protein deposits formed from cytoskeletal components, accumulate in presymptomatic stages of the disease. Recent findings indicate that “advanced glycation end products” (AGEs) are the major structural crosslinkers that cause the transformation of soluble neurofilament proteins to insoluble Lewy bodies. AGE formation is increased under conditions of oxidative stress, such as early GSH depletion, that are evident in the substantia nigra of PD patients, and is inhibited by radical scavengers and thiol antioxidants. Because AGEs not only are markers of oxidative stress but are also active participants in cell signaling by activation of glial cells to produce superoxide and nitric oxide, they can be considered part of a vicious cycle, which finally leads to neuronal cell death in the substantia nigra in PD.
Glial cells and inflammation in parkinson's disease: A role in neurodegeneration?
Authors: Hirsch E. C. , Hunot S. , Damier P. , Faucheux B. 
Published: February 2014

AbstractThe data reviewed here show that, in Parkinson's disease (PD), some dopaminergic neurons are more vulnerable than others to the pathologic process. The glial cells surrounding dopaminergic neurons may be involved in this selective vulnerability. One subpopulation of glial cells, in particular, may play a neuroprotective role by metabolizing dopamine and scavenging oxygen free radicals that are associated with dopamine metabolism. Another subpopulation of glial cells may be deleterious to dopaminergic neurons. This effect may be mediated by the production of nitric oxide and cytokines, which may in turn account for the oxidative stress observed in the substantia nigra of patients with PD. Finally, this inflammatory reaction may result in the induction of apoptosis.
Programmed cell death: Does it play a role in parkinson's disease?
Authors: Burke Robert E. , Kholodilov Nikolai G. 
Published: February 2014

AbstractIn recent years, the possibility that programmed cell death (PCD), which is mediated by genetic programs intrinsic to the cell, may underlie the degeneration of neurons that occurs in Parkinson's disease (PD) and allied disorders has become an important hypothesis. Although PCD was originally identified in tissues as a normal developmental phenomenon, there is no question that it can also occur in neurologic disease and models thereof. The possibility that PCD could occur in dopamine neurons in degenerative disease is made plausible by the observations that natural cell death, with the morphology of apoptosis, does occur in these neurons and that this event is regulated by developmental target interactions. In addition, it has been shown that apoptotic death can be induced in these neurons in some animal models of parkinsonism. We have shown, for example, that apoptosis can be induced during development by intrastriatal injection of the neurotoxin 6‐hydroxydopamine. Other investigators have shown that apoptosis can be induced in a chronic model of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyride toxicity. However, investigations in human PD brains have yielded mixed results thus far, with some investigators identifying evidence of apoptotic death but others not. Further investigation of human postmortem tissue will benefit from a more complete understanding of the molecular basis of PCD in dopamine neurons, such that its molecular features can be investigated, rather than strictly relying on the morphologic markers presently available.
Mitochondria in neurodegenerative apoptosis: An opportunity for therapy?
Authors: Tatton William G. , Chalmers‐Redman Ruth M. E. 
Published: February 2014

AbstractApoptotic cell death has been shown to constitute the terminal process in some neurodegenerative diseases, notably Alzheimer's disease and Parkinson's disease (PD). A decrease in mitochondrial membrane potential (ΔψM) causing opening of the permeability transition pore (PTP) in mitochondrial membranes has been implicated as a critical effector of apoptosis in a variety of non‐neural cells. Opening of the PTP leads to the release of so‐called apoptosis initiation factors that induce the degradative events of apoptosis, such as nuclear chromatin condensation and DNA fragmentation. We have extended those findings to a neuronal model of apoptosis caused by trophic withdrawal, by showing that a decrease in ΔψM is an early event occurring 2 to 6 hours before the degradative events of apoptosis. A deficiency in mitochondrial complex I activity has been demonstrated in the substantia nigra of postmortem brains and several peripheral tissues obtained from PD patients. Because ΔψM is generated by the pumping of protons out across the inner mitochondrial membrane at the mitochondrial complexes, particularly complex I, we hypothesized that the decrease in complex activity could result in a decrease in ΔψM that would render PD substantia nigra neurons vulnerable to apoptosis. In preliminary studies, we have found a decrease in ΔψM in fibroblasts obtained from some PD patients. If a decrease in ΔψM consequent on decreased complex activity is an intrinsic defect in some PD patients, it would open a number of new avenues for the reduction of neuronal apoptosis in PD. The oncoprotein BCL‐2 and the scavenger protein SOD‐1 have been shown to reduce apoptosis by facilitating closure of the PTP. A number of agents have been shown to maintain BCL‐2 and/or SOD‐1 synthesis in damaged nerve cells and thereby reduce apoptosis. Other agents, such as cyclosporin A and some benzodiazepine receptor‐binding agents, have been found to act directly on the PTP to reduce apoptosis. Accordingly, agents that maintain ΔψM and PTP closure may offer new and effective means of treating neurodegenerative apoptosis.
A fluorescent double‐labeling method to detect and confirm apoptotic nuclei in parkinson's disease
Authors: Tatton Nadine A. , Maclean‐Fraser A. , Tatton William G. , Perl Daniel P. , Warren C. Olanow 
Published: February 2014

AbstractIn situ end‐labeling (ISEL) has become a widely used method to determine whether cells die via apoptosis by detecting double‐stranded DNA breaks that are the result of endonuclease digestion. The enzyme terminal deoxynucleotidyl transferase can be used to label the digested 3′‐OH ends of DNA with biotin‐, digoxigenin‐, or fluorescent probe‐conjugated nucleotides. However, both single‐stranded and double‐stranded DNA breaks can be labeled by this method and therefore ISEL cannot unequivocally demonstrate apoptosis when used alone. We have developed a fluorescent double‐labeling method using ISEL combined with the cyanine dye YOYO‐1 that binds to DNA. When combined with confocal laser microscopy and deconvolution analysis, YOYO‐1 can demonstrate the presence or absence of nuclear chromatin condensation and thus confirm that ISEL‐positive nuclei are indeed apoptotic. Preliminary findings indicate that dopaminergic neurons in the substantia nigra compacta die via apoptosis in Parkinson's disease.
Levodopa Toxicity and Apoptosis
Authors: Melamed Eldad , Offen Daniel , Shirvan Anat , Djaldetti Ruth , Barzilai Ari , Ziv Ilan 
Published: February 2014

AbstractMany in vitro studies have shown that levodopa is a potent toxin which is lethal to various cultured neuronal and non‐neuronal cells. The in vitro toxicity of levodopa is linked mainly to its auto‐oxidation, which generates a variety of harmful free radical species including superoxide, hydrogen peroxide, and hydroxyl radicals, and also semiquinones and quinones produced via the dopa—melanin metabolic route. Such toxic effects of levodopa can be blocked by co‐treatment with antioxidants, particularly thiol‐containing compounds. Several studies have shown that levodopa kills cells by triggering apoptosis, an active, intrinsic cell suicide program. Exposure of cultured neurons to levodopa induced the characteristic apoptotic cascade, including cell shrinkage, membrane blebbing, and nuclear and DNA fragmentation. Although levodopa is extremely toxic in vitro, there is no evidence that it damages nigrostriatal dopaminergic neurons in vivo in experimental animals and in patients with Parkinson's disease (PD). Likewise, although there is some evidence for the occurrence of apoptosis in the parkinsonian substantia nigra, it is not known whether levodopa administration is capable of inducing or accelerating programmed cell death of residual pigmented nigral neurons in PD.
DATATOP: A decade of neuroprotective inquiry
Authors: Shoulson Ira ,   Parkinson Study Group
Published: February 2014

AbstractIn 1987, the DATATOP clinical trial was initiated to examine the benefits of deprenyl (selegiline) and α‐tocopherol in slowing the progression of Parkinson's disease (PD). After 14 ± 6 (mean ± SD) months of controlled observation, deprenyl 10 mg/day was found to significantly delay the time until enough disability developed to warrant the initiation of levodopa therapy. This effect was largely sustained during the overall 8.2 years of observation, including open‐label deprenyl treatment and a second treatment randomization to continue deprenyl or switch to placebo. There were no accompanying benefits of deprenyl in postponing levodopa‐related adverse effects or extending life. α‐Tocopherol produced no benefits. The 2.1% per year mortality rate of the DATATOP cohort was remarkably low, about the same as an age‐matched population without PD. Neuroprotective therapy remains an elusive goal for the experimental therapeutics of PD. Advances in understanding pathogenesis, a robust pipeline of rational treatments, and the advent of valid and reliable biologic markers hold promise in the coming decade for developing and achieving neuroprotective therapies for PD.
Dopamine agonists and neuroprotection in parkinson's disease
Authors: C. Warren Olanow  , Jenner Peter , Brooks David 
Published: February 2014

AbstractThere is increasing interest in the potential of dopamine agonists to provide a neuroprotective effect and to alter the natural course of levodopa‐treated Parkinson's disease (PD). Theoretically, such a protective effect might derive from (a) a levodopa sparing effect, (b) stimulation dopamine autoreceptors resulting in decreased dopamine synthesis, release, and turnover, (c) direct anti‐oxidant effects, and (d) restoration of dopaminergic tone to the dopamine‐denervated brain so as to restore inhibition to the subthalamic nucleus and thereby diminish STN‐mediated excitotoxicity. Preclinical studies have demonstrated that dopamine agonists reduce dopamine formation in comparison to levodopa, protect cultured dopaminergic neurons from a variety of toxins including levodopa, and protect dopaminergic neurons from toxins and age‐related degeneration in some rodent models of parkinsonism. Based on these findings, several clinical trials have been initiated in patients with early PD to test the effect of dopamine agonists on clinical and neuroimaging markers of disease progression.
Subthalamic nucleus‐mediated excitotoxicity in parkinson's disease: A target for neuroprotection
Authors: Rodriguez M. C. , Obeso J. A. , Olanow C. Warren 
Published: February 2014

AbstractDopamine deficiency causes disinhibition and overactivity of the subthalamic nucleus (STN). Output neurons from the STN are excitatory and use glutamate as a neurotransmitter. They project to the external and internal segments of the globus pallidum (GPe and GPi), the substantia nigra pars reticulata (SNr), and the pedunculopontine nucleus (PPN). In addition, STN neurons provide excitatory innervation to dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that contain glutamate receptors. Stimulation of the STN induces bursting activity in SNc dopaminergic neurons. This raises the possibility that the disinhibition of STN neurons that occurs as a result of a dopamine lesion might induce excitotoxic damage in target structures, including the SNc. In addition, the reduction in complex I activity found in the nigra in Parkinson's disease (PD) may cause mitochondrial dysfunction and make SNc dopaminergic neurons vulnerable to even physiologic concentrations of glutamate. We postulate that the dopamine loss that occurs in PD produces augmented STN activity which, in turn, causes further damage to vulnerable dopaminergic neurons, thereby creating a scenario for an increasing cycle of neuronal loss in the SNc. In addition, STN overactivity could, in theory, cause damage to the GPi, SNr, and PPN and thereby account for the development of parkinsonian features that do not respond to levodopa in patients with advanced disease. This hypothesis suggests that pharmacologic or surgical therapies that reduce STN neuronal overactivity or block glutamate receptors in the SNc and other target structures might be neuroprotective and might slow or halt the progression of neurodegeneration in PD.
A High‐Pressure Polymorph of Phosphorus Nitride Imide
Authors: Marchuk Alexey , Pucher Florian J. , Karau Friedrich W. , Schnick Wolfgang 
Published: February 2014

AbstractPhosphorus nitride imide, PN(NH), is of great scientific importance because it is isosteric with silica (SiO2). Accordingly, a varied structural diversity could be expected. However, only one polymorph of PN(NH) has been reported thus far. Herein, we report on the synthesis and structural investigation of the first high‐pressure polymorph of phosphorus nitride imide, β‐PN(NH); the compound has been synthesized using the multianvil technique. By adding catalytic amounts of NH4Cl as a mineralizer, it became possible to grow single crystals of β‐PN(NH), which allowed the first complete structural elucidation of a highly condensed phosphorus nitride from single‐crystal X‐ray diffraction data. The structure was confirmed by FTIR and 31P and 1H solid‐state NMR spectroscopy. We are confident that high‐pressure/high‐temperature reactions could lead to new polymorphs of PN(NH) containing five‐fold‐ or even six‐fold‐coordinated phosphorus atoms and thus rivalling or even surpassing the structural variety of SiO2.
Direct Solvothermal Synthesis of B/N‐Doped Graphene
Authors: Jung Sun‐Min , Lee Eun Kwang , Choi Min , Shin Dongbin , Jeon In‐Yup , Seo Jeong‐Min , Jeong Hu Young , Park Noejung , Oh Joon Hak , Baek Jong‐Beom 
Published: February 2014

AbstractHeteroatom‐doping into graphitic networks has been utilized for opening the band gap of graphene. However, boron‐doping into the graphitic framework is extremely limited, whereas nitrogen‐doping is relatively feasible. Herein, boron/nitrogen co‐doped graphene (BCN‐graphene) is directly synthesized from the reaction of CCl4, BBr3, and N2 in the presence of potassium. The resultant BCN‐graphene has boron and nitrogen contents of 2.38 and 2.66 atom %, respectively, and displays good dispersion stability in N‐methyl‐2‐pyrrolidone, allowing for solution casting fabrication of a field‐effect transistor. The device displays an on/off ratio of 10.7 with an optical band gap of 3.3 eV. Considering the scalability of the production method and the benefits of solution processability, BCN‐graphene has high potential for many practical applications.
Superparamagnetic Copper Ferrite Nanoparticles as an Efficient Heterogeneous Catalyst for the α‐Arylation of 1,3‐Diketones with CC Cleavage
Authors: Nguyen Anh T. , Nguyen Lan T. M. , Nguyen Chung K. , Truong Thanh , Phan Nam T. S. 
Published: February 2014

AbstractSuperparamagnetic CuFe2O4 nanoparticles were synthesized from CuCl2 and FeCl3 by a co‐precipitation method in ethylene glycol and characterized by several techniques, which included vibrating sample magnetometry, XRD, SEM, TEM, atomic absorption spectrometry, and nitrogen physisorption measurements. The CuFe2O4 nanoparticles could be used as a solid catalyst for the α‐arylation reaction of acetylacetone with iodobenzene to form phenylacetone as the principal product and 3‐phenyl‐2,4‐pentanedione as the byproduct. The reaction that used the CuFe2O4 nanoparticles as catalyst could proceed to completion with 95 % selectivity to phenylacetone. The CuFe2O4 nanoparticles could be separated easily from the reaction mixture by magnetic decantation and could be reused several times for the α‐arylation reaction without a significant degradation in catalytic activity.