Parkinson Disease: England

Hawkes CH. · Neuroscience Centre, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, United Kingdom. · Mov Disord. · Pubmed #18759359 No free full text.

Abstract: It is frequently assumed that idiopathic Parkinson's disease starts with several nonmotor symptoms and signs, but the evidence for this stage in the disease process is of variable quality. This review evaluates the more robust prospective or pathologically confirmed publications to establish whether there is a premotor period and if so what is its duration. The most informative studies are considered to be those concerned with olfaction, dysautonomia, and sleep disorder. Estimates for the duration of the prodromal phase vary from months to decades. It is concluded that there probably is an early phase in the disease where a variety of nonmotor features develop, but the sequence and time of onset of such features is not well established.

Jenner P. · King's College London, Guy's Campus, School of Health and Biomedical Sciences, London SE1 1UL, UK. · Nat Rev Neurosci. · Pubmed #18714325 No free full text.

Abstract: L-DOPA (L-3,4-dihydroxyphenylalanine) remains the most effective drug for the treatment of Parkinson's disease. However, chronic use causes dyskinesia, a complex motor phenomenon that consists of two components: the execution of involuntary movements in response to drug administration, and the 'priming' phenomenon that underlies these movements' establishment and persistence. A reinterpretation of recent data suggests that priming for dyskinesia results from nigral denervation and the loss of striatal dopamine input, which alters glutamatergic synaptic connectivity in the striatum. The subsequent response of the abnormal basal ganglia to dopaminergic drugs determines the manner and timing of dyskinesia expression. The combination of nigral denervation and drug treatment establishes inappropriate signalling between the motor cortex and the striatum, leading to persistent dyskinesia.

Roodveldt C, Christodoulou J, Dobson CM. · Department of Chemistry, University of Cambridge, Cambridge, United Kingdom. · J Cell Mol Med. · Pubmed #18671754 No free full text.

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence, in the brain, of intra-cellular protein inclusions highly enriched in aggregated alpha-synuclein (alphaSyn), known as Lewy bodies. The onset of PD is accompanied by a local immune reaction in regions of the brain affected by the inclusions, although the mechanism that leads to pathogenesis is far from clear. It is, however, established that disease onset and progression are characterized by sustained activation of microglia, which is linked to significant dopaminergic neuron loss in the substantia nigra. A recent body of evidence indicates that aggregated or modified alphaSyn can indeed trigger the activation of microglia, inducing a lethal cascade of neuroinflammation and eventually, neuronal loss, pointing at aggregated and modified forms of alphaSyn as a primary cause of PD pathogenesis. By releasing toxic factors, or by phagocytosing neighbouring cells, activated microglia and astrocytes may form a self-perpetuating cycle for neuronal degeneration. Additional findings suggest a link between alphaSyn and humoural-mediated mechanisms in PD. In this review, we attempt to recapitulate our current understanding of PD physiopathology focused on alphaSyn and its links with the immune system, as well as of novel and promising therapeutic avenues for the treatment of PD and of other synucleinopathies.

Mirsky R, Woodhoo A, Parkinson DB, Arthur-Farraj P, Bhaskaran A, Jessen KR. · Department of Cell and Developmental Biology, University College London, London, UK. · J Peripher Nerv Syst. · Pubmed #18601657 No free full text.

Abstract: Immature Schwann cells found in perinatal rodent nerves are generated from Schwann cell precursors (SCPs) that originate from the neural crest. Immature Schwann cells generate the myelinating and non-myelinating Schwann cells of adult nerves. When axons degenerate following injury, Schwann cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann cell dedifferentiation involves activation of specific receptors, intracellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c-Jun in development and after nerve transection. In vivo, Notch signalling regulates the transition from SCP to Schwann cell, times Schwann cell generation, controls Schwann cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c-Jun is required for Schwann cell proliferation and death and is down-regulated by Krox-20 on myelination. Forced expression of c-Jun in Schwann cells prevents myelination, and in injured nerves, c-Jun is required for appropriate dedifferentiation, the re-emergence of the immature Schwann cell state and nerve regeneration. Thus, both Notch and c-Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.

Hands S, Sinadinos C, Wyttenbach A. · Southampton Neuroscience Group, School of Biological Sciences, University of Southampton, Southampton SO16 7PX, UK. · Biochim Biophys Acta. · Pubmed #18582603 No free full text.

Abstract: The coordinated regulation of gene expression and protein interactions determines how mammalian nervous systems develop and retain function and plasticity over extended periods of time such as a human life span. By studying mutations that occur in a group of genes associated with chronic neurodegeneration, the polyglutamine (polyQ) disorders, it has emerged that CAG/glutamine stretches play important roles in transcriptional regulation and protein-protein interactions. However, it is still unclear what the many structural and functional roles of CAG and other low-complexity sequences in eukaryotic genomes are, despite being the most commonly shared peptide fragments in such proteomes. In this review we examine the function of genes responsible for at least 10 polyglutamine disorders in relation to the nervous system and how expansion mutations lead to neuronal dysfunction, by particularly focusing on Huntington's disease (HD). We argue that the molecular and cellular pathways that turn out to be dysfunctional during such diseases, as a consequence of a CAG expansion, are also involved in the ageing of the central nervous system. These are pathways that control protein degradation systems (including molecular chaperones), axonal transport, redox-homeostasis and bioenergetics. CAG expansion mutations confer novel properties on proteins that lead to a slow-progressing neuronal pathology and cell death similar to that found in other age-related conditions such as Alzheimer's and Parkinson's diseases.

Hamer M, Chida Y. · Psychobiology Group, Department of Epidemiology and Public Health, University College London, UK. · Psychol Med. · Pubmed #18570697 No free full text.

Abstract: BACKGROUND: The association between physical activity and risk of neurodegenerative diseases is not well established. We therefore aimed to quantify this association using meta-analytical techniques. METHOD: We searched Medline, the Cochrane Database of Systematic Reviews and Web of Science databases from 1990 to 2007 for prospective epidemiological studies of physical activity and incident dementia, Alzheimer's and Parkinson's disease. We excluded studies of physical activity and cognitive decline without diagnosis of a neurodegenerative disease. Information on study design, participant characteristics, measurement of exposure and outcome variables, adjustment for potential confounding, and estimates of associations was abstracted independently by the two investigators. RESULTS: We included 16 prospective studies in the overall analysis, which incorporated 163797 non-demented participants at baseline with 3,219 cases at follow-up. We calculated pooled relative risk (RR) using a random effects model. The RR of dementia in the highest physical activity category compared with the lowest was 0.72 [95% confidence interval (CI) 0.60-0.86, p<0.001], for Alzheimer's, 0.55 (95% CI 0.36-0.84, p=0.006), and for Parkinson's 0.82 (95% CI 0.57-1.18, p=0.28). CONCLUSIONS: Our results suggest that physical activity is inversely associated with risk of dementia. Future studies should examine the optimal dose of physical activity to induce protection, which presently remains unclear.

De Vos KJ, Grierson AJ, Ackerley S, Miller CC. · MRC Center for Neurodegeneration Research, Institute of Psychiatry, King's College, London SE5 8AF, United Kingdom. · Annu Rev Neurosci. · Pubmed #18558852 No free full text.

Abstract: Many major human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), display axonal pathologies including abnormal accumulations of proteins and organelles. Such pathologies highlight damage to the axon as part of the pathogenic process and, in particular, damage to transport of cargoes through axons. Indeed, we now know that disruption of axonal transport is an early and perhaps causative event in many of these diseases. Here, we review the role of axonal transport in neurodegenerative disease.

Gallagher DA, Schrag A. · Department of Clinical Neurosciences, Royal Free and University College Medical School, London, EnglandInstitute of Neurology, University College London, London, England. · CNS Drugs. · Pubmed #18547126 No free full text.

Abstract: Parkinson's disease is a common progressive neurodegenerative condition with multiple motor and nonmotor features contributing to impairment of health-related quality of life (HR-QOL). Pharmacological treatments have been directed primarily at dopamine replacement with levodopa and agents to improve its bioavailability, including DOPA decarboxylase inhibitors, catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors, as well as synthetic dopamine agonists. These treatments to restore motor function are often very successful in early Parkinson's disease, with objective improvement and concomitant improvement in subjective HR-QOL scores. However, as the disease progresses, motor complications and nonmotor symptoms predominate and are often refractory to therapeutic interventions. Antiparkinsonian medications have been shown to improve motor severity and motor complications of advancing disease, and there is increasing evidence that this can be translated into subjective improvement of HR-QOL from a patient's point of view. However, the degree of improvement is less marked on HR-QOL scores than on motor scores, and some studies do not show improvement of HR-QOL in parallel to motor improvements. A number of explanations are possible, including limitations of the scales used, trial designs and lack of clinical improvement from the patients' point of view. This review concentrates on clinical trials with an index of HR-QOL as an outcome measure, with particular emphasis on well designed, randomized, double-blind, placebo-controlled or active comparator-controlled methodology. Drugs that have been more recently added to the armamentarium of Parkinson's disease, including the oral (pramipexole, ropinirole and piribedil) and transdermal (rotigotine) non-ergotamine-derived dopamine agonists, the novel MAO-B inhibitor rasagiline and the COMT inhibitors tolcapone and entacapone, were included. The effect of each of these agents on overall HR-QOL and depression, a factor that has been shown to significantly contribute to HR-QOL in several multivariate analyses, is discussed.Overall, the literature search revealed 14 double-blind, placebo- or active comparator-controlled trials with an index of HR-QOL as an outcome measure. Entacapone resulted in HR-QOL improvement in nonfluctuating patients (one study) but not clearly in those with motor fluctuations (two studies). Tolcapone was only tested in patients with motor fluctuations and resulted in significant improvement in two of four studies using HR-QOL as an outcome measure. Rasagiline improved HR-QOL as monotherapy in early Parkinson's disease (one study), but not clearly in more advanced disease (one study). Rotigotine improved HR-QOL in both early Parkinson's disease (one study) and more advanced disease with motor fluctuations (one study). The impact of ropinirole and pramipexole on HR-QOL as monotherapy in early Parkinson's disease versus placebo has not been assessed, but both agents have resulted in improved HR-QOL in patients with motor fluctuations (ropinirole one study, pramipexole one study). The evidence for antidepressant efficacy of antiparkinsonian medications is limited.

Robinson PA. · Leeds Institute of Molecular Medicine, University of Leeds, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK. · Biochem J. · Pubmed #18537793 No free full text.

Abstract: Parkinson's disease (PD), the second most common age-related neurodegenerative disease, results in abnormalities in motor functioning. Many fundamental questions regarding its aetiology remain unanswered. Pathologically, it is not until 70-80% of the dopaminergic neurons from the substantia nigra pars compacta are lost before clinical symptoms are observed. Thus research into PD is complicated by this apparent paradox in that what appears to be the beginning of the disease at the clinical level is really the end point neurochemically. Consequently, we can only second guess when the disease started and what initiated it. The causation is probably complex, with contributions from both genetic and environmental factors. Intracellular proteinaceous inclusions, Lewy bodies and Lewy neurites, found in surviving dopaminergic neurons, are the key pathological characteristic of PD. Their presence points to an inability within these terminally differentiated cells to deal with aggregating proteins. Recent advances in our knowledge of the underlying disease process have come about from studies on models based on genes associated with rare hereditary forms of PD, and mitochondrial toxins that mimic the behavioural effects of PD. The reason that dopaminergic neurons are particularly sensitive may be due to the additional cellular stress caused by the breakdown of the inherently chemically unstable neurotransmitter, dopamine. In the present review, I discuss the proposal that in sporadic disease, interlinked problems of protein processing and inappropriate mitochondrial activity seed the foundation for age-related increased levels of protein damage, and a reduced ability to deal with the damage, leading to inclusion formation and, ultimately, cell toxicity.

Pienaar IS, Daniels WM, Götz J. · Department of Medical Physiology, University of Stellenbosch, Matieland, South Africa. · J Neural Transm. · Pubmed #18523721 No free full text.

Abstract: Despite the vast number of studies on Parkinson's disease (PD), its effective diagnosis and treatment remains unsatisfactory. Hence, the relentless search for an optimal cure continues. The emergence of neuroproteomics, with its sophisticated techniques and non-biased ability to quantify proteins, provides a methodology with which to study the changes in neurons that are associated with neurodegeneration. Neuroproteomics is an emerging tool to establish disease-associated protein profiles, while also generating a greater understanding as to how these proteins interact and undergo post-translational modifications. Furthermore, due to the advances made in bioinformatics, insight is created concerning their functional characteristics. In this review, we first summarize the most prominent proteomics techniques and then discuss the major advances in the fast-growing field of neuroproteomics in PD. Ultimately, it is hoped that the application of this technology will lead towards a presymptomatic diagnosis of PD, and the identification of risk factors and new therapeutic targets at which pharmacological intervention can be aimed.

Lees AJ. · Reta Lila Weston Institute of Neurological Studies, ION, UCL, London, UK. · CNS Neurosci Ther. · Pubmed #18482101 No free full text.

Abstract: The relative efficacy has not been adequately established for the two catechol-O-methyltransferase (COMT) inhibitors that are currently available for adjunctive therapy in Parkinson's disease; tolcapone and entacapone. A recent Cochrane meta-analysis of 14 studies in 2566 patients, conducted to assess the efficacy and safety of tolcapone and entacapone, found both to be statistically superior to placebo in increasing ON time and decreasing OFF time. The meta-analysis also showed that the weighted mean difference from baseline to endpoint in tolcapone-treated patients was twice that in entacapone-treated patients for both placebo-corrected ON time and OFF time. Withdrawal rates were generally lower for tolcapone. Two additional studies have examined the switch between tolcapone and entacapone. In 40 Parkinson's disease patients with fluctuations who were switched from tolcapone to entacapone, improvements in ON time and reductions in OFF time were approximately twice the magnitude for tolcapone than for entacapone. In a second study examining the switch from entacapone to tolcapone, the results for several exploratory variables also suggested that tolcapone has greater efficacy than entacapone. These findings indicate that tolcapone should be considered in all patients with entacapone-refractory motor fluctuations.

Flinn L, Bretaud S, Lo C, Ingham PW, Bandmann O. · MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK. · J Neurochem. · Pubmed #18466340 No free full text.

Abstract: The zebrafish, long recognized as a model organism for the analysis of basic developmental processes, is now also emerging as an alternative animal model for human diseases. This review will first provide an overview of the particular characteristics of zebrafish in general and their dopaminergic nervous system in particular. We will then summarize all work undertaken so far to establish zebrafish as a new animal model for movement disorders and will finally emphasize its particular strength - amenability to high throughput in vivo drug screening.

Benamer HT, de Silva R, Siddiqui KA, Grosset DG. · Department of Neurology, Queen Elizabeth Neuroscience Centre, Queen Elizabeth University Hospital, Birmingham, United Kingdom. · Mov Disord. · Pubmed #18442138 No free full text.

Abstract: Studies of specific populations have provided invaluable knowledge about Parkinson's disease (PD), especially in the field of genetics. The present report systematically reviews the medical literature on PD in Arabs. Medline and Embase were searched, and 24 article were identified: genetic (n = 17), epidemiological (n = 3), and clinical series (n = 5). Both autosomal dominant and recessive forms of inherited PD are described, associated with four genes (Parkin, PINK1, LRRK2, and PARK9). The G2019S LRRK2 mutation is more common in both familial (37-42%) and apparently sporadic PD (41%) in North African Arabs than in Europeans and North Americans (2-3%). The incidence of PD is reported at 4.5 per 100,000 person-years and reported prevalence at 27 to 43 per 100,000 persons. Hospital-based clinical series suggest that parkinsonism is the commonest movement disorder. Clinical features of PD in Arabs are not significantly different from those reported elsewhere. PD was reported as the cause of dementia in around 7% of Arabs. The majority of studies relate to the role of genes in the etiology of PD in North African Arabs. Further genetic, epidemiological and clinical studies from the majority of Arabic countries may enhance our understanding of PD.

Stowe RL, Ives NJ, Clarke C, van Hilten J, Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R. · University of Birmingham Clinical Trials Unit, Division of Medical Sciences, Robert Aitken Institute, Edgbaston, Birmingham, UK, B15 2TT. · Cochrane Database Syst Rev. · Pubmed #18425954 No free full text.

Abstract: BACKGROUND: Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty about their clinical and cost-effectiveness relative to levodopa. OBJECTIVES: This meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared to placebo or levodopa in early Parkinson's disease. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. SELECTION CRITERIA: Randomised trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson's disease. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality. MAIN RESULTS: Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse. AUTHORS' CONCLUSIONS: This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.

Lader M. · Institute of Psychiatry, King's College, London, England. · CNS Drugs. · Pubmed #18399709 No free full text.

Abstract: Parkinson's disease is a common condition, usually treated by dopaminergic agents, both ergot and non-ergot. Many behavioural abnormalities are associated with such usage, including impulse control disorders (ICDs), dopamine dysregulation syndrome and 'punding'. Pathological gambling, a form of ICD, comprises persistent and maladaptive gambling of various types that disrupts personal, family or occupational activity. Pathological gambling may be associated with other abnormal actions such as pathological shopping, hoarding and hypersexuality. The incidence varies widely from study to study but may be up to 7% of users of dopaminergic agents. Recognition of this problem has led drug regulatory agencies to add precautions concerning pathological gambling to official drug information for the entire class of antiparkinsonian medications. The literature is not entirely consistent and opinions differ greatly, but pramipexole (a dopamine D2 and D3 agonist), and perhaps ropinirole (also a D2/D3 agonist), may be especially likely to be associated with pathological gambling, although the precise nature of the relationship is unclear. Treatment involves reducing the dose of the medication or switching to another medication; unfortunately, the Parkinson's disease may worsen. The mechanism of this adverse effect is believed to be excessive dopaminergic stimulation but probably not specifically involving D3 receptors. A parallel to addictive behaviour with stimulant drugs has been noted.

Davie CA. · The Royal Free Hospital NHS Trust, Hampstead, London NW3 2QG, UK. · Br Med Bull. · Pubmed #18398010 No free full text.

Abstract: INTRODUCTION: Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Sources of data Literature search using Medline with keywords Parkinson's disease supplemented with previously published papers known to the author. AREAS OF AGREEMENT: There have been significant recent advances in the understanding of the pathogenesis of the disease. There has also been a greater realization that the disorder may be associated with significant non-motor disturbances in addition to the more commonly recognized motor complications. AREAS OF CONTROVERSY: Although there is growing circumstantial evidence, it remains to be proven whether any of the current treatments for PD have a neuroprotective effect. AREAS TIMELY FOR DEVELOPING RESEARCH: Although there is no cure, there are several management options for the early treatment of PD. As the disease progresses, further treatment options are available; however, the management of late-stage motor complications and non-motor symptoms remains particularly challenging and will benefit from further clinical research.

Limousin P, Martinez-Torres I. · Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, University College London, London, England, United Kingdom. · Neurotherapeutics. · Pubmed #18394572 No free full text.

Abstract: The surgical treatment of Parkinson's disease has been through a revival phase over the last 20 years with the development of deep brain stimulation (DBS). Thalamic DBS was developed first and has proven to be a very effective treatment for tremor. The limitation is the lack of effect on other symptoms. Other targets were therefore investigated, and the procedure was applied to the subthalamic nucleus (STN) and the internal globus pallidus (GPi). STN stimulation can improve a wide range of symptoms and is currently the preferred target for many patients. Nevertheless, the morbidity seems higher than with other targets, and the selection criteria have to be quite strict. When STN DBS is not advised, thalamic DBS remains an option for patients with severe tremor, and GPi stimulation for those with severe dyskinesias. DBS remains a symptomatic treatment for a limited number of patients; it does not seem to alter the disease progression, and many patients are not suitable. There is, therefore, the need for further research into other targets and other approaches.

Brooks DJ, Anonymous00186. · Faculty of Medicine at Imperial College, London, UK. · Nat Clin Pract Neurol. · Pubmed #18382437 No free full text.

Abstract: Currently, the clinical diagnosis of Parkinson's disease (PD) can be problematic, particularly at the early stages of the disease when the full spectrum of symptoms and signs might not yet be manifest. In addition, the mechanisms that underlie the nonmotor complications of PD, such as dementia and depression, are poorly understood, despite the fact that these symptoms largely determine the patient's quality of life at the end stage of the disease. This article reviews the latest advances in structural and functional imaging that have provided important insights into the structural, pathophysiological and pharmacological changes associated with PD. The contribution of inflammatory processes to the pathology of PD is discussed, as are the various possible mechanisms that lead to coexistent dementia and depression.

Mathias CJ. · Neurovascular Medicine Unit, Faculty of Medicine, Imperial College London at St Mary's Hospital, Praed Street, London, W2 1NY, UK. · Clin Auton Res. · Pubmed #18368304 No free full text.

Abstract: Neurogenic orthostatic hypotension is a cardinal feature of generalised autonomic failure and commonly is the presenting sign in patients with primary autonomic failure. Orthostatic hypotension can result in considerable morbidity and even mortality and is a major management problem in disorders such as pure autonomic failure, multiple system atrophy and also in Parkinson's disease. Treatment is ideally two pronged, using non-pharmacological and pharmacological measures. Drug treatment ideally is aimed at restoring adequate amounts of the neurotransmitter noradrenaline. This often is not achievable because of damage to sympathetic nerve terminals, to autonomic ganglia or to central autonomic networks. An alternative is the use of sympathomimetics (that mimic the effects of noradrenaline, but are not identical to noradrenaline), in addition to other agents that target physiological mechanisms that contribute to blood pressure control.L-threo-dihydroxyphenyslerine (Droxidopa) is a pro-drug which has a structure similar to noradrenaline, but with a carboxyl group. It has no pressor effects in this form. It can be administered orally, unlike noradrenaline, and after absorption is converted by the enzyme dopa decarboxylase into noradrenaline thus increasing levels of the neurotransmitter which is identical to endogenous noradrenaline. Experience in Caucasians and in Europe is limited mainly to patients with dopamine beta hydroxylase deficiency. This review focuses on two studies performed in Europe, and provides information on its efficacy, tolerability and safety in patients with pure autonomic failure, multiple system atrophy and Parkinson's disease. It also addresses the issue of whether addition of dopa decarboxylase inhibitors, when combined with l-dopa in the treatment of the motor deficit in Parkinson's disease, impairs the pressor efficacy of Droxidopa.

Schapira AH. · University Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK. · Eur J Neurol. · Pubmed #18353131 No free full text.

Abstract: Slowing or aborting the progress of neurodegeneration in Parkinson's disease (PD) remains the most important unmet need of this disorder. There are several recent developments in trial design and also in drugs under investigation for possible neuroprotective effect. Emphasis has been placed on clinical as opposed to imaging end-points and these include change in a clinical rating scale, e.g. United Parkinson's disease Rating Scale (UPDRS), or time to additional therapy. The introduction of the delayed-start, or wash-in, trial design adds an additional dimension to drug evaluation for neuroprotection. Compounds that have been recently tested in clinical trial include the monoamine oxidase-B inhibitor rasagiline, the anti-apoptotic agents TCH346 and CEP1347, and the promitochondrial agent creatine. The dopamine agonists have been evaluated for a neuroprotective effect using imaging end-points. Perhaps the most important and simplest concept for neuroprotection has been the theory that early dopaminergic support for the degenerating dopaminergic system per se provides significant long-term clinical benefit for PD patients.

Evans JR, Barker RA. · University of Cambridge, Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, UK. · Expert Opin Ther Targets. · Pubmed #18348680 No free full text.

Abstract: BACKGROUND: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. OBJECTIVE: In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. METHODS: Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: 'Parkinson's disease', 'Neurotrophic factors', 'BDNF' (Brain-derived neurotrophic factor), 'GDNF' and 'Neurturin'. Original articles were reviewed, and relevant citations from these articles were also appraised. CONCLUSION: NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.

Muzerengi S, Contrafatto D, Chaudhuri KR. · University Hospital Lewisham, National Parkinson Foundation Centre of Excellence, King's College, London, UK. · Parkinsonism Relat Disord. · Pubmed #18267282 No free full text.

Abstract: Non-motor symptoms are an important part of Parkinson's disease (PD) symptoms complex. They cause a significant burden on the quality of life of patients and their carers and remain a major cause of hospitalisation. Treatment of non-motor symptoms can be challenging as these symptoms are often unresponsive to conventional dopaminergic therapy. However, awareness that these symptoms are related to PD is vital as research into treatment and causation will be the cornerstone for delivering a comprehensive modern treatment for PD.

Rothwell J. · Sobell Department, Institute of Neurology, London, UK. · Parkinsonism Relat Disord. · Pubmed #18267274 No free full text.

Abstract: It is now possible to probe the plasticity of some neural circuits in the human motor cortex using transcranial magnetic stimulation (TMS). This article illustrates how changes in the plasticity of these circuits is linked to the expression of dyskinesias in Parkinson's disease, and may even underlie the tendency of some individuals to develop focal dystonia. Indeed, gradual normalisation of this excessive plasticity occurs after initiating deep brain stimulation of the internal globus pallidus in patients with generalised dystonia. It may therefore relate to the slow onset of clinical improvement that occurs over the first 6 weeks or so of treatment.

Redgrave P, Coizet V. · Department of Psychology, University of Sheffield, Sheffield, S10 2TP, UK. · Parkinsonism Relat Disord. · Pubmed #18267254 No free full text.

Abstract: The basal ganglia are a group of interconnected subcortical nuclei that represent one of the brain's fundamental processing units. In humans basal ganglia dysfunctions have been associated with numerous debilitating conditions, including Parkinson's disease. To appreciate fully how complicated systems can malfunction, it may first be necessary to understand how such networks work normally. The present review therefore provides an outline of basal ganglia architecture emphasising their interactions with brainstem structures. The potential functions of the basal ganglia network are then considered together along with resulting insights that may help our understanding of Parkinson's disease and other basal ganglia-related disorders.

Brooks DJ. · MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK. · Parkinsonism Relat Disord. · Pubmed #18267249 No free full text.

Abstract: In this article the value of structural and functional imaging in aiding the diagnosis and management of Parkinson's disease is reviewed. The underlying pathological mechanisms leading to tremor, coexistent dementia and depression in PD are considered and the role of imaging as a biomarker for testing neuroprotective agents debated.