Showing papers by "Susan H. Fox published in 2013"
TL;DR: It is proposed that to optimally alleviate this motor complication of Parkinson’s disease, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system.
Abstract: L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways.
280 citations
TL;DR: Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD‐MCI, and Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need.
Abstract: We examined the frequency of Parkinson disease with mild cognitive impairment (PD-MCI) and its subtypes and the accuracy of 3 cognitive scales for detecting PD-MCI using the new criteria for PD-MCI proposed by the Movement Disorders Society. Nondemented patients with Parkinson's disease completed a clinical visit with the 3 screening tests followed 1 to 3 weeks later by neuropsychological testing. Of 139 patients, 46 met Level 2 Task Force criteria for PD-MCI when impaired performance was based on comparisons with normative scores. Forty-two patients (93%) had multi-domain MCI. At the lowest cutoff levels that provided at least 80% sensitivity, specificity was 44% for the Montreal Cognitive Assessment and 33% for the Scales for Outcomes in Parkinson's Disease-Cognition. The Mini-Mental State Examination could not achieve 80% sensitivity at any cutoff score. At the highest cutoff levels that provided specificity of at least 80%, sensitivities were low (≤44%) for all tests. When decline from estimated premorbid levels was considered evidence of cognitive impairment, 110 of 139 patients were classified with PD-MCI, and 103 (94%) had multi-domain MCI. We observed dramatic differences in the proportion of patients who had PD-MCI using the new Level 2 criteria, depending on whether or not decline from premorbid level of intellectual function was considered. Recommendations for methods of operationalizing decline from premorbid levels constitute an unmet need. Among the 3 screening tests examined, none of the instruments provided good combined sensitivity and specificity for PD-MCI. Other tests recommended by the Task Force Level 1 criteria may represent better choices, and these should be the subject of future research.
137 citations
TL;DR: The overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.
Abstract: The pathological processes underlying Parkinson’s disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl d-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR5) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.
127 citations
TL;DR: Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa.
Abstract: Background Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson9s Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS). Objectives The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic. Methods We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable. Results Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS−). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS− patients (p Conclusion DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.
95 citations
TL;DR: More than 20 randomized, control trials (RCTs) in Parkinson's disease investigating drugs that target several of these non-opaminergic neurotransmitter systems for the treatment of motor features have been completed and at least 15 additional RCTs that are ongoing or planned.
Abstract: Neurotransmitters other than dopamine are recognized as having modulatory roles within the basal ganglia and can influence the basal ganglia dopaminergic system to alter activity of the direct and indirect pathways. Many nondopaminergic neurotransmitter systems have been implicated in the mechanisms contributing to the motor features of Parkinson's disease (PD). Thus, it is now well established that neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, noradrenergic, serotonergic, opioidergic, histaminergic, and adenosinergic systems, are affected in the pathogenesis of PD. Nondopaminergic neurotransmitter systems are thus targets for the development of novel therapies for motor symptoms and motor complications in PD. Over the last 5 years, more than 20 randomized, control trials (RCTs) in PD investigating drugs that target several of these nondopaminergic neurotransmitter systems for the treatment of motor features have been completed. There are at least 15 additional RCTs that are ongoing or planned. Here, we review these RCTs to highlight the potential nondopaminergic pharmacological therapies for treatment of motor features of PD. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs will likely yield novel approaches with positive clinical implications. © 2012 Movement Disorder Society
89 citations
TL;DR: The hypothesis that mood and anxiety disorders are intrinsic to the neurobiology of dystonia is examined, citing the available literature, which is derived mostly from research on focal isolated dystonias.
Abstract: Psychiatric disorders are highly prevalent in patients with dystonia and have a profound effect on quality of life. Patients with dystonia frequently meet criteria for anxiety disorders, especially social phobia, and major depressive disorder. Deficits in emotional processing have also been demonstrated in some dystonia populations. Onset of psychiatric disturbances in patients with dystonia often precedes onset of motor symptoms, suggesting that the pathophysiology of dystonia itself contributes to the genesis of psychiatric disturbances. This article examines the hypothesis that mood and anxiety disorders are intrinsic to the neurobiology of dystonia, citing the available literature, which is derived mostly from research on focal isolated dystonias. Limitations of studies are identified, and the role of emotional reactivity, especially in the context of pain secondary to dystonia, is recognized. Available evidence underscores the need to develop dystonia assessment tools that incorporate psychiatric measures. Such tools would allow for a better understanding of the full spectrum of dystonia presentations and facilitate research on the treatment of dystonia as well as the treatment of psychiatric illnesses in the context of dystonia. This article, solicited for a special Movement Disorders issue on novel research findings and emerging concepts in dystonia, addresses the following issues: (1) To what extent are psychiatric disturbances related to the pathophysiology of dystonia? (2) What is the impact of psychiatric disturbances on outcome measures of current assessment tools for dystonia? (3) How do psychiatric comorbidities influence the treatment of dystonia? Answers to these questions will lead to an increased appreciation of psychiatric disorders in dystonia, a better understanding of brain physiology, more nuanced research questions pertaining to this population, better clinical scales that can be used to further patient management and research, and improved patient outcomes. © 2013 Movement Disorder Society.
78 citations
TL;DR: Critically reviews studies assessing the SERT, as well as 5-HT1A and 5- HT2A receptors in idiopathic PD and animal models of PD, and discusses unmet challenges to effectively treat manifestations of PD using SERT antagonists, 5-ht1A agonists and5-HT2A antagonists.
Abstract: The understanding of Parkinson’s disease (PD) classically revolves around dopamine depletion within the striatum. However, PD is a multi-systemic disease in which extra-dopaminergic systems are affected. The serotonergic (5-HT) system is one of these and has been extensively studied in PD. Although the 5-HT system uses one transporter (SERT) and 14 receptor sub-types, most of the studies in PD have focussed on SERT and serotonergic type 1A and 2A receptors (5-HT1A and 5-HT2A). Post-mortem autoradiographic binding studies and in vivo imaging studies have suggested an involvement of the 5-HT system in PD-related anxiety, depression, psychosis and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Pre-clinical and clinical pharmacological studies have shown that SERT blockade might effectively alleviate depression and dyskinesia and, more recently, might exert disease-modifying effects. Enhancing the physiological activity of 5-HT1A receptors with 5-HT1A agonists might alleviate anxiety, dyskinesia and tremor, although a deleterious effect on the anti-parkinsonian efficacy of L-DOPA may ultimately limit the use of this class of compounds. Enhanced 5-HT2A-mediated neurotransmission has been associated with depression, dyskinesia, psychosis and tremor. The current article critically reviews studies assessing the SERT, as well as 5-HT1A and 5-HT2A receptors in idiopathic PD and animal models of PD, and discusses unmet challenges to effectively treat manifestations of PD using SERT antagonists, 5-HT1A agonists and 5-HT2A antagonists.
65 citations
TL;DR: The aim of the current review is to present important clinical studies investigating the potential therapeutic effects of 5-HT2A-R antagonists in both primary psychiatric disorders, such as schizophrenia and mood disorders, as well as in psychiatric manifestations of neurodegenerative disorders.
Abstract: Introduction: 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are widely expressed in the brain and have been implicated in mood and behavior. Based on the use of atypical antipsychotics in schizophrenia, antagonism of 5-HT2A-Rs initially emerged as a potential intervention capable of reducing the incidence of extrapyramidal symptoms, while exerting an effective antipsychotic action. More recently, highly selective 5-HT2A-R antagonists have been evaluated in the treatment of a wide range of other psychiatric disorders. Areas covered: The aim of the current review is to present important clinical studies investigating the potential therapeutic effects of 5-HT2A-R antagonists in both primary psychiatric disorders, such as schizophrenia and mood disorders, as well as in psychiatric manifestations of neurodegenerative disorders. We present an overview of 5-HT2A-Rs in normal brain function and the rationale for use in (neuro) psychiatric disease based on significant findings from genetic association studies, neur...
56 citations
TL;DR: The cognitive decline from premorbid baseline modifies the association between MCI and HR-QOL in PD and knowing both will allow a better appreciation of difficulties patients face in daily life.
Abstract: Background/Aims: To assess the impact of mild cognitive impairment (MCI) or cognitive decline on health-related quality of life (HR-QOL) in Parkinson's disease (P
51 citations
TL;DR: Using molecular modelling, the results provide validation for missense mutations in Na+,K+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.
Abstract: Missense mutations in ATP1A3 encoding Na+,K+-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na+,K+-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na+,K+-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na+,K+-ATPase α3, including upon the K+ pore and predicted K+ binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na+,K+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.
42 citations
TL;DR: TC-8831 displayed robust anti-dyskinetic actions and improved the quality of ON-time evoked by L-DOPA without any reduction in anti-parkinsonian benefit.
TL;DR: To report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in a 29‐year‐old patient with severe generalized dystonia secondary to Wilson's disease.
Abstract: Background: To report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in a 29-year-old patient with severe generalized dystonia secondary to Wilson’s disease. Methods: The primary outcome measure was the BurkeFahn-Marsden Dystonia Scale motor severity score (blinded assessment) and the secondary outcome measures were the Abnormal Involuntary Movement Scale (blinded assessment) and the Zaritt Caregiver Burden Interview score, at 20-week postoperative follow up. Results: There was a 14% improvement in the BurkeFahn-Marsden Dystonia Scale motor severity score. Abnormal Involuntary Movement Scale score remained unchanged while the Zaritt Caregiver Burden Interview score improved by 44.4%. Conclusions: Bilateralglobuspallidusdeepbrainstimulation can be effective in ameliorating dystonia and caregiver burden in Wilson s disease. Outcomes may depend on the stage of the disease at which the surgical procedureiscompleted. V C 2013MovementDisorderSociety
Journal Article•
TL;DR: Savinamide 50-100 mg/day met the primary efficacy objective of significantly improving ON time without any increase in troublesome dyskinesia, and there was improvement in multiple secondary efficacy measures, which confirm the efficacy and good tolerability demonstrated previously in Study 016.
Abstract: OBJECTIVE: To evaluate the efficacy and safety of flexible doses of safinamide, α-aminoamide with both dopaminergic and nondopaminergic mechanism of action, 50-100 mg/day as add-on therapy to stable doses of levodopa and other PD medications, in PD patients with motor fluctuations. BACKGROUND: Safinamide has previously demonstrated efficacy as add on to dopamine agonist in non fluctuating patients, and as add on to levodopa and other PD medications in patients with motor fluctuations at fixed doses of 50 and 100mg/day in 6 months treatment trials. DESIGN/METHODS: The SETTLE study evaluated effects of safinamide on motor fluctuations (primary efficacy endpoint: increase in “ON” time), UPDRS scores, QoL and non-motor symptoms in patients with PD on optimized anti-parkinsonian treatment over 24 weeks in a double-blind, placebo-controlled trial performed in North America, Europe, and Asia-Pacific regions. Analysis was hierarchical; if the primary endpoint was not significant, subsequent endpoint analyses were considered exploratory. RESULTS: 484 of 549 randomized patients completed 24 weeks9 treatment. Safinamide 50-100 mg/day significantly improved ON time (without worsening troublesome dyskinesia ), OFF time, UPDRS III, CGI-S, CGI-C, PDQ-39 and OFF time following the first morning levodopa dose (i.e. latency to ON) compared to placebo. The discontinuation rate, and serious AEs were similar across treatments. The most frequent AEs (≥ 5% in one group or more) were back pain, dyskinesia, fall, headache, nausea, and urinary tract infection. CONCLUSIONS: Safinamide 50-100 mg/day met the primary efficacy objective of significantly improving ON time without any increase in troublesome dyskinesia, and there was improvement in multiple secondary efficacy measures. These results confirm the efficacy and good tolerability demonstrated previously in Study 016 at daily doses of 50mg and 100 mg. Supported by: Newron/Merck Serono. Disclosure: Dr. Schapira has received personal compensation for activities with GSK, Orion-Novartis, Teva-Lundbeck, Serono, BI as a consultant. Dr. Schapira has received personal compensation in an editorial capacity for European Journal of Neurology. Dr. Schapira has received research support from BI. Dr. Fox has received personal compensation for activities with Merck Serono and Novartis. Dr. Fox has received research support from Merck Serono. Dr. Hauser has received personal compensation for activities with Boehringer Ingelheim Pharmaceuticals, Inc., Teva Neuroscience, Impax Pharmaceuticals, UCB Pharma, GE Healthcare, Ipsen, Novartis, Parkinson Study Group, Solvay S.A., Quintiles, Bi. and University of South Florida. Dr Hauser has received research support from PICO-Tesla, Schwarz Biosciences, Genzyme Corporation, Acadia, Solvay S.A., Impax, TEVA Neuroscience, Serono, Inc., Schering-Plough Corporation, Novartis, Ipsen, XenoPort Pharmaceuticals, and Chelse. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, EMD Serono, Merz Pharmaceuticals, Lundbeck, and Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc, Chelsea Therapeutics, Diana Helis Henry Medical Research Foundation, EMD Serono, Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, and Ipsen Limited. Dr. Jost has received personal compensation for activities with Allergan, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Desitin, GlaxoSmithKline, Inc., Merck Serono, and Merz Pharma. Dr. Kulisevsky has received personal compensation for activities with Merck Serono. Dr. Kulisevsky has received research support from Boehringer Ingelheim and Merck-Serono. Dr. Pahwa has received personal compensation from Teva Neuroscience, Merck Serono, Novartis, Medtronic, GE Healthcare, Impax, Ceregene, Noven, Adamas, St. Jude Medical for consulting. Dr. Pahwa has received personal compensation from Informa Healthcare as a journal co-editor. Dr. Pahwa has received personal compensation from Novartis, Impax, Merck Serono, BI, Schering, Adamas, Biotie, Phytopharm, Allon, Acadia, Xenoport, GlaxoSmithKline and NINDS for research support. Dr. Poewe has received personal compensation for activities with Abbott, AstraZeneca, Teva, Novartis, GSK, Boehringer-Ingelheim, UCB, Orion Pharma, Merck Serono, and Merz. Dr. Anand has received personal compensation for activities with Abbott, J&J, Takeda, Newron, Teva for consulting activities.
TL;DR: Investigating the effects of the brain-penetrant histone deacetylase inhibitor, RGFP109, on LID and L-DOPA anti-parkinsonian efficacy found it to represent a novel approach to reverse established LID in PD and improve quality of the anti- parkinsonian benefit provided by L- DOPA.
TL;DR: The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism and suggested that fast- off-D1 dopamine receptor antagonists are unlikely to be useful in the treatment of dyskinesia and psychosis in PD.
Abstract: 3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.
TL;DR: The data presented suggest that catechol‐O‐methyltransferase (COMT) inhibition in combination with low doses of L‐DOPA has potential as a strategy to alleviate dyskinesia.
Abstract: L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L-DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low-dose L-DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol-O-methyltransferase (COMT) inhibition, as an add-on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Dyskinesia was established by chronic treatment with L-DOPA. Two doses of L-DOPA were identified – high-dose L-DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub-threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON-time), parkinsonism and dyskinesia were determined. The ON-time after LDh was ∼170 min and the ON-time after LDl alone (∼98 min) was not significantly different to vehicle (∼37 min). In combination with LDl, entacapone significantly increased the ON-time (5, 15 and 45 mg/kg being ∼123, ∼148 and ∼180 min, respectively). The ON-time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON-time that was compromised by disabling dyskinesia was ∼56% with LDh, it was only ∼31% with LDl/entacapone 45 mg/kg. In addition to the well-recognized action of COMT inhibition to reduce wearing-OFF, the data presented suggest that COMT inhibition in combination with low doses of L-DOPA has potential as a strategy to alleviate dyskinesia.
TL;DR: Fine timing between the peak activities of various structures involved in go and stop processes, opens up further interesting questions in this exciting field and opens up new ways of looking at basal ganglia physiology.
Abstract: The “race model” of basal ganglia (BG) circuits function concurrently to achieve the balance between the “go” pathways mediated by striatonigral projections and the “stop” pathways mediated by the STN/substantia nigra pars reticulata (SNr). The final outcome depends on the modulatory effects of these two pathways on the output structure (SNr). Despite many studies that have explored this mutual response inhibition model using “stop-signal” reaction time paradigms, the exact nature of the function in the different BG structures, and the fine timing between these activities, remains elusive. The recent study by Schmidt et al. investigated this idea with their elegant study in normal rats trained in the stopsignal task. They used microelectrode tetrads to quantify the neuronal activities in various BG structures (striatum, STN, SNr, and globus pallidus) of freely behaving animals responding to go and stop signals provided by visual and auditory cues by entering into different apertures in their cage and collecting food pellets for successful trials. The outcome was a transient increased activity of the STN (approximately 15 ms after the stop cue) for both failed and correct stop cues, which promptly conveyed on to the SNr (approximately 13 ms after STN peak activity). However, the go signal mediated by striatonigral pathways were already initiated (the stop cue was presented approximately 50 ms before movement onset), the gamma-aminobutyric acid– mediated striatal signals overrode the glutamatergic STN stimulation and finally disinhibited BG output, resulting in movement. Thus, the green go signal of striatum and red stop signal of the STN maintains the traffic of BG circuits by inhibiting or activating the final motor output, depending on the timing of presentation of sensory cue to these structures. Although this concept of the race model is not new, this study, with fine timing between the peak activities of various structures involved in go and stop processes, opens up further interesting questions in this exciting field. How the striatal neuronal activity shuts off in the process of stop has to be validated to account for superior control of the striatum. Furthermore, the role of sensory afferent pathways from the cortex or thalamus needs to be further investigated during movement. Studying the coordination of these two pathways in disease models affecting basal ganglia disorders also needs to be performed. Nevertheless, this new idea and findings open up new ways of looking at basal ganglia physiology.
01 Oct 2013
TL;DR: It is found clinically that “hippo” is a common erroneous response to the rhinoceros item in Parkinson’s disease patients, which is unexpected given that naming deficits are uncommon in PD.
TL;DR: A view point is presented arguing that zinc should be the preferred drug for treating WD and that only a proportion of WD patients with neurological symptoms fully recover, suggesting that such patients are either not optimally managed or treated, and there is a need for better therapies for the neurological symptoms.
Abstract: metabolism. In Canada few neurologists see sufficient patients to become confident in managing and treating this disorder. Patients can present with liver and/or neuropsychiatric symptoms and so these few patients are spread across a number of disciplines including pediatric, liver or neurological clinics. There is a paucity of randomized controlled trials (RCTs) and Evidence Based Medicine reviews for helping such physicians treat WD; thus making it a further challenge to determine the most effective option for an individual patient. Rana and colleagues present a view point1 arguing that zinc should be the preferred drug for treating WD. The authors set out two scenarios, with illustrative cases, related to the use of the commercially available treatments; penicillamine, trientine and zinc. The first scenario is that the clinical symptoms are due to copper deposition in hepatic or brain tissue and the chelators, penicillamine or trientine reduce tissue copper levels by increasing excretion in the urine. However, worsening of neurological symptoms with penicillamine and trientine (although less common) is a significant problem. The second scenario is that WD is due to high circulating levels of copper. Thus use of zinc to bind dietary copper and prevents GI absorption with reduced serum free copper levels will improve symptoms without neurological worsening. Traditionally the commonest treatment strategy has been to use penicillamine, or more recently trientine, to achieve a rapid de-coppering and reversal of symptoms. Slower de-coppering over months is then achieved by using zinc for either maintenance (started with or after the chelators) or as monotherapy for asymptomatic carriers. Case series with long term follow-ups have generally supported this strategy. Thus use of zinc alone, as suggested by this view point, is less common due to the slower rate of de-coppering and the concern that this delay will worsen symptoms. The counter argument is that zinc has increased safety while achieving equal efficacy. However no RCTs have compared the use or timing of these agents, or the combination of chelation with zinc. Ongoing arguments between experts will continue until more definitive, objective studies are performed. There is a European database prospectively collecting data (www.eurowilson.org) and the North American WD Association http://www.wilsonsdisease.org/ supports ongoing research efforts. Of concern however is that published case-series continue to show that only a proportion of WD patients with neurological symptoms fully recover (where symptoms are carefully evaluated and reported) (e.g.2-4). This suggests that such patients are either not optimally managed or treated, and there is a need for better therapies for the neurological symptoms. This appears to be in contrast to liver disease in WD which responds better to drugs and liver transplant can be curative. Genetic studies may lead to better treatments but there remain many unknown issues,