Parkinson Disease: Massachusetts

Williams JA, Imamura M, Fregni F. · Department of Neurology, Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA. · J Rehabil Med. · Pubmed #19363560 No free full text.

Abstract: Brain stimulation for the treatment of neuropsychiatric diseases has been used for more than 50 years. Although its development has been slow, current advances in the techniques of brain stimulation have improved its clinical efficacy. The use of non-invasive brain stimulation has significant advantages, such as not involving surgical procedures and having relatively mild adverse effects. In this paper we briefly review the use of 2 non-invasive brain stimulation techniques, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as therapeutic approaches in physical and rehabilitation medicine. We also compare the effects of non-invasive central nervous system stimulation with techniques of non-invasive peri notpheral electrical stimulation, in order to provide new insights for future developments. Although the outcomes of these initial trials include some conflicting results, the evidence supports that rTMS and tDCS might have a therapeutic value in different neurological conditions. Studies published within the last year have examined new approaches of stimulation, such as longer intensities of stimulation, new electrode sizes for tDCS, novel coils for stimulation of deeper areas, and new frequencies of stimulation for rTMS. These new approaches need to be tested in larger clinical trials in order to determine whether they offer significant clinical effects.

Bloomfield DM. · 1Cardiovascular Clinical Research, Merck Research Laboratories, Boston, Massachusetts, USA. · Clin Pharmacol Ther. · Pubmed #19295536 No free full text.

Abstract: Electrocardiograms (ECGs) in patients with Parkinson's disease are affected by artifacts related to muscle tremor. Malik et al. report methods used in QTc study in patients with Parkinson's disease that markedly reduce the noise and variance of QTc in a sample of ECGs that are undeniably difficult to interpret. This study adds significant experience and novel methods that have the potential to further enhance the evaluation of the effect of a drug on QTc.

Kazantsev AG, Kolchinsky AM. · Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Bldg 114, 3300 16th St, Charlestown, MA 02129-4404, USA. · Arch Neurol. · Pubmed #19064744 No free full text.

Abstract: Selective death of nigrostriatal neurons, which leads to Parkinson disease, is explained by misfolding of brain protein alpha-synuclein. Herein, we review the data supporting this concept, propose a scheme of events leading to synuclein-induced neuronal death, and discuss protein deacetylase sirtuins as new potential therapeutic targets involved in this process.

Staropoli JF. · Department of Pathology, Massachusetts General Hospital, Gray-Jackson 249, MGH, 55 Fruit St Boston, MA 02114-2696, USA. · Bioessays. · Pubmed #18623069 No free full text.

Abstract: Dysregulation of genes that control cell-cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post-mitotic neurons under certain conditions. The gene for ataxia-telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss-of-function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss-of-function mutations in which account for about half of cases of early-onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re-expression sensitizes derivative cell lines to inhibitors of cell-cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long-held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders.

Saint-Hilaire MH. · Parkinson's Disease and Movement Disorders Center, Boston University School of Medicine, MA 02118 USA. · Med Health R I. · Pubmed #18549039 No free full text.

This publication has no abstract.

Calabrese EJ. · Department of Public Health, Environmental Health Sciences, University of Massachusetts, Amherst, Massachusetts 01003, USA. · Crit Rev Toxicol. · Pubmed #18432420 No free full text.

Abstract: This article is a comprehensive assessment of the quantitative features of the dose response for neuroprotective agents and their underlying mechanistic foundations. The data were derived from published studies using numerous primary neuronal cell cultures and neuronal cell lines. These biological models assessed normal developmental and aging processes, preconditioning adaptive responses, and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. The nature of the dose response was generally U-shaped with quantitative features similar to the hormetic dose-response model and independent of biological model, endpoint measured, and chemical class. The agents displaying the U-shaped dose response for neuronal survival include numerous endogenous agonists, plant-derived agents, synthetic drugs, and widely used chemicals including potent neurotoxins. That neuroprotective agents display similar dose-response relationships regardless of experimental system, potency, and endpoint is an important observation with widespread biomedical and clinical implications.

Kinoshita J, Clark T. · Alzheimer Research Forum, Waltham, MA, USA. · Methods Mol Biol. · Pubmed #18368375 No free full text.

Abstract: The Alzheimer Research Forum Web site ( http://www.alzforum.org ) is an independent research project to develop an online community resource to manage scientific knowledge, information, and data about Alzheimer disease (AD). Its goals are to promote rapid communication, research efficiency, and collaborative, multidisciplinary interactions. Introducing new knowledge management approaches to AD research has a potentially large societal value. AD is among the leading causes of disability and death in older people. According to the Alzheimer's Association, four million Americans currently suffer from AD. That number is expected to escalate to over 10 million in coming decades. Patients progress from memory loss to a bedridden state over many years and require near-constant care. In addition to imposing a heavy burden on family caregivers and society at large, AD and related neurodegenerative disorders are among the most complex and challenging in biomedicine. Researchers have produced an abundance of data implicating diverse biological mechanisms. Important factors include genes, environmental risks, changes in cell functions, DNA damage, accumulation of misfolded proteins, cell death, immune responses, changes related to aging, and reduced regenerative capacity. Yet there is no agreement on the fundamental causes of AD. The situations regarding Parkinson, Huntington, and amyotrophic lateral sclerosis (ALS) are similar. The challenge of integrating so much data into testable hypotheses and unified concepts is formidable. What is more, basic understanding of these diseases needs to intersect with an equally complex universe of pharmacology, medicinal chemistry, animal studies, and clinical trials. In this chapter, we will describe the approaches developed by Alzforum to achieve knowledge integration through information technology and virtual community-building. We will also propose some future directions in the application of Web-based knowledge management systems in neuromedicine.

Astradsson A, Cooper O, Vinuela A, Isacson O. · NINDS Udall Parkinson's Disease Research Center of Excellence, Harvard University and McLean Hospital, Belmont, Massachusetts 02478, USA. · Neurosurg Focus. · Pubmed #18341409 No free full text.

Abstract: In this review, the authors discuss recent advances in the field of cell therapy for Parkinson disease (PD). They compare and contrast recent clinical trials using fetal dopaminergic neurons. They attribute differences in cell preparation techniques, cell type specification, and immunosuppression as reasons for variable outcome and for some of the side effects observed in these clinical trials. To address ethical, practical, and technical issues related to the use of fetal cell sources, alternative sources of therapeutic dopaminergic neurons are being developed. The authors describe the progress in enrichment and purification strategies of stem cell-derived dopaminergic midbrain neurons. They conclude that recent advances in cell therapy for PD will create a viable long-term treatment option for synaptic repair for this debilitating disease.

Arle JE, Shils JL. · Department of Neurosurgery, The Lahey Clinic, Tufts University School of Medicine, 41, Mall Road, Burlington, MA 01867, United States. · Neurophysiol Clin. · Pubmed #18083501 No free full text.

Abstract: Intraoperative monitoring (IOM) adds new information to intraoperative surgical decision-making. When presented clearly and accurately, it can help guide decision processes during the procedure, but can be a detriment overall if the information is inaccurate or misleading. Troubleshooting abilities and vigilance of the IOM staff play a large role in bolstering the level of trust a surgeon develops in IOM. Additionally, a surgeon may impart his own interpretation and experience with this new information that can undermine or enhance its impact on the case. In this article, we explore these issues with IOM in general and as they relate to the special context of DBS for movement disorders.

Friehs GM, Park MC, Goldman MA, Zerris VA, Norén G, Sampath P. · Department of Clinical Neurosciences Program in Neurosurgery and New England Gamma Knife Center, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA. · Neurosurg Focus. · Pubmed #18081480 No free full text.

Abstract: Stereotactic radiosurgery (SRS) with the Gamma Knife and linear accelerator has revolutionized neurosurgery over the past 20 years. The most common indications for radiosurgery today are tumors and arteriovenous malformations of the brain. Functional indications such as treatment of movement disorders or intractable pain only contribute a small percentage of treated patients. Although SRS is the only noninvasive form of treatment for functional disorders, it also has some limitations: neurophysiological confirmation of the target structure is not possible, and one therefore must rely exclusively on anatomical targeting. Furthermore, lesion sizes may vary, and shielding adjacent radiosensitive neural structures may be difficult or impossible. The most common indication for functional SRS is the treatment of trigeminal neuralgia. Radiosurgical treatment for epilepsy and certain psychiatric illnesses is performed in several centers as part of strict research protocols, and radiosurgical pallidotomy or medial thalamotomy is no longer recommended due to the high risk of complications. Radiosurgical ventrolateral thalamotomy for the treatment of tremor in patients with Parkinson disease or multiple sclerosis, as well as in the treatment of essential tremor, may be indicated for a select group of patients with advanced age, significant medical conditions that preclude treatment with open surgery, or patients who must receive anticoagulation therapy. A promising new application of SRS is high-dose radiosurgery delivered to the pituitary stalk. This treatment has already been successfully performed in several centers around the world to treat severe pain in patients with end-stage cancer.

Logroscino G, Traynor BJ, Hardiman O, Chio' A, Couratier P, Mitchell JD, Swingler RJ, Beghi E, Anonymous00066. · Department of Epidemiology HSPH 3-819 Harvard University, 677 Huntington Avenue, Boston, Massachusetts 02115, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #18079297 No free full text.

Abstract: Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.

Leegwater-Kim J, Waters C. · Lahey Clinic, Department of Neurology, 41 Mall Road, Burlington, MA 01805, USA. · Expert Rev Neurother. · Pubmed #18052761 No free full text.

Abstract: For decades, the cornerstone of treatment for Parkinson's disease (PD) has been levodopa, which provides a smooth clinical response early in the course of disease. However, many PD patients develop motor complications on long-term levodopa therapy. Catechol-O-methyltransferase (COMT) is a selective and widely distributed enzyme involved in the catabolism of levodopa. Tolcapone and entacapone are selective and potent COMT inhibitors that slow the metabolism of levodopa, thus prolonging its effects. While both drugs act peripherally, tolcapone also inhibits COMT in the CNS. Tolcapone has been shown to be an effective adjunct in the treatment of PD in Phase II and III clinical trials, improving motor fluctuations and reducing levodopa requirements. Rare reports of severe hepatotoxicity, however, limited tolcapone's implementation in the treatment of PD. A reappraisal of the data for tolcapone treatment in PD has found that this risk is very small if proper hepatic monitoring guidelines are followed. This article reviews the pharmacology and clinical data on tolcapone, with particular focus on drug safety and the future role of tolcapone therapy in the treatment of PD.

Hung AY, Schwarzschild MA. · Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Curr Opin Neurol. · Pubmed #17620885 No free full text.

Abstract: PURPOSE OF REVIEW: To summarize recently published results of neuroprotection trials for Parkinson's disease, and discuss them in the context of evolving concepts in clinical study design and animal models. RECENT FINDINGS: Despite compelling preclinical evidence from laboratory models suggesting potential neuroprotective benefits, the antioxidant, antiapoptotic, antiexcitotoxic, immunomodulatory and neurotrophic agents studied to date have not shown clear benefit in human studies. The futility study design, an alternative approach focused on efficiently excluding less promising compounds, has been adopted recently to investigate four candidate neuroprotectants. A delayed-start trial design has also been introduced in a study of the monoamine oxidase inhibitor rasagiline, demonstrating a possible neuroprotective effect as well as its clear symptomatic benefit. In parallel with these clinical innovations, preclinical research initiatives are identifying new animal models that more closely resemble the clinical course and pathology of Parkinson's disease. SUMMARY: Angst over disappointing results of neuroprotection trials in Parkinson's disease has engendered efforts to refine animal models at one end of the therapeutics pipeline, and to optimize clinical trial design at the other. Building on new insights into the genetics, epidemiology and pathogenesis of Parkinson's disease, these recent improvements in 'translational infrastructure' will enhance the prospects of achieving the critical goal of slowing the progression of disability.

Lau FC, Shukitt-Hale B, Joseph JA. · USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA. · Subcell Biochem. · Pubmed #17612057 No free full text.

Abstract: It is estimated that by the year 2050 the elderly (aged 65 or older) population will double the population of children (aged 0-14) for the first time in history. The expansion of the elderly population has already taken a toll on health care systems. In order to alleviate the health care costs and increase the quality of living in the aging population, it is crucial to explore methods that may retard or reverse the deleterious effects of aging. Inflammation and oxidative stress play important roles in brain aging. Inflammatory markers, as well as cellular and molecular oxidative damage, increase during normal brain aging. This increase is accompanied by the concomitant decline in cognitive and motor performance in the elderly population, even in the absence of neurodegenerative diseases. Epidemiological studies have shown that consumption of diets rich in antioxidant and anti-inflammatory agents, such as those found in fruits and vegetables, may lower the risk of developing age-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Research from our laboratory suggests that dietary supplementation with fruit or vegetable extracts can decrease the age-enhanced vulnerability to oxidative stress and inflammation. Additional research suggests that the polyphenolic compounds found in fruits such as blueberries may exert their beneficial effects through signal transduction and neuronal communication. Thus, nutritional intervention may exert therapeutic protection against age-related deficits and neurodegenerative diseases.

Fregni F, Pascual-Leone A. · Harvard Medical School and the Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · Nat Clin Pract Neurol. · Pubmed #17611487 No free full text.

Abstract: In neurology, as in all branches of medicine, symptoms of disease and the resulting burden of illness and disability are not simply the consequence of the injury, inflammation or dysfunction of a given organ; they also reflect the consequences of the nervous system's attempt to adapt to the insult. This plastic response includes compensatory changes that prove adaptive for the individual, as well as changes that contribute to functional disability and are, therefore, maladaptive. In this context, brain stimulation techniques tailored to modulate individual plastic changes associated with neurological diseases might enhance clinical benefits and minimize adverse effects. In this Review, we discuss the use of two noninvasive brain stimulation techniques--repetitive transcranial magnetic stimulation and transcranial direct current stimulation--to modulate activity in the targeted cortex or in a dysfunctional network, to restore an adaptive equilibrium in a disrupted network for best behavioral outcome, and to suppress plastic changes for functional advantage. We review randomized controlled studies, in focal epilepsy, Parkinson's disease, recovery from stroke, and chronic pain, to illustrate these principles, and we present evidence for the clinical effects of these two techniques.

Cohen PD, Herman L, Jedlinski S, Willocks P, Wittekind P. · Parkinson Pipeline Project, Washington, DC 20015, USA. · Neurotherapeutics. · Pubmed #17599719 No free full text.

Abstract: A patient-centered paradigm for clinical research and medical care is presented as a solution to the problem of declining innovation and increasing costs and development time in the pipeline for new therapies. Fundamental differences in values and motivations among scientists, clinicians, industry sponsor, and patients in neurotherapeutics provide a framework for analysis of ethical conflicts and the loss of public confidence in medical research. Parkinson advocates' views on clinical trial participation, perceived risks and benefits, placebo controls, and sham surgery are presented. These views reflect the sense of urgency and the unique perspective that comes from living with this progressive, debilitating condition full time. A patient-centered paradigm that includes authentic voices of patients as collaborators at every stage of development will help to resolve conflicts, build trust, recruit trial participants, and accelerate new therapies. Key elements are adaptive clinical trial methods and the development of information technology for the assessment of outcomes and surveillance of safety over the life cycle of a medical product. Supported by the Parkinson's Disease Foundation, the Parkinson Pipeline Project is a grassroots group of Parkinson's patients whose goal is to represent an authentic voice for patients in the treatment development process. This group promotes education and communication between members of the Parkinson's community and active stakeholders in medical research, industry, and regulatory agencies. Its members are an example of a new breed of knowledgeable consumers, armed with first-hand access to research findings and reinforced by on-line connections to like-minded peers throughout the world.

Walsh EP. · Electrophysiology Division, Department of Cardiology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA. · Circulation. · Pubmed #17592091 links to  free full text

This publication has no abstract.

Seltzer B. · V.A. Boston Healthcare System, Department of Neurology, Harvard Medical School, Geriatric Research Center, Boston, MA 02130, USA. · Expert Opin Pharmacother. · Pubmed #17472546 No free full text.

Abstract: Donepezil hydrochloride is the most widely prescribed drug for Alzheimer's disease (AD). The main mechanism of action through which it influences cognition and function is presumed to be the inhibition of acetylcholinesterase enzyme in the brain; however, donepezil may also impact the pathophysiology of AD at several other points. Officially approved for mild-to-moderate and severe AD, donepezil has also been shown to be effective in early-stage AD, vascular dementia, Parkinson's disease dementia/Lewy body disease and cognitive symptoms associated with multiple sclerosis. In addition, one study suggested that donepezil may delay the onset of AD in subjects with mild cognitive impairment, a prodrome to AD. The pharmacokinetics, pharmacodynamics, safety/tolerability profile and drug interaction properties of donepezil make it an easy and safe agent to use. However, in general, the efficacy of donepezil is limited, and ongoing studies are investigating other agents that may ultimately overtake its present position as the mainstay of anti-AD therapy.

Gale JT, Amirnovin R, Williams ZM, Flaherty AW, Eskandar EN. · Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA. · Neurosci Biobehav Rev. · Pubmed #17466375 No free full text.

Abstract: Despite remarkable advances, the relationship between abnormal neuronal activity and the clinical manifestations of Parkinson disease (PD) remains unclear. Numerous hypotheses have emerged to explain the relationship between neuronal activity and symptoms such as tremor, rigidity and akinesia. Among these are the antagonist balance hypothesis wherein increased firing rates in the indirect pathway inhibits movement; the selectivity hypothesis wherein loss of neuronal selectivity leads to an inability to select or initiate movements; the firing pattern hypothesis wherein increased oscillation and synchronization contribute to tremor and disrupt information flow; and the learning hypothesis, wherein the basal ganglia are conceived as playing an important role in learning sensory-motor associations which is disrupted by the loss of dopamine. Deep brain stimulation (DBS) surgery provides a unique opportunity to assess these different ideas since neuronal activity can be directly recorded from PD patients. The emerging data suggest that the pathophysiologic changes include derangements in the overall firing rates, decreased neuronal selectivity, and increased neuronal oscillation and synchronization. Thus, elements of all hypotheses are present, emphasizing that the loss of dopamine results in a profound and multifaceted disruption of normal information flow through the basal ganglia that ultimately leads to the signs and symptoms of PD.

Horvitz JC, Choi WY, Morvan C, Eyny Y, Balsam PD. · Department of Psychology, Boston College, Chestnut Hill, MA 02467, USA. · Ann N Y Acad Sci. · Pubmed #17360799 No free full text.

Abstract: While extracellular dopamine (DA) concentrations are increased by a wide category of salient stimuli, there is evidence to suggest that DA responses to primary and conditioned rewards may be distinct from those elicited by other types of salient events. A reward-specific mode of neuronal responding would be necessary if DA acts to strengthen behavioral response tendencies under particular environmental conditions or to set current environmental inputs as goals that direct approach responses. As described in this review, DA critically mediates both the acquisition and expression of learned behaviors during early stages of training, however, during later stages, at least some forms of learned behavior become independent of (or less dependent upon) DA transmission for their expression.

Brass SD, Chen NK, Mulkern RV, Bakshi R. · Center for Neurological Imaging, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Top Magn Reson Imaging. · Pubmed #17179895 No free full text.

Abstract: Deposition of iron in the brain is proposed to play a role in the pathophysiology of the normal aging process and neurodegenerative diseases. Whereas iron is required for normal neuronal metabolism, excessive levels can contribute to the formation of free radicals, leading to lipid peroxidation and neurotoxicity. Magnetic resonance imaging (MRI) is a powerful tool to detect excessive iron in the brain and longitudinally monitor changes in iron levels. Iron deposition is associated with a reduction in the T2 relaxation time, leading to hypointensity on spin-echo and gradient-echo T2-weighted images. The MRI changes associated with iron deposition have been observed both in normal aging and in various chronic neurological diseases, including multiple sclerosis, Alzheimer disease, and Parkinson disease. Magnetic resonance imaging metrics providing information about iron concentrations include R2, R2', and R2*. The purpose of this review is to discuss the role of iron and its detection by MRI in various neurological disorders. We will review the basic biochemical properties of iron and its influence on MRI signal. We will also summarize the sensitivity and specificity of MRI techniques in detecting iron. The MRI and pathological findings pertaining to brain iron will be reviewed with respect to normal aging and a variety of neurological disorders. Finally, the biochemistry and pathophysiology surrounding iron, oxidative stress, free radicals, and lipid peroxidation in the brain will be discussed, including therapeutic implications. The potential role of iron deposition and its assessment by MRI provides exciting potential applications to the diagnosis, longitudinal monitoring, and therapeutic development for disorders of the brain.

Friedl KE, Grate SJ, Proctor SP, Ness JW, Lukey BJ, Kane RL. · U.S. Army Research Institute of Environmental Medicine, Natick, MA 01760-5007, United States. · Arch Clin Neuropsychol. · Pubmed #17127031 No free full text.

Abstract: Information on the mental status of soldiers operating at the limits of human tolerance will be vital to their management in future deployments; it may also allow earlier intervention for conditions such as undiagnosed Gulf War illnesses and Parkinson's Disease. The Army needs a parsimonious set of neuropsychological tests that reliably identify subtle changes for: (1) early detection of individual health and military performance impairments and (2) management of occupational and deployment health risks. Testing must characterize cognitive lapses in healthy individuals faced with relevant operational stressors (i.e., anxiety, information overload, thermal strain, hypoxia, fatigue, head impact, chemical or radiation exposures, metabolic challenges). This effort must also explore the neuropsychological methods in militarily relevant conditions to extend our understanding of relevant functional domains and how well they correspond to modes of testing. The ultimate objective is unobtrusive real-time mental status monitoring.

Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M. · MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129, USA. · Trends Neurosci. · Pubmed #17030429 No free full text.

Abstract: The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard 'dopamine replacement' treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.

Wurtman RJ. · Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. · Metabolism. · Pubmed #16979425 No free full text.

Abstract: Narcolepsy is a chronic neurologic disease characterized by excessive daytime sleepiness and one or more of three additional symptoms (cataplexy, or sudden loss of muscle tone; vivid hallucinations; and brief periods of total paralysis) related to the occurrence of rapid eye movement (REM) sleep at inappropriate times. The daytime sleepiness typically presents as a sudden overwhelming urge to sleep, followed by periods of sleep that last for seconds or minutes, or even longer. During daytime sleep episodes, patients may exhibit "automatic behavior," performing conventionalized functions (eg, taking notes), but not remembering having done so once they are awake. About 10% of narcoleptics are members of familial clusters; however, genetic factors alone are apparently insufficient to cause the disease, inasmuch as the most common genetic disorder, a mutation in chromosome 6 controlling the HLA antigen immune complex, although seen in 90% to 100% of patients, also occurs in as many as 50% of people without narcolepsy. A dog model of narcolepsy exhibits a mutation on chromosome 12 that disrupts the processing of the peptide neurotransmitter hypocretin. No such mutation characterizes human narcolepsy; however, cerebrospinal fluid (CSF) hypocretin levels are profoundly depressed in narcoleptic patients, and a specific reduction in hypocretin-containing neurons has been described. One hypothesis concerning the pathophysiology of narcolepsy proposes that the HLA subtype resulting from the mutation on chromosome 6 increases the susceptibility of hypocretin-containing brain neurons to immune attack. Because hypocretin may normally participate in the maintenance of wakefulness, the loss of neurons that release this peptide might allow REM sleep to occur at inappropriate times, ie, while the patient is awake, in contrast to its normal cyclic appearance after a period of slow-wave sleep. The cataplexy, hallucinations, and/or paralysis associated with REM episodes normally are unnoticed-or, at least, not remembered-when the transition to REM follows slow wave sleep, as is normally the case; however, they are remembered when, in people with narcolepsy, the REM episode starts during a period of wakefulness. The association of narcolepsy with a deficiency in a specific neurotransmitter, in this case, hypocretin, is reminiscent of the associations between Parkinson disease and dopamine, or early Alzheimer disease and acetylcholine.

Anderson WS, Lenz FA. · Johns Hopkins University School of Medicine, Baltimore, MA 21287, USA. · Nat Clin Pract Neurol. · Pubmed #16932575 No free full text.

Abstract: Over the past two decades, deep brain stimulation (DBS) has supplanted lesioning techniques for the treatment of movement disorders, and has been shown to be safe and efficacious. The primary therapeutic indications for DBS are essential tremor, dystonia and Parkinson's disease. In the case of Parkinson's disease, DBS is effective for treating the primary symptoms--tremor, bradykinesia and rigidity--as well as the motor complications of drug treatment. Progress has been made in understanding the effects of stimulation at the neuronal level, and this knowledge should eventually improve the effectiveness of this therapy. Preliminary studies also indicate that DBS might be used to treat Tourette's syndrome, obsessive-compulsive disorder, depression and epilepsy. As we will discuss in this review, the success of DBS depends on an appropriate rationale for the procedure, and on collaborations between neurologists and neurosurgeons in defining outcomes.