Parkinson Disease: Maryland

Hammoud DA, Hoffman JM, Pomper MG. · Department of Radiology, Johns Hopkins University School of Medicine, 1550 Orleans St, CRB-2, Room 492, Baltimore, MD 21231, USA. · Radiology. · Pubmed #17885179 links to  free full text

Abstract: The use of molecular imaging techniques in the central nervous system (CNS) has a rich history. Most of the important developments in imaging-such as computed tomography, magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography-began with neuropsychiatric applications. These techniques and modalities were then found to be useful for imaging other organs involved with various disease processes. Molecular imaging of the CNS has enabled scientists and researchers to understand better the basic biology of brain function and the way in which various disease processes affect the brain. Unlike other organs, the brain is not easily accessible, and it has a highly selective barrier at the endothelial cell level known as the blood-brain barrier. Furthermore, the brain is the most complex cellular network known to exist. Various neurotransmitters act in either an excitatory or an inhibitory fashion on adjacent neurons through a multitude of mechanisms. The various neuronal systems and the myriad of neurotransmitter systems become altered in many diseases. Some of the most devastating diseases, including Alzheimer disease, Parkinson disease, brain tumors, psychiatric disease, and numerous degenerative neurologic diseases, affect only the brain. Molecular neuroimaging will be critical to the future understanding and treatment of these diseases. Molecular neuroimaging of the brain shows tremendous promise for clinical application. In this article, the current state and clinical applications of molecular neuroimaging will be reviewed.

Voon V, Fox SH. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Dr, Bldg 10, Room 5S213, Bethesda, MD 20892-1428, USA. · Arch Neurol. · Pubmed #17698698 links to  free full text

Abstract: A range of behaviors presumed to be related to aberrant or excessive dopaminergic medications are being increasingly recognized in Parkinson disease. These behaviors are linked by their incentive- or reward-based and repetitive natures and include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, hobbyism, and compulsive medication use. Such behaviors can have potentially devastating psychosocial consequences and are often hidden. Whether these behaviors are simply related to dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson disease play a role is not known. We reviewed the literature on these behaviors in Parkinson disease, including definitions, epidemiological and potential pathophysiological features, and management. The study of these behaviors allows not only improved clinical management but also greater insight into a biologically mediated complex behavioral model.

Nahab FB, Peckham E, Hallett M. · Human Motor Control Section, NINDS/NIH, Bethesda, Maryland 20892-1428, USA. · Pract Neurol. · Pubmed #17636137 No free full text.

Abstract: The diagnosis and management of essential tremor appears deceptively simple. However, isolated mild tremor may be difficult to classify, and if the patients have any additional features the diagnosis is more difficult. Management can be challenging, despite the numerous treatments available, because so many patients are not benefited adequately and some not at all. However, as we gain a better understanding of the disorder, more effective therapies with fewer adverse effects are sure to follow.

Voon V, Potenza MN, Thomsen T. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland 20892-1428, USA. · Curr Opin Neurol. · Pubmed #17620886 No free full text.

Abstract: PURPOSE OF REVIEW: A range of impulse control and repetitive behaviors presumed to be related to dopaminergic medications has been recognized in Parkinson's disease. These behaviors are linked by their incentive or reward-based and repetitive natures and overlap with addictions. The behaviors include pathological gambling, hypersexuality, compulsive shopping, and compulsive eating and are related to punding and compulsive medication use. In patients on dopamine agonists, these behaviors as a group are relatively common, can have potentially devastating psychosocial consequences and are commonly hidden. RECENT FINDINGS: Recent studies have investigated prevalence rates and associated factors. The literature on these behaviors in Parkinson's disease, including definitions, epidemiology, pathophysiology and management, is reviewed. The relationship to medications, Parkinson's disease and individual susceptibility is examined. SUMMARY: These behaviors can affect up to 14% of Parkinson's disease patients on dopamine agonists. Clinicians should warn patients prior to initiating dopamine agonists and enquire about these behaviors during follow up.

Cookson MR, van der Brug M. · Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20982-3707, USA. · Exp Neurol. · Pubmed #17603039 links to  free full text

Abstract: Mutations in the SNCA gene are causal for familial Parkinson disease/Lewy body disease. alpha-Synuclein is a small acidic protein that binds loosely to the surface of vesicles and may play a role in synaptic dynamics, although its normal function remains somewhat unclear. What is clear is that point mutations or increased expression of wild type alpha-synuclein causes disease. A great deal of literature supports the overall hypothesis that alpha-synuclein is damaging to neurons because it is inherently prone to aggregation; mutations or increased concentration of the protein both increase this tendency. An unproven, but popular, contention is that the toxic species are small oligomers that are relatively soluble, which may react with membranes to damage key processes within the cell. The details of this process, especially in determining the order of events and the requirement of particular processes in cell death, are unclear. Derangements in vesicle processing, including synaptic function, protein turnover, mitochondrial function and oxidative stress, have all been suggested to occur. Whether there is a sequence of events or whether these are interacting effects is unclear, but the outcome is to trigger cell death, by both apoptotic and non-apoptotic mechanisms depending on the system studied. In this article, we develop a framework for thinking about alpha-synuclein in terms of initiating events and secondary processes that are required to trigger neuronal dysfunction and cell death.

Martin LJ. · Department of Pathology, Division of Neuropathology, Department of Neuroscience, Johns Hopkins University School ofMedicine, Baltimore, MD 21205-2196, USA. · Rev Neurosci. · Pubmed #17593875 No free full text.

Abstract: A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.

Shulman LM. · University of Maryland School of Medicine, Baltimore, MD 21201, USA. · Gend Med. · Pubmed #17584622 No free full text.

Abstract: Because estrogen has numerous effects on dopamine neurotransmission, many researchers are interested in its possible use to either slow the progression or reduce the risk of Parkinson's disease (PD). The incidence of PD is greater in men than in women. Gender differences in neurotoxicity have been observed, and basic research in experimental animals indicates that estrogen protects neurons from various forms of injury. However, the results of retrospective surveys of the neuroprotective effects of estrogen replacement in PD have been mixed, with some showing no effect on risk and others showing a reduction in risk. A mildly significant gender difference in disability and quality-of-life reporting has been noted, with women citing greater disability and reduced quality of life. Gender differences have been shown in response to treatment of PD, for example, in how levodopa is metabolized--women have greater levodopa bioavailability. In the Parkinson's Disease on Estrogen Therapy Replacement in the Menopause Years (POETRY) study, participants were found to have improved scores on the Unified Parkinson Disease Rating Scale. Based on the POETRY results, it is hypothesized that estrogen replacement therapy (ERT) may lead to improvement in PD symptoms and provide an opportunity to reduce the dosage of antiparkinsonian medication in women.

Daly JW. · Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892-0820, USA. · Cell Mol Life Sci. · Pubmed #17514358 No free full text.

Abstract: Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic agents for intervention in Alzheimer's disease, asthma, cancer, diabetes, and Parkinson's disease. Such compounds also have activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.

Galpern WR, Cudkowicz ME. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Blvd., Room 2225, Bethesda, MD 20892, USA. · Mitochondrion. · Pubmed #17485247 No free full text.

Abstract: The etiology of several neurodegenerative disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q-10 (CoQ10) acts both as an antioxidant and as an electron acceptor at the level of the mitochondria. In several animal models of neurodegenerative diseases including amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease, CoQ10 has shown beneficial effects. Based on its biochemical properties and the effects in animal models, several clinical trials evaluating CoQ10 have been undertaken in many neurodegenerative diseases. CoQ10 appears to be safe and well tolerated, and several efficacy trials are planned.

Goldstein DS. · Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA. · Cleve Clin J Med. · Pubmed #17455553 links to  free full text

Abstract: More than 40 neuroimaging studies have reported evidence for loss of sympathetic noradrenergic nerves in PD. Cardiac sympathetic denervation is virtually universal in patients with PD and neurogenic orthostatic hypotension. About one half of patients with PD who do not have orthostatic hypotension also have evidence for loss of noradrenergic innervation. The loss progresses over years, in a pattern suggesting "dying-back". Because patients with familial PD from mutation of the gene encoding alpha-synuclein or from triplication of the normal gene have low myocardial concentrations of 6-[18F]fluorodopamine-derived radioactivity, cardiac sympathetic denervation seems linked etiologically with alpha-synucleinopathy. Baroreflex-cardiovagal failure and cardiac sympathetic denervation can occur before onset of the movement disorder, suggesting that neurocardiologic testing might provide a biomarker for detecting presymptomatic or early PD and for following responses to putative neuroprotective treatments.

Hikosaka O. · Laboratory of Sensorimotor Research, National Eye Institute, National Institute of Health, Bethesda, MD 20892-4435, USA. · Ann N Y Acad Sci. · Pubmed #17360800 No free full text.

Abstract: Expectation of reward facilitates motor behaviors that enable the animal to approach a location in space where the reward is expected. It is now known that the same expectation of reward profoundly modifies sensory, motor, and cognitive information processing in the brain. However, it is still unclear which brain regions are responsible for causing the reward-approaching behavior. One candidate is the dorsal striatum where cortical and dopaminergic inputs converge. We tested this hypothesis by injecting dopamine antagonists into the caudate nucleus (CD) while the monkey was performing a saccade task with a position-dependent asymmetric reward schedule. We previously had shown that: (1) serial GABAergic connections from the CD to the superior colliculus (SC) via the substantia nigra pars reticulata (SNr) exert powerful control over the initiation of saccadic eye movement and (2) these GABAergic neurons encode target position and are strongly influenced by expected reward, while dopaminergic neurons in the substantia nigra pars compacta (SNc) encode only reward-related information. Before injections of dopamine antagonists the latencies of saccades to a given target were shorter when the saccades were followed by a large reward than when they were followed by a small reward. After injections of dopamine D1 receptor antagonist the reward-dependent latency bias became smaller. This was due to an increase in saccade latency on large-reward trials. After injections of D2 antagonist the latency bias became larger, largely due to an increase in saccade latency on small-reward trials. These results indicate that: (1) dopamine-dependent information processing in the CD is necessary for the reward-dependent modulation of saccadic eye movement and (2) D1 and D2 receptors play differential roles depending on the positive and negative reward outcomes.

Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. · Aging Cell. · Pubmed #17328689 No free full text.

Abstract: When properly controlled, Ca2+ fluxes across the plasma membrane and between intracellular compartments play critical roles in fundamental functions of neurons, including the regulation of neurite outgrowth and synaptogenesis, synaptic transmission and plasticity, and cell survival. During aging, and particularly in neurodegenerative disorders, cellular Ca2+-regulating systems are compromised resulting in synaptic dysfunction, impaired plasticity and neuronal degeneration. Oxidative stress, perturbed energy metabolism and aggregation of disease-related proteins (amyloid beta-peptide, alpha-synuclein, huntingtin, etc.) adversely affect Ca2+ homeostasis by mechanisms that have been elucidated recently. Alterations of Ca2+-regulating proteins in the plasma membrane (ligand- and voltage-gated Ca2+ channels, ion-motive ATPases, and glucose and glutamate transporters), endoplasmic reticulum (presenilin-1, Herp, and ryanodine and inositol triphosphate receptors), and mitochondria (electron transport chain proteins, Bcl-2 family members, and uncoupling proteins) are implicated in age-related neuronal dysfunction and disease. The adverse effects of aging on neuronal Ca2+ regulation are subject to modification by genetic (mutations in presenilins, alpha-synuclein, huntingtin, or Cu/Zn-superoxide dismutase; apolipoprotein E isotype, etc.) and environmental (dietary energy intake, exercise, exposure to toxins, etc.) factors that may cause or affect the risk of neurodegenerative disease. A better understanding of the cellular and molecular mechanisms that promote or prevent disturbances in cellular Ca2+ homeostasis during aging may lead to novel approaches for therapeutic intervention in neurological disorders such as Alzheimer's and Parkinson's diseases and stroke.

Gupta A, Dawson TM. · Department of Neurology, John Hopkins Hospital, Pathology 509, 600 North Wolfe Street, Baltimore, MD 21287, USA. · Neurosurg Clin N Am. · Pubmed #17244560 No free full text.

Abstract: Parkinson's disease (PD) affects more than 1 million people in the United States, which makes it one of the most common age-related neurodegenerative disorders, second only to Alzheimer disease. In light of this significant health problem, this review places emphasis on the exciting prospect of using stem cells as an emerging therapeutic option in this neurologic field. To that goal, the authors first describe the clinical, genetic, and pathologic features of PD and proceed with discussing notions about disease mechanism as well as current medical and surgical treatments before focusing on the advantages, limitations, and feasibility of stem cell therapy.

Baronti F. · Klinik Bethesda/Neurorehabilitation, Parkinson-Zentrum, Epileptologie, Tschugg (BE). · Ther Umsch. · Pubmed #17221822 No free full text.

Abstract: Although most parkinsonian patients greatly benefit from medical and/or surgical treatment, their clinical management should not be limited to these two interventions. Axial symptoms, freezing, postural instability, speech and swallowing problems may be drug-resistant, and disability may persist in spite of improvement of motor symptoms. A coordinate interdisciplinary approach facilitates the clinical management of the disease. Physiotherapy, occupational therapy and speech therapy may contribute to reduce impairment and improve quality of life; a psychological and social support of patients and caregivers helps them carrying the burden of the disease; counseling through a specialized nurse may give practical solutions to problems like bladder incontinence, symptomatic hypotension or hypersalivation. As sensory cueing may help patients bypassing the disease-specific motor control deficits, it should be included in training programs. Rehabilitatory interventions are part of the standards of care of Parkinson's disease and their efficacy is supported by several neurophysiological and clinical investigations. However, the poor methodological quality of most clinical studies as compared with the standard of pharmacological investigations fails to provide clear-cut evidence in favour of rehabilitation.

Martin LJ. · Department of Pathology, Division of Neuropathology and Neuroscience, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, USA. · J Neuropathol Exp Neurol. · Pubmed #17146283 No free full text.

Abstract: The causes of the selective neurodegeneration in Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS) are unknown and commonalities among these and other age-related neurodegenerative diseases continue to be sought. Morphologic, biochemical, molecular genetic, and cell/animal model studies suggest that mitochondria might be a convergence point for neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress. In PD, mutations in putative mitochondrial proteins have been identified recently and mitochondrial DNA mutations have been found in nigral neurons. In ALS, changes occur in mitochondrial respiratory chain enzymes and in mitochondrial cell death proteins, indicative of an activation of programmed cell death pathways. Mouse models are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria in neuronal death processes ranging from apoptosis to necrosis. This review presents how malfunctioning mitochondria might contribute to neuronal death in PD and ALS.

Rouault TA, Cooperman S. · Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. · Semin Pediatr Neurol. · Pubmed #17101452 No free full text.

Abstract: Brain iron uptake is regulated by the expression of transferrin receptor 1 in endothelial cells of the blood-brain barrier. Transferrin-bound iron in the systemic circulation is endocytosed by brain endothelial cells, and elemental iron is released to brain interstitial fluid, likely by the iron exporter, ferroportin. Transferrin synthesized by oligodendrocytes in the brain binds much of the iron that traverses the blood-brain barrier after oxidation of the iron, most likely by a glycophosphosinositide-linked ceruloplasmin found in astrocytic foot processes that ensheathe brain endothelial cells. Neurons acquire iron from diferric transferrin, but it is less clear how glial cells acquire iron. In aging mammals, iron accumulates in the basal ganglia, and iron accumulation is believed to contribute to neurodegenerative diseases, including Parkinson and Alzheimer disease. Here we consider the possibility that iron accumulations, which are often thought to facilitate free radical generation and oxidative damage, may contain insoluble iron that is unavailable for cellular use, and the pathology associated with iron accumulations may result from functional iron deficiency in some diseases.

Kane RL, Roebuck-Spencer T, Short P, Kabat M, Wilken J. · VA Maryland Healthcare System, United States. · Arch Clin Neuropsychol. · Pubmed #17101258 No free full text.

Abstract: In this article we review studies in which Automated Neuropsychological Assessment Metrics (ANAM) measures were used to screen for impairment in various clinical populations. These clinical groups include patients with multiple sclerosis, systemic lupus erythematosus, Parkinson's disease, Alzheimer's dementia, acquired brain injury, and migraine headache. Data are also presented from a group of outpatient referrals unselected with respect to clinical condition. Findings support the use of ANAM as a screening procedure for identifying the impaired patient.

Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A. · Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Building, 35 Convent Drive, Bethesda, MD 20892, USA. · Ann Neurol. · Pubmed #17068789 No free full text.

Abstract: Until 10 years ago, conventional wisdom held that Parkinson's disease was not a genetic disorder. Since that time, there have been a plethora of genetic findings, culminating in the cloning of several genes that derive from the loci given the nomenclature PARK1-PARK12 (OMIM 168600). Recently, these research findings have begun to impact clinical practice, and this impact is likely to increase. The primary purpose of this article is to outline these genetic advances, discuss their importance for current practice in clinical and related settings, and outline briefly how they are influencing research into the causes of and possible future treatments for this prevalent disorder.

Weiner WJ. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Rev Neurol Dis. · Pubmed #17047575 No free full text.

Abstract: Parkinson's disease is characterized by progressive slowness in activities of daily living and is the most common cause of parkinsonism, whose symptoms include resting tremor, cogwheel rigidity, and bradykinesia. The introduction of levodopa and its positive effect on motor dysfunction in Parkinson's disease has allowed neurologists to focus on motor fluctuations. "End-of-dose wearing-off" and "morning akinesia" are terms to describe the transition between a patient's relatively normal motor performance when levodopa is effective and when it has transiently lost its effect on motor responses and parkinsonian symptoms reemerge. The choices available to alleviate these motor fluctuations range from altering the patient's levodopa/carbidopa dosing schedule to the addition of other agents to the regimen, including dopamine receptor agonists, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, and amantadine, as well as implementing dietary changes. Therapeutic decisions can be difficult because older agents have not been compared in head-to-head trials to determine which drugs are better than others and the order in which they should be tried or added to the levodopa regimen; however, all of the available treatments provide a good possibility of benefit to the patient. Deep brain stimulation surgery is an option for patients with medically intractable severe motor fluctuations.

Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA. · Antioxid Redox Signal. · Pubmed #17034345 No free full text.

Abstract: When subjected to excessive oxidative stress, neurons may respond adaptively to overcome the stress, or they may activate a programmed cell death pathway called apoptosis. Apoptosis is characterized by alterations in mitochondria and the endoplasmic reticulum and activation of cysteine proteases called caspases. Increasing evidence suggests that apoptotic biochemical cascades are involved in the dysfunction and death of neurons in neurodegenerative disorders such as Alzheimer's, Parkinson, and Huntington's diseases. Studies of normal aging, of genetic mutations that cause disease, and of environmental factors that affect disease risk are revealing cellular and molecular alterations that may cause excessive oxidative stress and trigger neuronal apoptosis. Accumulation of self-aggregating proteins such as amyloid beta-peptide, tau, alpha-synuclein, and huntingtin may be involved in apoptosis both upstream and downstream of oxidative stress. Membrane-associated oxidative stress resulting in perturbed lipid metabolism and disruption of cellular calcium homeostasis may trigger apoptosis in several different neurodegenerative disorders. Counteracting neurodegenerative processes are an array of mechanisms including neurotrophic factor signaling, antioxidant enzymes, protein chaperones, antiapoptotic proteins, and ionostatic systems. Emerging findings suggest that the resistance of neurons to death during aging can be enhanced by modifications of diet and lifestyle.

Goldstein DS. · Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA. · J Neural Transm Suppl. · Pubmed #17017550 No free full text.

Abstract: This chapter provides an update about cardiovascular aspects of Parkinson disease (PD), with the following topics: (1) Orthostatic hypotension (OH) as an early finding in PD; (2) neurocirculatory abnormalities in PD + OH independent of levodopa treatment; (3) cardiac and extracardiac noradrenergic denervation in PD + OH; (4) progressive loss of cardiac sympathetic innervation in PD without OH.

Dawson TM. · Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · J Neural Transm Suppl. · Pubmed #17017531 No free full text.

Abstract: Parkinson's Disease (PD) is a common neurodegenerative disorder that is characterized by the progressive loss of dopamine (DA) neurons. Accompanying the loss the of DA neurons is the accumulation of Lewy bodies and neurites, intracytoplasmic proteinaceous inclusions that contain alpha-synuclein, synphilin-1, components of the ubiquitin proteasomal pathway and parkin. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, DJ-1, PINK-1, LRRK2, and parkin. Understanding the molecular mechanisms by which mutations in familial-linked genes cause PD holds great promise for unraveling the mechanisms by which DA neurons degenerate in PD. Parkin is E3-ubiquitin-protein ligase that ubiquitinates itself and promotes its own degradation. Familial associated mutations of parkin have impaired ubiquitin ligase function suggesting that this may be the cause of familial autosomal recessive PD. Parkin might be required for formation of Lewy bodies as Lewy bodies are absent in patients with parkin mutations. Parkin interacts with and ubiquitinates the alpha-synuclein interacting protein, synphilin-1. Formation of Lewy-body-like ubiquitin-positive cytosolic inclusions occurs upon coexpression of alpha-synuclein, synphilin-1 and parkin. Nitric oxide inhibits Parkin's E-3 ligase activity and its protective function by nitric oxide through S-nitrosylation both in vitro and in vivo. Nitrosative and oxidative stress link parkin function with the more common sporadic form of Parkinson's disease and the related alpha-synucleinopathy, DLBD. Development of new therapies for PD and other disorders associated with nitrosative and oxidative stress may follow the elucidation of the pathways by which NO S-nitrosylates and inhibits parkin. Moreover, parkin and alpha-synuclein are linked in common pathogenic mechanism through their interaction with synphilin-1 and parkin may be important for the formation of Lewy bodies.

Chard SE. · Department of Sociology and Anthropology, University of Maryland, Baltimore County, Baltimore, Maryland 21250, USA. · NeuroRx. · Pubmed #17012066 No free full text.

Abstract: Over the past decade, community neurorehabilitation has emerged as a promising extension of neurological rehabilitation. The goal of community neurorehabilitation is to maximize functional ability and quality of life through multidimensional rehabilitation that occurs while the individual is living in a home versus acute or transitory care setting. Because of its multidisciplinary focus, many variations of community neurorehabilitation teams have been implemented. Critical gaps exist, however, in understanding of the influence of structural and procedural differences among programs, as well as patient level variables such as social support, on recovery. This paper examines the current evidence of the effectiveness of community neurorehabilitation through a review of the findings of systematic reviews and meta-analyses of four neurological conditions: stroke, multiple sclerosis, traumatic brain injury, and Parkinson's disease. It focuses in particular on the data regarding physical therapy and occupational therapy, which are two of the primary components of community neurorehabilitation programs.

Biskup S, Moore DJ. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Bioessays. · Pubmed #16998822 No free full text.

Abstract: As individuals enter their 80s, they are inevitably confronted with the problem of neuronal loss in the brain. The incidence of the common movement disorder 'mild parkinsonian signs' (MPS) is approximately 50% over the age of 85 years. It has long been known that the loss of dopaminergic neurons in the substantia nigra pars compacta is a neuropathological hallmark of Parkinson's disease (PD). Recently, two papers present clear evidence for a high burden of mitochondrial DNA deletions within substantia nigra neurons in aged individuals and individuals with PD, pointing towards a common pathway inevitably leading to neuronal dysfunction and death.

Weiner WJ. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. · Nat Clin Pract Neurol. · Pubmed #16990820 No free full text.

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