Parkinson Disease: US Federal Service

Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. · Ann N Y Acad Sci. · Pubmed #19076369 links to  free full text

Abstract: Glutamate's role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis, and neuron survival in the developing and adult mammalian nervous system. Cell-surface glutamate receptors are coupled to Ca(2+) influx and release from endoplasmic reticulum stores, which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF), which, in turn, modifies neuronal glutamate sensitivity, Ca(2+) homeostasis, and plasticity. Neurotrophic factors may modify glutamate signaling directly, by changing the expression of glutamate receptor subunits and Ca(2+)-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins, and antiapoptotic Bcl-2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer's disease to psychiatric disorders. By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.

Adibhatla RM, Hatcher JF. · Department of Neurological Surgery, Cardiovascular Research Center, Neuroscience Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI., William S. Middleton Veterans Affairs Hospital, Madison, WI 53792, USA. · Subcell Biochem. · Pubmed #18751914 links to  free full text

Abstract: Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.

Hallett M. · Human Motor Control Section, NINDS, NIH, Bethesda, Maryland 20892-1428, USA. · Mov Disord. · Pubmed #18668625 No free full text.

Abstract: Freezing of gait appears to result from a number of fundamental problems in patients with Parkinson disease. Automaticity is impaired, putting more stress on voluntary mechanisms. Internal drivers of movement are impaired, likely because of deficient basal ganglia function. Deficiency of internal forces to initiate movement is a major factor in freezing. This deficiency gives a greater influence to external or sensory factors. The sensory factors can both help or hinder freezing. Analogous to the problem with set-shifting, there is also some difficulty in regulation of internal versus external factors and in regulation of different external factors.

Harvey BK, Wang Y, Hoffer BJ. · Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore 21224, MD, USA. · Acta Neurochir Suppl. · Pubmed #18642640 links to  free full text

Abstract: In the case of Parkinson's disease (PD), classical animal models have utilized dopaminergic neurotoxins such as 6-hydroxydopamine (6OHDA) and 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). More recently, human genetic linkage studies have identified several genes in familial forms of PD. Transgenic models have been made that explore the function of PD-linked genes (e.g. alpha-synuclein, DJ-1, LRRK2, Parkin, UCH-L1, PINK1). Recent evidence suggests mitochondrial dysfunction may play a major role in PD. Manipulation of mitochondrial respiratory genes (e.g. mitochondrial transcription factor A or TFAM) also elicits a PD phenotype in mice. Transgenic mice (MitoPark) were developed that have TFAM selectively knocked out in dopaminergic neurons. The nigral dopamine neurons of MitoPark mice show respiratory chain dysfunction, accompanied by the development of intraneuronal inclusions and eventual cell death. In early adulthood, the MitoPark mice show a slowly progressing loss of motor function that accompanies these cellular changes. The MitoPark mouse enables further study of the role of mitochondrial dysfunction in DA neurons as an important mechanism in the development of PD. Transgenic technology has allowed new insights into mechanisms of neurodegeneration for a number of neurological disorders. This paper will summarize recent studies on several transgenic models of PD.

McCall S, Vilensky JA, Gilman S, Taubenberger JK. · Department of Clinical Pathology, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, USA. · J Neurovirol. · Pubmed #18569452 No free full text.

Abstract: Since encephalitis lethargica's (EL) prevalence in the 1920s, epidemiologic and clinical debate has persisted over whether EL was caused by, potentiated by, or merely coincident with the Spanish influenza pandemic. Epidemiologic analyses generally suggest that the disorders were coincidental. Beginning in the 1970s, modern experiments on archival brain samples mainly failed to confirm a direct relationship between influenza and EL. These experimental studies have technical limitations, e.g., the appropriateness of antibodies, polymerase chain reaction (PCR) primers and controls, and the extreme paucity and age of available material. These factors render the case against influenza less decisive than currently perceived. Nevertheless, there is little direct evidence supporting influenza in the etiology of EL. Almost 100 years after the EL epidemic, its etiology remains enigmatic, raising the possibility of a recurrence of EL in a future influenza pandemic.

Wick JY, Zanni GR. · National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA. · Consult Pharm. · Pubmed #18540790 No free full text.

Abstract: Essential tremor (ET), traditionally considered benign, is a serious neurologic condition with life-altering repercussions. Its involuntary, rhythmic oscillations involve alternating, irregular, or simultaneous contractions of agonist and antagonist muscles. It is the most common of the 20 known tremor disorders and often confused with Parkinson's disease. Numerous drugs can aggravate ET, and alcohol consumption may alleviate it. Its etiology is unknown. Proven drug treatments are currently limited to propranolol and primidone. This article reviews ET with examples from history to demonstrate points.

Chiocco MJ, Harvey BK, Wang Y, Hoffer BJ. · Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. · Parkinsonism Relat Disord. · Pubmed #18267258 No free full text.

Abstract: Parkinson's disease (PD) is a slowly progressive disorder with no known etiology. Pathologically, there is a loss of the dopaminergic neurons in the substantia nigra that project to the striatum. Current available therapies for PD are targeted to the restoration of striatal dopamine. These approaches may alleviate symptoms transiently, but fail to slow the progression of disease. One emergent therapeutic approach is the use of neurotrophic factors to halt or reverse the loss of dopaminergic neurons. There have been intensive research efforts both preclinically and clinically testing the efficacy and safety of neurotrophic factors for the treatment of PD. In this review, we discuss the neuroprotective and neuroregenerative properties of various trophic factors, both old and recent, and their status as therapeutic molecules for PD.

Heindel JJ. · Division of Extramural Research and Training, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. · Basic Clin Pharmacol Toxicol. · Pubmed #18226058 No free full text.

Abstract: There is a major paradigm shift taking place in science that while simple is profound. The new paradigm suggests that susceptibility to disease is set in utero or neonatally as a result of the influences of nutrition and exposures to environmental stressors/toxicants. In utero nutrition and/or in utero or neonatal exposures to environmental toxicants alter susceptibility to disease later in life as a result of their ability to affect the programming of tissue function that occurs during development. This concept, which is still a hypothesis undergoing scientific testing and scrutiny, is called the developmental basis of health and disease. If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time! Certainly, not all exposures that result in increased disease or dysfunction occur during development. This paradigm shift just suggests that this is a sensitive window of exposure that should be examined more thoroughly. This overview focuses on animal models for the assessment of this new scientific paradigm and the animal data that now supports it.

Rempe S, Hayden JM, Robbins RA, Hoyt JC. · Carl T. Hayden VA Medical Center, Research (RS/151), Building 27, 650 East Indian School Road, Phoenix, AZ 85012, USA. · Endocr Metab Immune Disord Drug Targets. · Pubmed #18220943 No free full text.

Abstract: Tetracycline and its derivatives, such as chlortetracycline, oxytetracycline, minocycline, doxycycline, methacycline and lymecycline, are naturally occurring or semi-synthetic polyketide compounds that exhibit a well known broad-spectrum antibacterial activity that interferes with prokaryotic protein synthesis at the ribosome level. In addition to this well known antibacterial activity these compounds also exhibit a variety of additional, less well known properties. Among them are separate and distinct anti-inflammatory properties. Tetracycline and related compounds have been shown to be effective chemotherapeutic agents in a wide variety of chronic inflammatory diseases and conditions. These include periodontitis, rosacea, acne, auto-immune diseases such as rheumatoid arthritis and protection of the central nervous system against trauma and neurodegenerative diseases such as stroke, multiple sclerosis and Parkinson disease. Tetracycline and related compounds appear to be beneficial for treatment of several chronic inflammatory airway diseases. Among them are asthma, bronchiectasis, acute respiratory distress syndrome, chemical induced lung damage and cystic fibrosis. The clinical use of tetracycline-type drugs in treatment of chronic airway inflammation is becoming a topic of intense interest. Recent findings in this area have led to an understanding of the myriad physiological, cellular and molecular mechanisms of the inflammatory response and how this response may be controlled to limit damage to host cells and tissues. This review presents a brief summary of the recent research in the area of tetracycline and its derivatives in control of pulmonary inflammation.

Muthane UB, Ragothaman M, Gururaj G. · Departments of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India. · J Assoc Physicians India. · Pubmed #18173026 No free full text.

Abstract: Improving economy and health in developing countries like India, has increased the life span and changed the emphasis from communicable to noncommunicable diseases. This is likely to increase the prevalence of movement disorders and, age-related diseases like Parkinson's disease (PD). We review Indian epidemiological studies to describe: a) Prevalence of movement disorders, b) methodological issues and c) potential of epidemiological research in a country with multiple ethnic races and environmental risks for PD. Most Indian epidemiological studies do not specifically assess PD and figures are from studies evaluating all neurological diseases. Well-designed Indian studies on PD and essential tremors estimate prevalence rates in Parsis who are ethnically different from Indians. We compare Indian prevalence studies with other parts of the world to examine the role of ethnicity in PD. Lack of accurate epidemiological data on PD and movement disorders creates an urgent need for properly designed and conducted epidemiological studies in India. This will help find out their load, identify areas of focus, create public health policies for elderly Indians and, possibly, provide etiological clues to the pathogenesis of PD.

Greggio E, Singleton A. · Cell Biology & Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20982, USA. · Expert Rev Proteomics. · Pubmed #18067416 No free full text.

Abstract: Parkinson's disease (PD) is a severe, progressive, age-associated, neurodegenerative disorder. Current therapies are symptomatic and not effective at halting or significantly slowing the disease progress. The search for etiologic-based therapies has focused largely on genetic findings made in familial forms of this disease. Mutations of five genes have been unequivocally linked to PD; two of these, LRRK2 and PINK1, encode kinases and as such are attractive tools with which to understand the disease process; furthermore, preliminary functional data suggests that these proteins, or the pathways in which they are involved, are viable therapeutic targets. Here we explore the current data and thoughts regarding LRRK2 and PINK1 and discuss further avenues of research to understand the pathologic effects of mutations at these loci and potential points of therapeutic intervention, such as within these kinases or in associated pathways such as Jun N-terminal kinase and Akt pathways.

Martin JL, Ancoli-Israel S. · Veteran's Affairs Greater Los Angeles Healthcare System, Geriatric Research, Education and Clinical Center, 16111 Plummer Street, North Hills, CA 91343, USA. · Clin Geriatr Med. · Pubmed #18035230 links to  free full text

Abstract: Nighttime sleep disruption is characteristic of long-term care residents, is typically accompanied by daytime sleepiness, and may be caused by a multitude of factors. Causal factors include medical and psychiatric illness, medications, circadian rhythm abnormalities, sleep disordered breathing and other primary sleep disorders, environmental factors, and lifestyle habits. There is some suggestion that these factors are amenable to treatment; however, further research on the implementation of treatments within the long-term care setting is needed. Additional work is also needed to understand the administrative and policy factors that might lead to systemic changes in how sleep is viewed and sleep problems are addressed in long-term care settings.

Mines M, Ding Y, Fan GH. · Department of Veterans Affairs and the Department of Biomedical Sciences, Division of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37208, USA. · Curr Med Chem. · Pubmed #17979699 No free full text.

Abstract: Chemokines and chemokine receptors, primarily found to play a role in leukocyte migration to the inflammatory sites or to second lymphoid organs, have recently been found expressed on the resident cells of the central nervous system (CNS). These proteins are important for the development of the CNS and are involved in normal brain functions such as synaptic transmission. Increasing lines of evidence have implicated an involvement for chemokines and their receptors in several neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), human immunodeficiency virus-associated dementia (HAD), multiple sclerosis (MS), and stroke. Specific inhibition of the biological activities of chemokine receptors could gain therapeutic benefit for these neurodegenerative disorders. In recent years, non-peptide antagonists of chemokine receptors have been disclosed and tested in relevant pharmacological models and some of these inhibitors have entered clinical trials. The aim of this review is to outline the recent progress regarding the role of chemokines and their receptors in neurodegenerative diseases and the advancements in the development of chemokine receptor inhibitors as potential therapeutic approaches for these neurodegenerative diseases.

Cookson MR, Dauer W, Dawson T, Fon EA, Guo M, Shen J. · Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892-3707, USA. · J Neurosci. · Pubmed #17978026 links to  free full text

Abstract: The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN (phosphatase and tensin homolog)-induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future.

Fishman PS. · Department of Neurology, University of Maryland, School of Medicine and The Baltimore VAMC, Baltimore, Maryland 21201, USA. · Mov Disord. · Pubmed #17973325 No free full text.

Abstract: Although resting tremor is the most identifiable sign of Parkinson's disease, its underlying basis appears to be the most complex of the cardinal signs. The variable relationship of resting tremor to other symptoms of PD has implications for diagnosis, prognosis, medical and surgical treatment. Structural lesions very rarely cause classic resting tremor, with likely contributions to tremor by a network of neurons both within and outside the basal ganglia. Patients with only resting tremor show dopaminergic deficits with radioligand imaging, but severity of tremor correlates poorly in such dopamine imaging studies. Correlation of tremor severity to changes in radioligand studies is also limited by the use of mostly qualitative measures of tremor severity. A complex pharmacologic basis of parkinsonian resting tremor is supported by treatment studies. Although levodopa is clearly effective for resting tremor, several agents have shown efficacy that appears to be superior or additive to that of levodopa including anticholinergics, clozapine, pramipexole, and budipine. Although the thalamus has the greatest body of evidence supporting its role as an effective target for surgical treatment of tremor, recent studies suggest that the subthalamic nucleus may be a reasonable alternative target for patients with Parkinson's disease and severe tremor as the predominant symptom.

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.

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.

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.