Parkinson Disease: Maryland

Gupta A, Dawson VL, Dawson TM. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Ann Neurol. · Pubmed #19127586 No free full text.

Abstract: Currently, there is no proven neuroprotective or neurorestorative therapy for Parkinson's disease (PD). Several advances in the genetics of PD have created an opportunity to develop mechanistic-based therapies that hold particular promise for identifying agents that slow and even halt the progression of PD, as well as restore function. Here we review many of the advances in the last decade regarding the identification of new targets for the treatment of PD based on understanding the molecular mechanisms of how mutations in genes linked to PD cause neurodegeneration.

Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA. · Physiol Rev. · Pubmed #19126755 links to  free full text

Abstract: The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

Robottom BJ, Mullins RJ, Shulman LM. · Department of Neurology, University of Maryland School of Medicine, 22 South Greene Street N4W46, Baltimore, MD 21201, USA. · Expert Rev Neurother. · Pubmed #19086876 No free full text.

Abstract: Pregnancy in Parkinson's disease (PD) is an uncommon occurrence. Available reports suggest that there may be a worsening of PD symptom severity related to pregnancy. In this special report, medical literature on pregnancy in PD will be reviewed with regard to disease progression and the safety of antiparkinsonian medications. A case report of pregnancy in a woman with PD will be described. It is speculated that the symptoms of PD may be affected by changing hormone levels.

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.

Bras J, Singleton A, Cookson MR, Hardy J. · Molecular Genetics Unit, National Institutes on Aging, Bethesda, MD, USA. · FEBS J. · Pubmed #19021754 No free full text.

Abstract: Heterozygous loss-of-function mutations at the glucosecerebrosidase locus have recently been shown to be a potent risk factor for Lewy body disease. Based on this observation, we have re-evaluated the likelihood that the different PARK loci (defined using clinical criteria for disease) may be misleading attempts to find common pathways to pathogenesis. Rather, we suggest, grouping the different loci which lead to different Lewy body disease may be more revealing. Doing this, we suggest that several of the genes involved in disparate Lewy body diseases impinge on ceramide metabolism and we suggest that this may be a common theme for pathogenesis.

González-Fernández M, Daniels SK. · Department of Physical Medicine and Rehabilitation, Johns Hopkins University, School of Medicine, 600 North Wolfe Street, Phipps 174, Baltimore, MD 21287, USA. · Phys Med Rehabil Clin N Am. · Pubmed #18940646 No free full text.

Abstract: Dysphagia is a common problem in neurologic disease. The authors describe rates of dysphagia in selected neurologic diseases, and the evaluation and treatment of dysphagia in this population. Applicable physiology and aspects of neural control are reviewed. The decision-making process to determine oral feeding versus alternative means of alimentation is examined.

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.

Weiner WJ. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Rev Neurol Dis. · Pubmed #18660741 No free full text.

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Weiner WJ. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Rev Neurol Dis. · Pubmed #18660736 No free full text.

Abstract: The diagnosis of Parkinson's disease remains a clinical diagnosis with no confirmatory laboratory or imaging studies available. The classic diagnostic criteria include 2 of 3 cardinal motor features of parkinsonism (resting tremor, cogwheel rigidity, and bradykinesia) on examination. Interest in a "premotor diagnosis" of Parkinson's disease is based on the hope that neuroprotective therapy could be initiated earlier and affect disease course. However, there is no proven method to diagnose Parkinson's disease prior to the onset of motor signs and there is no proven neuroprotective treatment. Once the diagnosis is made, the neurologist must decide, with the patient, whether to institute treatment at the time of diagnosis or whether to institute treatment when functional disability evolves. There are multiple possible initial pharmacologic choices for the initial treatment of Parkinson's disease, including monoamine oxidase type B inhibitors, dopamine receptor agonists, and levodopa/carbidopa.

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.

Moore DJ. · Institute for Cell Engineering and Department of Neurology, Johns Hopkins University School of Medicine, Broadway Research Building, 733 North Broadway, Baltimore, MD 21205, USA. · Parkinsonism Relat Disord. · Pubmed #18602856 No free full text.

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are an important cause of late-onset, familial and sporadic Parkinson's disease. LRRK2 is a large unique protein containing both GTPase and kinase enzymatic domains together with multiple protein-protein interaction domains. LRRK2 initially appears to function as a GTPase-regulated protein kinase. The majority of pathogenic mutations lead to enhanced kinase activity of LRRK2. Disease-associated mutations in LRRK2 also promote the formation of cytoplasmic inclusions and induce neuronal toxicity in cultured cells in a kinase-dependent manner. These and other important aspects of LRRK2 biology and pathophysiology are discussed in detail in this review.

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.

Weiner WJ. · Department of Neurology, Maryland Parkinson's Disease and Movement Disorders Center, University of Maryland School of Medicine, 22 S Greene St, N4W46, Baltimore, MD 21201, USA. · Arch Neurol. · Pubmed #18541790 links to  free full text

Abstract: The term Parkinson disease defines a specific clinical condition characterized by a typical history and characteristic signs. This review examines the historical evolution of the concept of Parkinson disease and how the misunderstanding of Parkinson disease may be hindering clinical research trials. It is proposed that this syndrome be called Parkinson diseases or parkinsonism type 1 through infinity.

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.

Yang JL, Weissman L, Bohr VA, Mattson MP. · Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. · DNA Repair (Amst). · Pubmed #18463003 links to  free full text

Abstract: By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders-Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.

Martin LJ. · Department of Pathology, Division of Neuropathology, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. · J Neuropathol Exp Neurol. · Pubmed #18431258 links to  free full text

Abstract: DNA damage is a form of cell stress and injury that has been implicated in the pathogenesis of many neurologic disorders, including amyotrophic lateral sclerosis, Alzheimer disease, Down syndrome, Parkinson disease, cerebral ischemia, and head trauma. However, most data reveal only associations, and the role for DNA damage in direct mechanisms of neurodegeneration is vague with respect to being a definitive upstream cause of neuron cell death, rather than a consequence of the degeneration. Although neurons seem inclined to develop DNA damage during oxidative stress, most of the existing work on DNA damage and repair mechanisms has been done in the context of cancer biology using cycling nonneuronal cells but not nondividing (i.e. postmitotic) neurons. Nevertheless, the identification of mutations in genes that encode proteins that function in DNA repair and DNA damage response in human hereditary DNA repair deficiency syndromes and ataxic disorders is establishing a mechanistic precedent that clearly links DNA damage and DNA repair abnormalities with progressive neurodegeneration. This review summarizes DNA damage and repair mechanisms and their potential relevance to the evolution of degeneration in postmitotic neurons.

Niedermeyer E. · Sinai Hospital, Division of Neurology, Baltimore, Maryland, USA. · Clin EEG Neurosci. · Pubmed #18318418 No free full text.

Abstract: A report of severe akinetic episodes in patients with Parkinson disease (PD) has been the stimulus for the following discussion of akinesia and its variants. Severe persistent akinesia may occur in frontal lobe impairment. Therefore, it is likely that extension of the Parkinsonian dysfunction into the frontal lobe causes severe akinesia which should be separated from the very common Parkinsonian hypokinesia. Another very common clinical phenomenon of PD is sudden freezing. Hence the frontal lobe--hardly regarded as a region of special interest in the realm of PD--can be the cause of severe and dangerous complications of PD. The term "arrest reaction" or "motor arrest" denotes a similar freezing. It is recommended to restrict these terms to certain forms of frontal lobe epilepsy. This discussion of hypokinetic and akinetic states should also include catatonia: a form of schizophrenia with a special type of akinesia. Though without major neuropathological substratum, this condition can, in extremely rare cases, lead to severe hyperthermia and fatal outcome (presumably via hypothalamic dysfunction).

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.

Ross CA, Smith WW. · Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Parkinsonism Relat Disord. · Pubmed #18267256 No free full text.

Abstract: PD is the second most common neurodegenerative disease, and affects 5% of the population by the age of 85. PD is a multi-factorial disease with a complex etiology including genetic risk factors, environmental exposure and aging. The pathogenesis is not fully understood. Here we review research on the genetic and environmental causes of PD and the current research models. None of the single models replicate all the features of PD. Genetic models (possibly including more than one mutation) in combination with toxins or other environmental manipulation may provide better models of PD pathogenesis.

Dawson TM. · Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Parkinsonism Relat Disord. · Pubmed #18267244 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic neurons leading to bradykinesia, rest tremor and rigidity. Although the majority of PD is sporadic, rare genetic causes of PD are providing tremendous insight into the pathogenesis of PD. Here I shortly review the major genes implicated in autosomal dominant and autosomal recessive PD. Understanding how mutations in these PD associated genes holds particular promise for development of new therapies to treat 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.

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.

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.