Parkinson Disease: Texas

Madhusoodanan KS, Murad F. · The Brown Foundation Institute of Molecular Medicine, University of Texas Houston Health Science Center, 1825 Pressler Street, Houston, TX 77030, USA. · Neurochem Res. · Pubmed #17043768 No free full text.

Abstract: Nitric oxide (NO) is a short lived diatomic free radical species synthesized by nitric oxide synthases (NOS). The physiological roles of NO depend on its local concentrations as well as availability and the nature of downstream target molecules. At low nanomolar concentrations, activation of soluble guanylyl cyclase (sGC) is the major event initiated by NO. The resulting elevation in the intracellular cyclic GMP (cGMP) levels serves as signals for regulating diverse cellular and physiological processes. The participation of NO and cGMP in diverse physiological processes is made possible through cell type specific spatio-temporal regulation of NO and cGMP synthesis and signal diversity downstream of cGMP achieved through specific target selection. Thus cyclic GMP directly regulates the activities of its downstream effectors such as Protein Kinase G (PKG), Cyclic Nucleotide Gated channels (CNG) and Cyclic nucleotide phosphodiesterases, which in turn regulate the activities of a number of proteins that are involved in regulating diverse cellular and physiological processes. Localization and activity of the NO-cGMP signaling pathway components are regulated by G-protein coupled receptors, receptor and non receptor tyrosine kinases, phosphatases and other signaling molecules. NO also serves as a powerful paracrine factor. At micromolar concentrations, NO reacts with superoxide anion to form reactive peroxinitrite, thereby leading to the oxidation of important cellular proteins. Extensive research efforts over the past two decades have shown that NO is an important modulator of axon outgrowth and guidance, synaptic plasticity, neural precursor proliferation as well as neuronal survival. Excessive NO production as that evoked by inflammatory signals has been identified as one of the major causative reasons for the pathogenesis of a number of neurodegenerative diseases such as ALS, Alzheimers and Parkinson diseases. Regenerative therapies involving transplantation of embryonic stem cells (ES cells) and ES cell derived lineage committed neural precursor cells have recently shown promising results in animal models of Parkinson disease (PD). Recent studies from our laboratory have shown that a functional NO-cGMP signaling system is operative early during the differentiation of embryonic stem cells. The cell type specific, spatio-temporally regulated NO-cGMP signaling pathways are well suited for inductive signals to use them for important cell fate decision making and lineage commitment processes. We believe that manipulating the NO-cGMP signaling system will be an important tool for large scale generation of lineage committed precursor cells to be used for regenerative therapies.

Shahed J, Jankovic J. · Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, 6550 Fannin, Suite 1801, Houston, TX, USA. · Parkinsonism Relat Disord. · Pubmed #16887374 No free full text.

Abstract: Although essential tremor (ET) and Parkinson's disease (PD) are considered distinct disorders, there is overlap in some clinical features. In some PD patients, a long-standing postural tremor in the hands may precede the onset of parkinsonian features by several years or decades. Furthermore, large families with both ET and PD phenotypes have been described and autopsy studies have demonstrated Lewy body pathology in brains of ET patients. Functional neuroimaging suggests that some ET patients have dopaminergic deficit. We examine here the evidence for and against an association between ET and PD, and critically review data supporting the notion that a subset of ET patients is predisposed to developing PD.

Jankovic J. · Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, The Smith Tower, Suite 1801, 6550 Fannin, Houston, TX 77030, USA. · Mt Sinai J Med. · Pubmed #16878274 links to  free full text

Abstract: Although levodopa remains the most effective symptomatic drug for Parkinson's disease (PD), its use is limited by the emergence of motor fluctuations and dyskinesias, particularly in young-onset patients. Dopamine agonists, catechol-O-methyltransferasee inhibitors and other anti-parkinsonian drugs have been found to diminish or prevent these complications and possibly to exert disease-modifying effects. The finding that the subthalamic nucleus (STN) and the globus pallidum internus (GPi) are abnormally active in PD has led to effective surgical treatments designed to improve patients' quality of life. The relative benefits of targeting STN or GPi with high-frequency stimulation are still being debated. Experimental therapeutics of PD include novel delivery systems, anti-apoptotic strategies and implantation of genetically engineered cells, and stem cells. Despite encouraging results from early pre-clinical and clinical studies, trials of human fetal grafts and intraventricular and intraparenchymal infusion of glial cell-line-derived neurotrophic factor have not shown clinically meaningful benefits. Future therapeutic strategies should focus not only on ameliorating the symptoms of PD, but also on neuroprotective or neurorescue therapies that can favorably modify the natural course of the disease and slow the progression of both motor and nonmotor manifestations of PD.

Trail M, Fox C, Ramig LO, Sapir S, Howard J, Lai EC. · Parkinson's Disease Research, Education and Clinical Center, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA. · NeuroRehabilitation. · Pubmed #16340101 No free full text.

Abstract: Researchers estimate that 89% of people with Parkinson's disease (PD) have a speech or voice disorder including disorders of laryngeal, respiratory, and articulatory function. Despite the high incidence of speech and voice impairment, studies suggest that only 3-4% of people with PD receive speech treatment. The authors review the literature on the characteristics and features of speech and voice disorders in people with PD, the types of treatment techniques available, including medical, surgical, and behavioral therapies, and provide recommendations for the current efficacy of treatment interventions and directions of future research.

Jankovic J, Chen S, Le WD. · Department of Neurology, Parkinson Disease Research Lab, Baylor College of Medicine, Houston, TX 77030, USA. · Prog Neurobiol. · Pubmed #16243425 No free full text.

Abstract: Nurr1, a transcription factor belonging to the orphan nuclear receptor superfamily, is critical in the development and maintenance of the dopaminergic system and as such it may have role in the pathogenesis of Parkinson' disease (PD). Human Nurr1 gene has been mapped to chromosome 2q22-23 and Nurr1 protein is predominantly expressed in central dopaminergic neurons. Nurr1 interacts with other factors critical for the survival of mensencephalic dopaminergic neurons and it appears to regulate the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and l-aromatic amino acid decarboxylase (AADC), all of which are important in the synthesis and storage of dopamine. Experimental studies in Nurr1 knock-out mice indicate that Nurr1 deficiency results in impaired dopaminergic function and increased vulnerability of those midbrain dopaminergic neurons that degenerate in PD. Decreased Nurr1 expression is found in the autopsied PD midbrains, particularly in neurons containing Lewy bodies, as well as in peripheral lymphocytes of patients with parkinsonian disorders. Several variants in Nurr1 gene have been reported in association with PD. All these studies suggest that Nurr1 is not only essential in the development of mensencephalic dopaminergic neurons and maintenance of their functions, but it may also play a role in the pathogenesis of PD.

Veazey C, Aki SO, Cook KF, Lai EC, Kunik ME. · Houston Center for Quality of Care and Utilization Studies, Veterans Affairs Medical Center (152), 2002 Holcombe Blvd., Houston, TX 77030, USA. · J Neuropsychiatry Clin Neurosci. · Pubmed #16179652 links to  free full text

Abstract: Parkinson's disease (PD) is a progressive neurological condition with debilitating symptoms, and depression is a common comorbid condition of this disease. The authors review existing literature on the prevalence and treatment of depression in PD. Prevalence estimates of depression vary widely, ranging from 7%-76%. This variation is due to inconsistent methodology. Treatment options for depression in PD include medication therapy, electroconvulsive therapy (ECT), and psychotherapy. There are few randomized controlled trials of these treatment options. The authors argue for more systematic and controlled research examining both the prevalence and treatment of depression in PD.

Diamond A, Jankovic J. · Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, 6550 Fannin Street, Suite 1801, Houston, TX 77030, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #16107348 links to  free full text

Abstract: Deep brain stimulation (DBS) is a viable treatment alternative for patients with Parkinson's disease (PD), essential tremor (ET), dystonia, and cerebellar outflow tremors. When poorly controlled, these disorders have detrimental effects on the patient's health related quality of life (HRQoL). Instruments that measure HRQoL are useful tools to assess burden of disease and the impact of therapeutic interventions on activities of daily living, employment, and other functions. We systematically and critically reviewed the literature on the effects of DBS on HRQoL in PD, ET, dystonia, and cerebellar outflow tremor related to multiple sclerosis.

Gildenberg PL. · Baylor Medical College, Houston Stereotactic Concepts, Houston, TX 77030, USA. · Stereotact Funct Neurosurg. · Pubmed #16006778 No free full text.

Abstract: Neuromodulation, as defined as the use of electrical stimulation by implanted stimulators to treat various neurological conditions, has developed gradually from long experience with electrical stimulation of the nervous system. Indications are still evolving, and the field is advancing at an ever increasing rate.

Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Neurology. · Pubmed #15985567 No free full text.

Abstract: Research into the causes of Parkinson disease (PD) has accelerated recently with the discovery of novel gene mutations. The majority of PD cases, however, remain idiopathic and in those cases environmental causes should be considered. Several recent reports have focused on welding and manganese toxicity as potential risk factors for parkinsonism and some have even proposed that welding is a risk factor for PD. The controversy has stimulated this review, the primary aim of which is to critically and objectively examine the evidence or lack of evidence for a relationship among welding, manganese, parkinsonism, and PD.

Ashour R, Tintner R, Jankovic J. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Lancet Neurol. · Pubmed #15963445 No free full text.

Abstract: Striatal deformities of the hand and foot are abnormal postures that are common in patients with advanced Parkinson's disease (PD); they can present in the early stages of PD and in other parkinsonian disorders. Over a century ago, Charcot and Purves-Stewart recognised these deformities, which cause substantial functional disability and discomfort. The term striatal is used because pathology in the neostriatum (putamen and caudate) has been suggested to cause the deformities, but the pathogenesis is unknown. Misdiagnosis of the deformities is common-particularly when they occur early and in the absence of cardinal parkinsonian signs, such as tremor, bradykinesia, and rigidity-because the hand deformities are similar to those in rheumatoid arthritis, equinovarus foot deformity typically suggests an orthopaedic problem, and toe extension may be thought to be the Babinski sign of upper-motor-neuron syndromes. Here we review the background and clinical features of these deformities to highlight these commonly unrecognised and poorly understood parkinsonian signs.

Stewart RM, Desaloms JM, Sanghera MK. · Human Performance Lab, Presbyterian Hospital of Dallas, Jackson Building, 8200 Walnut Hill Lane, Dallas, TX 75231, USA. · J Neurosci Nurs. · Pubmed #15902954 No free full text.

Abstract: High-frequency stimulation of the subthalamic nucleus is a neurosurgical procedure for the alleviation of motor symptoms of Parkinson's disease and debilitating medication-induced dyskinesias. Stimulation is achieved with electrodes implanted stereotactically in the subthalamic nucleus by a neurosurgeon specializing in stereotactic surgery and a team composed of an anesthesiologist, a neurophysiologist, certified nurses and nurse practitioners and, at some centers, a neurologist. The teamwork continues in the recovery room and the intensive care unit, where the patient may experience transient adverse behavioral effects. Two weeks after surgery, the neurostimulator is activated and programmed. The medications also are adjusted to complement stimulation to maximize the therapeutic effects and minimize the stimulation-induced side effects. For those patients who are deconditioned or have major speech, gait, or balance problems, rehabilitation therapy is employed.

Everse J, Coates PW. · Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. · Free Radic Biol Med. · Pubmed #15855048 No free full text.

Abstract: Extensive research has been done to elucidate the underlying molecular events causing neurodegenerative diseases such as Parkinson disease, yet the cause and the individual steps in the progression of such diseases are still unknown. Here we advance the hypothesis that, rather than or in addition to inorganic radical molecules, heme-containing peroxidase enzymes may play a major role in the etiology of Parkinson disease. This hypothesis is based on the following considerations: (1) several heme-containing enzymes with peroxidase activity are present in the substantia nigra pars compacta; (2) these peroxidases have the ability to catalyze the oxidation of proteins and lipids; (3) certain heme peroxidases are known to destroy cells in vivo; (4) heme peroxidases have the stability and specificity that could account for the fact that specific molecules and cells are subject to damage in Parkinson disease, rather than a random destruction; (5) heme peroxidase activity could account for certain reactions in connection with parkinsonism that thus far have not been adequately explained; and (6) the participation of a heme peroxidase could explain some recent observations that are inconsistent with the oxyradical theory. The peroxidase-catalyzed oxidative pathway proposed here does not preclude the participation of apoptosis as an additional mechanism for cell destruction.

Jankovic J. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. · Mov Disord. · Pubmed #15822109 No free full text.

Abstract: Fluctuations in the symptoms of Parkinson's disease (PD), such as wearing-off and on-off effects, and dyskinesias are related to a variety of factors, including duration and dosage of levodopa, age at onset, stress, sleep, food intake, and other pharmacokinetic and pharmacodynamic mechanisms. The majority of patients, particularly those with young onset of PD, experience these levodopa-related adverse effects after a few years of treatment. Assessment of these motor complications is difficult because of the marked clinical variability between and within patients. Daily diaries have been used in clinical trials designed to assess the effects of various pharmacological and surgical interventions on motor fluctuations and dyskinesias. The most common type of dyskinesia, called "peak-dose dyskinesia", usually consists of stereotypical choreic or ballistic movements involving the head, trunk, and limbs, and occasionally, the respiratory muscles, whereas tremor and punding are less-common complications. Dystonia is also typically seen in patients with diphasic dyskinesia and wearing-off effect. Recognition of the full spectrum of clinical phenomenology of levodopa-related motor complications is essential for their treatment and prevention.

Sanghera MK, Desaloms JM, Stewart RM. · Presbyterian Hospital of Dallas, Dallas, TX, USA. · J Neurosci Nurs. · Pubmed #15673205 No free full text.

Abstract: Parkinson's disease (PD) is a debilitating neurodegenerative disorder affecting more than 1.2 million people in the United States. Genetic and environmental toxins are believed to be risk factors in acquiring the disease. PD is characterized by tremors, rigidity, bradykinesia, poor gait, and postural instability. These cardinal symptoms improve with medication such a levo-dopa (L-dopa). However, over time, as the disease progresses, the patient becomes refractory to medication, or medication produces debilitating side effects. When this occurs or when there are worsening of symptoms, neurosurgical treatment is recommended, particularly deep brain stimulating (DBS) electrodes implanted in the subcortical subthalamic nucleus (STN). Over the last 5 years STN DBS has gained acceptance and become the neurosurgical treatment of choice for PD. To achieve maximum beneficial effects with minimum adverse effects from the surgery, the expertise of an integrated team of physicians and nurses is essential. A clear understanding of the different aspects of the procedure, including the risks and benefits of the treatment, assists neuroscience nurses in communicating with the PD patient, and providing the most appropriate, knowledge-based pre- and postoperative care.

Chen Q, He Y, Yang K. · Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA. · Curr Gene Ther. · Pubmed #15638712 No free full text.

Abstract: Therapy for Parkinson's disease (PD), a common neurological disorder characterized by pathological degeneration of the nigrostriatal dopaminergic system, remains unsatisfactory. Gene therapy is considered one of the most promising approaches to developing a novel effective treatment for PD. Among the numerous candidate genes that have been tested as therapeutic agents, those encoding tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I and aromatic L-amino acid decarboxylase all boost dopamine production, while glial cell line-derived neurotrophic factor promotes the survival of dopaminergic neurons and is generally believed to possess the greatest potential for successful restoration of the dopaminergic system. The genes encoding vesicular monoamine transporter-2 and glutamic acid decarboxylase have also produced therapeutic effects in animal models of PD. Both viral and non-viral vectors, each with its particular advantages and disadvantages, have been used to deliver these genes into the brain. Whether or not regulatable expression systems are essential to successful gene therapy for PD remains a critical issue in the clinical application of this emerging treatment. Here we review the current status of gene therapy for PD, including the application of control systems for transgene expression in the brain.

Rachakonda V, Pan TH, LE WD. · Department of Neurology, Baylor College of Medicine, Houston, TX, USA. · Cell Res. · Pubmed #15538967 links to  free full text

Abstract: Biomarkers are very important indicators of normal and abnormal biological processes. Specific changes in pathologies, biochemistries and genetics can give us comprehensive information regarding the nature of any particular disease. A good biomarker should be precise and reliable, distinguishable between normal and interested disease, and differential between different diseases. It is believed that biomarkers have great potential in predicting chances for diseases, aiding in early diagnosis, and setting standards for the development of new remedies to treat diseases. New technologies have enabled scientists to identify biomarkers of several different neurodegenerative diseases. The followings, for instance, are only a few of the many new biomarkers that have been recently identified: the phosphorylated tau protein and aggregated Beta-amyloid peptide for Alzheimer's disease (AD), Alpha-synuclein contained Lewy bodies and altered dopamine transporter (DAT) imaging for Parkinson's disease (PD), SOD mutations for familial amyotrophic lateral sclerosis (ALS), and CAG repeats resulted from Huntington's gene mutations in Huntington's disease (HD). This article will focus on the most-recent findings of biomarkers belonging to the four mentioned neurodegenerative diseases.

Woodlee MT, Schallert T. · Institute for Neuroscience, The University of Texas at Austin, Austin, TX 78712, USA. · Restor Neurol Neurosci. · Pubmed #15502262 No free full text.

Abstract: The effects of extreme disuse or overuse of the limbs in rat models of Parkinson's disease and stroke are discussed. In unilaterally lesioned rats, immobilizing one forelimb in a cast forces complete disuse of this limb and extreme overuse of the uncasted limb. This procedure has diverse effects on histological and behavioral outcomes in these models, depending upon how and when it is applied relative to the lesion. Effects on behavioral outcome, post-lesion plasticity events, and expression of trophic factors are discussed. The effects of forced disuse or overuse vary among lesion types and can include neuroprotection, changes in synaptogenesis, or even exaggeration of tissue loss. The diversity of behavior-driven structural changes in the brain underscores the potential importance of carefully tailoring physical restorative therapy to specific neurological problems in order to optimize outcomes. In addition, we stress the need to recognize the reciprocal influence that behavior and the brain can have upon each other.

Dewey RB. · Department of Neurology, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. · Neurol Clin. · Pubmed #15501361 No free full text.

This publication has no abstract.

Jiang YH, Beaudet AL. · Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. · Curr Opin Pediatr. · Pubmed #15273504 No free full text.

Abstract: PURPOSE OF REVIEW: The goal of this review is to provide an overview of rapidly evolving information on a new group of genetic inborn errors affecting ubiquitination and proteasomal degradation of proteins and to suggest a classification scheme for these disorders. The relevant genes encode ubiquitin, ubiquitin enzymes (E1 and many E2s and E3s), deubiquitinating enzymes, proteasomal subunits, and substrates undergoing ubiquitination. RECENT FINDINGS: Since the initial recognition that Angelman syndrome is caused by maternal deficiency of the E6-AP ubiquitin E3 ligase (gene symbol UBE3A), several. other disorders of E3 ligases have been identified, including autosomal recessive juvenile Parkinson disease, the APECED form of autoimmune polyendocrinopathy syndrome, von Hippel-Lindau syndrome, and congenital polycythemia. Disorders that disturb ubiquitin regulatory signaling include at least two subtypes of Fanconi anemia, the BRCA1 and BRCA2 forms of breast and ovarian cancer susceptibility, incontinentia pigmenti, and cylindromatosis. Many disorders affect ubiquitin pathways secondarily. SUMMARY: The authors propose both a genetic and a functional classification for disorders of ubiquitination and proteasomal degradation, as follows. Genetic classes include mutations in (1) the UBB ubiquitin gene; (2) enzymes of ubiquitination including E1, E2, E3, and related proteins; (3) deubiquitinases; (4) proteasomal subunits; and (5) substrates of ubiquitination. Functional classes include defects in (1) proteolytic degradation, (2) ubiquitin signaling, and (3) subcellular localization of substrates. Additional functional classes are likely to be defined, and individual disorders may involve multiple functional defects.

Martinelli PT, Schulze KE, Nelson BR. · Department of Dermatology, Baylor College of Medicine, Houston, Texas 77030, USA. · Dermatol Surg. · Pubmed #15209793 No free full text.

Abstract: BACKGROUND: Implantable electrical devices are becoming increasingly common in the patient population presenting for Mohs micrographic surgery. In addition to understanding the potential intraoperative complications with implantable cardioverter-defibrillators and pacemakers, the Mohs surgeon needs to be aware of the relatively new treatment of movement disorders using implanted deep brain stimulators. OBJECTIVE: We present only the second reported case of Mohs surgery in a patient with a deep brain stimulator. In an attempt to help minimize adverse events during a procedure, we review the more commonly encountered electrical devices as well as the newer deep brain stimulators. We provide guidelines for the avoidance of electromagnetic interference during an electrosurgical procedure. METHODS: This 76-year-old patient with Parkinson's disease and an implanted deep brain stimulator underwent Mohs surgery for excision of a squamous cell carcinoma on the ear. In an attempt to minimize electromagnetic interference with his implanted device, hemostasis was obtained with the aid of a battery-operated heat-generating handheld electrocautery device. RESULTS: The patient tolerated the procedure well without complications or reports of discomfort. CONCLUSION: Patients with implanted electrical devices are subject to electromagnetic interference during an electrosurgical procedure. Care must be taken in this expanding patient population during a Mohs surgical procedure.

McClure SM, York MK, Montague PR. · Human Neuroimaging Lab, Center for Theoretical Neuroscience, Division of Neuroscience, Baylor College of Medicine, Houston, Texas, USA. · Neuroscientist. · Pubmed #15155064 No free full text.

Abstract: Experimental work in animals has identified numerous neural structures involved in reward processing and reward-dependent learning. Until recently, this work provided the primary basis for speculations about the neural substrates of human reward processing. The widespread use of neuroimaging technology has changed this situation dramatically over the past decade through the use of PET and fMRI. Here, the authors focus on the role played by fMRI studies, where recent work has replicated the animal results in human subjects and has extended the view of putative reward-processing neural structures. In particular, fMRI work has identified a set of reward-related brain structures including the orbitofrontal cortex, amygdala, ventral striatum, and medial prefrontal cortex. Moreover, the human experiments have probed the dependence of human reward responses on learned expectations, context, timing, and the reward dimension. Current experiments aim to assess the function of human reward-processing structures to determine how they allow us to predict, assess, and act in response to rewards. The authors review current accomplishments in the study of human reward processing and focus their discussion on explanations directed particularly at the role played by the ventral striatum. They discuss how these findings may contribute to a better understanding of deficits associated with Parkinson's disease.

Dewey RB. · Department of Neurology, UT Southwestern Medical Center, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, Dallas, TX 75390-9036, USA. · Neurology. · Pubmed #15037664 No free full text.

Abstract: Motor fluctuations in Parkinson's disease (PD) typically develop after 4-6 years of therapy, and affect approximately half of all patients. The wearing-off effect is the most common type, and "delayed-on," "no-on," and "on-off" effects, as well as dyskinesias, may also develop as the disease progresses. Collectively, motor fluctuations represent a significant source of disability in advanced PD patients, and their mitigation is a major goal of patient management. Adjunctive medications, including dopamine agonists, amantadine, MAO-B inhibitors, and COMT inhibitors, each may reduce the frequency or duration of "off" periods, but none does so completely, and each contributes its own side effects which may limit optimal dosing. Surgery is another strategy to reduce "off" time, and both pallidotomy and deep brain stimulation of the globus pallidus or the subthalamic nucleus have been shown to be highly effective in this regard. However, surgery may be contraindicated in elderly advanced patients who could most benefit from its effect on "off" time. The unmet need for treatment of "off" episodes suggests the potential utility of an agent such as apomorphine injectable, which can reliably trigger an "on" response within 10-15 minutes of injection.

Le W, Appel SH. · Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Curr Opin Pharmacol. · Pubmed #15018843 No free full text.

Abstract: Recent progress has documented the presence of at least 10 disease-related genes or loci linked to Parkinson's disease. Analysis of the genotypes and phenotypes of these mutant genes has revealed a broad spectrum of clinical and pathological presentations, many of which share a common feature of alteration in the ubiquitin proteasome system. Further understanding of the pathogenesis of these inherited cases of Parkinson's disease and development of transgenic animal models bearing these mutations should provide novel insight into the causes of nigral cell death and meaningful strategies for future therapy.

Thomas M, Le WD. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Curr Pharm Des. · Pubmed #14965330 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by cardinal features of tremor, bradykinesia, rigidity and postural instability. In addition to the motor symptoms patients experience cognitive decline eventually resulting in severe disability. Pathologically PD is characterized by neurodegeneration in the substantia nigra pars compacta (SNc) with intracytoplasmic inclusions known as Lewy bodies. In addition to the SNc there is neurodegeneration in other areas including cerebral cortex, raphe nuclei, locus ceruleus, nucleus basalis of meynert, cranial nerves and autonomic nervous system. Recent evidence supports the role of inflammation in Parkinson's disease. Apoptosis has been shown to be one of the pathways of cell death in PD. Minocycline, a tetracycline derivative is a caspase inhibitor, and also inhibits the inducible nitric oxide synthase which are important for apoptotic cell death. Furthermore, Minocycline has been shown to block microglial activation of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonism animal models and protect against nigrostriatal dopaminergic neurodegeneration. In this review, we present the current experimental evidence for the potential use of tetracycline derivative, minocycline, as a neuroprotective agent in PD.

Harris ED. · Department of Biochemistry and Biophysics, Faculty of Nutrition, Texas A&M University, College Station, Texas 77843-2128, USA. · Crit Rev Clin Lab Sci. · Pubmed #14653357 No free full text.

Abstract: An oxygen-rich atmosphere obligated living organisms to cope with reactive oxygen species (O2-, H2O2, OH*) that were the unavoidable by-products of cellular metabolism. As a redox cofactor Cu was selected as a co-catalyst for numerous biological processes, many involving the utilization of oxygen. Inadequate or excessive intake of Cu can be pathogenic and life-threatening. Mutations to genes that code for Cu-transporting ATPase enzymes are the molecular basis of Wilson and Menkes diseases and more recently Cu has been identified as a preemptory factor in amyloid and prion diseases. This review is dedicated to bringing historical and timely information on Cu transport, metabolism and homeostasis to the attention of those not familiar with this important mineral. Other comprehensive reviews are available to the interested readers.