What is Parkinsons Disease

The Parkinson's-Reversing Breakthrough

The Parkinson's Breakthrough Program entails the most effective and natural strategies people can use to heal the root cause of Parkinson's Disease. It is a digital manual aimed at showing the users the most effective method for overcoming Parkinson's without high-priced prescription drugs riddled with harmful side effects.The program was not created to be a quick fix. In fact, like different programs, it is tasking. Yet, you will not have to spend a lot of time dealing with it. The system requires your full attention, perseverance, and discipline. For the period of its usage, you will have the opportunity to use to eat some food ingredients that will detoxify you.The methods employed in this book are natural ones that have been proven by many specialists. The users will be privy to what to do and what not to do to treat the underlying root cause of their Parkinson's and the way they can reverse the symptoms naturally and effectively. The system comes with bonus E-books- Lessons from The Miracle Doctors, Mind Control in the USA', and 10 Deadly Health Myths of The 21st Century. The book is in a digital format (PDF) and has been created at a very affordable price. Read more here...

The ParkinsonsReversing Breakthrough Summary


4.7 stars out of 13 votes

Contents: Ebook
Author: Matt Traverso
Official Website: www.parkinsons-disease-cure.com
Price: $47.00

Access Now

My The ParkinsonsReversing Breakthrough Review

Highly Recommended

Recently several visitors of websites have asked me about this book, which is being promoted quite widely across the Internet. So I ordered a copy myself to figure out what all the publicity was about.

Do not wait and continue to order The Parkinson's-Reversing Breakthrough today. If anytime, within Two Months, you feel it was not for you, they’ll give you a 100% refund.

Content Carbidopa Levodopa

Each 10 100 tablet contains carbi-dopa, 10 mg, and levodopa, 100 mg. Each 25 100 tablets contains carbido-pa, 25 mg, and levodopa, 100 mg. Each 25 250 tablet contains carbi-dopa, 25 mg, and levodopa, 250 mg. Each sustained-release tablet contains carbidopa, 50 mg, and levodo-pa, 200 mg. (breakdown) of levodopa. Since peripheral decarboxylation is inhibited, this allows more levodopa to be available for transport to the brain, where it will be converted to dopa-mine, thus relieving the symptoms of parkinsonism. It is recommended that both carbidopa and levodopa be given together (e.g., Sinemet). However, the dosage of levodopa must be reduced by up to 80 when combined with carbidopa. This decreases the incidence of levodopa-induced side effects. NOTE Pyridox-ine will not reverse the action of car-bidopa levodopa. tv2, carbidopa 1-2 hr when given with levodopa, the t1 2 of levodopa increases from 1 hr to 2 hr (may be as high as 15 hr in some clients). About 30 carbidopa is excreted...

Evidence for Apoptosis in Parkinsons Disease

Parkinson's disease (PD) has been classically considered a predominantly environmentally related disorder with known etiologies, including MPTP toxin exposure, carbon monoxide exposure, postencephalitic related (1919 epidemic), manganese exposure, and other putative chemical exposures involving injury to mitochondrial complex I enzymes. Nevertheless, most cases are idiopathic without demonstrable etiology, and clearly some cases are genetically influenced. The knowledge that PD is related to progressive dopaminergic cell loss in the substantia nigra with symptomatology usually appearing at 80 to 90 cell depletion and the evidence connecting Parkin-sonism to environmental exposures has led to an oxidative stress theory for the pathogenesis of PD and an emphasis on apoptosis as a possible mechanism of cell loss.109110 Evidence for apoptosis in Parkinson's disease has been provided from both animal models and human material for the key cell population at risk, the dopaminergic neurons of...

Proposed Diagnostic Criteria for Parkinsons Disease

Group A Characteristic of Parkinson's disease iii. Documentation of a lesion or condition associated with parkinsonism and plausibly connected to the patient's symptom (e.g., focal brain lesion or recent neuroleptic exposure). II. Possible Parkinson's disease C. Either substantial and sustained response to levodopa or a dopamine agonist has been documented Or Patient has not had an adequate trial of levodopa or a dopamine agonist. III. Probable Parkinson's disease C. Substantial and sustained response to levodopa or a dopamine agonist has been documented. IV. Definite Parkinson's disease A. All criteria for possible or probable Parkinson's disease are met And Adapted with permission from Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson's disease. Arch Neurol 1999 56 33-39.

Differential Diagnosis of Parkinsonism

Parkinson's disease is a progressive neurological disease with the following clinical characteristics. Asymmetric findings Levodopa response dyskinesia Lewy bodies The clinical heterogeneity of Parkinson's disease makes it difficult to differentiate it from other parkinsonian disorders based on the clinical criteria alone. The pathological examination may prove the diagnosis of Parkinson's disease wrong in 10 -15 of patients. Pathologically, Lewy bodies are present in pigmented neurons of the substantia nigra and other central nervous system areas. There is a therapeutic response to levodopa, which tends to support the diagnosis of Parkinson's disease (in over 77 of patients the response is good or excellent ), but the drug cannot be used to differentiate reliably between Parkinson's disease from other parkinsonian disorders.

Substantia Nigra Neurons

Leslie Iversen

Although Dale offered a very good lead in the peripheral nervous system to search for putative transmitters released from dendritic processes, it was the central nervous system which offered us the first unequivocal example of such a phenomenon. A great deal of this is due to the cytoarchitecture of the substantia nigra (SN) dopaminergic cell neurons. The majority of their cell bodies are neatly packed in the SN pars compacta, and their axonal processes project dorsally and rostrally toward the neostriatum (caudate and putamen, Ungerstedt, 1971), while their long, branched dendrites radiate profusely through the pars reticulata. This description of the SN dopaminergic neurons corresponds well with Ramon y Cajal's (1904) description The Golgi method shows these neurons to have different shapes, predominantly triangular and provided with very long, shaggy and discretely divided dendrites, which expand throughout almost all the nucleus (meaning the area) . The identification of dopamine...

Antiparkinson Agents

Carbidopa Levodopa Diphenhydramine hydrochloride Levodopa Pergolide mesylate Pramipexole Ropinirole hydrochloride Selegiline hydrochloride Trihexyphenidyl hydrochloride General Statement Parkinson's disease is a progressive disorder of the nervous system, affecting mostly people over the age of 50. Parkinson-ism is a frequent side effect of certain antipsychotic drugs, including pro-chlorperazine, chlorpromazine, and reserpine. Drug-induced symptoms usually disappear when the responsible agent is discontinued. The cause of Parkinson's disease is unknown however, it is associated with a depletion of the neurotransmit-ter dopamine in the nervous system. Administration of levodopa the precursor of dopamine relieves symptoms in 75 -80 of the clients. Anticholinergic agents also have a beneficial effect by reducing tremors and rigidity and improving mobility, muscular coordination, and motor performance. They are often administered together with levodopa. Certain antihistamines, notably...

Parkinsons Disease

Albanese A, Diagnostic criteria for Parkinson's disease. Neurol Sci, 2003 24 S23-S26. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson's disease. Arch Neurol 1999 56 33-39. Hedera P, Lerner AJ, Castellani R, Friedland RP. Concurrence of Alzheimer's disease, Parkinson's disease, diffuse Lewy body disease, and amyotrophic lateral sclerosis. J Neurol Sci 1995 128 219-224. Riley DE, Chelimsky TC. Autonomic nervous system testing may not distinguish multiple system atrophy from Parkinson's disease. J Neurol Neurosurg Psychiatry 2003 74 56-60.

Current Clinical Neurology

Attarian, 2006 Psychiatry for Neurologists, edited by Dilip V. Jeste and Joseph H. Friedman, 2006 Status Epilepticus A Clinical Perspective, edited by Frank W. Drislane, 2005 Thrombolytic Therapy for Acute Stroke, Second Edition, edited by Patrick D. Lyden, 2005 Parkinson's Disease and Nonmotor Dysfunction, edited by Ronald F. Pfeiffer Robert H. Paul, Ronald Cohen, Brian R. Ott, and Stephen Salloway, 2005 Atypical Parkinsonian Disorders Clinical and Research Aspects, edited by Irene Litvan, 2005 Handbook of Neurocritical Care, edited by Anish Bhardwaj, Marek A. Mirski, and Michael Benatar, 2003 Surgical Treatment of Parkinson's Disease and Other Movement Disorders, edited by

Social Cost and Market

Various projections indicate that sales of drugs to treat neurological diseases alone will approach 20 billion by 2007 reflecting an absence of effective treatments for AD and the use of generic L-dopa as first-line treatment for Parkinson's disease. Drugs for the treatment of psychiatric disorders represent a much larger market with sales of the selective 5HT reuptake inhibitor (SSRI) class of antidepressants currently in the 10 billion range. Together the current market for CNS drugs is in excess of 70 billion. Should effective drugs be identified for the treatment of AD, this will account for an additional 6-8 billion in sales given the incidence of these diseases and their long-term nature. At the decade beginning in 2001, the global CNS drug market (including pain) was approximately 50 billion1 with estimates of 105 billion in 2005, 200 billion in 2010, and one estimate2 approaching 1.2 trillion.

Central Nervous System Disorders Psychiatric and Neurodegenerative

Neurodegenerative disease involves a defined degenerative process in which neurons are lost either by necrosis or apopotosis. This category is typified by slow chronic disorders that include Parkinson's disease and AD, but also includes more acute cell loss due to traumatic insults including stroke (brain attack) and spinal or brain damage. There are major issues with diagnosis in the absence of robust biomarkers.6 For example, there are cases where the AD disease phenotype is predominant and where the diagnosis of AD has not been supported by autopsy.

Addictionsubstance abuse

In addition to substance abuse there a number of addictions some of which are included in DSM-IV-TR under the classification of impulse control disorders which include kleptomania, pathological gambling, pyromania, and tricotillomania. Interestingly, recent reports have described an increase in compulsive gambling in Parkinson's disease patients receiving DA agonist treatment.

Neurodegenerative Diseases

Neurodegenerative diseases (see 6.08 Neurodegeneration) include AD Parkinson's disease amyotrophic lateral sclerosis (ALS) demyelinating diseases, e.g., multiple sclerosis neuropathies, e.g., diabetic, HIV, and chemotoxin-induced Down's syndrome (DS) prion diseases, e.g., Creutzfeldt-Jakob disease tauopathies, e.g., Pick's disease, frontal temporal dementia with Parkinsonism (FTDP) trinucleotide repeat or polyglutamine (polyQ) diseases, e.g., Huntington's disease (HD) spinocerebellar ataxias (SCA) dentatorubral-pallidolysian atrophy (DRPLA) Friedreich's ataxia multiple systems atrophy (MSA) stroke and traumatic brain injury.

Autoimmuneneuromuscular disorders

A number of autoimmune neuroinflammatory disorders (see 6.09 Neuromuscular Autoimmune Disorders) affect either the central or peripheral nervous system. Many of these disorders are exceptionally rare such as Moersch-Woltman syndrome (stiff-man), Lambert-Eaton myasthenic syndrome, and myasthenia gravis (MG). While uncommon, these disorders tend to be highly debilitating as they directly alter neuromuscular transmission. The most common of these disorders is MG which affects an estimated 60 000 people in the USA. The primary pathology underlying MG appears to be the production of autoantibodies directed against the alpha subunit of the neuromuscular nicotinic acetylcholine receptor. Through direct interference and complement-mediated lysis of the postsynaptic muscle membrane, the autoantibodies cause disruption in the motor endplate that leads to a weakness in skeletal muscle throughout the body. The autoimmune disorder systemic lupus erythematosus (SLE) and the neuroinflammatory...

First Generation Typical Antipsychotic Drugs

The serendipitous finding in 1951 that the major tranquilizer, chlorpromazine 1, was effective in treating delusions and hallucinations associated with schizophrenia and other psychotic disorders marks the beginning of modern therapy for schizophrenia.3 Unfortunately, treatment with chlorpromazine was accompanied by the development of EPS, some appearing even after the first dose (e.g., dystonias, akathisia). Other adverse effects were delayed for days or weeks such as parkinsonism, and the sometimes fatal neuroleptic malignant syndrome. Tardive dyskinesia, characterized by abnormal involuntary movements of the tongue, facial muscles, or limb muscles, develops in about 20 of patients and may be irreversible. Chlorpromazine also increased prolactin secretion leading to gynecomastia, galactorrhea, menstrual irregularities, sexual dysfunction, and possibly bone loss over the long term. Sedation, hypotension, and weight gain were also common with chlorpromazine. Despite these concerns,...

Chemical Transmission

I would like to thank my Cambridge, Oxford and McGill collaborators who have contributed to all aspects of the research discussed in this review, in particular my past graduate students. The investigations quoted here were supported while in the UK by grants from The Medical Research Council, The Wellcome Trust and the E.P. Abraham Cephalosporin Trust. I would like to thank my present research group in Canada at the McGill Department of Pharmacology and Therapeutics for bringing new interests to my current research activities, to the CIHR and the NIH (NIA) for supporting my ongoing research projects and to Sid Parkinson and Mona-Lisa Bolduc for effective editorial assistance. Bjorklund, A., and Lindvall, O., 1975, Dopamine in dendrites of substantia nigra neurons suggestions for a role Cheramy, A., Leviel, V., and Glowinski, J., 1981, Dendritic release of dopamine in the substantia nigra, Nature 289 537. Cuello, A. C., and Iversen, L. L., 1978, Interactions of dopamine with other...

How Does MS Affect the Nervous System

The central nervous system (CNS) is the part of the nervous system involved in MS. The CNS includes the brain and spinal cord. The nerves in the CNS communicate with each other through long, wire-like processes that have a central fiber (axon) surrounded by an insulating material (myelin). In MS, the immune system cells produce inflammation that injures the myelin. In addition, damage occurs to the axon. This damage is known as degeneration, which is the process that occurs in aging-related neurologic diseases such as Alzheimer's and Parkinson's disease. The injury to the myelin and axons results in a slowing or blocking of nerve impulses that prevents the affected parts of the nervous system from functioning normally.

Dementia With Lewy Bodies

Combining both features of a primary degenerative dementia and an akinetic-rigid, parkinsonian syndrome with prominent behavioral features, dementia with Lewy bodies (DLB) illustrates some of the shortcomings of current nosological schemata. Lewy bodies are the pathological hallmark of Parkinson's disease, where they are primarily restricted to substantia nigra and pigmented brainstem nuclei. However, the presence of Lewy bodies in the cerebral cortex coupled with behavioral symptoms, such as visual hallucinations, led to the recognition of DLB as a distinct syndrome. Complicating this assessment is the presence of AD pathology in about 50 of autopsies of clinically diagnosed cases of DLB, leading to the concept of a Lewy body variant of AD. A number of diagnostic criteria have been proposed and are summarized in Table 46. A number of studies, utilizing varying proportions of DLB cases have reported validity, and reliability of the clinical criteria of DLB, often in relation to...

Physiologic Abnormalities

Other than the anatomic and functional causes of constipation described above, a host of other, less common medical problems may present with constipation. Systemic illness such as diabetes mellitus, multiple sclerosis, hypothy-roidism, hypopituitarism, and porphyria may cause or exacerbate constipation. Neurologic disorders, including brain and spinal cord neoplasms, central nervous system trauma, and Parkinson's disease, are known to be associated with constipation, significantly altering the quality of life.

Mechanisms of Apoptosis in Neurological Disorders

Nigra in Parkinson's disease, and in the penumbral region of infarcts seen in cerebrovascular disease.26-29 Excitotoxicity induced via activation of NMDA receptors and also that induced by application of kainic acid to the hippocampi has linked apoptosis and hippocampal sclerosis to the occurrence of epilepsy.30 Defects in antiapoptotic genes such as CLN3 and NAIP and SMN in the juvenile form of Batten disease and spinal muscular atrophy type 1, respectively, coexist with massive neuronal loss and have inexorably coupled these inherited neurodegenerative diseases most intimately with the occurrence of apoptosis.31-33

Catechol Omethyltransferase inhibitors

Expected to have higher levels of transynaptic catecholamines due to a reduced COMT degradation of NE and DA. COMT inhibitors (entacapone (40) and tolcapone (41)) could therefore be beneficial as adjuncts to L-dopa not only in Parkinson's disease but also in the coincident depressive illness associated with rapid cycling.

Studies in MS and Other Conditions

Limited studies indicate that aspartame may provoke migraine headaches and worsen depression. Interestingly, one migraine medication that dissolves in the mouth, known as rizatriptan or Maxalt-MLT, actually contains aspartame and may worsen headache in those with aspartame-provoked migraines. In terms of other neurologic disorders, clinical studies do not indicate that aspartame worsens Parkinson's disease or epilepsy.

Differential Diagnosis

Constipation is a disorder and not a disease. It may be secondary to several diseases, including colonic disease (stricture, cancer, anal fissure, proctitis), metabolic and endocrine disturbances (hypercalcemia, hypothyroidism, diabetes mellitus), neurologic disorders (Parkinson's disease, spinal cord lesions), or pharmaco-logic (antidepressive) (Table 5.2). Therefore, exclusion of both intestinal and systemic organic etiologies is an imperative step prior to referring the patient with functional symptoms to the physiology laboratory. Barium enema or colonoscopy is usually indicated and the primary pathology treated. Additional tests, dictated by the history and physical examination, may be necessary to exclude the above-named diseases. Parkinson's disease

Multiplicity and ligand specificity

Two forms of the enzyme exist, MAO-A and MAO-B, that are encoded by separate genes.53 These enzymes are 80 similar, and possess overlapping, albeit sometimes distinctive, substrate specificities. Serotonin, norepinephrine, and epinephrine are the major endogenous substrates for MAO-A. The indoleamine nucleus of serotonin appears in a few drug classes, notably the triptan class of antimigraine drugs. These drugs are metabolized by MAO-A via pathways that ultimately generate carboxylic acid metabolites.40 The acetylenic compound, clorgyline, is a selective mechanism-based inhibitor of MAO-A, and reversible inhibitors of the enzyme are under development as antidepressant drugs. Amongst the neurotransmitters, dopamine is selectively metabolized by MAO-B. Another acetylenic compound, deprenyl, is a selective mechanism-based inhibitor of MAO-B and the levo enantiomer, selegiline, is marketed as Eldepryl and used as an adjunct to l-DOPA in Parkinsonism. The rationale here is to minimize...

Nonproteinogenic amino acids

Only a few important representatives of the non-proteinogenic amino acids are mentioned here. The basic amino acid ornithine is an analogue of lysine with a shortened side chain. Transfer of a carbamoyl residue to ornithine yields citrulline. Both of these amino acids are intermediates in the urea cycle (see p.182). Dopa (an acronym of 3,4-dihydroxy-phenylalanine) is synthesized by hydroxyla-tion of tyrosine. It is an intermediate in the biosynthesis of catecholamines (see p. 352) and of melanin. It is in clinical use in the treatment of Parkinson's disease. Selenocys-teine, a cysteine analogue, occurs as a component of a few proteins e.g., in the enzyme glutathione peroxidase (see p. 284).

Catechol Omethyltransferase

Catechol O-methyltransferase (COMT) typically metabolizes catecholamines and estrogens, forming mixtures of ortho and para methoxy metabolites118 Drug substrates include L-dopa, 2-hydroxy ethinylestradiol and isoproteranol and COMT inhibitors have therapeutic value in the treatment of Parkinsonism. The enzyme is the product of a single gene located on chromosome 22q11.2, but two forms of the protein exist soluble COMT (S-COMT, 25 kDa) and membrane-bound COMT (M-COMT, 30kDa), whose additional 50 amino acids provide the hydrophobic anchor for membrane localization. S-COMT predominates in peripheral tissues and M-COMT is the main form of the enzyme in brain tissue.119 COMT activity is inherited in an autosomal recessive manner. Individuals with low activity inherit a form of the enzyme that is thermolabile. A single G to A transition at codon 108 158 of the cytosolic membrane gene results in a Val to Met substitution which forms the molecular basis for the well-recognized interindividual...

Olfactory Disturbances Dysosmia

Cirrhosis And Cerebral Edema

Unilateral anosmia may be caused by a tumor (meningioma). Korsakoff syndrome can render the patient unable to identify odors. Viral infections (influenza), heavy smoking, and toxic substances can damage the olfactory epithelium trauma (disruption of olfactory nerves, frontal hemorrhage), tumors, meningitis, or radiotherapy may damage the olfactory pathway. Parkinson disease, multiple sclerosis, Kallmann syndrome (congenital anosmia with hypogonadism), meningoen-cephalocele, albinism, hepatic cirrhosis, and renal failure can also cause olfactory disturbances.

Practical examples and applications

Another example of successful clinical application of neural stimulation is the deep brain stimulator (DBS). This device is currently being evaluated for the treatment of Parkinsonian tremor.42 Seizures in the tha-lamic region of the brain are believed to cause some types of tremor that can render the afflicted individual unable to control movements. By electrically stimulating the thalamus, it is hypothesized that the seizures are moderated or depressed, allowing other areas of the brain to function properly to allow voluntary motor control. While the exact mechanism of DBS is not clear, the results can be dramatic. In a matter of minutes, Parkinson's patient can go from being unable to stand due to tremor to being able to easily walk across a room.

Clusterin mRNA Distribution in the Rodent and Human Brains

Cell type specificity of clusterin mRNA was determined by in situ hybridization in combination with immunohistochemistry.38 Colocalization of clusterin mRNA with neuron-specific enolase or tyrosine hydroxylase immunoreactivities confirmed neuronal expression of clusterin transcripts in the hippocampal pyramidal layer and hilar region, in subsets of neurons of the substantia nigra, as well as in the red nucleus, the trigeminal motor, facial, somatosensory mesencephalic, and other nuclei.38 Fig. 2.1. (opposite) Photomicrographs showing the distribution and levels of clusterin mRNA in selected coronal sections of the adult rat brain. Sections were hybridized with a 35S -labeled (antisense) riboprobe (for details see Danik et al26). Positive hybridization signals with different intensities are observed in various brain structures. 4V, fourth ventricle 3, oculomotor nucleus 7, facial nucleus CG, central gray CH, choroid plexus D3V, dorsal third ventricle DM, dorsomedial hypothalamic...

Cerebral Hemispheres Internal Structures

Internal Capsule Thalamus

The corpus striatum has important connections with the substantia nigra, thalamus and the subthalamus. The major afferent inputs to the corpus striatum are from the substantia nigra, the thalamus and the cerebral cortex. Nigrostriatal fibers are dopaminergic, and have both excitatory and inhibitory effects. Degeneration of this system results in Parkinson's disease (see p. 370). The thalamostriatal projections arise in the intralaminar nuclei of the ipsilateral thalamus. The corticostri-atal afferents are extensive there are afferents from motor areas of the frontal lobe to the putamen. Fibers from cortical association areas project to the caudate nucleus. The most prominent white matter (see also next spread) consists of the association and the commissural fibers connecting the corresponding regions of the hemispheres. .substantia nigra

Experimental Paradigms To Study Somatodendritic Dopamine Release

The critical role of the nigrostriatal pathway in movement has been convincingly demonstrated by the motor deficits of Parkinson's disease that accompany loss of nigrostriatal DA and which can be ameliorated by the DA precursor, L-DOPA (Wichman and DeLong 1996 Carlsson, 2002). Both somatodendritic and axon-terminal release are required for basal ganglia-mediated movement (Robertson and Robertson, 1989 Timmerman and Abercrombie, 1996 Crocker, 1997 Bergquist et al., 2003). Evidence for this is reviewed in detail in Bergquist and Nissbrandt, 2004. The cellular and receptor targets of somatodendritic dopamine in SN and VTA that underlie these behavioural effects are discussed in the following section.

Additional Readings Books

Eighty-one patients with multiple sclerosis and Parkinson's disease undergoing upper cervical chiropractic care to correct vertebral subluxation a retrospective analysis. J Vertebral Sublux Res 2004 August 1-9. Ernst E. Chiropractic care attempting a risk-benefit analysis. Am J Public Health 2002 92 1603-1604.

Injury and Autoimmunity

Autoantibodies, including antibodies reactive with neural antigens, can be found in normal healthy subjects and although of low titre these can be of high affinity.63 Such antibodies appear to be more frequently seen in patients with a variety of neurological diseases, particularly those of a chronic neurodegenerative type,64 65 and chronic viral encephalopathy.66 Antineurofilament antibodies occur with higher frequency in patients with CJD, familial Alzheimer's, and Parkinson's dementia, but also in viral encephalopathies such as subacute sclerotic panencephalomyelitis (SSPE) and acute herpes simplex encephalitis.67

Receptor Regulation Of Release

The modulation of DA 0 by D2 receptors is less marked in VTA than in SNc, consistent with the higher expression and protein levels of the D2 receptor in ventral tier DA neurons (Hurd et al, 1994). As for differential DAT expression discussed above, regional variation in the management of somatodendritic DA transmission in VTA and SNc by autoreceptor regulation might also contribute to differential susceptibility of these cell groups to degeneration in Parkinson's disease.

The Physiological Role Of Somatodendritic Dopamine Release In Motor Control

As indicated in the introduction of this chapter, a reason for the interest in somatodendritic dopamine release is the possibility of finding new remedies for Parkinson's disease, and exploring the aetiology of this second most common neurodegenerative disorder. The clinical characteristics of Parkinson's disease can be diverse, but always include at least two of the following symptoms hypokinesia bradykinesia, tremor, rigidity and postural imbalance with a semiflected stance. W ith progression o f the disease, there is also a risk of autonomic failure and an increased risk of depression and dementia, symptoms that develop as complications to a more generalised neurodegeneration. The classical Parkinsonian symptoms can be related to an imbalance in basal ganglia activity, mainly due to the loss of dopaminergic neurones in substantia nigra. Since the early findings by Ehringer and Hornykiewicz (1960), the focus of interest has been on the resulting loss of terminal dopamine release in...

Disease State Diagnosis

PD is primarily a movement disorder resulting from the loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). It is diagnosed by the presence of resting tremor, bradykinesia (slowness of voluntary movement), rigidity (stiff muscles, expressionless face), and postural instability (poor recovery of balance). The gait of individuals with PD is also distinctive, with a tendency to lean unnaturally forwards or backwards, a diminished arm swing, and a shuffling step. Although loss of DA-containing neurons is a hallmark pathological feature of the disease, other neuronal populations are also affected.62 Structures that are initially affected in stages 1-2 of PD include the vagal nerve, the dorsal motor nucleus and the olfactory bulb, and the anterior olfactory nucleus. At stage 3, involvement of basal portions of the midbrain and forebrain and a number of cholinergic nuclei and the tuberomamillary nucleus is apparent. At stage 4, portions of the cerebral cortex are...

Experimental Disease Models 608331 Neurotoxin models

Several neurotoxins have been used to produce selective dopaminergic neuron loss to model sporadic disease, and, in some species, e.g., the nonhuman primate, parkinsonism-like symptoms are evident following exposures.67 The three major toxins used to lesion the brain are (MPTP 52), 6-hydroxydop-amine (6-OHDA 53), and rotenone 54. Unilateral lesion of the substantia nigra, medial forebrain bundle, or striatum with 6-OHDA produces dopaminergic neuron loss, albeit at different rates, leading to a 'hemiparkinson' model where the injected side of the brain exhibits degeneration. Administration of DA agonists like apomorphine or the stimulant amphetamine elicits rotation or circling toward the contralateral side in animals, unmasking the DA loss. Although 6-OHDA causes dopaminergic neuron loss, other neurons affected in PD (e.g., lower brainstem nuclei and locus coeruleus) are unaffected and Lewy bodies do not occur. The MPTP model of PD is based on the idiopathic parkinsonism seen in...

Biperiden hydrochloride

See also Antiparkinson Drugs and Cholinergic Blocking Agents. Action Kinetics Tolerance may develop to this synthetic anticholin-ergic. Tremor may increase as spas-ticity is relieved. Slight respiratory and CV effects. Time to peak levels 60-90 min. Peak levels 4-5 mcg L. ti 2 About 18-24 hr. Uses Parkinsonism, especially of the postencephalitic, arteriosclerotic, and idiopathic types. Drug-induced (e.g., phenothiazines) extrapyramidal manifestations.

Unmet Medical Needs

As with AD, a large unmet medical need in PD is the development of drugs that slow disease progression. A paucity of established biomarkers for early disease diagnosis confounds indicators of treatment efficacy. This is particularly evident for drugs in which there is no symptomatic benefit demonstrated, since clinical trials of long duration ( 18-24 months) need to be carried out with large patient numbers in order to power the study appropriately to see perhaps small but significant effects. For drugs that do have symptomatic effects, neuroprotective events of the compounds can be established using a drug wash-out study design. This strategy has been used for selegine and pramipexole, but as of yet no drug is approved and has US FDA labeling indicative of a disease-modifying effect.

EncephalitisDRG cew 020

Complications from encephalitis can be short term or lifelong. Bronchial pneumonia and respiratory tract infections may complicate the course of encephalitis. Patients may go into a coma and experience all the complications of immobility, such as contractures and pressure ulcers. Other complications include epilepsy, parkinsonism, behavioral and personality changes, and mental retardation. A comatose state may last for days, weeks, or months after the acute infectious state.

Sustained Release Tablets

Parkinsonism, clients not receiving levodopa. Parkinsonism, clients receiving levodopa. pa may be given at a dose of 25 mg with the first daily dose of carbido-pa levodopa. If necessary, additional carbidopa, at doses of 12.5 or 25 mg, may be given with each dose of car-bidopa levodopa. In clients taking 10 mg carbido-pa 100 mg levodopa, 25 mg carbi-dopa may be given with the first dose each day. Additional doses of 12.5 or 25 mg may be given during the day with each dose. If the client is taking 25 mg carbidopa 250 mg levodopa, a dose of 25 mg carbidopa may be given with any dose, as needed. The maximum daily dose of carbidopa is 200 mg.

Afferent Regulation Of Noradrenaline Release

The first reports describing dendritic neurotransmitter release were concerned with dopamine release in the substantia nigra (Geffen et al., 1976 Korf et al., 1976). One of the properties of dendritic release is its impulse flow driven nature, as electrical stimulation of the medial forebrain bundle induced dopamine metabolism in the substantia nigra as well as the striatum (Korf et al., 1977). Microdialysis experiments in which carbachol or clonidine were infused into the LC indeed suggests that changes in electrical impulse flow of LC neurons parallel changes in local release of noradrenaline. However other dual-probe experiments described in this Chapter, where cirazoline, flesinoxan or BRL44408 were infused into the LC, indicated that certain receptor interactions are able to modify strongly the release of noradrenaline in the LC without affecting the electrical activity of these neurons.

Basal Ganglia Disease Loss of Nigrostriatal Pathway

Parkinson's disease (see also p. 370) is a progressive loss of movement accompanied by affective disorders. The etiology of Parkinson's disease is unknown. Most patients do not exhibit symptoms until the fifth or sixth decade. Motor symptoms are akinesia, bradykinesia, oculomotor disturbance (e.g. absence of blinking), so-called cogwheel rigidity, and loss of postural reflexes. Patients exhibit both normal and shuffling gait, have flexed posture and a 'pill-rolling' tremor of frequency 3 to 6 per second. There is evidence that the cause of the tremor is an abnormality of transmission between the cerebral cortex and the motoneuron cell body. This conclusion is supported by the discovery that MPTP a contaminant of illicitly prepared heroin, caused parkinsonian symptoms in 20-year-old users. At autopsy, the pars compacta of the substantia nigra was virtually devoid of dopaminergic neurons.

Evidence for Apoptosis in Motor Neuron Disease ALS and Related Disorders

Motor neuron disease or amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) represents a neurodegenerative disorder in which apoptotic cell death has been invoked as a key pathogenetic mechanism. In ALS, progressive loss of upper and lower motor neurons results in extreme disability and ultimately death. As in AD and Parkinson's disease, both environmental and genetic factors have been suggested.131 Apoptotic cell death of motoneurons has been related to immunological attack and to failure of cell defenses against oxidative damage.132,133 The discovery of Cu,Zn-superoxide dismutase mutations as a cause for some cases of familial ALS has strongly supported a role for apoptosis since the effect of the mutation is to convert an antioxidant defense enzyme into a proapoptotic gene.134 Furthermore, other rare cases of familial ALS have been associated with NAIP mutations.135 This suggests that ALS may well be very similar to Parkinson's disease and late-onset AD in that a number of...

In Search of a Mechanisms of Action

At least in narcoleptic dogs, via a mechanism independent of the hypocretin receptor.36 Additionally, in DAT knockout mice, modafinil-like methamphetamine and the selective DAT blocker, GBR 12909, lacked wake-promoting effects.36 Increases in dopamine release in the rat nucleus accumbens were observed following modafinil administration but this was secondary to a reduction in GABAergic transmission that led to a reduction of GABAA receptor signaling in dopamine terminals.37 Modafinil dose-dependently reduced g-amino-butyric acid (GABA) outflow from the cortex of awake guinea-pig,38 and from the striatum, pallidum, and substantia nigra,39 and, more importantly, from the medial preoptic area and posterior hypothalamus of the awake rat.40 The latter are hypothalamic fields where functional inhibition of GABA release by modafinil may be relevant for its vigilance-promoting effects. Modafinil also increased glutamate release in the ventrolateral and ventromedial thalamic areas,...

Chemical structure of virustatic antimetabolites

Amantadine (C) specifically affects the replication of influenza A (RNA) viruses, the causative agent of true influenza. These viruses are endocytosed into the cell. Release of viral DNA requires protons from the acidic content of endosomes to penetrate the virus. Presumably, amantadine blocks a channel protein in the viral coat that permits influx of protons thus, uncoating is prevented. Moreover, amantadine inhibits viral maturation. The drug is also used prophylactically and, if possible, must be taken before the outbreak of symptoms. It also is an antiparkinsonian (p. 188).

In Search and Discovery of Potential New Therapeutic Indications

The search for additional indications for modafinil naturally focused on diseases associated with wake deficits and somnolence. The effects of the drug in an animal model of sleep-disordered breathing suggested that modafinil might be effective in reducing sleepiness associated with sleep apnea,50 and this was subsequently demonstrated in the clinic.51-53 Other disorders where somnolence or sedation was concomitant with the disease, e.g., Parkinson's disease,54-56 myotonic dystrophy,57-60 fibromyalgia,61 amyotrophic lateral sclerosis,62 multiple sclerosis,63 cerebral lymphoma,64 or resulting from the side-effects of other medications such as antidepressants,65 antipsychotics,66 dopaminergic D2 agonists,67,68 opioids,69 or valproic acid,70 have also proven to be amenable to treatment with modafinil.

The Pontocerebellar Module

Dysarthria Etiology

Injury to the pontocerebellar module can result in severe disruption of movement. The ipsilateral side is affected because pontocerebellar efferents project to the contralateral motor cortex, which in turn projects caudally in corticospinal fibers that decussate in the pyramids. Injury is more serious if both cerebellar cortex and dentate nucleus are injured. These lesions result in a partial or complete loss of coordinated movement, termed dys-synergia or decomposition of movement. Patients may exhibit ataxia, or unsteady gait, hypotonia, which is a loss of muscle tone, and may tend to fall on the lesioned side. Tremor often accompanies the lesions, and is most noticeable during movement (intention tremor). (Note that in Parkinson's disease the tremor is more noticeable when the patient is not moving.) Tremor is also evident when the patient stretches out an arm i.e. works against gravity (static tremor). A diagnostic symptom is impaired check or rebound, when the patient cannot...

Connections of the Basal Ganglia

Indirect Pathway Basal Ganglia

The basal ganglia receive inputs from the cerebral cortex, send efferents to it, and inter-communicate extensively. Much of the information received from the cortex contains somatotopically-arranged data. In addition, there are thalamic connections. Most afferent projections to the basal ganglia terminate within the neo-striatum. The three major contributors to the basal ganglia are the cerebral cortex, the intralaminar nuclei of the thalamus, and dopaminergic pathways from the midbrain. The dopaminergic striatum inputs from the mesencephalon (midbrain) are known to be involved in at least one motor disease. The destruction of this pathway is the cause of Parkinson's disease (see p. 370).

Cerebral Cortex And Swimming

Mesolimbic Mesocortical Pathway

Dopamine (DA) is the major cate-cholamine neurotransmitter of the mammalian CNS, comprising at least 50 of the total CNS catecholamine content. There are four major dopaminergic pathways in the brain. The mesolimbic pathway originates in the ventral tegmental region of the midbrain, near the substantial nigra, and projects to several higher centers of the limbic system, including the amygdala, the frontal and cingulate cortex, the nucleus acumbens, the olfactory tubercle, and the septum. These areas mediate mood changes and cognitive function, and are believed to be the sites where drugs such as cocaine and amphetamines produce their stimulant effects. Other CNS drugs such as antidepressants, which block MAO, and antischizophrenia neu-roleptic drugs, which block DA receptors, may act in these regions. The nigrostriatal pathway projects from the substantia nigra to the corpus striatum, and specifically to the putamen and caudate nuclei, which are implicated in the control of fine motor...

Basal Ganglia Neurotransmitters and Receptors

Subcorticale Ganglia Dopamine Receptor

The dopaminergic nigrostriatal pathway is the largest brain pathway using dopamine as neurotransmitter, and has been extensively studied not least because of its importance in degenerative brain disease. It has been found recently that there is an interaction between striatal dopaminergic inputs and those that use as neurotransmitter the nucleoside ade-nosine. In addition, hybridization studies have revealed the presence of subtypes of dopamine and adenosine receptors, situated both pre- and postsynaptically on presynaptic terminals and cell bodies respectively, in striatum, globus pallidus, and the substantia nigra. These findings underline the complexity of action of dopamine in the basal ganglia. There is some evidence about the actions of dopamine in the striatum. Most of the cell bodies in the striatum are GABA ergic, and are projection neurons, and the next numerous are cholinergic inter-neurons. The GABAergic projection neurons to the globus pallidus also contain enkaphalins,...

Corticobasal Degeneration

First described in the 1960s, corticobasal degeneration is also known as cortical-basal ganglionic degeneration. It typically comes on as an asymmetric parkinsonian syndrome, most often in the sixth decade or later. Long considered a rare disorder, the description of additional cases and case series in recent years has widened the clinical spectrum. Cortical manifestations of corticobasal degeneration include not only dementia and alien limb sign, but also apraxia and cortical sensory loss. The basal ganglionic component includes parkinsonism and limb dystonia. There may be postural tremor and a focal reflex myoclonus. Dementia may be the presenting sign. Not all patients exhibit the alien limb sign throughout the clinical course.

Caraway Carum carvi Apiaceae

It is claimed by some that caraway has been cultivated and consumed in Europe longer than any other condiment, but there is, at least as yet, no long archaeological record to support this. The ancient Greeks used caraway, along with poppy seed, in bread, foreshadowing one of the principal uses of caraway today. The first century Greek physician, Dioscorides, mentioned caraway as both a herb and a tonic. The Roman Apicius used caraway in some of his recipes. By the 12th century, caraway was known to the Arabs as karauya and listed among the plants cultivated in Morocco. In England, caraway appears in a record compiled in 1390 by the master cooks of Richard II, while, in 1629, Parkinson considered its fleshy taproot to be superior to that of parsnip. The leaves are also edible the young leaves are said to make a good salad, while larger leaves may be cooked like spinach.

Extrapyramidal Motor Pathways

Rubrospinal Tract

The extrapyramidal pathways are those motor pathways that do not pass through the pyramids of the medulla oblongata. They consist of central pathways that modulate CNS motor areas in cerebral cortex, cerebellum, the brain stem, and spinal cord. The primary function of the extrapyramidal system is the 'fine-tuning' of voluntary movement to render it amenable to higher levels of conscious control. The absence of such fine-tuning becomes obvious in conditions such as parkinsonism (see p. 370), when voluntary movement is hampered through the presence of uncontrollable tremor in the hands, for example. Extrapyramidal fibers may originate in the frontal or parietal cortex, and travel to the cerebellum, or to other major extrapyramidal sites such as the striatum, the substantia nigra, reticular formation, tegmental nuclei, and the red nucleus. The corticopontocerebellar tracts, for example, connect the cerebral cortex with the contralateral cerebellum. Since the cerebellum also receives...

Proposed Research Criteria for Corticobasal Degeneration

Early dementia, early vertical gaze palsy, rest tremor, severe autonomic disturbances, sustained responsiveness to levodopa, lesions on imaging studies indicating another pathological condition. Movement disorders akinetic rigid syndrome-levodopa resistant, and limb dystonia and reflex focal myoclonus. (Adapted with permission from Litvan I, Bhatia KP, Burn DJ, et al. SIC task force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Dis 2003 18 467-486, and from John Wiley and Sons.)

Diagonal Band Of Broca

Diagonal Band Broca

Cholinergic neuron systems occur in the peripheral and central nervous systems. In the CNS, they are widespread, and release ACh opposite muscarinic (M) and ni-cotinic (N) receptors. M receptors outnumber N receptors 10-100-fold in the CNS. In the CNS, major cholinergic pathways originate from cell bodies in the septum, diagonal band of Broca, and basal nucleus in the ventral forebrain, and project to the hippocampus, interpeduncu-lar nuclei, and neocortex, respectively. Cortical cholinergic innervation appears to play a role in memory, and may be involved in the etiology of Alzheimer's disease (see p. 376). Within the striatum there are smaller cholinergic neurons involved in control of fine movement blockade of these muscarinic receptors with atropine, a muscarinic antagonist, can be used to treat parkinsonian tremor. There are cholinergic cell bodies in the brain stem tegmentum, and these project to hypothalamus and thalamus. Choliner-gic cell bodies of the cranial parasympa-thetic...

Diagnostic Criteria for Essential Tremor

Medications, alcohol, Parkinsonism, dystonia, other basal ganglionic discoders, and hyperthyroidism are not potential etiological factors. 2. Use of medications, alcohol, Parkinsonism, dystonia, other basal ganglionic disorders, and hyperthyroidism are nor potential etiological factors.

Relationship Approaches to Absorption Distribution Metabolism and Excretion Predictions

A second class of conjugating enzymes that attracted great interest are the catechol O-methyltransferases (COMTs). These enzymes catalyze the methylation of various catechol derivatives such as catecholamines, catechol estrogens, and their metabolites, and several drug metabolites. There are two forms of COMTcoded by a single gene the soluble, cytosolic form (s-COMT) and the membrane-bound form (mb-COMT), found in the rough endoplasmic reticulum. COMT inhibitors are used as drugs in the treatment of Parkinson's disease. CoMFA analyses133,134 have revealed the key role played by the electrostatic field in predicting the enzyme kinetic parameters of s-COMT. These studies underline how CoMFA results are sensitive to the method used to calculate atomic charge calculation. Semi-empirical charge calculations performed clearly better than fully empirical ones. The CoMFA results are in agreement with docking analyses of the s-COMT crystal structure, which have revealed the interaction between...

Multiplesystem Atrophy

Multiple-system atrophy is a progressive disorder with features of parkinsonism, cerebellar, autonomic, urinary, and corticospinal dysfunction. It is of unknown etiology. It most commonly affects middle-aged individuals, and both genders are affected equally. Disease course is variable and median survival from first symptoms is about 9 years. The parkinsonian features are usually unresponsive to levodopa therapy. There may be gait and limb ataxia, orthostatic hypotension, erectile dysfunction, constipation, and decreased sweating. Whereas multiple-system atrophy is a distinct neuropathological entity, the consensus diagnostic criteria depend on specific clinical features. Pathologically, glial cytoplasmic inclusions and degeneration are found throughout the basal ganglia, substantia nigra, brainstem autonomic nuclei, and Purkinje cells of the cerebellum.

Secondary Sleep Disorders

Secondary Sleep Disorders

Sleep can be impaired by dementia, Parkinson disease, dys-tonia, respiratory disturbances secondary to neuromuscular disease (muscular dystrophy, amyotrophic lateral sclerosis), epilepsy (nocturnal attacks), and headache syndromes (cluster headaches, migraine). Fatal familial insomnia is a genetic disorder of autosomal dominant inheritance (p. 252). Sleep disorders due to systemic disease. Sleep can be impaired by pulmonary diseases (asthma, COPD), angina pectoris, nocturia, fibromyalgia, and chronic fatigue syndrome.

Diagnostic Categories of Multiple System Atrophy

Possible MSA one criterion plus two features from seperate domains. When the criterion is Parkinsonism, a poor levodopa response qualifies as one feature (hence only one additional future is required). II. Probable MSA criterion for autonomic failure urinary dysfunction, plus poor levodopa-responsive Parkinsonism or cerebellar dysfunction.

Exclusion Criteria for the Diagnosis of MSA

AIn practice, multiple-system atrophy is most frequently confused with Parkinson's disease or progressive supranuclear palsy (PSP). Mild limitation of upward gaze alone is nonspecific, whereas a prominent ( 50 ) limitation of upward gaze of any limitation of downward gaze suggests PSP. Before the onset of vertical gaze limitation, a clinically obvious slowing of voluntary vertical saccades is usually easily detectable in PSP and assists in the early differentiation of these two disorders.

[hahlowPAIRihdohl Pregnancy Category C

Contraindications Use with extreme caution, or not at all, in clients with parkinsonism. Lactation. Special Concerns PO dosage has not been determined in children less than 3 years of age IM dosage is not recommended in children. Geriatric clients are more likely to exhibit or-thostatic hypotension, anticholiner-gic effects, sedation, and extrapyramidal side effects (such as parkinsonism and tardive dyskinesia). Side Effects Extrapyramidal symptoms, especially akathisia and dys-tonias, occur more frequently than with the phenothiazines. Overdos-age is characterized by severe extrapyramidal reactions, hypotension, or sedation. The drug does not elicit photosensitivity reactions like those of the phenothiazines.

Potential Roles for apoE and apoJ in CNS Disease

Further studies to understand the structure and function of apoE and apoJ-containing lipoproteins produced by cells within the brain is likely to provide important insights into the role of these proteins in neurodegenerative and other diseases of the CNS. This issue will be considered in regard to Alzheimer's disease (AD) and brain repair following CNS injury. Genetic epidemiological studies have shown that the e4 allele of apoE is a major risk factor for AD.43 In addition, recent data suggests that apoE4 is also a risk factor for poor outcome after head trauma,44,45 cerebral hemorrhage,46 cardiac bypass,47 and possibly stroke.48 ApoE4 also appears to influence the age of onset of Parkinson's disease.49 In regard to AD, one hypothesis is that the association between apoE4 and AD is due to the ability of apoE to interact with the Ap protein. Ap deposition in the AD brain appears to be an early and important pathogenetic event in AD.50 A recent in vivo study highlights the potential...

Regulation Of Somatodendritic Dopamine By Uptake Transporters

Plasma membrane uptake of DA by the DA transporter (DAT) is fundamental to the regulation of DA 0, such that DAT-mediated uptake, coupled with diffusion, defines the sphere of influence of somatodendritically, as well as synaptically released DA (Cragg et al., 2001 Cragg and Rice 2004). Electrophysiological studies suggest a physiological role for uptake in the modulation of somatodendritic DA 0 (Lacey et al., 1990). Regulation of DA 0 by uptake differs between the SNc and VTA, however. Ventral tier neurons of the SNc have greater mRNA and protein levels of DA transporter (and D2 DA receptor) than dorsal tier cells in dorsal SNc and VTA (Blanchard et al., 1994 Hurd et al., 1994 Sanghera et al., 1994 Ciliax et al., 1995 Freed et al., 1995). It is relevant to note that ventral tier SNc cells are more susceptible to degeneration in Parkinson's disease than dorsal tier cells in either VTA or SNc (Yamada et al., 1990 Fearnley and Lees, 1991 Gibb and Lees, 1991). This pattern of...

Progressive Supranuclear Palsy

First described by Steele, Richardson, and Olzweski in 1964, progressive supranuclear palsy (PSP) is also known by its acronym. The original descriptions focused on the parkinsonian movement disorder with progressive eye movement abnormality and frequent falls. Dementia also occurs as part of the clinical expression of PSP. PSP is almost never familial in nature. More recent investigations have tended to widen the scope of the clinical spectrum, and clinical overlaps occur, particularly with corti-cobasal degeneration. PSP may be misdiagnosed as PD or vascular dementia. False-negative diagnoses confirmed pathologically may include not only corticobasal degeneration but also multiple-system atrophy, central nervous system Whipple's disease, diffuse Lewy body disease, subcortical gliosis, and prion diseases.

Additional Contraindications

Special Concerns Use in children should be restricted to those unresponsive to or intolerant of other anti-inflammatory agents efficacy has not been determined in children less than 14 years of age. Geriatric clients are at greater risk of developing CNS side effects, especially confusion. To be used with caution in clients with history of epilepsy, psychiatric illness, or parkinsonism and in the elderly. Indomethacin should be used with extreme caution in the presence of existing, controlled infections. Additional Side Effects Reactivation of latent infections may mask signs of infection. More marked CNS manifestations than for other drugs of this group. Aggravation of depression or other psychiatric problems, epilepsy, and parkinsonism.

National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy Clinical

Symmetric akinesia or rigidity, proximal more than distal abnormal neck posture, especially retrocollis poor or absent response of parkinsonism to levodopa early dysphagia and dysarthria early onset of cognitive impairment including more than two of apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior, or frontal release signs (Adapted with permission from Litvan I, Bhatia KP, Burn DJ, et al. SIC task force appraisal of clinical diagnostic criteria for Parkinsonian disorders. Mov Dis 2003 18 467-486.)

Wireless Implantable Microsystem

Silicon micromachined electrode arrays permit the long-term monitoring of neural activity in vivo as well as the insertion of electronic signals into neural ensembles or networks at the cellular level. Such electrode arrays are facilitating significant advances in the understanding of the nervous system, and merged with on-chip circuitry, signal processing, microfluid-ics, and wireless interfaces, they are forming the basis for a family of neural prostheses for the possible treatment of disorders such as blindness, deafness, paralysis, severe epilepsy, and Parkinson's disease.

Components of the Basal Ganglia

Mouse Striatum Substantia Nigra

The subthalamic nucleus lies ventral to the thalamus, at the junction of the thalamus and the midbrain. The substan-tia nigra (see also p. 23) lies in the mid-brain, and consists of two distinct zones there is a darkly staining dorsal zone, called the pars compacta, and a pale ventral zone called the pars reticulata, with neuronal cell bodies similar to those seen in the globus pallidus. Substantia nigra is a Latin term meaning black substance in humans, the area appears black when stained because of dopaminergic cell bodies rich in neuromelanin. striatum), and the globus pallidus (paleo-striatum). Associated with these are the parabrachial pontine reticular formation, which contains the pedunculopontine tegmental nucleus, the subthalamic nucleus and the substantia nigra. The ventral nuclei are situated beneath the anterior commissure, and include the nucleus accumbens, basal nucleus of Meynert, the olfactory tubercle, and the substantia in-nominata. These nuclei are closely...

Sudden Death on a Physiological Basis

Up to this point in the discussion of sudden cardiac death, lesions of the heart that are visible either grossly or microscopically have been described. Sudden cardiac death on a physiological basis without a visible etiology can also occur. Thus, sudden death can be, though rarely, one of the sequelae of Wolff -Parkinson-White syndrome.140 Sudden cardiac death is also seen in conjunction with the Q-T interval syndrome.1 There are two forms of this syndrome the congenital hereditary form and the acquired form. The Jervell and Lange-Nielsen syndrome and the Romano-Ward syndrome are the two hereditary forms. The acquired form is secondary to drugs, electrolyte abnormalities, toxic substances, hypothermia, anorexia nervosa, and diet programs involving liquid protein diets. In the acquired form of the Q-T interval syndrome, removing the inciting factor abolishes the syndrome. The mechanism of death in both anorexia nervosa and dieting with liquid protein diets is the same development of a...

Immunological Properties of Glatiramer Acetate

GA treatment also increased survival time and improved motor function in a mouse model of amyotrophic lateral sclerosis.65 Adoptive transfer of GA-specific Tcells was effective in protecting dopaminergic neurons in a mouse model of Parkinson disease.66 Taken together, these results show that GA may have neuroprotective functions in human neurodegenerative diseases.

Severe Mental Illness And Hiv Risk

Currently there is no significant difference between the pharmacologic treatment of schizophrenia in an HIV-infected individual and the treatment of an uninfected person. It is important to take into consideration interactions between HAART medications and antipsychotics psychiatrists and HIV practitioners must work together closely during initiation of or changes in antiretroviral or antipsychotic treatment, as concomitant alterations in dosing may be needed. Many antipsychotics are associated with severe side effects, such as tardive dyskinesia and Parkinsonian syndromes known as extrapyramidal symptoms (EPS). They also have effects on metabolism, including weight gain, increased insulin resistance, and increased lipids that may complicate similar effects produced by antiviral medications. There may be drug interactions with antiviral treatment as well, although these remain unpredictable for the most part (Treisman and Angelino, 2004). Antipsychotic medications have been shown to...

Central Nervous System

A variety of colorectal dysfunction can be attributed to lesions of the central nervous system. Those disorders that are seen most commonly in clinical practice will be discussed, namely cere-brovascular accidents, spinal cord injury, multiple sclerosis, Parkinson's disease, and spina bifida. Gastrointestinal impairment, specifically constipation, in individuals with Parkinson's disease is common and prevalent,60-64 occurring in as many as two thirds of the patients diagnosed with the disease.65,66 In a study by Siddiqui et al67 involving 68 patients diagnosed with Parkinson's disease, autonomic dysfunction was assessed by comparing gastrointestinal, urinary, sexual, cardiovascular, and thermoregulatory symptoms with a matched control group. The study found that patient's with Parkinson's disease experienced a higher frequency and severity of autonomic dysfunction, and that among the gastrointestinal symptoms that were assessed, patients reported decreased bowel movements as compared...

Figure 46 Chemical structures of selected smallmolecule monoamine neurotransmitters

The dopamine transporter (DAT) - a Na+ and CP-dependent neuronal transmembrane protein - was first cloned in the early 1990s, and is involved in locomotor control, including functions lost in Parkinson's disease. DAT is also involved in reward systems, and thus in addiction to drugs such as amphetamine and cocaine, and in ADHD and Tourette's syndrome, among other illnesses.367-371 Indeed, the actions of many small molecule neurotransmitters containing a basic amine are modulated through transporter sites, including those of adrenaline and noradrenaline (epinephrine or norepinephrine), dopamine, histamine, and serotonin (Figure 46). That is, transporters serve to modulate synaptic neurotransmitter levels through reuptake into nerve terminals, and once inside they are taken up into vesicles via different transporters (Figure 47). These effects lend themselves to being studied via in vivo imaging techniques, as outlined later.

Implications of Confabulation Theory

For example, it may be possible within a few years to build an integrated functional mathematical model of cerebral cortex, thalamus, basal ganglia, subthalamus, red nucleus, substantia nigra, hippocampus, amygdala, hypothalamus, spinal cord, locus coeruleus, pons, and cerebellum. This model may well answer most of the large questions of neuroscience that remain after confabulation theory.

Chronic Exit Site Care of Healed Exit Site

Since with the use of Amuchina 10 solution, there was a higher incidence of local irritation at the exit-site in comparison to povidone-iodine 10 , the subsequent study evaluated randomly Amuchina 5 (ExSept) solution comparing povidone-iodine 10 for exit-site care in PD 22 . Thirty nine PD patients were studied over a period of 470 patient-months. Eighteen PD patients received exit-site care with Amuchina 5 solution and 21 received exit-site care with povidone-iodine 10 solution. Protocol used in this study was similar to the previous study using Amuchina10 solution for the exit-site care. The mean age, months on PD, number of diabetic and non-diabetic patients were not different (table 2). The ESI TI rates were 0.66 episode patient year in the Amuchina group and 0.59 episode patient year in the povidone-iodine group, respectively (table 2). The ESI TI rates were not statistically different between two groups. Eleven patients in the Amuchina group had varying degrees of irritation at...

Diffuse Lewy Body Disease

Diffuse Lewy body disease (DLBD) is considered to be a variant or overlapping condition lying between Alzheimer's disease and Parkinson's disease. Clinical differentiation may therefore be difficult. In most patients with DLBD, however, psychosis and dementia are often found to precede parkinsonism (gait disturbance, rigidity, and resting tremor). The differentiation between DLBD and other parkinsonian syndromes, especially progressive supranuclear palsy, is particularly difficult when a patient with parkinsonism and dementia is also found to have oculomotor deficit. Neuroimaging studies, including magnetic resonance imaging (MRI) and positron-emission tomography (PET) scanning, cannot reliably differentiate between Parkinson's disease, Alzheimer's disease, and DLBD. Immunocytochemical staining techniques using antibodies against ubiquitin have improved the identification of Lewy bodies. More than 30 of patients with Alzheimer's disease have Lewy bodies in the cortex and substantia...

Mean LOS 63 days Description Medical Degenerative Nervous System Disorders

Parkinsonism is a clinical condition that is characterized by the following gradual slowing of voluntary movement (bradykinesia) muscular rigidity stooped posture distinctive gait with 698 Parkinson's Disease short, accelerating steps diminished facial expression and resting tremor. Parkinson's disease occurs with progressive parkinsonism in the absence of a toxic or known etiology and is a progressively degenerative disease of the substantia nigra and basal ganglia. Parkinson's disease is also called paralysis agitans. Degeneration of the substantia nigra in the basal ganglia of the midbrain leads to depletion of the neurotransmitter dopamine, which is normally produced and stored in this location. Dopamine promotes smooth, purposeful movements and modulation of motor function. Depletion of dopamine leads to impairment of the extrapyramidal tracts and consequent loss of movement coordination.

Tomato Lycopersicon esculentum Solanaceae

The cultivated tomato is thought to have originated from the cherry tomato, Lycopersicon esculen-tum var cerasiforme, which occurs wild in Peru, Ecuador, and elsewhere in tropical America. It was probably first domesticated in Mexico. Early in the 16 th century it was brought to Europe by the Spaniards. Its name is derived from the Aztec name xitomatl. It was at first regarded as a poisonous plant in Europe and known as Pomme d'amour, love apple, and golden apple, although it was clearly regarded as a food plant in Mexico and many varieties had been developed by the American Indians before the Spanish conquest. The culinary barrier seems to have been broken first in Italy, and gradually the taste for eating them spread around the Mediterranean and then northwards through Europe where they were long treated with suspicion. This may partly have been because of the color of their fruits and partly because they were related to poisonous plants of the nightshade family. Parkinson grew them...

Choosing a Data Collection and Management System

The VA Cooperative Studies Program Persian Gulf trial was mandated by Congress and had to start right away. Therefore the pure paper-based data collection approach was chosen. The VA Cooperative Studies Program Parkinson's Trial started with pure paper-based data collection, and, as resources became available, data collection was migrated to DataLabs. The VA Cooperative Studies Program Diabetes Mellitus trial 39 was a very large trial. The limited manpower and financial recourses prohibited using an electronic-based system, so the pure paper-based system was used.

Discharge And Home Healthcare Guidelines

Be sure the patient or caregiver understands all medications, including the dosage, route, action, and adverse reactions. Avoid the use of alcohol, reserpine, pyridoxine, and phenothiazine while taking levodopa. In general, recommend massage and relaxation techniques, and reinforce exercises recommended by the physical therapist. Several techniques facilitate mobility and enhance safety in Parkinson's disease patients. Instruct the patient to try the following strategies (1) To assist in maintaining balance, concentrate on taking larger steps with feet apart, keeping back straight and swinging the arms (2) to overcome akinesia, tape the frozen leg to initiate movement (3) to reduce tremors, hold objects (coins, keys, or purse) in the hand (4) to obtain partial control of tremors when seated, grasp chair arms (5) to reduce rigidity before exercise, take a warm bath (6) to initiate movement, rock back and forth (7) to prevent spine flexion, periodically lie prone and avoid using a neck...

Delayed Manifestations

CNS neurotoxicity predominates Confined to basal ganglia globus pallidus, putamen, hippocampus (CT confirmation) resulting in toxic parkinsonism, with bradykinesia, dystonia, dysarthria, no rigidity (L-dopa resistant). Chronic low-level cyanide toxicity occurs in (1) Tobacco amblyopia (male smokers) (2) tropical (cassava root) ataxic neuropathy, (3) Leber's hereditary optic atrophy (males). Mechanism low endogenous stores of CN-detoxify-ing hydroxocobalamin and thiosulfate. Results from depletion of detoxifying substances by chronic low-grade CN poisoning from cigarette smoking (tobacco amblyopia and Leber's heredity optic atrophy) or frequent cassava root ingestion (tropical ataxic neuropathy).

Compression within the Spiral Groove of the Humerus

Lesions of the radial nerve occur most commonly in this region. The lesions are usually due to displaced fractures of the humeral shaft after inebriated sleep, during which the arm is allowed to hang off the bed or bench ( Saturday night palsy ), during general anesthesia, or from callus formation due to an old humeral fracture. There may be a familial history, or underlying diseases such as alcoholism, lead and arsenic poisoning, diabetes mellitus, polyarteritis nodosa, serum sickness, or advanced Parkinsonism.

Clinical and Medical Uses of Chronometry

Cognitive effects of normal aging, mild cognitive impairment, senile dementia, traumatic brain and closed head injuries, mortality, under-nutrition and malnutrition in children, eating disorders, parasitic infections, neurological effects of HIV and AIDS, drug effects and addictions, multiple sclerosis, sleep disorders, diabetes, attention deficit and hyperactivity disorder (ADHD), stroke, vascular dementia, degenerative brain diseases associated with aging (Huntington, Alzheimer, Parkinson), epilepsy, chronic fatigue syndrome, hypoxia, post-traumatic stress disorder (PTSD), psychiatric disorders (anxiety, schizophrenia, depression, bipolar), yoga and meditation, chemical, pharmaceutical, and nutriceutical (e.g., Gingko biloba) agents.

Neuronal PCD Subsequent to Ischemia or Hypoxia

Premature neuronal death is observed with a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS). Although frankly necrotic cells are observed in some instances, PCD has long been suspected to play an important role in many neurodegenerative diseases. In recent years, descriptive and experimental studies have begun to provide support for this hypothesis (reviewed in References 198-200). Mounting evidence suggests that excessive apoptosis plays a role in the pathogenesis of Huntington's disease, Parkinson's disease, and ALS as well. For Huntington's disease and ALS, both of which are associated with defined genetic alterations, knockout or overexpression studies indicate that the disease gene products act to regulate apoptotic cell death.207,208 Similarly, in an in vivo Parkinson's disease model, apoptotic cell death has been

Normative and Ipsative Applications

Overall average of the scores itself might be of diagnostic significance in its own right, the particular profile of high and low scores on the separate tests (e.g., different RT paradigms) offers the possibility of greater diagnostic specificity. But the kind of research that would be most informative regarding this possibility has not yet been done. First of all, it would call for a factor analysis in a normally diverse population, of a number of standard RT paradigms to determine the extent to which they reflect different latent factors besides the large general factor, or g, that appears to be common to all RT paradigms. To make this determination, it would require at least three forms of tests intended to measure the main information processing feature of each paradigm. For example, say we have three or more different forms or stimulus modalities of (a) the inspection time (IT) paradigm for measuring stimulus intake speed, (b) the Hick paradigm measuring RT of stimulus...

Visions for the Future

During my recent discussions with Arvid Carlsson, he presented convincing arguments in favor of in vivo screening in drug research. Carlsson Research Company has synthesized compounds, such as (-)-OSU 6162 (5) and ACR 16 (6), which are so-called dopamine stabilizers. If the release of dopamine is too high, these compounds will decrease it, and if the release is too low, they will increase it to an acceptable level. Thus the same compounds can either block or stimulate dopamine receptors in the CNS. In test studies in patients seriously ill with Parkinson's disease and Huntington's chorea, (-)-OSU 6162 has shown close to miraculous effect, as well as clear positive effects in schizophrenic patients. However, a fundamental characteristic of these compounds is that they have low, or even zero, affinity for the receptors in classical binding models, and would therefore be considered inactive and uninteresting in an HTS screen

Restless Legs Syndrome

Restless legs syndrome (RLS) features nocturnal involuntary limb movements that can cause insomnia because of frequent sleep disruption, and often affects bed partners because of frequent myoclonic-type jerking. It generally begins in early adulthood and affects from 2 to 5 of the population. RLS may run in families, with susceptibility genes identified on chromosomes 12q and 14q. RLS has also been associated with Parkinson's disease, pregnancy, end-stage renal disease, iron deficiency anemia, peripheral neuropathy, and diabetes.

Natural Disease without Anatomical Manifestations

Medical history is absolutely necessary to make the diagnosis. Some examples are Wolfe-Parkinson-White syndrome, the prolonged Q-T syndrome, etc. In one case, an interview with the family revealed a history of fluttering or pounding heartbeats, a funny pulse, suggestive that the individual had an underlying physiological lesion of the conduction system of the heart predisposing him to develop an arrhythmia.

Ropinirole hydrochloride

Action Kinetics Mechanism is not known but believed to involve stimulation of postsynaptic D2 dopamine receptors in caudate-putamen in brain. Causes decreases in both systolic and diastolic BP at doses above 0.25 mg. Rapidly absorbed. Peak plasma levels 1-2 hr. Food reduces maximum concentration. tV2, elimination 6 hr. First pass effect extensively metabolized in liver. Uses Treat signs and symptoms of id-iopathic Parkinson's disease. Contraindications Lactation. Special Concerns Safety and efficacy have not been determined in children.

Ashley Reynolds Georgette Kanmogne Irena Kadiu and Howard E Gendelman

This review serves to highlight both the research advances made in understanding the effects of HIV on the nervous system and what remains undone. Particular attention is given to the effects of the virus on the nervous system at the molecular and cellular levels as well as within the infected human host. A parallel focus is on prospects for increasing ART effectiveness and availability. An emerging and interesting aspect of disease pathogenesis remains in the many similarities now known between the pathogen-esis of HIV-associated cognitive impairments and that of other neurodegenerative disorders (for example, Parkinson's and Alzheimer's disease). Similarities abound at the level of glial inflammation and dysreg-ulation of innate immune responses. Whether caused by virus or misfolded and aggregated proteins, all of these processes underlie the tempo and progression of disease (Hirsch et al., 2003 Butovsky et al., 2005 Minghetti, 2005 Zhang et al., 2005 Craft et al., 2006 Ghafouri et...

Summary And Conclusions

Regardless of the source, endogenously generated H202 reverses conventional glutamatergic excitation by opening KAtp channels to inhibit striatal DA release. These findings help clarify normal DA-glutamate interactions in striatum. Moreover, because DA-glutamate dysfunction has been implicated as a causal factor in Parkinson's disease (Olanow and Tatton, 1999 Chase and Oh, 2000 Greenamyre, 2001), schizophrenia (Deutsch et al., 2001 Sawa and Snyder, 2002), and addiction (Koob, 2000 Hyman and Malenka, 2001), exploration of this process may also suggest novel pathways through which dysfunction could occur. One final point is that neuromodulation by H202 is a double-edged sword an imbalance between H202 generation and regulation could result in oxidative stress, which has been implicated in nigrostriatal degeneration in Parkinson's disease (Cohen, 1994 Sonsalla et al., 1997 Olanow and Tatton, 1999 Xu et al., 2002) and, more recently, as a causal factor in schizophrenia (Do et al., 2000...

The Fibroblast Growth Factor Fgf Family

In the developing and adult central nervous system FGFR1, 2, and 3 display a broad distribution in a distinct pattern.19-29 High levels of FGFR1 are localized to astrocytes, low levels to oligodendrocytes.30 Selected neuronal populations (e.g., amygdala and substantia nigra) also express FGFR1.30 In addition, heparan sulfate proteoglycans, such as syndecan, seem to function as low-affinity FGF binding sites.3132 In neural tissue, the binding specificity of heparan sulfate proteoglycan for FGFs undergoes changes during development.33 34

Overview of Current Electrical Treatments for Arrhythmias

Ablation therapy - used where the site of the genesis of arrhythmias is known and is ablated by techniques of guided cryoablation, or radiofrequency ablation using intracardiac catheters, and x-ray guidance. By such means, anatomic or functional re-entry circuits can be abolished. It can be effective in up to 97 of cases of supraventricular tachycardia, and in 88-99 in cases of aberrant AV pathways such as occur in Wolf-Parkinson-White syndrome. It can also be effective in VT, but it has varying effectiveness for AF.

Expression Of Fgfs In The Injured And Diseased Cns

In Parkinson's disease, there is a preferential loss of dopaminergic neurons in the substantia nigra. Immunocytochemical studies of human Parkinsonian brains revealed a loss of FGF-2 in substantia nigra neurons.100101 Treatment with the neurotoxin (MPTP) as a mouse model for this disease induces lesions of dopaminergic neurons and elevates transcript levels of FGF-1 and FGF-2 in the striatum but not in the substantia nigra.102 Furthermore, iodinated FGF-2 was shown to be anterogradely transported from the substantia nigra to the striatum.103 FGF seems to be involved in other neurological disorders, too. Brains from Alzheimer patients, for example, display substantially enhanced specific FGF-2 staining of neurons and astrocytes.104 In Alzheimer's disease, neurofibrillary tangles and neuritic plaques are formed in the cortex and hippocampus.105 The neuritic plaques are reported to be dense accumulations of amyloid material derived from the amyloid precursor protein (APP), a...

FGFs And The Treatment Of Cns Injuries

Another possible way to take advantage of the neurotrophic capacities of FGF-2 is in the context of neural transplantation. The clinical use of fetal nigral and adrenal medullary grafts as an intracerebral source of dopamine in patients with Parkinson's disease is limited, at least in part, because of the poor survival of the donor tissue.162163 Enhancement of the graft survival can be achieved by co-grafting of fetal dopaminergic neurons with a FGF-2 source like, for example, genetically modified cells which produce FGF-2.164 In addition, in viro propagation of fetal precursor cells before transplantation leads to a long-term survival of the graft.165 Alternative gene delivery techniques include the use of viral vectors and the ex vivo technology.166 The ex vivo approach allows manipulation of the cells in culture for reimplantation after isolation from the patient.

Email Trigones.net Loc Us

Parkinson's disease substantia nigra means 'substance' e.g. substantia gelatinosa of spinal cord gray matter substantia nigra of the midbrain column of small neurons in a column that runs the length of the spinal cord at the apex of the dorsal horn gray matter area under the anterior commissure (subcommissural region) often called the basal nucleus, or nucleus basalis of Mey-nert, after the Austrian neuropsychiatrist has widespread cholinergic projections to the cerebral cortex of special current interest since these neurons selectively degenerate in Alzheimer's disease dark band of cells, many being pigmented with melanin, lying between the tegmentum and crus cerebri destruction of these cells causes Parkinson's disease

Discussion and Conclusion

Hamilton, G. Carroll, K. DeHaan, R. Parkinson, A. J. Biochem. Mol. Toxicol. 2000, 14, 177-188. 28. Madan, A. Usuki, E. Burton, L. A. Ogilvie, B. W Parkinson, A. Drugs and Pharmaceutical Sciences. In Drug-Drug Interactions Rodriguez, A. D., Ed. Marcel Dekker New York, 2002 Vol. 116, pp 217-294. 92. LeCluyse, E. L. Madan, A. Hamilton, G. Caroll, K. Dehaan, R. Parkinson, A. J. Biochem. Mol. Toxicol. 2000, 14, 177-188.

Fields Of Expertise Within Toxicology

The central nervous system is one of the most complex organs in living systems 17 . Neurotoxicity can be manifested rather globally, or very specifically, depending on the poison. One example of a very specific toxicity occurs with MPTP, a notorious meperidine analogue that can destroy the substantia nigra and leads to a very severe Parkinson-like syndrome. Another example of rather global neurotoxicity occurs with lead encephalopathy. Other metals can also be highly neurotoxic.

RCH2NR2R3 O2 H2O rcho hnr2r3 H2O2

(MPTP) is an interesting example of metabolism-related selective toxicity. It is toxified via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP +) to the 1-methyl-4-phenyl pyridinium salt (MPP+). MPP+ is taken up by a high-affinity reuptake system specifically localized in the nigrostriatal dopaminergic neurons and blocks their mitochondrial energy metabolism. This leads to death of these neurons, which causes Parkinson's disease. Within the neurons only MAO can metabolize MPTP, while in other tissues CYP- and FMO-catalyzed detoxification reactions compete with MAO for the substrate. This combination of selective uptake into cells possessing a selective pattern of drug-metabolizing enzymes causes the selective neurotoxicity. MPTP is an experimental chemical. Related compounds such as beta-carboline or tetrahydroisoquinoline are present at low concentrations in food. Whether they behave in a similar way to MPTP and therefore are neurotoxicologically important by...

More Products

All About Parkinsons Disease

Download The Parkinson's-Reversing Breakthrough Now

You can safely download your risk free copy of The Parkinson's-Reversing Breakthrough from the special discount link below.

Download Now