Park2

PARK2 is an autosomal recessive familial PD caused by mutations of parkin. Clinical features of PARK2 were first described by Yamamura et al. (1973). They reported 16 patients (13 familial patients in 5 unrelated families and 3 sporadic cases) clinical features of 11 patients from the initial 4 families were essentially identical. Ages of onset were between 17 and 28 years in 10 out of 11 patients and 42 in the remaining one. All the patients showed tremor, rigidity, bradykinesia, and postural...

Sleep fragmentation

Nocturnal sleep disturbances and excessive daytime sleepiness are frequent in Parkinson's disease. Nocturnal sleep disturbance affects from 60 to 98 of patients with Parkinson's Disease (PD) (Kales et al., 1971 Lees et al., 1988 Larsen, 2003). Of these, approximately 25 report moderate to severe nighttime sleep problems (Tandberg et al., 1999). The most common nighttime sleep complaint of PD patients is frequent nocturnal awakenings or sleep fragmentation (Factor et al., 1990). In comparison to...

C G Goetz

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA Summary. Several new advances facilitate current understanding of the progression of Parkinson's disease. The application of statistical modeling techniques has helped to estimate rates of clinical decline in the context of symptomatic interventions. These approaches may allow a new means for testing neuroprotection effects even when patients are on dopaminergic treatment. Further, the development of new...

The discovery of the pressor effect of DOPS and its blunting by decarboxylase inhibitors

Mount Sinai School of Medicine, New York, NY, USA Summary. In the 1950s it was found that an artificial aminoacid, 3,4-threo-dihydroxy-phenylserine (DOPS), was converted to nor-epinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxy-lase (AADC), bypassing the need for the rate limiting enzyme dopamine beta hydroxylase. Trying to replicate the success of dihydroxy-phenylalanine (DOPA) in the treatment of Parkinson disease, treatment with DOPS was attempted in patients...

DA is severely reduced in PD striatum

Several eyewitness accounts have recently been written about the historical events and consequences of the discovery of the DA deficiency in PD (Sourkes, 2000 Hornykiewicz, 2001a, b, 2002a, b). Early in 1959, Hornykiewicz, aware of DA's localisation in the basal ganglia, started a study on DA in postmortem brain of patients with PD and other basal ganglia disorders. He and his collaborator Herbert Ehringer analyzed the brains of 17 adult non-neurological controls, 6 brains of patients with...

Sleep and hallucinations

Approximately 40 of PD patients have dopaminergic drug induced hallucinations (Fenelon et al., 2000). Up to 82 of PD patients with drug-induced hallucinations (Pappert et al., 1999) have a sleep disturbance. A recent clinic based study showed that three factors are independently predictive of visual hallucinations severe cognitive impairment, duration of PD and daytime sleepiness (Fenelon et al., 2000). Abnormalities in REM sleep have also been associated with the occurrence of hallucinations...

Vision

When asked about vision (Lee and Harris, 1999) PD patients report problems 1) judging distance and motion in the street, 2) reaching for objects, and 3) moving through narrow spaces within their homes. ''It's not as simple as it looks I am still going, but I have run out of space to move in my space, our space, is nothing like your space our space gets bigger and smaller '' (from a parkinsonian patient, in Sacks, 1990). Primary visual processes in PD have been summarized in recent reviews...

Pathophysiology of dystonia M Hallett

Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA Summary. Understanding of the pathophysiology of dystonia derives primarily from studies of focal dystonias. Physiological investigations have revealed a number of abnormalities that may reflect the genetic substrate that predisposes certain individuals to develop dystonia. There is a loss of inhibition in the central nervous system, and a loss of surround inhibition specifically. Plasticity is increased, and there are sensory...

Origin and specification of mDA neurons

Specification of neuronal fates begins with the acquisition of anterior-posterior (A P) Fig. 1. Schematic representation of the anterior posterior (A) and dorsal ventral (B) patterning of the brain and the emergence of mDA neurons (red) with specific identity to regional molecular coding. A Drawing of an E12.5 mouse brain in a sagittal plane showing the location of fully differentiated mDA neurons (red) in specific brain segments (M-P3). B Drawing of an E12.5 mouse midbrain in a coronal plane,...

Potential sources of increased SN iron in PD

Iron misregulation in the brain may have genetic and non-genetic causes. There are several rare movement disorders associated with neurodegeneration, and genetic abnormalities in iron regulation resulting in iron deposition in the brain (Thomas and Jankovic, 2004). For example, patients with neuroferritinopa-thy suffer from parkinsonism and the iron deposition in the basal ganglia is caused by a mutation in the gene encoding the ferritin light chain on chromosome 19q13.3. Non-genetic causes of...

Hypersomnolence excessive daytime sleepiness EDS in PD

Excessive daytime sleepiness (EDS) is a frequent complaint of PD patients. The description of ''sleep attacks'' and motor vehicle accidents in PD patients taking either pramipexole or ropinirole published in 1999 stimulated interest in this topic (Frucht et al., 1999). In one community based study (Tandberg et al., 1999), EDS was seen in 15.5 of PD patients compared to 4 of patients with diabetes mellitus and 1 of controls. EDS was associated with more severe PD, greater PD-related disability,...

Criteria for success are essentially the result of team cooperation

The patient's selection is extremely important, concerning essentially idiopathic Parkinson's disease and the quality of the levodopa response is one of the major predictors of success (Charles et al., 2002). The surgical procedure depends on the quality of the targeting which is based on neuroradiology but also on electrophysiology using micro recording as stimulation and the quality of the surgical steps. The microrecording is quite often debated and, depending on the teams, might be...

Material and methods

Mesencephalic cell cultures were prepared from the ventral mesencephalon of day 15.5 rat embryos (Lannuzel et al., 2002, 2003). Survival of dopaminergic neurons was quantified by counting the number of cells immunoreactive for tyrosine hydroxylase (TH) and all neurons, regardless of their neurotransmitter immuno-reactive for microtubule-associated protein-2 (MAP-2). Extraction of alkaloids and annonacin The roots of A. muricata were dried, powdered and extracted with methanol (Lannuzel et al.,...

Hallucinations

The association between sleep fragmentation, vivid dreams and hallucinations in PD was reported early in cross-sectional studies, but not confirmed in a recent prospective longitudinal study by Goetz et al. (2005). On the other hand, Pachetti et al. (2005) recently reported in a large group of PD patients that hallucinations were two to three times more frequent in patients with RBD than without. This was the first time this association was examined, making RBD an independent risk factor for...

M30 a novel multifunctional neuroprotective drug with potent iron chelating and brain selective monoamine oxidaseab

Zheng2, and M. B. H. Youdim1 1 Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Technion-Faculty of Medicine, Haifa, and 2 Weizmann Institute of Science, Department of Organic Chemistry, Rehovot, Israel Summary. Iron and monoamine oxidase activity are increased in brain of Parkinson's disease (PD). They are associated with autoxidation and oxidative deamination of dopa-mine by MAO resulting in the generation...

Statistical modeling to document disease progression

The Unified Parkinson's Disease Rating Scale is the most widely utilized tool for rating PD impairment and disability (Fahn et al., 1987). It has gained world-wide acceptance and is the primary end-point measure for most PD-related clinical trials. Its clinimetric profile has been established over two decades since its development, and reliability validity testing has corroborated its value (Goetz et al., 2003). The scale consists of four sub-scales with scores that can be summed for a Total...

Pathophysiology of olfactory deficits in Parkinsons disease

Oxidative stress-induced degeneration of do-paminergic neurons in the substantia nigra is an important pathological feature of PD. The presence of numerous dopaminergic neurons in the olfactory bulb might lead one to assume that olfactory dysfunction in PD is related to a loss of these neurons. In an effort to substantiate this assumption, anatomists in our research institute performed a quantitative analysis of the number of do-pamine neurons in the post-mortem human olfactory bulb. Quite...

CYP2D6 phenotypic variability

CYP2D6 has attracted great attention to PD researchers because it participates in the metabolism of the parkinsonism-inducing toxin MPTP, herbicides (like atrazine and paraquat) and organophosphate pesticides. Moreover, it has been long known that there is considerable phenotypic variability in the enzyme activity of CYP2D6. CYP2D6 activity (or phenotype) was traditionally measured phar-macokinetically in terms of a metabolic ratio (MR), defined as the ratio of parent substrate (usually...

Amphetamines toxicity

Substituted amphetamines, namely metham-phetamine (MA) and methylen-dioxymeth-amphetamine, are widely used to induce selective nigrostriatal DA degeneration in mice. Both amphetamines induce the formation of multilamellar inclusion bodies ( ' ' whorls'') in nigral DA neurons (Figs. 1,2), which can be stained by antibodies against a-synuclein and ubiquitin (Fornai et al., 2004). These effects occur after few repeated, two h apart, neurotoxin administration, as opposed to what observed with bolus...

Antiapoptotic gene therapy in Parkinsons disease

Department of Neurodegeneration & Restorative Research, Center of Neurology and DFG Research Center Molecular Physiology of the Brain'' (CMPB), University of G ttingen, G ttingen, Germany Summary. Apoptosis, whether caspase-dependent or caspase-independent, has been implicated as one of the important mechanisms leading to the death of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Major advances of our understanding of apoptosis have been achieved in studies of...

Two practical consequences

Inaugurating the nigrostriatal DA pathway When the DA deficiency in PD was discovered, nothing was known about DA's cellular localisation in the brain. In Huntington's disease, Ehringer and Hornykiewicz (1960) had found normal striatal DA. Since in Huntington's disease there is a severe loss of striatal neurons accompanied by marked gliosis, the normal striatal DA suggested that the amine was probably contained in terminals of fibre tracts originating outside the striatum. Rolf Hassler had...

UPDRS revision Mdsupdrs

As part of a program to evaluate scales in use for assessing PD, a Movement Disorder Society Task (MDS) Force conducted a critique of the UDPRS in 2003. Because several advances in the current understanding of PD had occurred since the scale was originally developed, the Task Force recommended a revision (Goetz et al., 2003). Based on this critique, the MDS initiated this process in 2004, has developed a new scale, termed the MDS-UPDRS, and clinimetric testing will conclude in 2007 (Goetz et...

References

Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3 1301-1306 Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein dye binding. Anal Biochem 72 248-254 Crow JP (1997) Dichlorodihydrofluorescein and dihy-drorhodamine 123 are sensitive indicators of peroxynitrite in vivo Implications for...

New face of neuromelanin K L Double and G M Halliday

Prince of Wales Medical Research Institute, Sydney, Australia Summary. The massive, early and relatively circumscribed death of the dopaminergic neurons of the substantia nigra in Parkinson's disease has not yet been adequately explained. The characteristic feature of this brain region is the presence of neuromelanin pigment within the vulnerable neurons. We suggest that neuromelanin in the Parkinson's disease brain differs to that in the normal brain. The interaction of neuromelanin with iron...

Molecular mechanisms of Park2

Recently, two groups independently reported the generation of model mice lacking the parkin gene, which display certain abnormalities of dopamine metabolism (Itier et al., 2003 Goldberg et al., 2003). However, these parkin knockout mice had only subtle phenotypes exhibiting grossly normal brain morphology. In contrast, full-length human parkin antisense knocked-down endogenous parkin protein in differentiated human neuroblastoma cells (SH-SY5Y), 12 to 36 hours after infection and reduced cell...

The nigrostriatal DA pathway and PD

In sporadic PD there is increasing evidence that mitochondrial dysfunction, with reduced formation of ATP and increased formation of reactive oxygen species (ROS) leading to oxidative damage, plays an important role in the pathogenesis (Dauer and Przedborski, 2003 Beal, 2000). Both genetic susceptibility factors and environmental factors such as toxins, virus infections and hypercaloric diet may be involved in the etiology (Barja, 2004 Fuente-Fernandez and Calne, 2002). Braak et al. (2004) have...

Y Mizuno N Hattori H Yoshino Y Hatano K Satoh H Tomiyama and Y Li

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan Summary. To date 11 forms of familial Parkinson's disease (PD) have been mapped to different chromosome loci, of which 6 genes have been identified as the causative genes, i.e., alpha-synuclein (SNCA),parkin, UCH-L1, PINK1, DJ-1, and LRRK2. For UCH-L1, additional families with this mutation are necessary before concluding that UCH-L1 is the definite causative gene for PARK5, as only one family so far has been...

Role of iron metabolism in the pathogenesis of PD

Iron is increasingly implicated in the pathogenesis of PD. However, it is not clear yet, whether the increase of iron in PD is a secondary phenomenon or a causal factor of neuronal death. Results of transcranial ultrasound studies indicate that this method is valuable to detect an alteration of the sub-stantia nigra (SN) in PD that is associated with increased SN iron content (''SN hyper-echogenicity'') (Berg et al., 2002). A familiar predisposition to SN hyperechogenicity indicates a possible...

Placebo Effect And Reward Circuitry

Theoretical model for the placebo effect The expectation of reward (i.e., expectation of clinical benefit) after placebo administration activates dopamine (DA) neurons of the ventral tegmental area (VTA), which leads to the release of dopamine (DA) not only in the ventral striatum (nucleus accumbens, NAcc), but also in the prefrontal cortex (PFC). This PFC activation, in turn, sets in motion disease-specific mechanisms, such as DA release in the dorsal striatum to improve motor function...

Introduction

In 1985, a member of our group serendipi-tously achieved unexpected data on MPTP toxicity by demostrating, for the first time, that a compound, diethyldithiocarbamate (DDC), potentiates MPTP toxicity in the mouse model (Corsini, 1985). The DDC-induced enhancement of MPTP toxicity in mice has been extensively confirmed by numerous reports in which Authors give the results of their studies on MPTP metabolism in general and on MPP+ kinetics (the toxic metabolite) in particular, pursuing the...

Cardiac and extracardiac noradrenergic denervation in PD OH

More than 25 studies over the past several years have agreed remarkably on the finding that virtually all patients with PD have a loss of sympathetic innervation of the heart, as demonstrated by low myocardial concentrations of radioactivity after injection of the sympathoneural imaging agents, 123I-metaiodobenzylguanidine and 6- 18F fluorodopamine, neurochemical assessments during right heart catheterization (Goldstein et al., 2000), and post-mortem histopathol-ogy (Orimo et al., 2001, 2002...

C L Comella

Neurological Sciences, Rush University Medical Center, Chicago, IL, USA Summary. Sleep disturbances are frequent in Parkinson disease. These disorders can be broadly categorized into those that involve nocturnal sleep and excessive daytime sleepiness. The disorders that are often observed during the night in PD include sleep fragmentation that may be due to recurrent PD symptoms, sleep apnea, Restless Leg Syndrome periodic limb movements and REM sleep behavior disorder. Excessive daytime...

Cyp2d6

This CYP has been most often associated with Parkinson's disease CYP2D6 inactivates the neurotoxins MPTP and TIQ as well as a variety of pesticides and endogenous neurochemicals. Genetic variation affects CYP2D6 expression levels in brain in the same way as in liver, for example individuals who are heterozygous for the *4 deletion allele have lower brain CYP2D6 levels than wild type individuals, and individuals homo-zygous for the *4 allele do not express CYP2D6 in brain, as found in liver...

The heterogeneity of midbrain dopaminergic mDA neurons

The mDA system (A8-A10 cell groups) is involved in many brain functions including motor control, reward, emotional and motivated behavior, and is of clinical importance because of its implication in neurological and psychiatric disorders. The A9 cell group located in the substantia nigra pars compacta (SNc) has preferred projections to the dorsal striatum forming the nigrostriatal pathway, which is involved in the control of movement. The mDA system further includes the ventral tegmental area...

Kynurenines and other neurodegenerative disorders

The kynurenines are known to exert noteworthy neuroactive properties on the excitatory glutamate receptors, in particular on the NMDA receptors. The neurotoxic effects of excitatory amino acids play an important role in the pathogenesis of various neurodegenera-tive disorders, causing impairment in the cellular energy metabolism. Glutamate-mediated excitotoxic damage decreases the voltage-dependent Mg2+ blockade, causes abnormalities in cellular Ca2+ homeostasis and elevates the production of...

Triggering endogenous neuroprotective mechanisms in Parkinsons disease studies with a cellular model

Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA Summary. Glial cell line-derived neuro-trophic factor (GDNF) has been implicated in the protection of dopamine (DA) neurons from oxidative stress in animal models of Parkinson's disease (PD). We have now shown that GDNF can also protect against the effects of 6-hydroxydopamine (6-OHDA) in a dopaminergic cell line and in cultures of primary DA neurons prepared from rat sub-stantia nigra (SN). This appears to involve a rapid...

Decreased Ferritin In Substantia Nigra Parkinson

Aisen P, Leibman A (1972) Lactoferrin and transferrin a comparative study. Biochem Biophys Acta 257 314-323 Aisen P, Wessling-Resnick M, Leibold EA (1999) Iron metabolism. Curr Opin Chem Biol 3 200-206 Anderson BF, Baker HM, Norris GE, Rice DW, Baker EN (1989) Structure of human lactoferrin crystal-lographic structure analysis and refinement at 2.8A resolution. J Molec Biol 209 711-734 Andrew R, Watson DG, Bet SA, Midgley JM, Wenlong H, Perry RK (1993) The determination of 6-hydro-xydopamines...

Outlook

Eight years after the identification of the involvement of a-synuclein in the pathogenesis of PD, the genetic cause of a large number of familial PD cases has been identified. The number of PD genes has been grown to six but will increase even further. In addition, several susceptibility genes such as Omi HtrA2, synphilin-1, ceruloplasmin, and per-iphilin have been identified and extend our understanding of the neurodegenerative process. With the generation of numerous animal models...

Overview of dopaminergic development in zebrafish

The formation of dopaminergic groups has been studied by analysis of expression of tyrosine hydroxylase (th), dopamine transporter (dat), and dopamine beta hydroxylase (dbh) (Holzschuh et al., 2001, 2003a) as well as by immunohistochemistry for Tyrosine hydroxylase (TH) (Kaslin and Panula, 2001 Rink and Wullimann, 2002). We will focus here on the embryonic and larval DA systems -additional small DA groups may be present in adult zebrafish. While we try to use the prosomere model (Puelles and...

Clues from analytic studies

In analytic epidemiologic studies, proposed risk factors for disease are compared between persons with PD (cases) and those without PD (controls). A critical limitation of this approach is the inability to directly determine whether an association between a risk factor and PD is causative. In humans, ethical considerations limit experiments to prevention and treatment experiments investigating causes are performed in animals, and results may not easily be extrapolated to humans. In general,...

A new look at levodopa based on the Elldopa study

Department of Neurology, Columbia University, New York, NY, USA Summary. Levodopa has been the gold standard for Parkinson's disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these...

Receptorreceptor interactions and development of A2A antagonists for treatment of PD

The first indications for the existence of intramembrane receptor-receptor interactions were obtained in 1980 with substance P modulating the binding characteristics of high affinity 5-HT agonist binding sites in membrane preparations of the CNS, reflecting a possible increase in the number of high affinity 5-HT agonist binding sites (Agnati et al., 1980b). In 1981 it was possible to demonstrate that CCK-8 modulated the affinity and number of striatal D2 antagonist binding sites (Fuxe et al.,...

Parkinsons disease premotor clinicopathological correlations E Ch Wolters1 and H Braak2

1 Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands 2 Institute for Clinical Neuroanatomy, J.W. Goethe University, Frankfurt Main, Germany Summary. Parkinsonism is a clinical syndrome characterized by bradykinesia, hypo- akinesia, muscular rigidity, and resting tremor, mainly caused by Parkinson's disease PD . Progressive loss of nigral neurons with Lewy bodies is considered an essential neuro-pathological feature. Recent studies, however, indicate that nigral...

The MPTP model

1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine MPTP is a neurotoxin which is widely used as an experimental tool to induce nigrostria-tal degeneration in mice. After administration of neurotoxic regimens of MPTP a marked loss of striatal DA can be observed. However, with the schedules of MPTP administration usually employed, i.e. 2-3 bolus injections a few h apart, nigrostriatal degeneration is not associated with the onset of inclusion bodies in DA neurons. The mechanism of action of MPTP is...

Ladostigil a novel multifunctional drug for the treatment of dementia comorbid with depression

Bejar1, and S. Shoham2 1 Department of Pharmacology, Hebrew University Hadassah School of Medicine, and 2 Research Department, Herzog Hospital Jerusalem, Israel Summary. Ladostigil is a novel drug that inhibits acetyl and butyrylcholinesterase, and monoamine oxidase MAO A and B selectively in the brain. It reverses memory deficits induced by chronic inhibition of cortical cytochrome oxidase in rats and has anxiolytic and antidepressant-like activity in...

Involvement of multiple survival signal transduction pathways in the neuroprotective neurorescue and APP processing

Sagi, S. Mandel, and M. B. H. Youdim Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel Summary. Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase MAO -B...

Animal models of Parkinsons disease based on a genetic etiology

Several genes and loci involved in inherited forms of PD have been identified during the past ten years. It is anticipated that more mutations will be identified in the coming years for already identified loci or newly characterized inherited forms of the disease. Animal models based on a mutation in the PARK-1 gene a-synuclein have attracted great interest because the protein that is modified in this form of the disease accumulates in Lewy bodies in sporadic cases of PD. Thus, even though...

Ravindranath R P Kommaddi and H V

Division of Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana, India Summary. Cytochromes P450 is a family of heme proteins that metabolize xenobiotics including drugs. Unique human brain cyto-chrome P450 enzymes metabolize xenobiotics including drugs to active inactive metabolites through biotransformation pathways that are different from the well-characterized ones in liver. We have identified an alternate spliced functional transcript of...

The Hoehn and Yahr Scale 1967

It is a truism that Parkinson's Disease was and is a clinical diagnosis there are no laboratory tests, no imaging techniques, no genetic markers to confirm the diagnosis. It is the clinician's decision. This judgment nicely combines the art and science of medicine but the first attempt to supply a scientific basis for this judgment appeared in Hoehn and Yahr 1967 . This is Melvin Yahr's most famous paper at least 2886 citations by mid-January, 2004 because it laid the foundation for measuring...