Parkinson's Disease Reviews: 2003
(212 References)
(2003). "The diagnosis of Parkinson's disease." Neurol Sci 24 Suppl 3: S157-64.
(2003). "Diagnosis and treatment of Parkinson's disease: a systematic review of the literature." Evid Rep Technol Assess (Summ)(57): 1-4.
(2003). "Glossary of the clinical manifestations of Parkinson's disease." Neurol Sci 24 Suppl 3: S214-5.
(2003). "Treatment of Parkinson's disease." Neurol Sci 24 Suppl 3: S165-213.
Abbruzzese, G. and A. Berardelli (2003). "Sensorimotor integration in movement disorders." Mov Disord 18(3): 231-40.
Although current knowledge attributes movement disorders to a dysfunction of the basal ganglia-motor cortex circuits, abnormalities in the peripheral afferent inputs or in their central processing may interfere with motor program execution. We review the abnormalities of sensorimotor integration described in the various types of movement disorders. Several observations, including those of parkinsonian patients' excessive reliance on ongoing visual information during movement tasks, suggest that proprioception is defective in Parkinson's disease (PD). The disturbance of proprioceptive regulation, possibly related to the occurrence of abnormal muscle-stretch reflexes, might be important for generating hypometric or bradykinetic movements. Studies with somatosensory evoked potentials (SEPs), prepulse inhibition, and event-related potentials support the hypothesis of central abnormalities of sensorimotor integration in PD. In Huntington's disease (HD), changes in SEPs and long-latency stretch reflexes suggest that a defective gating of peripheral afferent input to the brain might impair sensorimotor integration in cortical motor areas, thus interfering with the processing of motor programs. Defective motor programming might contribute to some features of motor impairment in HD. Sensory symptoms are frequent in focal dystonia and sensory manipulation can modify the dystonic movements. In addition, specific sensory functions (kinaesthesia, spatial-temporal discrimination) can be impaired in patients with focal hand dystonia, thus leading to a "sensory overflow." Sensory input may be abnormal and trigger focal dystonia, or defective "gating" may cause an input-output mismatch in specific motor programs. Altogether, several observations strongly support the idea that sensorimotor integration is impaired in focal dystonia. Although elemental sensation is normal in patients with tics, tics can be associated with sensory phenomena. Some neurophysiological studies suggest that an altered "gating" mechanism also underlies the development of tics. This review underlines the importance of abnormal sensorimotor integration in the pathophysiology of movement disorders. Although the physiological mechanism remains unclear, the defect is of special clinical relevance in determining the development of focal dystonia.
Abosch, A. and A. Lozano (2003). "Stereotactic neurosurgery for movement disorders." Can J Neurol Sci 30 Suppl 1: S72-82.
Stereotactic neurosurgery for the treatment of movement disorders focuses primarily on the treatment of Parkinson's disease (PD), essential tremor (ET), and dystonia. The surgical targets in use are the subthalamic nucleus (STN) and the globus pallidus internus (GPi) for PD, GPi for dystonia, and ventralis intermedius (Vim) nucleus of the thalamus for ET. Following target selection, procedures include the generation of lesions or the placement of deep brain stimulating electrodes in the selected target. Additionally, transplantation has been used in the treatment of PD. The indications, outcomes, and risks of the various procedures are reviewed.
Agid, Y., I. Arnulf, et al. (2003). "Parkinson's disease is a neuropsychiatric disorder." Adv Neurol 91: 365-70.
Ahlskog, J. E. (2003). "Parkinson's disease: is the initial treatment established?" Curr Neurol Neurosci Rep 3(4): 289-95.
Recent studies have suggested that initial dopamine agonist therapy with pramipexole or ropinirole may slow the progression of Parkinson's disease (PD) and also reduce the subsequent risk of levodopa motor complications. This presumed effect on PD progression, however, could be artifactual, resulting from the influence of chronic drug treatment on regulation of dopamine system proteins. With respect to levodopa motor complications, there is no dispute that pramipexole and ropinirole are effective in reducing levodopa dyskinesias and motor fluctuations; however, it is not clear that they must be started early, as opposed to initiation only after the levodopa complications develop. Levodopa therapy has numerous advantages that include greater efficacy, much lesser expense, simpler administration, and a lower frequency of hallucinosis and somnolence. Carbidopa/levodopa, pramipexole, and ropinirole are all appropriate first choices in the treatment of PD.
Ahlskog, J. E. (2003). "Slowing Parkinson's disease progression: recent dopamine agonist trials." Neurology 60(3): 381-9.
In recent clinical trials, chronic treatment of patients with PD with pramipexole or ropinirole was associated with a slower decline of imaged striatal dopaminergic signal, compared to levodopa monotherapy. Although this could reflect slowed progression of PD, equally plausible is a pharmacologic effect on proteins that interact with the imaging radioligands. To date, there is no compelling evidence favoring dopamine agonists over levodopa; either is an appropriate choice for initial treatment of PD.
Albanese, A. (2003). "Diagnostic criteria for Parkinson's disease." Neurol Sci 24 Suppl 1: S23-6.
The diagnosis of Parkinson's disease is not easy. Developments in basic research have indicated pathophysiological links among parkinsonian syndromes that are still classified as independent entities. On the other hand, genetic studies are dividing forms that fit into the clinical diagnosis of Parkinson's disease. The diagnostic criteria used in current practice are by no means satisfactory, but cannot yet be replaced by new comprehensive criteria based on laboratory evidence.
Albanese, A. and C. Colosimo (2003). "Dihydroergocriptine in Parkinson's disease: clinical efficacy and comparison with other dopamine agonists." Acta Neurol Scand 107(5): 349-55.
The present paper reviews clinical studies on the use of dihydroergocriptine (DHEC), an ergot derivative with dopamine agonist activity, for the treatment of Parkinson's disease. This compound is a hydrogenated ergot derivative structurally quite similar to bromocriptine, from which it differs because of the hydrogenation in C9 C10 and the lack of bromine in C2. DHEC has a potent D2-like receptor agonist and a partial D1-like receptor agonist activity; because of this biochemical profile, it has been suggested that DHEC may produce fewer side-effects and have clinical efficacy equal to that of a classical dopamine agonist. Several open-label and double-blind studies indicate that DHEC is an efficacious remedy for parkinsonian signs and symptoms. Further studies are necessary to compare DHEC to new dopamine agonists (pergolide, cabergoline, ropinirole, and pramipexole) which have been more recently marketed.
Albin, R. L. and K. A. Frey (2003). "Initial agonist treatment of Parkinson disease: a critique." Neurology 60(3): 390-4.
The evidence supporting initial dopamine agonist treatment of PD is reviewed. The two rationales for initial agonist treatment are reduced frequency of motor complications and possible relative neuroprotection by dopamine agonists. The basic science supporting these rationales is equivocal. The clinical evidence for advantages of initial agonist treatment is incomplete. More data are required to determine the optimal initial treatment for PD.
Alves da Costa, C. (2003). "Recent advances on alpha-synuclein cell biology: functions and dysfunctions." Curr Mol Med 3(1): 17-24.
Alpha-synuclein is a recently discovered protein that was first identified as the major non amyloid component of senile plaques, the cerebral lesion likely responsible for Alzheimer's disease. The role of alpha-synuclein in another brain disease namely Parkinson's disease, has been more deeply documented. It appears that alpha-synuclein fills up the intracytoplasmic inclusions called Lewy bodies that likely contribute to the etiology of Parkinson's disease. Furthermore, rare familial forms of Parkinson's disease have been shown to be linked to autosomal dominant mutations of alpha-synucleins. Is alpha-synuclein a bridge between Alzheimer's and Parkinson's diseases? Could it be seen as a common denominator for these two neurodegenerative diseases? These issues could be better addressed by further delineating the physiological function of alpha-synuclein and, as a corollary, the dysfunction taking place along with the diseases. Here, I will review the recent advances concerning the physiology of alpha-synuclein and will particularly focus on the post-traductional events leading to drastic biophysical transformations. I will describe recent works suggesting that these modifications directly modulate the normal function of alpha-synuclein, likely accounting for the dysfunction associated with Parkinson's disease and perhaps contributing to Alzheimer's pathology.
Anderson, K. E. and J. Mullins (2003). "Behavioral changes associated with deep brain stimulation surgery for Parkinson's disease." Curr Neurol Neurosci Rep 3(4): 306-13.
Evaluation for psychiatric and cognitive dysfunction is a crucial part of preoperative assessment for deep brain stimulation (DBS) surgery. All candidates for DBS should be treated for active psychiatric disorders, and the treatment team should also screen for past psychiatric history, which may predispose to postoperative psychiatric illness. A wide range of behavioral symptoms have been seen following DBS, including depression, hallucinations or true psychosis, mania, and impulsivity. Suicidal ideation should be treated aggressively. Cognitive changes may occur, but data are currently too limited to make predictions regarding subtle effects on cognition. However, patients with dementia may experience further decline in cognitive function following DBS.
Andrade, M. J. and A. Trepa (2003). "[Vesical-sphincter dysfunction in the Parkinsonism]." Acta Med Port 16(1): 21-4.
Further to a brief review of the vesical-sphincterian neuroanatomy and neurophisology, we analyse the vesical-sphincterian dysfunction in the Parkinson disease and its relation with this illness, with the drugs used in its treatment and with eventual prostatic problems. We therefore conclude that each case should be studied individually.
Andrews, R. J. (2003). "Neuroprotection trek--the next generation: neuromodulation I. Techniques--deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation." Ann N Y Acad Sci 993: 1-13; discussion 48-53.
Neuromodulation denotes controlled electrical stimulation of the central or peripheral nervous system. The three forms of neuromodulation described in this paper-deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation-were chosen primarily for their demonstrated or potential clinical usefulness. Deep brain stimulation is a completely implanted technique for improving movement disorders, such as Parkinson's disease, by very focal electrical stimulation of the brain-a technique that employs well-established hardware (electrode and pulse generator/battery). Vagus nerve stimulation is similar to deep brain stimulation in being well-established (for the treatment of refractory epilepsy), completely implanted, and having hardware that can be considered standard at the present time. Vagus nerve stimulation differs from deep brain stimulation, however, in that afferent stimulation of the vagus nerve results in diffuse effects on many regions throughout the brain. Although use of deep brain stimulation for applications beyond movement disorders will no doubt involve placing the stimulating electrode(s) in regions other than the thalamus, subthalamus, or globus pallidus, the use of vagus nerve stimulation for applications beyond epilepsy-for example, depression and eating disorders-is unlikely to require altering the hardware significantly (although stimulation protocols may differ). Transcranial magnetic stimulation is an example of an external or non-implanted, intermittent (at least given the current state of the hardware) stimulation technique, the clinical value of which for neuromodulation and neuroprotection remains to be determined.
Asanuma, M., I. Miyazaki, et al. (2003). "[New aspects of neuroprotective effects of nonsteroidal anti-inflammatory drugs]." Nihon Shinkei Seishin Yakurigaku Zasshi 23(3): 111-9.
Nonsteroidal anti-inflammatory drugs (NSAIDs) exert anti-inflammatory, analgesic and antipyretic activities and are involved in the suppression of prostaglandin synthesis by inhibiting cyclooxygenase (COX), a prostaglandin synthesizing enzyme. It has been recently revealed that NSAIDs also possess inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors and nuclear receptors which are related to inflammatory reactions. Since it has been reported that inflammatory processes are associated with the pathophysiology of several neurodegenerative diseases and that NSAIDs inhibit amyloid beta-protein-induced neurotoxicity to reduce the risk for Alzheimer's disease, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs. It has been clarified that the drugs exert neuroprotective effects, which are not related to their COX-inhibiting property, on pathophysiology of various neurological disorders. In this article, new aspects of neuroprotective effects of NSAIDs have been reviewed, especially, in Alzheimer's disease and Parkinson's disease, discussing various pharmacological effects of NSAIDs other than their inhibitory action on COX.
Asanuma, M., I. Miyazaki, et al. (2003). "Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease." Neurotox Res 5(3): 165-76.
Dopamine (DA)- or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to be involved not only in adverse reactions induced by long-term L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA- or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-alpha-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The melanin-synthetic enzyme tyrosinase in the brain may rapidly oxidize excess amounts of cytosolic DA and L-DOPA, thereby preventing slowly progressive cell damage by auto-oxidation of DA, thus maintainng DA levels. Since tyrosinase also possesses catecholamine-synthesizing activity in the absence of tyrosine hydroxylase (TH), the double-edged synthesizing and oxidizing functions of tyrosinase in the dopaminergic system suggest its potential for application in the synthesis of DA, instead of TH in the degeneration of dopaminergic neurons, and in the normalization of abnormal DA turnover in the long-term L-DOPA-treated Parkinson's disease patients.
Barzilai, A., D. Daily, et al. (2003). "The molecular mechanisms of dopamine toxicity." Adv Neurol 91: 73-82.
Beal, M. F. (2003). "Mitochondria, oxidative damage, and inflammation in Parkinson's disease." Ann N Y Acad Sci 991: 120-31.
The pathogenesis of Parkinson's disease (PD) remains obscure, but there is increasing evidence that impairment of mitochondrial function, oxidative damage, and inflammation are contributing factors. The present paper reviews the experimental and clinical evidence implicating these processes in PD. There is substantial evidence that there is a deficiency of complex I activity of the mitochondrial electron transport chain in PD. There is also evidence for increased numbers of activated microglia in both PD postmortem tissue as well as in animal models of PD. Impaired mitochondrial function and activated microglia may both contribute to oxidative damage in PD. A number of therapies targeting inflammation and mitochondrial dysfunction are efficacious in the MPTP model of PD. Of these, coenzyme Q(10) appears to be particularly promising based on the results of a recent phase 2 clinical trial in which it significantly slowed the progression of PD.
Beal, M. F. (2003). "Bioenergetic approaches for neuroprotection in Parkinson's disease." Ann Neurol 53 Suppl 3: S39-47; discussion S47-8.
There is considerable evidence suggesting that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease (PD). This possibility has been strengthened by recent studies in animal models, which have shown that a selective inhibitor of complex I of the electron transport gene can produce an animal model that closely mimics both the biochemical and histopathological findings of PD. Several agents are available that can modulate cellular energy metabolism and that may exert antioxidative effects. There is substantial evidence that mitochondria are a major source of free radicals within the cell. These appear to be produced at both the iron-sulfur clusters of complex I as well as the ubiquinone site. Agents that have shown to be beneficial in animal models of PD include creatine, coenzyme Q(10), Ginkgo biloba, nicotinamide, and acetyl-L-carnitine. Creatine has been shown to be effective in several animal models of neurodegenerative diseases and currently is being evaluated in early stage trials in PD. Similarly, coenzyme Q(10) is also effective in animal models and has shown promising effects both in clinical trials of PD as well as in clinical trials in Huntington's disease and Friedreich's ataxia. Many other agents show good human tolerability. These agents therefore are promising candidates for further study as neuroprotective agents in PD.
Behnke, S., D. Berg, et al. (2003). "Does ultrasound disclose a vulnerability factor for Parkinson's disease?" J Neurol 250 Suppl 1: I24-7.
Transcranial ultrasound is a new tool allowing the detection of abnormalities in the echomorphology of the substantia nigra (SN) in patients with Parkinson's disease (PD). Several lines of evidence suggest that the changes in the echo-pattern represent a risk factor as: i) the majority of PD patients exhibit this echo-feature, ii) the presence of such changes in healthy controls is related to a reduced (18)F-Dopa-uptake and clinical signs of nigrostriatal dysfunction. The reason for the change of echogenicity is suggested to be an increased iron content in the substantia nigra causing oxidative stress and neuronal cell damage. This hypothesis of changes in SN echomorphology reflecting a risk factor of PD has to be proved in longitudinal studies.
Benabid, A. L., L. Vercucil, et al. (2003). "Deep brain stimulation: what does it offer?" Adv Neurol 91: 293-302.
Benecke, R. (2003). "Diffuse Lewy body disease - a clinical syndrome or a disease entity?" J Neurol 250 Suppl 1: I39-42.
Most clinicians and researchers still accept diffuse Lewy body disease (DLBD) as a clinicopathological entity. Dementia with fluctuating cognitive deficits, a parkinsonian syndrome, and visual hallucinations are the core symptoms of this proposed disease entity. From a neuropathological point of view, many examples of patients with progressive dementia showing evidence of extensive Lewy body formation in the cerebral cortex together with the occurrence of Lewy bodies in substantia nigra and locus coeruleus have been identified. Confusingly, a large majority of cases showing typical features of DLBD also present with an Alzheimer pathology in the hippocampus and cerebral cortex. It is far from clear that DLBD represents a specific disease entity rather an intermediate variant between Alzheimer disease and idiopathic parkinsonian syndromes. Nevertheless, from a clinical point of view it may be of importance to characterize patients with a symptomatology of DLBD because important management issues such as avoidance of severe neuroleptic sensitivity reactions, dopaminergic antiparkinsonian treatment and a beneficial response to cholinesterase inhibitors can be applied.
Bezard, E., C. E. Gross, et al. (2003). "Presymptomatic compensation in Parkinson's disease is not dopamine-mediated." Trends Neurosci 26(4): 215-21.
The symptoms of Parkinson's disease (PD) appear only after substantial degeneration of the dopaminergic neuron system (e.g. an 80% depletion of striatal dopamine)--that is, there is a substantive presymptomatic period of the disease. It is widely believed that dopamine-related compensatory mechanisms are responsible for delaying the appearance of symptoms. Recent advances in understanding the presymptomatic phase of PD have increased our understanding of these dopamine-related compensatory mechanisms and have highlighted the role of non-dopamine-mediated mechanisms both within and outside the basal ganglia. This increased knowledge of plasticity within cortical-basal-ganglia-thalamocortical circuitry as dopaminergic neuron degeneration progresses has implications for understanding plasticity in neural circuits generally and, more specifically, for developing novel therapeutics or presymptomatic diagnostics for PD.
Biglan, K. M. and R. G. Holloway (2003). "Surrogate endpoints in Parkinson's disease research." Curr Neurol Neurosci Rep 3(4): 314-20.
Biomarkers are important tools in understanding the underlying mechanisms of causation, progression, and treatment effects in Parkinson's disease (PD). In addition, these biomarkers may be utilized as surrogate endpoints that, when used appropriately, can lead to important advances in therapeutics in a timely and cost-effective manner. This paper outlines the definition, role, validity process, and risks associated with surrogate endpoints. The use of biomarkers in recent PD clinical trials is discussed and potential shortcomings and unanswered questions related to interpreting these outcomes are reviewed. Finally, the significant challenges that lie ahead for validating and interpreting surrogate endpoints in PD are addressed.
Birnboim, S. (2003). "The automatic and controlled information-processing dissociation: is it still relevant?" Neuropsychol Rev 13(1): 19-31.
The purpose of this paper is to examine the "dual-process" information-processing model of Schneider and Shiffrin (Schneider, W., and Shiffrin, R. M., Psychol. Rev. 84: 1-66, 1977; see also Shiffrin, R. M., and Schneider, W., Psychol. Rev. 84: 127-190, 1977) in light of the research data that have accumulated since the model was introduced more than 20 years ago. First, a brief introduction of the basic model of automatic and controlled information processing will be given. Second, some alternatives to the basic model that were developed over the last two decades will be reviewed. Third, data from neuropsychology and cognitive neuroscience that have a bearing upon this framework will be considered. Finally, some comments on the current usefulness of the dual-process framework for neuropsychological research will be offered.
Bjorklund, A., S. B. Dunnett, et al. (2003). "Neural transplantation for the treatment of Parkinson's disease." Lancet Neurol 2(7): 437-45.
Blanchet, P. J. (2003). "The fluctuating Parkinsonian patient--clinical and pathophysiological aspects." Can J Neurol Sci 30 Suppl 1: S19-26.
Although levodopa-related motor response complications remain challenging from a pathophysiological and therapeutic standpoint, major advances have been made in the last decade, supporting the development of several promising drugs. Eventually, these drugs may help us to prevent, alleviate, or even "deprime" these frequent and disabling complications. Knowledge of the basic mechanisms and hypotheses underlying this fascinating conversion in the parkinsonian brain allows neurologists to understand the rationale behind emerging treatment strategies.
Blanchet, P. J., L. V. Metman, et al. (2003). "Renaissance of amantadine in the treatment of Parkinson's disease." Adv Neurol 91: 251-7.
Braak, H., U. Rub, et al. (2003). "Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen." J Neural Transm 110(5): 517-36.
The progressive, neurodegenerative process underlying idiopathic Parkinson's disease is associated with the formation of proteinaceous inclusion bodies that involve a few susceptible neuronal types of the human nervous system. In the lower brain stem, the process begins in the dorsal motor nucleus of the vagus nerve and advances from there essentially upwards through susceptible regions of the medulla oblongata, pontine tegmentum, midbrain, and basal forebrain until it reaches the cerebral cortex. With time, multiple components of the autonomic, limbic, and motor systems become severely impaired. All of the vulnerable subcortical grays and cortical areas are closely interconnected. Incidental cases of idiopathic Parkinson's disease may show involvement of both the enteric nervous system and the dorsal motor nucleus of the vagus nerve. This observation, combined with the working hypothesis that the stereotypic topographic expansion pattern of the lesions may resemble that of a falling row of dominos, prompts the question whether the disorder might originate outside of the central nervous system, caused by a yet unidentified pathogen that is capable of passing the mucosal barrier of the gastrointestinal tract and, via postganglionic enteric neurons, entering the central nervous system along unmyelinated praeganglionic fibers generated from the visceromotor projection cells of the vagus nerve. By way of retrograde axonal and transneuronal transport, such a causative pathogen could reach selectively vulnerable subcortical nuclei and, unimpeded, gain access to the cerebral cortex. The here hypothesized mechanism offers one possible explanation for the sequential and apparently uninterrupted manner in which vulnerable brain regions, subcortical grays and cortical areas become involved in idiopathic Parkinson's disease.
Brandstadter, D. and W. H. Oertel (2003). "Depression in Parkinson's disease." Adv Neurol 91: 371-81.
Broggi, G., A. Franzini, et al. (2003). "Surgery of Parkinson's disease: inclusion criteria and follow-up." Neurol Sci 24 Suppl 1: S38-40.
Parkinson's disease (PD) is a progressive disturbances of movement that affects mainly the motor system. Prolonged pharmacological administration may result in insufficient control of symptoms and significant side effects. Deep brain stimulation (DBS), targeted at the STN, is a recent surgical procedure that, according to the symptoms response, allows modification of stimulation parameters; its effects are also reversible. In this paper management of surgical patients is reported. It includes patient selection, inclusion and exclusion criteria, postoperative clinical protocol. The evaluation rating scale such as UPDRS, Dyskinesias Rating Scale and Self-Reporting Questionnaire usually administrated on PD patients are analyzed. Surgical inclusion criteria are (1) idiopathic PD, (2) IV or V Hoehn-Yahr stage, (3) severe motor disability, and (4) no dementia or psychiatric abnormalities. Postoperative clinical protocol is analyzed and parameter of stimulation after surgery and at the follow up are reported. Generally DBS allows an improvement of rigidity and tremor; bradykinesia also improves with high frequency stimulation. Results obtained by continuous stimulation show a mean improvement of UPDRS of about 60% and a significant reduction in the drug intake.
Brooks, D. J. (2003). "PET studies on the function of dopamine in health and Parkinson's disease." Ann N Y Acad Sci 991: 22-35.
Positron emission tomography (PET) can detect the presence of striatal, pallidal, midbrain, and cortical dopamine terminal dysfunction in vivo in Parkinson's disease (PD). In addition, dopamine release during motor tasks can be assessed as reflected by changes in receptor availability to PET ligands. Furthermore, the functional effects of focal dopamine replacement via implantation of fetal cells or glia-derived neurotrophic factor (GDNF) infusion into putamen can be monitored. In this review, the insight that PET has given us concerning the role of dopamine in motor control is presented, and the functional substrates underlying PD symptomatologies are discussed.
Brooks, D. J. (2003). "Imaging end points for monitoring neuroprotection in Parkinson's disease." Ann Neurol 53 Suppl 3: S110-8; discussion S118-9.
In this review, the potential role of positron emission tomography and single-photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD.
Brotchie, J. M. (2003). "CB1 cannabinoid receptor signalling in Parkinson's disease." Curr Opin Pharmacol 3(1): 54-61.
Signalling at CB(1) cannabinoid receptors plays a key role in the control of movement in health and disease. In recent years, an increased understanding of the physiological role of transmission at CB(1) receptors throughout the basal ganglia circuitry has led to the identification of novel therapeutic approaches to both the symptoms of Parkinson's disease and the side effects of current anti-parkinsonian therapies, especially L(3,4) dihydroxyphenylalamine (levodopa)-induced dyskinesia. Thus, because activation of basal ganglia CB(1) receptors can modulate neurotransmission and contribute to synaptic plasticity in a manner similar to that described in other brain regions, it also appears that endocannabinoids might modulate cell-cell signalling via effects on neurotransmitter re-uptake and postsynaptic actions mediating cross talk between multiple receptor types. Recent studies in animal models and in the clinic suggest that CB(1) receptor antagonists could prove useful in the treatment of parkinsonian symptoms and levodopa-induced dyskinesia, whereas CB(1) receptor agonists could have value in reducing levodopa-induced dyskinesia.
Brown, P. (2003). "Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson's disease." Mov Disord 18(4): 357-63.
Alterations of basal ganglia physiology in parkinsonism may consist of two elements, an increase in the firing rate of neurones and a change in the pattern of synchronisation of discharges between neurones. Recent findings suggest the presence of two principal modes of synchronised activity within the human subthalamo-pallidal-thalamo-cortical circuit, at <30 Hz and >60 Hz. These oscillations are dynamically and systematically modulated by task, thereby suggesting a functional role in movement. More importantly, the two frequency modes are inversely affected by movement, consistent with opposing actions, and differentially expressed according to the prevailing level of dopaminergic activity. It is argued that the balance between these modes determines the effects of basal ganglia-thalamocortical projections on the motor areas of the cortex. The lower frequency oscillations facilitate slow idling rhythms in the motor areas of the cortex, whereas synchronisation at high frequency restores dynamic task-related cortical ensemble activity in the gamma band.
Burke, W. J. (2003). "3,4-dihydroxyphenylacetaldehyde: a potential target for neuroprotective therapy in Parkinson's disease." Curr Drug Target CNS Neurol Disord 2(2): 143-8.
The simplest explanation for the selective loss of substantia nigra (SN) dopamine (DA) neurons in Parkinson's disease (PD) is that DA or a metabolite is neurotoxic. Recently, a series of investigations implicate the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as the critical endogenous toxin which triggers DA neuron loss in PD: 1. Hereditary PD contains mutations in the gene for alpha-synuclein (alpha-syn). Investigations implicate a DA metabolite as mediator of alpha-syn neurotoxicity, and DOPAL is 1000-fold more toxic than DA in vivo. 2. A deficit in mitochondrial complex I is found in PD SN. Inhibition of complex I causes increases in DOPAL levels and death of DA neurons in vitro and in vivo. 3. L-DOPA, the precursor of DA, which is used to treat PD, is toxic and contributes to the progression of PD. L-DOPA-treated rats have an 18-fold increase in striatal DOPAL. 4. Free hydroxyl radicals (.OH) trigger aggregation of alpha-syn to its toxic form. DOPAL with H(2)O(2) generates.OH radicals. These investigations provide several therapeutic strategies to limit DOPAL toxicity and progression of PD: 1. Delaying the start of L-DOPA therapy by early use of DA receptor agonists, which may also be free radical scavengers, limits the amount of DOPAL formed from L-DOPA. 2. Nonspecific MAO inhibitors may more effectively decrease production of DOPAL from DA than MAO-B inhibitors. 3. Newer more potent and targeted free radical scavengers could block DOPAL toxicity. 4. Coenzyme Q(10) increases complex I activity and nicotine adenine dinucleotide (NAD) synthesis, and thereby could enhance DOPAL catabolism by aldehyde dehydrogenase, which uses NAD as a cofactor. 5. DA uptake blockers could be used to limit intraneuronal DOPAL production. 6. Tauroursodeoxycholic acid, an inhibitor of apoptosis shown to be effective in models of Huntington's disease, may also prove effective in blocking DOPAL toxicity in PD. 7. Agents which block aggregation of alpha-syn should limit DOPAL toxicity.
Carbon, M., C. Edwards, et al. (2003). "Functional brain imaging in Parkinson's disease." Adv Neurol 91: 175-81.
Carod-Artal, F. J. (2003). "[Neurological syndromes linked with the intake of plants and fungi containing a toxic component (I). Neurotoxic syndromes caused by the ingestion of plants, seeds and fruits]." Rev Neurol 36(9): 860-71.
INTRODUCTION: A wide range of plants, seeds and fruits used for nutritional and medicinal purposes can give rise to neurotoxic symptoms. DEVELOPMENT: We review the neurological pathology associated with the acute or chronic consumption of plants, seeds and fruits in human beings and in animals. Of the plants that can trigger acute neurotoxic syndromes in humans, some of the most notable include Mandragora officinalis, Datura stramonium, Conium maculatum (hemlock), Coriaria myrtifolia (redoul), Ricinus communis, Gloriosa superba, Catharanthus roseus, Karwinskia humboldtiana and Podophyllum pelatum. We also survey different neurological syndromes linked with the ingestion of vegetable foodstuffs that are rich in cyanogenic glycosides, Jamaican vomiting sickness caused by Blighia sapida, Parkinson dementia ALS of Guam island and exposition to Cycas circinalis, Guadeloupean parkinsonism and exposition to Annonaceae, konzo caused by ingestion of wild manioc and neurolathyrism from ingestion of Lathyrus sativus, the last two being models of motor neurone disease. Locoism is a chronic disease that develops in livestock feeding on plants belonging to Astragalus and Oxytropis sp., Sida carpinifolia and Ipomea carnea, which are rich in swainsonine, a toxin that inhibits the enzyme alpha mannosidase and induces a cerebellar syndrome. CONCLUSIONS: The ingestion of neurotoxic seeds, fruits and plants included in the diet and acute poisoning by certain plants can give rise to different neurological syndromes, some of which are irreversible.
Ceballos-Baumann, A. O. (2003). "Functional imaging in Parkinson's disease: activation studies with PET, fMRI and SPECT." J Neurol 250 Suppl 1: I15-23.
Activation studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) represent a powerful tool to study the functional anatomy of Parkinson's disease (PD). Activation studies offer the opportunity to study regional cerebral function in man in vivo under different conditions with the analysis of task specific changes in regional cerebral blood flow (rCBF) with PET or in the blood oxygenation level dependent (BOLD) effect with fMRI. The combination of PET and deep brain stimulation is particularly attractive to study the effects of discrete perturbations at different target structures throughout the basal ganglia-thalamocortical circuitries. The use of rCBF PET and fMRI to study the pathophysiology of PD in the motor and sensory system and mechanisms of dopaminergic therapy as well as surgical interventions will be reviewed.
Chiocca, E. A. (2003). "Gene therapy: a primer for neurosurgeons." Neurosurgery 53(2): 364-73; discussion 373.
Gene therapy involves the transfer of genes into cells with therapeutic intent. Although several methods can accomplish this, vectors based on viruses still provide the most efficient approach. For neurosurgical purposes, preclinical and clinical applications in the areas of glioma therapy, spinal neurosurgery, and neuroprotection for treatment of Parkinson's disease and cerebral ischemia are reviewed. In general, therapies applied in the neurosurgical realm have proven relatively safe, despite occasional, well-publicized cases of morbidity and death in non-neurosurgical trials. However, continued clinical and preclinical research in this area is critical, to fully elucidate potential toxicities and to generate truly effective treatments that can be applied in neurological diseases.
Clarke, C. E. (2003). "Dopamine agonist monotherapy in early Parkinson's disease." Hosp Med 64(1): 8-11.
While levodopa therapy for Parkinson's disease is still considered the gold standard, motor complications are significant disadvantages of treatment. Monotherapy with dopamine agonists may present an alternative approach with a reduced likelihood of developing dyskinesias. Further studies are required before a definitive judgment can be made.
Collier, T. J., K. Steece-Collier, et al. (2003). "Cellular models to study dopaminergic injury responses." Ann N Y Acad Sci 991: 140-51.
The study of immature midbrain dopamine (DA) neurons and dopaminergic cell lines in culture provides an opportunity to analyze mechanisms of cell death and avenues of potential intervention relevant to Parkinson's disease (PD) in a controlled environment. Use of cell culture models has provided evidence for different sets of intracellular changes associated with DA neuron death following exposure to the neurotoxins 6-hydroxydopamine and MPP+, supporting roles for oxidative stress and impaired energy metabolism as significant factors endangering these cells. Interference with death of cultured DA neurons has provided an initial test system that has yielded all the identified neurotrophic factors for DA neurons. More recent work suggests that combinations of molecules secreted by myelinating glial cells and their precursors provide even greater neuroprotection for DA neurons. Most recently, culture systems have been used to implicate microglial activation in DA neuron injury, providing impetus to the investigation of antiinflammatory agents as potential therapeutics for PD. Thus, cell culture models provide an important bidirectional link between mechanistic studies and clinically relevant observations.
Comella, C. L. (2003). "Sleep disturbances in Parkinson's disease." Curr Neurol Neurosci Rep 3(2): 173-80.
Disorders of sleep and daytime alertness are frequent in Parkinson's disease patients and arise from a number of diverse factors. The most common complaint of night-time sleep disturbance in Parkinson's disease is sleep fragmentation. Sleep fragmentation can be associated with recurrent parkinsonian symptoms, the effect of medications, concomitant medical disorders such as nocturia, or psychiatric disorders such as depression or anxiety. Likewise, nocturnal sleep disturbance may arise from sleep apnea, periodic limb movements of sleep, or rapid eye movement (REM) sleep behavior disorder. Nocturnal sleep deprivation may lead to excessive daytime sleepiness. Other potential sources of daytime sleepiness include the effects of medications or disruption of central sleep mechanisms due to the pathologic processes of Parkinson's disease itself. Diagnosis of sleep disturbances and daytime sleepiness requires a direct interview of the patient and the caregiver, and may involve consultation with the sleep specialist or medical physician. Treatment is aimed toward improving night-time sleep and daytime drowsiness by addressing the causative factors.
Cookson, M. R. (2003). "Parkin's substrates and the pathways leading to neuronal damage." Neuromolecular Med 3(1): 1-13.
CDATA[Mutations in the Parkin gene are associated with Parkinson s disease (PD). The gene product has been shown to be an E3 protein-ubiquitin ligase, catalyzing the addition of ubiquitin to target proteins prior to their destruction via the proteasome. This activity is thus key in regulating the turnover of substrate proteins. A predictive hypothesis for how this results in PD is that the misregulation of proteasomal degradation of Parkin s substrates is deleterious to neurons. Several different laboratories have identified alternate candidate proteins. In this review, the likelihood of each of the proposed substrates for parkin being robust will be evaluated. The distribution and abundance of the proteins will be examined for clues as to which are the pathologically important substrates for parkin. The possibility that loss of regulation of turnover of one or more of these substrates contributes to the selective neurodegeneration seen in PD is also discussed.
Corti, O. and A. Brice (2003). "[Parkinson's disease: what have we learned from the genes responsible for familial forms?]." Med Sci (Paris) 19(5): 613-9.
Parkinson's disease is characterized by the progressive and selective loss of the dopaminergic neurons in the substantia nigra and the presence of ubiquitinated protein inclusions termed Lewy bodies. In the past six years, four genes involved in rare inherited forms of Parkinson's disease have been identified: mutations in the alpha-synuclein and ubiquitin carboxyterminal hydrolase L1 genes (UCH-L1) cause autosomal dominant forms, whereas mutations in the Parkin and DJ-1 genes are responsible for autosomal recessive forms of the disease. A toxic gain of function related to the ability of alpha-synuclein to assemble into insoluble amyloid fibrils may underlie neuronal cell death in parkinsonism due to alpha-synuclein gene mutations. In contrast, loss of protein function appears to be the cause of the disease in parkinsonism due to mutations in the genes encoding Parkin and UCH-L1, which are key enzymes of the ubiquitin-proteasome pathway. The presence of alpha-synuclein, Parkin and UCH-L1 in Lewy bodies suggests that dysfunction of pathways involved in protein folding and degradation is not only involved in the pathogenesis of familial Parkinson's disease, but could also play a role in the frequent sporadic form of the disease (idiopathic Parkinson's disease).
Crevits, L. (2003). "Abnormal psychophysical visual perception in Parkinson's disease patients." Acta Neurol Belg 103(2): 83-7.
Several visual dysfunctions in Parkinson's disease (PD) are described. Most of them are subtle or only demonstrated by stimulus-specific electrophysiologic or psychophysical testing. However, these minor deficits are thought to be of clinical relevance as they are related to direct or indirect complaints. Special emphasis is laid on visual hallucinations. These are most likely of multifactorial origin. The relation between hallucinations in PD and in dementia with Lewy bodies has to be elaborated further. Visual loss, as a possible and reversible cause of visual hallucinations should be actively sought and corrected as far as possible. An underlying role of dopaminergic retinal cells in visual dysfunction of PD patients is widely recognised. However, whether the basic abnormality resides also in the visual cortex remains to be elucidated. Other neurotransmitters may also be involved. It has not been answered whether visual dysfunction might distinguish PD from other forms of parkinsonism.
Crosby, N. J., K. H. Deane, et al. (2003). "Amantadine for dyskinesia in Parkinson's disease." Cochrane Database Syst Rev(2): CD003467.
BACKGROUND: Abnormal involuntary movements known as dyskinesias are amongst the most disabling side-effects of levodopa therapy. It is thought that amantadine, an NMDA-receptor antagonist, may reduce dyskinesias in patients with Parkinson's disease without worsening Parkinsonian symptoms. OBJECTIVES: To compare the efficacy and safety of adjuvant amantadine therapy versus placebo in treating dyskinesia in patients with Parkinson's disease, already established on levodopa, and suffering from motor complications. SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted. SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of dyskinesia in patients with a clinical diagnosis of idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion. MAIN RESULTS: Three randomised controlled trials were found comparing amantadine with placebo in the treatment of dyskinesia in patients with idiopathic Parkinson's disease. Three trials were excluded on the basis that they had no control group and a further three did not state whether they randomised the treatment that participants received. The included trials were double-blind cross-over studies involving a total of 53 patients. All three studies failed to present data from the first arm, instead presenting results as combined data from both treatment arms and both placebo arms. Two trials had no wash-out interval between the treatment periods. In view of the risk of a carry-over effect into the second arm, the results of these trials were not analysed. The final trial had a one week wash-out interval but only examined 11 participants. One study reported side-effects of amantadine in 8 of the 18 participants, including confusion and worsening of hallucinations. Another reported reversible edema of both feet in one of eleven participants. REVIEWER'S CONCLUSIONS: Due to lack of evidence it is impossible to determine whether amantadine is a safe and effective form of treatment for levodopa-induced dyskinesias in patients with Parkinson's disease.
Crosby, N., K. H. Deane, et al. (2003). "Amantadine in Parkinson's disease." Cochrane Database Syst Rev(1): CD003468.
BACKGROUND: Although levodopa is the most common drug prescribed to relieve the symptoms of Parkinson's disease it is associated with motor and psychiatric side-effects. Consequently, interest has turned to alternative drugs with improved side-effect profiles to replace or augment levodopa. Amantadine, originally used as an antiviral drug, has been shown to improve the symptoms of Parkinson's disease. OBJECTIVES: To compare the efficacy and safety of amantadine therapy (monotherapy or adjuvant therapy) versus placebo in treating people with Parkinson's disease. SEARCH STRATEGY: Electronic searches of The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001), MEDLINE (1966-2001), EMBASE (1974-2001), SCISEARCH (1974-2001), BIOSIS (1993-2001), GEROLIT (1979-2001), OLDMEDLINE (1957-1965), LILACS (1982-2001), MedCarib (17th Century - 2001), PASCAL (1973-2001), JICST-EPLUS (1985-2001), RUSSMED (1973-2001), DISSERTATION ABSTRACTS (2000-2001), SIGLE (1980-2001), ISI-ISTP (1990-2001), Aslib Index to Theses (2001), Clinicaltrials.gov (2001), metaRegister of Controlled Trials (2001), NIDRR (2001) and NRR (2001) were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of amantadine were contacted. SELECTION CRITERIA: Randomised controlled trials comparing amantadine with placebo in the treatment of patients with a clinical diagnosis of idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by NC and KD onto standardised forms and disagreements were resolved by discussion. MAIN RESULTS: Six randomised controlled trials were found comparing amantadine monotherapy or adjuvant therapy with placebo in the treatment of idiopathic Parkinson's disease. Five examined amantadine as adjuvant therapy with optimal levels of levodopa or anticholinergics and one examined amantadine as an adjuvant therapy with minimum tolerated levels of anticholinergics or as a monotherapy. Five were double-blind cross-over studies and one was a double-blind parallel group study. In total they examined 215 patients. The parallel group study allowed the randomisation codes to be broken and allowed patients in the placebo group to then receive amantadine. This could have led to bias. One study did not present the results of the placebo arm of the trial, hence we could not determine the difference between the two treatment groups. Two cross-over studies presented the results of the combined data from both treatment and placebo arms. The risk of carry-over effect into the second arm meant that these results could not be analysed. The final two studies presented at least some of their data from the end of the first arm of the trials. However only means were given, without standard deviations, so we could not determine the statistical significance of any difference between the amantadine and placebo groups. Although the authors did report on the side-effects from amantadine (such as livido recticularis, dry mouth and blurred vision), they state that none of them were severe. REVIEWER'S CONCLUSIONS: A considerable amount of evidence on the effectiveness of amantadine has accrued from non-controlled trials, often in patients with Parkinsonian conditions other than idiopathic Parkinson's disease. However, rigorous analysis of the six randomised controlled trials of amantadine reveals insufficient evidence of its efficacy and safety in the treatment of idiopathic Parkinson's disease.
Crosby, N. J., K. H. Deane, et al. (2003). "Beta-blocker therapy for tremor in Parkinson's disease." Cochrane Database Syst Rev(1): CD003361.
BACKGROUND: The tremor of Parkinson's disease can cause considerable disability for the individual concerned. Traditional antiparkinsonian therapies such as levodopa have only a minor effect on tremor. Beta-blockers are used to attenuate other forms of tremor such as Essential Tremor or the tremor associated with anxiety. It is thought that beta-blockers may be of use in controlling the tremor of Parkinson's disease. OBJECTIVES: To compare the efficacy and safety of adjuvant beta-blocker therapy against placebo for the treatment of tremor in patients with Parkinson's disease. SEARCH STRATEGY: Electronic searches of MEDLINE, EMBASE, SCISEARCH, BIOSIS, GEROLIT, OLDMEDLINE, LILACS, MedCarib, PASCAL, JICST-EPLUS, RUSSMED, DISSERTATION ABSTRACTS, SIGLE, ISI-ISTP, Aslib Index to Theses, The Cochrane Controlled Trials Register, Clinicaltrials.gov, metaRegister of Controlled Trials, NIDRR, NRR and CENTRAL were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of beta-blockers were contacted. SELECTION CRITERIA: Randomised controlled trials of adjuvant beta-blocker therapy versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two of the authors onto standardised forms and disagreements were resolved by discussion. MAIN RESULTS: Four randomised controlled trials were found comparing beta-blocker therapy with placebo in patients with idiopathic Parkinson's disease. These were double-blind cross-over studies involving a total of 72 patients. Three studies did not present data from the first arm, instead presenting results as combined data from both treatment arms and both placebo arms. The risk of a carry-over effect into the second arm meant that these results were not analysed. The fourth study presented data from each arm. This was in the form of a mean total score for tremor for each group. Details of the baseline scores, the numbers of patients in each group and standard deviations were not provided, meaning that the magnitude and significance of any changes due to therapy could not be calculated. One study reported a substantial fall in heart rate in 14 of the 22 patients, with one patient withdrawing after his heart rate dropped to 56 beats per minute (baseline heart rate was not reported). REVIEWER'S CONCLUSIONS: In view of this lack of evidence, it is impossible to determine whether beta-blocker therapy is effective and safe for the treatment of tremor in Parkinson's disease. The high frequency of bradycardia in one trial raises some concerns about the prescription of beta-blockers to normotensive elderly patients but the study was too small for the true degree of risk to be calculated.
D'Souza, C., A. Gupta, et al. (2003). "Management of psychosis in Parkinson's disease." Int J Clin Pract 57(4): 295-300.
Psychosis is one of the most disabling complications associated with Parkinson's disease (PD) and occurs in up to 30% of PD patients treated chronically with antiparkinsonian drugs. Visual hallucinations, with or without delirium and paranoid delusions, are the most frequent symptoms. Psychosis complicating PD can be more disabling than the motor symptoms of PD; it frequently poses a serious threat to the patient's ability to maintain independence and is the single greatest risk factor for nursing home placement. Choosing an antipsychotic drug for a PD patient is a common clinical dilemma. The conventional antipsychotic drugs are poorly tolerated in PD because of their predictable and at times profound worsening in parkinsonian motor symptoms. The recent availability of atypical antipsychotic drugs that can control psychotic symptoms without compromising motor function has led to significant advances in therapeutic strategies in the management of PD psychosis in the community. This article reviews data on the use of atypical antipsychotics in patients with PD and the current recommendations on their use in the management of PD psychosis.
Dawson, T. M. and V. L. Dawson (2003). "Rare genetic mutations shed light on the pathogenesis of Parkinson disease." J Clin Invest 111(2): 145-51.
Dekker, M. C., V. Bonifati, et al. (2003). "Parkinson's disease: piecing together a genetic jigsaw." Brain 126(Pt 8): 1722-33.
The role of genetics in the pathogenesis of Parkinson's disease has been subject to debate for decades. In recent years, the discovery of five genes and several more loci has provided important insight into its molecular aetiology. Some Parkinson's disease genes possibly cause Parkinson's disease by protein aggregation. The presence of Lewy bodies in carriers of mutations in one gene and their absence in carriers of another, however, still point towards a complex pathogenic network, with Parkinson's disease as a common clinical end point. The recent identification of the fourth and fifth Parkinson's disease genes suggests multiple pathways-an impaired oxidative stress defence for mutations in DJ-1, and a defect in another signalling pathway for mutations in NR4A2. Despite knowledge of genetics in familial Parkinson's disease, our knowledge of the common, late-onset form of Parkinson's disease remains limited. In non-familial Parkinson's disease, genes and environment probably interact to give rise to the disease. We review advances in the genetics of Parkinson's disease, focusing on the monogenic forms and their clinical and population-genetic consequences.
Deuschl, G., R. Wenzelburger, et al. (2003). "Deep brain stimulation of the subthalamic nucleus for Parkinson's disease: a therapy approaching evidence-based standards." J Neurol 250 Suppl 1: I43-6.
DBS of the STN is one of the most promising new therapies for the treatment of PD. However - like many other therapies for PD - the present stage of the scientific assessment does not yet suffice the rigid criteria of evidence-based medicine. Further studies should specifically address the questions of efficacy and side effects as well as the impact on quality of life.
Dev, K. K., K. Hofele, et al. (2003). "Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease." Neuropharmacology 45(1): 14-44.
Alpha-synuclein (alphaSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer's disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as alpha-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of alphaSN. This molecular form of alphaSN contrasts sharply with normal alphaSN, which is an abundant soluble presynaptic protein in brain neurons. alphaSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an alphaSN gene. Implicated in neurotoxicity are two alphaSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, alphaSN fibrils and protofibrils, soluble protein complexes of alphaSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated alphaSN species. Unlike rare forms of fPD caused by mutations in alphaSN, disease mechanisms in most alpha-synucleinopathies implicate wildtype alphaSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve alphaSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic alphaSN forms damage neurons. Here, we summarize the main structural features of alphaSN and its functions, and discuss the molecular alphaSN species implicated in human disease and transgenic animal models of alpha-synucleinopathy in fly and rodents.
Dev, K. K., H. van der Putten, et al. (2003). "Part I: parkin-associated proteins and Parkinson's disease." Neuropharmacology 45(1): 1-13.
Parkin is an E3 ligase that plays an important role in the ubiquitin/proteosome pathway responsible for protein degradation events. Mutations in parkin result in a loss-of-function and lead to Parkinson's disease, a progressive neurological disorder of movement. Presumably, this occurs due to the toxic build-up of proteins that are no longer effectively cleared/degraded by the parkin-dependent ubiqutin/proteosome pathway. To date, three types of proteins have been shown to interact with parkin. Firstly, the E2 ubiquitin conjugating proteins called UbcH7 and UbcH8 interact with parkin. Secondly, putative substrates interacting with parkin include a synaptic vesicle associated GTPase named CDCrel-1; a G protein-coupled receptor named Pael; a novel from of alpha-synuclein; and an alpha-synuclein interacting protein synphilin-1. Thirdly and more recently, a PDZ domain containing scaffolding protein CASK/Lin2 has been shown to interact with the PDZ binding motif of parkin. A network of PDZ-interacting proteins has potential to form a complex web of molecules that surround parkin and regulate its subcellular localisation and function.
Di Matteo, V. and E. Esposito (2003). "Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis." Curr Drug Target CNS Neurol Disord 2(2): 95-107.
Aging is a major risk factor for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). An unbalanced overproduction of reactive oxygen species (ROS) may give rise to oxidative stress which can induce neuronal damage, ultimately leading to neuronal death by apoptosis or necrosis. A large body of evidence indicates that oxidative stress is involved in the pathogenesis of AD, PD, and ALS. Several studies have shown that nutritional antioxidants (especially vitamin E and polyphenols) can block neuronal death in vitro, and may have therapeutic properties in animal models of neurodegenerative diseases including AD, PD, and ALS. Moreover, clinical data suggest that nutritional antioxidants might exert some protective effect against AD, PD, and ALS. In this paper, the biochemical mechanisms by which nutritional antioxidants can reduce or block neuronal death occurring in neurodegenerative disorders are reviewed. Particular emphasis will be given to the role played by the nuclear transcription factor -kB (NF-kB) in apoptosis, and in the pathogenesis of neurodegenerative disorders, such as AD, PD, and ALS. The effects of ROS and antioxidants on NF-kB function and their relevance in the pathophysiology of neurodegenerative diseases will also be examined.
Doyle, S. R. and M. J. Kremer (2003). "AANA journal course. Update for nurse anesthetists. Parkinson disease." Aana J 71(3): 229-34.
In this Journal course, the manifestations, etiologic and pathophysiologic factors, and incidence of Parkinson disease are reviewed along with current medical management. Medications and other factors that have an impact on the course of Parkinson disease are discussed. Suggested preanesthetic, intraoperative, and postoperative interventions are provided.
Driscoll, M. and B. Gerstbrein (2003). "Dying for a cause: invertebrate genetics takes on human neurodegeneration." Nat Rev Genet 4(3): 181-94.
If invertebrate neurons are injured by hostile environments or aberrant proteins they die much like human neurons, indicating that the powerful advantages of invertebrate molecular genetics might be successfully used for testing specific hypotheses about human neurological diseases, for drug discovery and for non-biased screens for suppressors and enhancers of neurodegeneration. Recent molecular dissection of the genetic requirements for hypoxia, excitotoxicity and death in models of Alzheimer disease, polyglutamine-expansion disorders, Parkinson disease and more, is providing mechanistic insights into neurotoxicity and suggesting new therapeutic interventions. An emerging theme is that neuronal crises of distinct origins might converge to disrupt common cellular functions, such as protein folding and turnover.
Duyckaerts, C., M. Verny, et al. (2003). "[Recent neuropathology of parkinsonian syndromes]." Rev Neurol (Paris) 159(5 Pt 2): 3S11-8.
The understanding of the molecular mechanisms underlying Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy has made significant progress in the recent years. Lewy body appears to be principally made of alpha-synuclein, a presynaptic protein. It also contains ubiquitin and some components of the proteasome: this suggests that alteration of protein catabolism may be involved in its formation. In favor of this hypothesis, it should be noted that Parkin, a protein that is mutated in autosomal recessive Parkinson disease, is a ubiquitin ligase. Immunohistochemistry has shown that alpha-synuclein accumulates not only in the cell body of the neurones (Lewy body) but also in their processes (Lewy neurites); it has emphasized the severity of the pathology in the nucleus basalis of Meynert, amygdala, CA2-3 sector of the hippocampus and cerebral cortex. Cortical Lewy bodies are not considered any more the marker of dementia with Lewy bodies: they are, indeed, found in true Parkinson disease cases. In progressive supranuclear palsy, 4 repeats tau accumulates in the cytoplasm of neurones and glia. At electron microscopy, the accumulation is made of straight filaments. It involves not only the neurones (where it is the main constituent of the neurofibrillary tangles) but also the glia. Astrocytic tuft is to day considered the morphological marker of progressive supranuclear palsy. Tau protein accumulates in the cell body of the oligodendrocyte as a "coiled body"; the protein is also integrated in the myelin sheath, when the cytoplasm of the oligodendrocyte wraps around the axon. This explains the numerous "threads" that are visible in cases of progressive supranuclear palsy. Striato-nigral degeneration, sporadic olivo-ponto-cerebellar atrophy and primitive orthostatic hypotension are various clinico-pathologic aspects of the same disorder: multiple system atrophy. It is also characterized by a morphological marker: the accumulation of alpha-synuclein in the cytoplasm of glial cells, particularly oligodendrocytes. The term synucleinopathy has been proposed to describe both idiopathic Parkinson disease and multiple system atrophy. The reason explaining the cellular topography of alpha-synuclein accumulation, neuronal in Parkinson disease, glial in multiple system atrophy is still unknown.
Eberhardt, O. and J. B. Schulz (2003). "Apoptotic mechanisms and antiapoptotic therapy in the MPTP model of Parkinson's disease." Toxicol Lett 139(2-3): 135-51.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model constitutes the best-characterized toxin paradigm for Parkinson's disease, faithfully replicating most of its clinical and pathological hallmarks. Many lines of evidence point to a significant contribution of apoptosis to cell death after application of 1-methyl-4-phenylpyridinium (MPP(+)) in cell culture or MPTP in vivo. This holds true for apoptotic DNA strand breaks, activation of the JNK pathway and caspases, induction of Par-4 protein and the protection conferred by interference with p53, Apaf-1 or Bax signalling. In MPTP models, intervention in upstream events of apoptosis, e.g. by inhibition of the JNK pathway, provides morphological and functional rescue. In contrast, inhibition of the propagation and execution phase of apoptosis, e.g. by inhibition of caspases, blocks or delays cell death but may not recover neuronal function. At this stage, the combination of an anti-apoptotic together with a neurorestorative therapy may be promising.
Emre, M. (2003). "Dementia associated with Parkinson's disease." Lancet Neurol 2(4): 229-37.
Dementia affects about 40% of patients with Parkinson's disease; the incidence of dementia in these patients is up to six times that in healthy people. Clinically, the prototype of dementia in PD is a dysexecutive syndrome. Loss of cholinergic, dopaminergic, and noradrenergic innervation has been suggested to be the underlying neurochemical deficits. Nigral pathology alone is probably not sufficient for the development of dementia. Although there is some controversy with regard to the site and type of pathology involved, dementia is likely to be associated with the spread of pathology to other subcortical nuclei, the limbic system, and the cerebral cortex. On the basis of more recent studies, the main pathology seems to be Lewy-body-type degeneration with associated cellular and synaptic loss in cortical and limbic structures. Alzheimer's disease-type pathology is commonly associated with dementia but less predictive. Recent evidence from small studies suggests that cholinesterase inhibitors may be effective in the treatment of dementia associated with PD.
Etminan, M., S. Gill, et al. (2003). "Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson's disease: a meta-analysis." Drug Saf 26(6): 439-44.
BACKGROUND: Pramipexole and ropinirole are relatively new dopamine agonists, both of which have proven efficacy in the treatment of Parkinson's disease. There is, however, uncertainty regarding differences in the adverse event profiles associated with each drug.Objective: To compare the adverse events of pramipexole and ropinirole as reported in the peer-reviewed medical literature. METHODS: We systematically reviewed the medical literature to identify randomised controlled trials of pramipexole and ropinirole used in the management of Parkinson's disease. Computerised databases (including Medline, Embase, the Cochrane Library, and the International Pharmaceutical Abstracts) were used to identify pertinent articles for inclusion in this study. Trials that compared the dopamine agonists to either levodopa or placebo were included. ANALYSIS: Adverse events with these drugs included dizziness, nausea, hypotension, hallucinations, and somnolence. We made two separate analyses. In the first analysis, we estimated the pooled relative risk (RR) of adverse events with either pramipexole or ropinirole as compared with levodopa. In the second analysis, the pooled RRs of adverse events with pramipexole and ropinirole were compared with placebo. We used the random-effects model of DerSimonian and Laird to estimate the RRs and their corresponding 95% CIs. We tested for study heterogeneity using Q statistics. RESULTS: There was no significant difference in the risk of dizziness, nausea, or hypotension with either drug individually or in combination when compared with levodopa. The risk of hypotension was approximately four times higher with ropinirole than pramipexole when each drug was individually compared with placebo (6.46 [95% CI 1.47-28.28] for ropinirole, and 1.65 [0.88-3.08] for pramipexole). The pooled RR (for pramipexole and ropinirole combined) of hallucinations was 1.92 (95% CI 1.08-3.43) when compared with levodopa. Relative to placebo, pramipexole had a significantly higher risk of hallucinations than ropinirole (pramipexole 5.2 [95% CI 1.97-13.72] vs ropinirole 2.75 [95% CI 0.55-13.73]). There was no significant difference in the risk of somnolence between the two drugs when each was individually compared with levodopa. When compared with placebo, the pooled RR (pramipexole and ropinirole combined) of somnolence was 3.16 (95% CI 1.62-6.13). Relative to placebo, the risk of somnolence was 2.01 (95% CI 2.17-3.16) with pramipexole and 5.73 (95% CI 2.34-14.01) with ropinirole. CONCLUSIONS: Use of ropinirole seems to be associated with a higher risk of hypotension and somnolence than use of pramipexole when compared with placebo. Use of pramipexole seems to be associated with a higher risk of hallucinations than use of ropinirole when compared with placebo.
Facca, A. G. and W. C. Koller (2003). "Differential diagnosis of parkinsonism." Adv Neurol 91: 383-96.
Fahn, S. (2003). "Description of Parkinson's disease as a clinical syndrome." Ann N Y Acad Sci 991: 1-14.
Parkinsonism is a clinical syndrome comprising combinations of motor problems-namely, bradykinesia, resting tremor, rigidity, flexed posture, "freezing," and loss of postural reflexes. Parkinson's disease (PD) is the major cause of parkinsonism. PD is a slowly progressive parkinsonian syndrome that begins insidiously and usually affects one side of the body before spreading to involve the other side. Pathology shows loss of neuromelanin-containing monoamine neurons, particularly dopamine (DA) neurons in the substantia nigra pars compacta. A pathologic hallmark is the presence of cytoplasmic eosinophilic inclusions (Lewy bodies) in monoamine neurons. The loss of DA content in the nigrostriatal neurons accounts for many of the motor symptoms, which can be ameliorated by DA replacement therapy-that is, levodopa. Most cases are sporadic, of unknown etiology; but rare cases of monogenic mutations (10 genes at present count) show that there are multiple causes for the neuronal degeneration. The pathogenesis of PD remains unknown. Clinical fluctuations and dyskinesias are frequent complications of levodopa therapy; these, as well as some motor features of PD, improve by resetting the abnormal brain physiology towards normal by surgical therapy. Nonmotor symptoms (depression, lack of motivation, passivity, and dementia) are common. As the disease progresses, even motor symptoms become intractable to therapy. No proven means of slowing progression have yet been found.
Fariss, M. W. and J. G. Zhang (2003). "Vitamin E therapy in Parkinson's disease." Toxicology 189(1-2): 129-46.
Though the etiology is not well understood, late-onset Parkinson's disease (PD) appears to result from several key factors including exposure to unknown environmental toxicants, toxic endogenous compounds and genetic alterations. A plethora of scientific evidence suggest that these environmental and endogenous factors cause PD by producing mitochondrial (mito) oxidative stress and damage in the substantia nigra, leading to cell death. Thus assuming a critical role for mito oxidative stress in PD, therapies to treat or prevent PD must target these mito and protect them against oxidative damage. The focus of this article is to briefly review the experimental and clinical evidence for the role of environmental toxicants and mito oxidative stress/damage in PD as well as discuss the potential protective role of mito d-alpha-tocopherol (T) enrichment and vitamin E therapy in PD. New experimental data are presented that supports the enrichment of mito with T as a critical event in cytoprotection against toxic mito-derived oxidative stress. We propose that chronic, high dose vitamin E dietary supplementation or parenteral vitamin E administration (e.g. vitamin E succinate) may serve as a successful therapeutic strategy for the prevention or treatment of PD (by enriching substantia nigra mito with protective levels of T).
Faulkner, M. A., J. M. Bertoni, et al. (2003). "Gabapentin for the treatment of tremor." Ann Pharmacother 37(2): 282-6.
OBJECTIVE: To review the use of the antiepileptic drug gabapentin for the treatment of various types of tremor. DATA SOURCES: A search of biomedical literature was completed through MEDLINE and EMBASE (1993-May 2002) to identify all clinical trials pertaining to the use of gabapentin for the treatment of tremor in humans. DATA SYNTHESIS: Outcome data from the few published studies have varied widely. Patient groups have been small, and conclusions have been based largely on subjective patient and investigator ratings. CONCLUSIONS: A trial of gabapentin is warranted in patients who fail therapy with traditional agents. Improvement should be measured by a patient's perceived functional ability.
Fenelon, G. (2003). "[Secondary parkinsonian syndromes]." Rev Neurol (Paris) 159(5 Pt 2): 3S39-49.
Secondary parkinsonism (SP) is caused by an identified structural, toxic, or metabolic mechanism. The first group of SP syndromes includes disorders caused by a primary pathological process in the brain. The second group includes disorders with a primary extrinsic or ubiquitous causal factor resulting either from reversible dysfunction of the basal ganglia or structural disorders related to the predominant or selective vulnerability to aggression of the basal ganglia. The pathophysiological aspects SP are developed here, particularly vascular syndromes and syndromes secondary to hydrocephalus. In both conditions, it is rare that SP resembles Parkinson's disease. The pathophysiology is poorly understood, but would involve, in most cases, corticostratial and/or thalamocortical connections in the basal ganglia system. For the clinician, the practical problem is frequently to determine whether a patient's parkinsonism can be related to an identifiable cause or whether there is an associated Parkinson's disease or other degenerative disease. When both a known cause of parkinsonism and Parkinson's disease are present, the cause may be asymptomatic, reveal Parkinson's disease, have an aggravating effect on the underlying disease, or modify its clinical expression.
Filart, R. A. and J. R. Bach (2003). "Pulmonary physical medicine interventions for elderly patients with muscular dysfunction." Clin Geriatr Med 19(1): 189-204, viii-ix.
The respiratory consequences of respiratory muscle impairment, with or without bulbar muscle weakness, usually involve inadequate ventilation and airway secretion encumbrance and may progress to respiratory failure. This article focuses on muscular dysfunction of the bulbar and respiratory musculature in elderly patients with neuromuscular diseases or central nervous system disorders. In addition, the article discusses application of pulmonary physical medicine principles for patients with predominantly restrictive pulmonary disorders caused primarily by muscular dysfunction. Diagnostic evaluation, respective clinical courses and responses to therapy, and the use of noninvasive ventilatory support outside of an acute care setting are also reviewed.
Fiskum, G., A. Starkov, et al. (2003). "Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's disease." Ann N Y Acad Sci 991: 111-9.
Mitochondrial dysfunction, due to either environmental or genetic factors, can result in excessive production of reactive oxygen species, triggering the apoptotic death of dopaminergic cells in Parkinson's disease. Mitochondrial free radical production is promoted by the inhibition of electron transport at any point distal to the sites of superoxide production. Neurotoxins that induce parkinsonian neuropathology, such as MPP(+) and rotenone, stimulate superoxide production at complex I of the electron transport chain and also stimulate free radical production at proximal redox sites including mitochondrial matrix dehydrogenases. The oxidative stress caused by elevated mitochondrial production of reactive oxygen species promotes the expression and (or) intracellular distribution of the proapoptotic protein Bax to the mitochondrial outer membrane. Interactions between Bax and BH3 death domain proteins such as tBid result in Bax membrane integration, oligomerization, and permeabilization of the outer membrane to intermembrane proteins such as cytochrome c. Once released into the cytosol, cytochrome c together with other proteins activates the caspase cascade of protease activities that mediate the biochemical and morphological alterations characteristic of apoptosis. In addition, loss of mitochondrial cytochrome c stimulates mitochondrial free radical production, further promoting cell death pathways. Excessive mitochondrial Ca(2+) accumulation can also release cytochrome c and promote superoxide production through a mechanism distinctly different from that of Bax. Ca(2+) activates a mitochondrial inner membrane permeability transition causing osmotic swelling, rupture of the outer membrane, and complete loss of mitochondrial structural and functional integrity. While amphiphilic cations, such as dibucaine and propranolol, inhibit Bax-mediated cytochrome c release, transient receptor potential channel inhibitors inhibit mitochondrial swelling and cytochrome c release induced by the inner membrane permeability transition. These advances in the knowledge of mitochondrial cell death mechanisms and their inhibitors may lead to neuroprotective interventions applicable to Parkinsons's disease.
Fornai, F., P. Lenzi, et al. (2003). "Recent knowledge on molecular components of Lewy bodies discloses future therapeutic strategies in Parkinson's disease." Curr Drug Target CNS Neurol Disord 2(3): 149-52.
Lewy bodies (LB) were first described by Lewy in 1912 [1] as neuronal pale eosinophilic inclusions which became a pathological hallmark of Parkinson s disease (PD). In his original study, Lewy defined these inclusions as pale eosinophilic cytoplasmic structures, and studies since then have revealed LB to be ubiquitin-, alpha-synuclein-, and parkin-containing inclusions. This suggests that knowledge of the biochemical steps involved in the genesis of LB might disclose a final common pathway which might be responsible for different types of inherited and sporadic parkinsonism. This would lead to the identification of new therapeutic targets for interfering with disease progression. Although LB were originally described solely in PD, in the last decade these inclusions were described in a spectrum of degenerative disorders ranging from pure movement disorders to dementia. This suggests that common biochemical alterations leading to the formation of intracellular inclusions might underlie various pathological conditions. Consequently, the knowledge of the biochemical steps involved in the formation of neuronal inclusions could represent a key to develop new therapeutic strategies. In recent years it has been possible to develop both in vitro and in vivo neuronal inclusions resembling Lewy bodies. These experimental approaches have ranged from the use of alpha-synuclein transgenic mice to the continuous exposure to a mitochondrial complex I inhibitor. The aim of the present paper is to review briefly, recent advances on Lewy body research to achieve new insight into the etiology of PD and the molecular events leading to neurodegeneration.
Friedman, J. H. (2003). "Atypical antipsychotics in the EPS-vulnerable patient." Psychoneuroendocrinology 28 Suppl 1: 39-51.
'Typical' antipsychotic agents can lead to a variety of extrapyramidal symptoms (EPS), including parkinsonism. The efficacy of a number of atypical antipsychotics in reducing psychosis without a detrimental effect on motor function has been studied in the group of patients most vulnerable to EPS, those who already have parkinsonian symptoms. Multiple open-label studies with clozapine strongly suggested that at low doses the drug was an effective antipsychotic and did not impair motor function. This was confirmed by two double-blind, placebo-controlled studies. A disadvantage of clozapine is that it can cause agranulocytosis and therefore patients require ongoing hematological monitoring. Studies with both risperidone and olanzapine have produced conflicting results, with some patients showing an overall improvement and others exhibiting severe deterioration of motor function. As with clozapine, multiple open-label studies with quetiapine have consistently demonstrated that it improves psychosis without impairing motor function. Double-blind trials are yet to be performed: however, the existing data, coupled with the lack of required blood monitoring, have led some experts to recommend quetiapine as the drug of choice for treatment of drug-induced psychosis in patients with parkinsonism. The atypical antipsychotics have also been tested in the largest group of EPS-vulnerable patients, the demented elderly. Results from a number of trials are described here. These data are more difficult to interpret as the number of variables is far greater than for the population with parkinsonism. However, the evidence to date indicates a generally low incidence of tardive dyskinesia with atypical antipsychotics.
Garcia Ramos, G. and J. F. Tellez Zenteno (2003). "[Contributions of genetics to neurology]." Rev Invest Clin 55(2): 207-15.
Garcia-Borreguero, D., O. Larrosa, et al. (2003). "Parkinson's disease and sleep." Sleep Med Rev 7(2): 115-29.
Sleep disorders are common in Parkinson's disease (PD), as almost two thirds of PD patients report them. From a clinical point of view, they can be classified into disorders of initiation and maintenance of sleep (DIMS), parasomnias, and excessive daytime sleepiness (EDS). Among the causes of DIMS are degenerative changes in the CNS affecting centers for sleep regulation, persistence into the night of daytime PD-related symptoms, concomitant medical or psychiatric disease, disruption of circadian rhythms, and effects of dopaminergic (and other) medication on sleep regulation. Parasomnias might further contribute to sleep disturbance, as they can be accompanied by motor desinhibition during REM sleep. Parasomnias can precede by several years the presence of daytime PD symptoms. EDS has been over the last years the focus of attention for both sleep and movement disorders specialists, due to the fact that it might predispose to traffic accidents. However, the so-called "sleep attacks" never occur without preexisting somnolence. Thus, a careful sleep history can be helpful to determine which patients are exposed to suffer them. Although EDS was initially attributed to the effects of dopaminergic medication, it seems likely that several disease-related factors might also play an important role. An adequate education of the PD patients in sleep hygiene measures and a skilled use of the medication seem necessary to prevent sleep disturbance.
Gasser, T. (2003). "Overview of the genetics of parkinsonism." Adv Neurol 91: 143-52.
Gerlach, M., P. Foley, et al. (2003). "The relevance of preclinical studies for the treatment of Parkinson's disease." J Neurol 250 Suppl 1: I31-4.
An essential element of pharmaceutical development, defined as the period between the discovery of a new agent and its market release, is provided by the "preclinical studies". They consist of the in vitro and in vivo studies performed before examination of the agent in human subjects. Regulatory authorities prescribe specific requirements regarding the nature and number of preclinical studies. In the present paper, we discuss the relevance of these studies for the treatment of Parkinson's disease (PD) on the basis of three examples: the L-DOPA ( L-3,4-dihydroxyphenylalanine, levodopa) story; the development of selegiline as a palliative and neuroprotective drug; and the safety concerns regarding tolcapone, an inhibitor of central and peripheral catechol-O-methyltransferase (COMT).
Giasson, B. I. and V. M. Lee (2003). "Are ubiquitination pathways central to Parkinson's disease?" Cell 114(1): 1-8.
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. The major motor disabilities of PD are associated with the extensive loss of dopaminergic neurons in the substantia nigra pars compacta. The physiological changes and biochemical pathways involved in the selective demise of these neurons are still unclear. Recent studies have demonstrated that alterations or reductions in ubiquitin-mediated proteasome function can be causal of at least some forms of parkinsonism, and multiple lines of evidence suggest that this mechanism of protein degradation may play an important role in the etiology of PD.
Glorioso, J. C., M. Mata, et al. (2003). "Therapeutic gene transfer to the nervous system using viral vectors." J Neurovirol 9(2): 165-72.
The past few years have been marked by substantial progress in preclinical studies of therapeutic gene transfer for neurologic disease using viral-based vectors. In this article, the authors review the data regarding (1). treatment of focal neuronal degeneration, exemplified by Parkinson disease, ischemia, and trauma models; (2). treatment of global neurologic dysfunction, exemplified by the mucopolysaccharidoses and other storage diseases; (3). peripheral nervous system diseases including motor neuron disease and sensory neuropathies; and (4). the use of vectors expressing neurotransmitters to modulate functional neural activity in the treatment of pain. The results suggest that a number of different viral vectors may be appropriate for gene transfer to the central nervous system for specific disease processes, and that for the peripheral nervous system herpes simplex virus-based vectors appear to have special utility. The results of the first human gene therapy trials for neurologic disease, which are just now beginning, will be crucial in defining the next step in the development of this therapy.
Goetz, C. G. (2003). "Treatment of advanced Parkinson's disease: an evidence-based analysis." Adv Neurol 91: 213-28.
Golbe, L. I. (2003). "Alpha-synuclein and Parkinson's disease." Adv Neurol 91: 165-74.
Gony, M., M. Lapeyre-Mestre, et al. (2003). "Risk of serious extrapyramidal symptoms in patients with Parkinson's disease receiving antidepressant drugs: a pharmacoepidemiologic study comparing serotonin reuptake inhibitors and other antidepressant drugs." Clin Neuropharmacol 26(3): 142-5.
To compare the risk of occurrence of "serious" extrapyramidal symptoms (EPS) between selective serotonin reuptake inhibitors and other antidepressant drugs in patients with Parkinson's disease (PD), the authors performed a retrospective study using the French Pharmacovigilance Database (i.e., the database recording all serious adverse drug reactions reported in France by physicians to the National French Pharmacovigilance Network). Patients with PD were identified from the case reports including at least one antiparkinsonian drug (except anticholinergics). The authors studied patients with PD exposed to at least one antidepressant (classified as imipraminics, selective serotonin reuptake inhibitors, or "other") drug. EPS were defined as aggravation of the parkinsonian symptoms. Of the76,640 case reports registered in the database between January 1, 1995, and December 31, 2000, 916 were identified as patients treated with at least one antiparkinsonian drug, including 199 treated with antidepressant drugs. Among them the authors found nine case reports of EPS (i.e., 4.5% of the patients with PD treated with at least one antidepressant). The odds ratio for EPS was 2.18 (0.47-11.35) for selective serotonin reuptake inhibitors, 1.17 (0.22-5.50) for imipraminics, and 0.74 (0.10-4.06) for other antidepressants. This study failed to find any significant difference in the occurrence of serious EPS according to the different classes of antidepressant drugs in patients with PD treated with dopaminergic antiparkinsonian drugs.
Gordin, A., S. Kaakkola, et al. (2003). "Position of COMT inhibition in the treatment of Parkinson's disease." Adv Neurol 91: 237-50.
Grunblatt, E., R. Schlosser, et al. (2003). "Preclinical versus clinical neuroprotection." Adv Neurol 91: 309-28.
Guttman, M., S. J. Kish, et al. (2003). "Current concepts in the diagnosis and management of Parkinson's disease." Cmaj 168(3): 293-301.
Parkinson's disease is a progressive neurological disorder characterized by rest tremor, bradykinesia, rigidity and postural instability. The cause is unknown, but growing evidence suggests that it may be due to a combination of environmental and genetic factors. Treatment during the early stage of Parkinson's disease has evolved, and evidence suggests that dopamine agonist monotherapy may prevent the response fluctuations that are associated with disease progression. L-dopa therapy, however, remains the most efficacious treatment. Treatment during the advanced stage focuses on improving control of a number of specific clinical problems. Successful management of motor response fluctuations (e.g., "wearing off," on-off fluctuations, nighttime deterioration, early morning deterioration and dyskinesias) and of psychiatric problems is often possible with specific treatment strategies. Surgical treatment is an option for a defined patient population.
Hadj Tahar, A., R. Grondin, et al. (2003). "New insights in Parkinson's disease therapy: can levodopa-induced dyskinesia ever be manageable." Adv Neurol 91: 51-64.
Hallett, M. (2003). "Parkinson revisited: pathophysiology of motor signs." Adv Neurol 91: 19-28.
Hardy, J. (2003). "The relationship between Lewy body disease, Parkinson's disease, and Alzheimer's disease." Ann N Y Acad Sci 991: 167-70.
The nosological relationship between Parkinson's disease, dementing syndromes with Lewy bodies, and Alzheimer's disease has been the subject of continuing debate. Here I argue, on the basis of recent data from families with hereditary versions of these diseases and from transgenic modeling, that these nosological debates are inevitable, impossible to resolve, and a product of the fact that we define diseases as entities rather than processes.
Henningson, C. T., Jr., M. A. Stanislaus, et al. (2003). "28. Embryonic and adult stem cell therapy." J Allergy Clin Immunol 111(2 Suppl): S745-53.
Stem cells are characterized by the ability to remain undifferentiated and to self-renew. Embryonic stem cells derived from blastocysts are pluripotent (able to differentiate into many cell types). Adult stem cells, which were traditionally thought to be monopotent multipotent, or tissue restricted, have recently also been shown to have pluripotent properties. Adult bone marrow stem cells have been shown to be capable of differentiating into skeletal muscle, brain microglia and astroglia, and hepatocytes. Stem cell lines derived from both embryonic stem and embryonic germ cells (from the embryonic gonadal ridge) are pluripotent and capable of self-renewal for long periods. Therefore embryonic stem and germ cells have been widely investigated for their potential to cure diseases by repairing or replacing damaged cells and tissues. Studies in animal models have shown that transplantation of fetal, embryonic stem, or embryonic germ cells may be able to treat some chronic diseases. In this review, we highlight recent developments in the use of stem cells as therapeutic agents for three such diseases: Diabetes, Parkinson disease, and congestive heart failure. We also discuss the potential use of stem cells as gene therapy delivery cells and the scientific and ethical issues that arise with the use of human stem cells.
Hirsch, E. C., T. Breidert, et al. (2003). "The role of glial reaction and inflammation in Parkinson's disease." Ann N Y Acad Sci 991: 214-28.
The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF-alpha, Il-1beta, IFN-gamma), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase-3 and caspase-8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF-alpha receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR-gamma agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.
Hirsch, E. C., G. Orieux, et al. (2003). "Nondopaminergic neurons in Parkinson's disease." Adv Neurol 91: 29-37.
Homann, C. N., K. Wenzel, et al. (2003). "Sleep attacks--facts and fiction: a critical review." Adv Neurol 91: 335-41.
Horstink, M. W., E. Strijks, et al. (2003). "Estrogen and Parkinson's disease." Adv Neurol 91: 107-14.
Huang, Z., R. de la Fuente-Fernandez, et al. (2003). "Etiology of Parkinson's disease." Can J Neurol Sci 30 Suppl 1: S10-8.
There is growing recognition that Parkinson's disease (PD) is likely to arise from the combined effects of genetic predisposition as well as largely unidentified environmental factors. The relative contribution of each varies from one individual to another. Even in situations where more than one family member is affected, the predominant influence may be environmental. Although responsible for only a small minority of cases of PD, recently identified genetic mutations have provided tremendous insights into the basis for neurodegeneration and have led to growing recognition of the importance of abnormal protein handling in Parkinson's as well as other neurodegenerative disorders. Abnormal protein handling may increase susceptibility to oxidative stress; conversely, numerous other factors, including oxidative stress and impaired mitochondrial function can lead to impaired protein degradation. A limited number of environmental factors are known to be toxic to the substantia nigra; in contrast, some factors such as caffeine intake and cigarette smoking may protect against the development of PD, although the mechanisms are not established. We review the various genetic and environmental factors thought to be involved in PD, as well as the mechanisms that contribute to selective nigral cell death.
Hunot, S. and E. C. Hirsch (2003). "Neuroinflammatory processes in Parkinson's disease." Ann Neurol 53 Suppl 3: S49-58; discussion S58-60.
Parkinson's disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, its cause remains unknown and the mechanism of nerve cell death uncertain. Apart from the massive loss of dopaminergic neurons, PD brains also show a conspicuous glial reaction together with signs of a neuroinflammatory reaction manifested by elevated cytokine levels and upregulation of inflammatory-associated factors such as cyclooxygenase-2 and inducible nitric oxide synthase. Mounting evidence also suggests a possible deleterious effect of these neuroinflammatory processes in experimental models of the disease. We propose that, in PD, neuroinflammation plays a role in the cascade of events leading to nerve cell death, thus propagating the neurodegenerative process. In this review, we summarize and discuss the latest findings regarding neuroinflammatory aspects in PD.
Ikebe, S., T. Harada, et al. (2003). "Prevention and treatment of malignant syndrome in Parkinson's disease: a consensus statement of the malignant syndrome research group." Parkinsonism Relat Disord 9 Suppl 1: S47-9.
We report a consensus statement of the collaborative research group on the prevention and treatment of malignant syndrome (MS) in Parkinson's disease. The syndrome is quite similar to neuroleptic MS. Although sudden withdrawal of levodopa was the most frequent cause, many other precipitating events were found such as intercurrent infections, dehydration, hot weather, discontinuation of other anti-parkinsonian drugs, and "wearing off" phenomenon.Awareness of this syndrome is most important for its early detection and the prompt commencement of treatment. MS should be suspected whenever the body temperature rises above 38 degrees C without an apparent cause. Treatment consists of ample intravenous fluid, cooling the body, anti-parkinsonian drugs (particularly levodopa and bromocriptine), dantrolene sodium, and antibiotics if infection is present. Rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure constitute serious complications.
Isacson, O., L. M. Bjorklund, et al. (2003). "Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells." Ann Neurol 53 Suppl 3: S135-46; discussion S146-8.
New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD.
Ischiropoulos, H. and J. S. Beckman (2003). "Oxidative stress and nitration in neurodegeneration: cause, effect, or association?" J Clin Invest 111(2): 163-9.
Jenner, P. (2003). "Oxidative stress in Parkinson's disease." Ann Neurol 53 Suppl 3: S26-36; discussion S36-8.
Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease (PD). However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to, or is a consequence of, these events. Oxidative damage to lipids, proteins, and DNA occurs in PD, and toxic products of oxidative damage, such as 4-hydroxynonenal (HNE), can react with proteins to impair cell viability. There is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. Recently, altered ubiquitination and degradation of proteins have been implicated as key to dopaminergic cell death in PD. Oxidative stress can impair these processes directly, and products of oxidative damage, such as HNE, can damage the 26S proteasome. Furthermore, impairment of proteasomal function leads to free radical generation and oxidative stress. Oxidative stress occurs in idiopathic PD and products of oxidative damage interfere with cellular function, but these form only part of a cascade, and it is not possible to separate them from other events involved in dopaminergic cell death.
Jenner, P. (2003). "The contribution of the MPTP-treated primate model to the development of new treatment strategies for Parkinson's disease." Parkinsonism Relat Disord 9(3): 131-7.
Current research into Parkinson's disease (PD) is directed at developing novel agents and strategies for improved symptomatic management. The aim of this research is to provide effective and maintained symptom control throughout the course of the disease without loss of efficacy and without priming the basal ganglia for the onset of dyskinesia. To achieve these objectives, it is important to have relevant animal models of PD in which new pharmacological agents and treatment strategies can be assessed prior to clinical assessment. At present, the most effective experimental model of PD is the methyl phenyl tetrahydropyridine (MPTP)-treated primate. Primates treated with MPTP develop motor disturbances resembling those seen in idiopathic PD, including bradykinesia, rigidity and postural abnormalities. In addition, MPTP-treated primates are responsive to all commonly used antiparkinsonian agents and display treatment-associated motor complications such as dyskinesia, wearing-off and on-off, which occur during the long-term treatment of the illness.This review examines how studies conducted in MPTP-treated primates have contributed to the development of dopaminergic therapies. There is now accumulating evidence that the pulsatile manner in which short-acting agents stimulate striatal dopamine receptors is a key contributing factor to the priming of the basal ganglia for dyskinesia induction. It has been suggested that providing more continuous stimulation of dopamine receptors will avoid the development of motor complications, particularly dyskinesia. So far, the actions of all commonly used antiparkinsonian drugs assessed in MPTP-treated primates have proved to be highly predictive of drug action in PD. These primate studies have demonstrated that long-acting dopamine agonists and levodopa given in combination with a catechol-O-methyl transferase (COMT) inhibitor (to increase its relatively short half-life), induce significantly less dyskinesia than occurs with standard levodopa therapy.
Jost, W. H. (2003). "Autonomic dysfunctions in idiopathic Parkinson's disease." J Neurol 250 Suppl 1: I28-30.
Most patients with Parkinson's disease experience autonomic dysfunction at some point in the course of their disease. In contrast to autonomic dysregulation in multisystem atrophy, they are less severe, and they frequently cause troublesome symptoms only in advanced stages of the disease. The quality of life is nevertheless substantially restricted. Cardiovascular, gastrointestinal and urogenital autonomic dysfunction is predominant. Appropriate diagnosis and treatment can greatly benefit the patient. An interdisciplinary approach is desirable in most cases.
Kakishita, K., N. Nakao, et al. (2003). "[Restoration of brain function by cell transplantation]." Nippon Rinsho 61(3): 457-62.
The first trial of restoring brain functions with cell grafting was performed in 1979 using a rat model of Parkinson's disease. Fetal nigral tissue was demonstrated to survive grafted tissue and to repair motor dysfunction in the model rat. The encouraging results indicate that cell transplantation may be useful to restore brain functions in neurodegenerative disorders in which a certain type of neuronal populations is specifically damaged. This review article discussed the possibility of cell transplantation therapy in several neurodegenerative disorders, such as Parkinson's disease, Huntington's disease and Alzheimer's disease.
Katzenschlager, R., C. Sampaio, et al. (2003). "Anticholinergics for symptomatic management of Parkinson's disease." Cochrane Database Syst Rev(2): CD003735.
BACKGROUND: Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features. OBJECTIVES: To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment. SEARCH STRATEGY: The literature search included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), MEDLINE (1966 to 2001), Old Medline (1960-1965), Index Medicus (1927 - 1959), as well as handsearching the neurology literature including the reference lists of identified articles, other reviews and book chapters. SELECTION CRITERIA: Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events. MAIN RESULTS: The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment. REVIEWER'S CONCLUSIONS: As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.
Keijsers, N. L., M. W. Horstink, et al. (2003). "Online monitoring of dyskinesia in patients with Parkinson's disease." IEEE Eng Med Biol Mag 22(3): 96-103.
Kieburtz, K. (2003). "Designing neuroprotection trials in Parkinson's disease." Ann Neurol 53 Suppl 3: S100-7; discussion S107-9.
A major goal of the neuroscience community is to develop neuroprotective treatment strategies that will slow or forestall the progression of Parkinson's disease, one of the most common adult-onset neurodegenerative disorders, affecting approximately 1 million people in North America. Although prior research to identify neuroprotective interventions has not been conclusive, recent advances in the understanding of the pathogenesis of Parkinson's disease, including the development of relevant animal models, provide the opportunity for rational clinical trials to assess neuroprotective treatments.
Kirik, D. and A. Bjorklund (2003). "Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors." Trends Neurosci 26(7): 386-92.
Defective handling of proteins is a central feature of major neurodegenerative diseases. The discovery that neuronal dysfunction or degeneration can be caused by mutations in single cellular proteins has given new opportunities to model the underlying disease processes by genetic modification of cells in vitro or by generation of transgenic animals carrying the disease-causing gene. Recent developments in recombinant viral-vector technology have opened up an interesting alternative possibility, based on direct gene transfer to selected subregions or subsets of neurons in the brain. Using the highly efficient adeno-associated virus or lentivirus vectors, recent reports have shown that overexpression of mutated human huntingtin or alpha-synuclein in neurons in the striatum or substantia nigra induces progressive neuropathology and neurodegeneration, similar to that seen in Huntington's and Parkinson's diseases. Targeted overexpression of disease-causing genes by recombinant viral vectors provides a new and highly flexible approach for in vivo modeling of neurodegenerative diseases, not only in mice and rats but also in primates.
Kish, S. J. (2003). "Biochemistry of Parkinson's disease: is a brain serotonergic deficiency a characteristic of idiopathic Parkinson's disease?" Adv Neurol 91: 39-49.
Korczyn, A. D. (2003). "Dopaminergic drugs in development for Parkinson's disease." Adv Neurol 91: 267-71.
Kordower, J. H. (2003). "In vivo gene delivery of glial cell line--derived neurotrophic factor for Parkinson's disease." Ann Neurol 53 Suppl 3: S120-32; discussion S132-4.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects approximately 1,000,000 Americans. The cause of the disease remains unknown. The histopathological hallmarks of the disease are dopaminergic striatal insufficiency secondary to a loss of dopaminergic neurons in the substantia nigra pars compacta and intracellular inclusion called Lewy bodies. Currently, only symptomatic treatment for PD is available. Although some treatments are efficacious for many years, all have significant limitations and new therapeutic approaches are needed. Gene therapy is ideal for delivering therapeutic molecules to site-specific regions of the central nervous system. Via gene therapy, a piece or pieces of DNA placed into a carrying vector encoding for a substance of interest can be introduced into specific cells. Although there are several ways that gene therapy can be applied for PD, this review focuses on in vivo gene delivery of glial cell line-derived neurotrophic factor (GDNF) as a neuroprotective strategy for PD.
Kudo, T. (2003). "[Involvement of unfolded protein responses in neurodegeneration]." Nihon Shinkei Seishin Yakurigaku Zasshi 23(3): 105-9.
Various stresses cause the accumulation of unfolded proteins in the endoplasmic reticulum (ER). To manage the state, cells have the unfolded protein responses (UPR). If the UPR is unsuccessful, ER-mediated apoptosis occurs. To date, three types of UPR, i.e. the induction of chaperones, the translation block, and ER-associated degradation (ERAD) have been reported. To sense the accumulation of unfolded proteins, the ER has IRE1, PERK, and ATF6. The pathways mediated by IRE1 and ATF6 cause the induction of chaperones. The pathway mediated by PERK causes a translation block. The induction of caspase 12, the activation of the JNK pathway, and the induction of CHOP have been reported as apoptosis caused by ER stress. The stability of the cell is based on the balance between UPR and ER-mediated apoptosis. Recently several diseases have been reported to be related to ER stress. We reported that mutant presenilin 1 causes a vulnerability to ER stress because it attenuates the activation of IRE1, PERK, and ATF6. Recent reports have also shown that Parkinson disease and polyglutamine diseases are relevant to ER stress. Therefore it is suggested that the ER stress story is the common mechanism for neurodegerative disorders.
Kumar, A., Z. Huang, et al. (2003). "Mechanisms of motor complications in treatment of Parkinson's disease." Adv Neurol 91: 193-201.
Kuwabara, Y. (2003). "[Current status of nuclear neuroimaging]." Fukuoka Igaku Zasshi 94(2): 26-30.
Lai, Y. Y. and J. M. Siegel (2003). "Physiological and anatomical link between Parkinson-like disease and REM sleep behavior disorder." Mol Neurobiol 27(2): 137-52.
Parkinson's disease (PD) is a progressive neurodegenerative disease that is caused by a loss of neurons in the ventral midbrain. Parkinsonian patients often experience insomnia, parasomnias, and daytime somnolence. REM sleep behavior disorder (RBD) is characterized by vigorous movements during REM sleep, and may also be caused by neuronal degeneration in the central nervous system (CNS); however, the site of degeneration remains unclear. Both Parkinsonism and RBD become more prevalent with aging, with onset usually occurring in the sixties. Recent findings show that many individuals with RBD eventually develop Parkinsonism. Conversely, it is also true that certain patients diagnosed with Parkinsonism subsequently develop RBD. Postmortem examination reveals that Lewy bodies, Lewy neurites, and alpha-synuclein are found in brainstem nuclei in both Parkinsonism and RBD patients. In this article, we will discuss evidence that Parkinsonism and RBD are physiologically and anatomically linked, based on our animal experiments and other studies on human patients.
Lang-Rollin, I., H. Rideout, et al. (2003). "Ubiquitinated inclusions and neuronal cell death." Histol Histopathol 18(2): 509-17.
Ubiquitinated inclusions and selective neuronal cell death are considered the pathological hallmarks of Parkinson's disease and other neurodegenerative diseases. Recent genetic, pathological and biochemical evidence suggests that dysfunction of ubiquitin-dependent protein degradation by the proteasome might be a contributing, if not initiating factor in the pathogenesis of these diseases. In neuronal cell culture models inhibition of the proteasome leads to cell death and formation of fibrillar ubiquitin and alpha-synuclein-positive inclusions, thus modeling some aspects of Lewy body diseases. The processes of inclusion formation and neuronal cell death share some common mechanisms, but can also be dissociated at a certain level.
Larsen, J. P. (2003). "Sleep disorders in Parkinson's disease." Adv Neurol 91: 329-34.
Lau, Y. S. and G. E. Meredith (2003). "From drugs of abuse to parkinsonism. The MPTP mouse model of Parkinson's disease." Methods Mol Med 79: 103-16.
Lev, N., E. Melamed, et al. (2003). "Apoptosis and Parkinson's disease." Prog Neuropsychopharmacol Biol Psychiatry 27(2): 245-50.
Parkinson's disease (PD) is a severe and progressive neurodegenerative disease. It is the second most common neurodegenerative disease, after Alzheimer's disease. It is caused by the selective loss of the dopaminergic neurons in the substantia nigra (SN) pars compacta. Although subject to intensive research, the etiology of PD is still enigmatic and treatment is basically symptomatic. Many factors are thought to operate in the mechanism of cell death of the nigrostriatal dopaminergic neurons in PD. In recent years, evidence for the role of apoptotic cell death in PD arises from morphological, as well as molecular, studies in cell cultures, animal models for PD, as well as human studies on postmortem brains from PD patients. These studies indicate that apoptosis takes place in PD and that there is a proapoptotic environment in the nigrostriatal region of parkinsonian patients. It is of utmost importance to conclusively determine the mode of cell death in PD because new "antiapoptotic" compounds may offer a means of protecting neurons from cell death and of slowing the rate of neurodegeneration and disease progression.
Lim, K. L., V. L. Dawson, et al. (2003). "The cast of molecular characters in Parkinson's disease: felons, conspirators, and suspects." Ann N Y Acad Sci 991: 80-92.
Parkinson's Disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCHL1). All three PD-linked gene products are related directly or indirectly to the functioning of the cellular ubiquitin proteasomal system (UPS), suggesting that UPS dysfunction may be important in PD pathogenesis. Indeed, emerging evidence indicates that derangements of the UPS may be one of the underlying mechanisms of PD pathogenesis. The function of parkin as an ubiquitin protein ligase positions it as an important player in both familial and idiopathic PD. We recently demonstrated that parkin mediates a nondegradative form of ubiquitination on synphilin-1 that could contribute to synphilin-1's aggregation in PD. Our results implicate parkin involvement in the formation of Lewy bodies associated with sporadic PD. This review discusses the role of the UPS, as well as the modus operandi of the three PD candidate felons (alpha-synuclein, parkin, and UCHL1) along with their conspirators in bringing about dopaminergic cell death in PD.
Liu, B. and J. S. Hong (2003). "Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention." J Pharmacol Exp Ther 304(1): 1-7.
Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.
Loftis, J. M. and A. Janowsky (2003). "The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications." Pharmacol Ther 97(1): 55-85.
The N-methyl-D-aspartate (NMDA) receptor is an example of a heteromeric ligand-gated ion channel that interacts with multiple intracellular proteins by way of different subunits. NMDA receptors are composed of seven known subunits (NR1, NR2A-D, NR3A-B). The present review focuses on the NR2B subunit of the receptor. Over the last several years, an increasing number of reports have demonstrated the importance of the NR2B subunit in a variety of synaptic signaling events and protein-protein interactions. The NR2B subunit has been implicated in modulating functions such as learning, memory processing, pain perception, and feeding behaviors, as well as being involved in a number of human disorders. The following review provides a summary of recent findings regarding the structural features, localization, functional properties, and regulation of the NR2B subunit. The review concludes with a section discussing the role of NR2B in human diseases.
Lozano, A. M. (2003). "Surgery for Parkinson's disease, the five W's: why, who, what, where, and when." Adv Neurol 91: 303-7.
Luedtkea, R. R. and R. H. Mach (2003). "Progress in developing D3 dopamine receptor ligands as potential therapeutic agents for neurological and neuropsychiatric disorders." Curr Pharm Des 9(8): 643-71.
The dopamine D3 receptor has been the subject of a tremendous amount of research since its discovery in 1990. A previous review of this subject [3] described the advances in molecular biology and neuroanatomical localization of the D3 receptor, with a special emphasis on schizophrenia. In the current review, we attempt to describe recent advances in the biochemistry and pharmacology of the D3 receptor from the molecular to the behavioral level. Evidence linking an alteration in D3 receptor function as playing an important role in the etiology of a variety of CNS disorders, including schizophrenia, Parkinson's Disease, and substance abuse is also provided. Also discussed are the recent developments in attempting to map the ligand-binding domains of the D2 and D3 receptors. A. survey of the literature, including a description of the medicinal chemistry approaches toward developing D3-selective ligands, is also presented in this review.
Lythgoe, M. F., N. R. Sibson, et al. (2003). "Neuroimaging of animal models of brain disease." Br Med Bull 65: 235-57.
The main aim of this review is to describe some of the many animal models that have proved to be valuable from a neuroimaging perspective. This paper complements other articles in this volume, with a focus on animal models of the pathology of human brain disorders for investigations with modern non-invasive neuroimaging techniques. The use of animal model systems forms a fundamental part of neuroscience research efforts to improve the prevention, diagnosis, understanding and treatment of neurological conditions. Without such models it would be impossible to investigate such topics as the underlying mechanisms of neuronal cell damage and death, or to screen compounds for possible anticonvulsant properties. The adequacy of any one particular model depends on the suitability of information gained during experimental conditions. It is important, therefore, to understand the various types of animal model available and choose an appropriate model for the research question.
Maguire-Zeiss, K. A. and H. J. Federoff (2003). "Convergent pathobiologic model of Parkinson's disease." Ann N Y Acad Sci 991: 152-66.
The etiology of Parkinson's disease (PD) has yet to be delineated. Human genetic studies as well as neurotoxicant and transgenic animal models of PD suggest that multiple events trigger the initiation of this progressive age-related neurodegenerative disorder. In addition, we propose that despite disparate disease triggers a convergent pathobiologic pathway exists leading to cell death. The common pathway model posits that both familial and sporadic forms of Parkinson's disease obligately share a common pathophysiological substrate. Herein we discuss the evidence for a common pathway model of Parkinson's disease through a review of synuclein transgenic models and outline an approach for the identification of shared therapeutic targets. We end with a discussion of a potential alternative therapy for Parkinson's disease.
Mandel, S., O. Weinreb, et al. (2003). "Using cDNA microarray to assess Parkinson's disease models and the effects of neuroprotective drugs." Trends Pharmacol Sci 24(4): 184-91.
The remarkable progress made by molecular biology and molecular genetics during the past decade, and the advent of the novel tools of genomics and proteomics, are expected to reveal differential expression profiles of thousands of genes and proteins involved in the degeneration of dopamine-containing cells in Parkinson's disease and allow more focused treatments according to individual genotypes. Of particular interest is the application of microarrays in drug discovery and design to identify 'fingerprints' as potential candidate targets for drug intervention. The major microarray findings relevant to Parkinson's disease and its neurotoxin-induced animal and cell models will be discussed, with particular reference to the neuroprotective therapeutic potential that could arise from the development of drugs 'a la carte'.
Mano, Y. (2003). "[Physiopathology and rehabilitation of nervous system diseases of the aged]." Nippon Naika Gakkai Zasshi 92(3): 430-5.
Marek, K., D. Jennings, et al. (2003). "Dopamine agonists and Parkinson's disease progression: what can we learn from neuroimaging studies." Ann Neurol 53 Suppl 3: S160-6; discussion S166-9.
Marek, K., D. Jennings, et al. (2003). "Single-photon emission tomography and dopamine transporter imaging in Parkinson's disease." Adv Neurol 91: 183-91.
Maries, E., B. Dass, et al. (2003). "The role of alpha-synuclein in Parkinson's disease: insights from animal models." Nat Rev Neurosci 4(9): 727-38.
Marras, C. and A. E. Lang (2003). "Measuring motor complications in clinical trials for early Parkinson's disease." J Neurol Neurosurg Psychiatry 74(2): 143-6.
Martignoni, E., G. Riboldazzi, et al. (2003). "Motor complications of Parkinson's disease." Neurol Sci 24 Suppl 1: S27-9.
Long-term treatment with levodopa in Parkinson's disease results in the development of motor complications, including drug failure, reduced duration of antiparkinsonian action (wearing off phenomenon), sudden shifts between under-treated and over-treated states (on-off phenomenon), freezing and involuntary movements such as levodopainduced dyskinesia. These motor complications can sometimes be solved with changes in the drug regimen, particularly the addition of dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors and/or changes in levodopa dose, formulation and number of doses. Amantadine and selegiline can also be helpful in reducing motor fluctuations.
Martin, W. R. and M. Wieler (2003). "Treatment of Parkinson's disease." Can J Neurol Sci 30 Suppl 1: S27-33.
Parkinson's disease is a progressive neurodegenerative disorder that demands a holistic approach to treatment. Both pharmacologic and nonpharmacologic interventions play an important role in the comprehensive management of this disorder. While levodopa remains the single most effective medication for symptomatic treatment, dopamine agonists are playing an increasingly important role. Motor complications of dopaminergic therapy are a significant issue, particularly in patients with more advanced disease who have been on levodopa for several years. All therapeutic interventions must be tailored to the individual and modified as the disease progresses, with the goal of minimizing significant functional disability as much as possible.
Mathisen, P. M. (2003). "Gene discovery and validation for neurodegenerative diseases." Drug Discov Today 8(1): 39-46.
Treatment of neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis (ALS), represents a major challenge for the pharmaceutical industry. These disorders have common and unique molecular pathological characteristics that result in serious reductions in nervous-system functionality. Key to developing novel and efficacious therapeutics is the discovery of new gene targets. Genomic, proteomics and bioinformatic analyses are identifying vast amounts of genes whose expression is associated with the pathology of a specific disease. Extensive validation studies performed in parallel with drug development are crucial for the selection of appropriate target genes. This review outlines some of the current progress in gene discovery for neurodegenerative disease.
Mattson, M. P. (2003). "Gene-diet interactions in brain aging and neurodegenerative disorders." Ann Intern Med 139(5 Pt 2): 441-4.
While there are many examples of people who live for 100 years or more with little evidence of a decline in brain function, many others are not so fortunate and experience a neurodegenerative disorder, such as Alzheimer disease or Parkinson disease. Although an increasing number of genetic factors that may affect the risk for neurodegenerative disorders are being identified, emerging findings suggest that dietary factors play major roles in determining whether the brain ages successfully or experiences a neurodegenerative disorder. Dietary factors may interact with disease-causing or predisposing genes in molecular cascades that either promote or prevent the degeneration of neurons. Epidemiologic findings suggest that high-calorie diets and folic acid deficiency increase the risk for Alzheimer disease and Parkinson disease; studies of animal models of these disorders have shown that dietary restriction (reduced calorie intake or intermittent fasting) and dietary supplementation with folic acid can reduce neuronal damage and improve behavioral outcome. Animal studies have shown that the beneficial effects of dietary restriction on the brain result in part from increased production of neurotrophic factors and cytoprotective protein chaperones in neurons. By keeping homocysteine levels low, folic acid can protect cerebral vessels and prevent the accumulation of DNA damage in neurons caused by oxidative stress and facilitated by homocysteine. Although additional studies are required in humans, the emerging data suggest that high-calorie diets and elevated homocysteine levels may render the brain vulnerable to age-related neurodegenerative disorders, particularly in persons with a genetic predisposition to such disorders.
Mattson, M. P. and T. B. Shea (2003). "Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders." Trends Neurosci 26(3): 137-46.
Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine -- a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders. A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.
McAuley, J. H. (2003). "The physiological basis of clinical deficits in Parkinson's disease." Prog Neurobiol 69(1): 27-48.
Despite the fact that Parkinson's disease (PD) is a relatively common neurological condition, the physiological derangements that result in its clinical features remain unclear. On combining findings from psychophysical, clinical and electrophysiological studies, an overriding theme is proposed that PD deficits are essentially quantitative rather than qualitative in nature. This may arise because the normal function of the basal ganglia is to activate neural processes selectively, providing appropriate diversion of "attentional" resources for decision-making aspects of motor tasks and appropriate "energising" of the executive aspects of such tasks. It is suggested that these concepts of attention, an idea stemming from psychophysical studies, and of energisation, which has derived from kinematic studies, may in fact reflect the same universal process of selective facilitation of particular processes and inhibition of others. In PD, without efficient facilitation, tasks may still be performed but less well than in normal individuals. Possible underlying mechanisms of basal ganglial function are discussed in the context of new findings on direct and indirect pathway actions and the role that oscillatory modulations may play in achieving selective facilitation is explored. Further investigation of disturbances of such mechanisms in PD may prove important in understanding the underlying pathophysiology of the condition.
McDonald, W. M., I. H. Richard, et al. (2003). "Prevalence, etiology, and treatment of depression in Parkinson's disease." Biol Psychiatry 54(3): 363-75.
Parkinson's disease (PD) is primarily a disease of elderly individuals with a peak age at onset of 55 to 66 years. It is characterized by bradykinesia, rigidity, tremor, and postural instability; and affects approximately 1 million individuals in the US and is the second most common neurodegenerative disease next to Alzheimer's disease. The motor symptoms of PD are the focus of pharmacotherapy, yet the nonmotor symptoms (e.g., dementia, psychosis, anxiety, insomnia, autonomic dysfunction, and mood disturbances) can be the most disturbing, disabling, and misunderstood aspects of the disease. Depressive symptoms occur in approximately half of PD patients and are a significant cause of functional impairment for PD patients. There is accumulating evidence suggesting that depression in PD is secondary to the underlying neuroanatomical degeneration, rather than simply a reaction to the psychosocial stress and disability. The incidence of depression is correlated with changes in central serotonergic function and neurodegeneration of specific cortical and subcortical pathways. Understanding comorbid depression in PD may therefore add to the understanding of the neuroanatomical basis of melancholia.
McKeith, I. G., D. J. Burn, et al. (2003). "Dementia with Lewy bodies." Semin Clin Neuropsychiatry 8(1): 46-57.
The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.
McNaught, K. S. and C. W. Olanow (2003). "Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson's disease." Ann Neurol 53 Suppl 3: S73-84; discussion S84-6.
The etiopathogenesis of Parkinson's disease (PD) has been elusive. Recently, several lines of evidence have converged to suggest that defects in the ubiquitin-proteasome system and proteolytic stress underlie nigral pathology in both familial and sporadic forms of the illness. In support of this concept, mutations in alpha-synuclein that cause the protein to misfold and resist proteasomal degradation cause familial PD. Similarly, mutations in two enzymes involved in the normal function of the ubiquitin-proteasome system, parkin and ubiquitin C-terminal hydrolase L1, are also associated with hereditary PD. Furthermore, structural and function defects in 26/20S proteasomes with accumulation and aggregation of potentially cytotoxic abnormal proteins have been identified in the substantia nigra pars compacta of patients with sporadic PD. Thus, a defect in protein handling appears to be a common factor in sporadic and the various familial forms of PD. This hypothesis may also account for the vulnerability of the substantia nigra pars compacta in PD, why the disorder is age related, and the nature of the Lewy body. It has also facilitated the development of experimental models that recapitulate the behavioral and pathological features of PD, and hopefully will lead to the development of novel neuroprotective therapies for the disorder.
Menager, C. and K. Kaibuchi (2003). "[Rho proteins: their function in neurons]." Med Sci (Paris) 19(3): 358-63.
Neurons possess a polarized morphology. In general, each neuron has several dendrites but only one axon. Such morphology is the basis for directionalized rapid signaling, information flowing from the short dendrites to the long axon. The mechanisms involved in the establishment of the neuronal polarity remain largely unknown. However, recently, members of Rho family proteins have been implicated in the regulation of neuronal morphology especially development of neuronal polarity, axon outgrowth and guidance, dendritic tree elaboration and synapse formation. Moreover, the Rho GTPases have been reported to be directly or indirectly involved in some neurological conditions such as X-linked mental retardation as well as Alzheimer's and Parkinson's diseases. These findings demonstrate the importance of Rho GTPases in the development, maintenance and function of the nervous system.
Micieli, G., P. Tosi, et al. (2003). "Autonomic dysfunction in Parkinson's disease." Neurol Sci 24 Suppl 1: S32-4.
Autonomic dysfunction in patients with Parkinson's disease (PD) has been recognized since the original description by James Parkinson in 1817. Autonomic failure can be the clinical presentation of other diseases like pure autonomic failure (PAF) and multiple system atrophy (MSA). Both the central and peripheral autonomic nervous systems can be affected in PD. Rajput and Rozdilsky described cell loss and Lewy bodies within the sympathetic ganglia and antibodies to sympathetic neurons have been detected in PD patients. Lewy bodies can be seen in autonomic regulatory regions, including the hypothalamus, sympathetic (intermediolateral nucleus of the thoracic cord and sympathetic ganglia), and parasympathetic system (dorsal, vagal, and sacral parasympathetic nuclei). Lewy bodies were also found in the adrenal medulla and in the neural plexi innervating the gut, heart and pelvis. Symptoms of dysautonomia are variable, and include cardiovascular symptoms, gastrointestinal, urogenital, sudomotor and thermoregulatory dysfunction, pupillary abnormalities and sleep and respiratory disorders. They may represent a useful tool in the differential diagnosis of "atypical" or "complicated" parkinsonisms.
Mizuno, Y., H. Takubo, et al. (2003). "Malignant syndrome in Parkinson's disease: concept and review of the literature." Parkinsonism Relat Disord 9 Suppl 1: S3-9.
We reviewed literature on malignant syndrome occurring in patients with Parkinson's disease (PD) during the course of drug therapy. Clinical features were high fever, marked rigidity, consciousness disturbance, autonomic dysfunction, and elevation of serum creatine kinase. The clinical features were essentially similar to those of neuroleptic malignant syndrome. The immediate triggering event was, most often, discontinuation or reduction of anti-parkinsonian drugs, particularly of levodopa. But no anti-parkinsonian drug was the exception to the induction of malignant syndrome. Serious complications were severe pneumonia, disseminated intravascular coagulation, and acute renal failure. Early treatment with intravenous fluid infusion and external body cooling are essential for good recovery. Bromocriptine and dantrolene sodium were used frequently. It has been claimed that they are effective; however, randomized controlled studies are needed to explicitly prove the efficacy of these drugs in malignant syndrome associated with PD.
Montastruc, J. L., L. Schmitt, et al. (2003). "[Pathological gambling behavior in a patient with Parkinson's disease treated with levodopa and bromocriptine]." Rev Neurol (Paris) 159(4): 441-3.
The occurrence of a pathological gambling behavior in a 61-year-old patient with idiopathic Parkinson's disease treated with dopaminergic drugs is reported. This is the first case reported with bromocriptine. The main characteristics and the mechanism of this recently described and a unexpected, adverse drug reaction are discussed.
Mori, H., N. Hattori, et al. (2003). "Genotype-phenotype correlation: familial Parkinson disease." Neuropathology 23(1): 90-4.
Kindreds with Mendelian inheritance of Parkinson disease (PD) have been known since a long time ago. Nine loci have been mapped in familial PD by linkage study and four causative genes have been cloned. This paper discusses Park 1 and Park 2, the identification of which has brought about many advances in the studies on pathomechanism of PD. Investigations of these genes in familial PD have expanded their clinical and pathological phenotypes. However, to clarify the effect of mutations on these phenotypes, additional post-mortem neuropathological studies are required.
Narabayashi, H. and Y. Mizuno (2003). "Preface: Malignant syndrome in Parkinson's disease." Parkinsonism Relat Disord 9 Suppl 1: S1.
Nass, R. and R. D. Blakely (2003). "The Caenorhabditis elegans dopaminergic system: opportunities for insights into dopamine transport and neurodegeneration." Annu Rev Pharmacol Toxicol 43: 521-44.
The neurotransmitter dopamine (DA) plays a central role in the coordination of movement, attention, and the recognition of reward. Loss of DA from the basal ganglia, as a consequence of degeneration of neurons in the substantia nigra, triggers postural instability and Parkinson's disease (PD). DA transporters (DATs) regulate synaptic DA availability and provide a conduit for the uptake of DA mimetic neurotoxins, which can be used to evoke neuronal death and Parkinson-like syndrome. Recently, we have explored the sensitivity of DA neurons in the nematode Caenorhabditis elegans to the Parkinsonian-inducing neurotoxin 6-hydroxydopamine (6-OHDA) and found striking similarities, including DAT dependence, to neurodegeneration observed in mammalian models. In this review, we present our findings in the context of molecular and behavioral dimensions of DA signaling in C. elegans with an eye toward opportunities for uncovering DAT mutants, DAT regulators, and components of toxin-mediated cell death.
Parkinson, D. (2003). "Pharmacological interventions to manage coronary heart disease." Nurs Times 99(27): 48-9.
The white paper, Saving Lives: Our Healthier Nation (Department of Health, 1999), set a target to reduce the death rate from heart disease by 40 per cent for people aged under 75 by 2010. To meet this, the National Service Framework for Coronary Heart Disease (DoH, 2000) set out a plan to ensure agreed standards of care are available to everyone. One focus is to prevent illness through secondary prevention.
Pfeiffer, R. F. (2003). "Gastrointestinal dysfunction in Parkinson's disease." Lancet Neurol 2(2): 107-16.
There is growing recognition that gastrointestinal dysfunction is common in Parkinson's disease (PD). Virtually all parts of the gastrointestinal tract can be affected, in some cases early in the disease course. Weight loss is common but poorly understood in people with PD. Dysphagia can result from dysfunction at the mouth, pharynx, and oesophagus and may predispose individuals to aspiration (accidental inhalation of food or liquid). Gastroparesis can produce various symptoms in patients with PD and may cause erratic absorption of drugs given to treat the disorder. Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency, and difficulty with the act of defecation itself with excessive straining and incomplete emptying. Recognition of these gastrointestinal complications can lead to earlier and potentially more effective therapeutic intervention.
Pfendler, K. C. and E. Kawase (2003). "The potential of stem cells." Obstet Gynecol Surv 58(3): 197-208.
Although stem cells have held the fascination of scientists for years, the attention of the general public has recently been captured by the derivation of human embryonic stem cells. In this review we describe the historical experiments leading up to the isolation of human embryonic stem cells and discuss recent advances in our understanding of both embryonic and somatic stem cells. Select examples are used to illustrate the potential of stem cells, both in the sense of their ability to differentiate into specific cell types and in the sense of their power to treat various diseases and conditions. Also discussed are recent studies describing current progress toward the treatment of Parkinson disease, spinal cord injuries, diabetes, and cardiac disease. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to describe the various types of stem cells, outline potential clinical uses of stem cells, and summarize the somatic cell transdifferentiation debate.
Pisani, A., P. Bonsi, et al. (2003). "Targeting striatal cholinergic interneurons in Parkinson's disease: focus on metabotropic glutamate receptors." Neuropharmacology 45(1): 45-56.
In the early sixties, anticholinergic drugs were introduced in the pharmacological treatment of Parkinson's disease (PD). The rationale behind their utilisation in the treatment of the disease was based on the evidence of an imbalance between the dopaminergic inputs and the intrinsic cholinergic innervation within the striatum. Metabotropic glutamate (mGlu) receptors have been shown to play a key role in striatal function both in physiological conditions and in experimental models of diseases affecting this brain area. Indeed, compelling electrophysiological and morphological evidence shows that mGlu receptors are highly expressed at cellular level and exert a profound modulatory role on cholinergic interneurons excitability. This review will provide a brief survey of studies on the localization and function of mGlu receptors in cholinergic interneurons. The potential relevance of these findings in the control of motor function and in the treatment of PD will be discussed.
Polgar, S., M. E. Morris, et al. (2003). "Reconstructive neurosurgery for Parkinson's disease: a systematic review and preliminary meta-analysis." Brain Res Bull 60(1-2): 1-24.
This systematic review and meta-analysis aimed to identify the determinants for best practice and establish current benchmarks for recovery following reconstructive neurosurgery for people with Parkinson's disease. Eleven studies reporting results for 95 grafted patients were selected on the grounds of using optimal surgical techniques and the Core Assessment Program for Intracerebral Transplantation (CAPIT) protocol for data collection. Consistent trends demonstrating high levels of recovery were identified on most outcome measures. Determinants for best practice were identified as selecting younger patients; using low dose immunosuppression; bilateral grafting; and employing strategies to ensure the quantity and viability of the grafted cells. Secondary analysis of data demonstrated a correlation of rho=0.666 (P<0.05) between increases in striatal dopaminergic activity and UPDRS Motor (off) scores. Overall effect size 'd' was found to be 1.129 UPDRS Motor (off) condition and 0.719 for UPDRS Total (off) condition. The design of the studies and the variable standards for reporting the data precluded the use of more powerful and accurate meta-analyses. It was recommended that the creation of a collaborative database would improve the extraction of data and allow for more powerful statistical analyses for evaluating the overall harm and benefits associated with reconstructive neurosurgery.
Probstfield, J. L. (2003). "How cost-effective are new preventive strategies for cardiovascular disease?" Am J Cardiol 91(10A): 22G-27G.
Costs of providing a particular medical service can be measured, but it is more difficult to assess whether the service provides good value for the money spent. Rigorous trials have demonstrated the health benefits connected with interventions for treatment and prevention of cardiovascular disease (CVD), and in-depth analyses of the costs associated with many of those interventions have been performed. Careful use of terminology clearly differentiating among cost-minimization (relative costs of proved equivalent therapeutics), cost-effectiveness (lives saved or years of life added), and cost-benefit (total net effect in monetary terms) analyses is warranted. Although trials commonly assess clinical effectiveness as reductions in mortality or CVD-specific outcomes, improvement in quality of life may be equally important and is expressed in quality-adjusted life-years. Comparisons between therapies can be assessed as a cost-effectiveness ratio. Extensive cost-effectiveness studies have been conducted on many important cardiovascular therapies: (1) beta-blockers and diuretics for multiple CVD outcomes, mortality, and prevention of recurrent myocardial infarction (MI); (2) statins for both primary and secondary prevention of CVD; (3) enalapril for prevention and treatment of congestive heart failure; (4) tissue plasminogen activator treatment of acute MI; (5) coronary artery bypass graft for left main, single-, and 2-vessel coronary artery disease, or severe angina; (6) physician counseling for smoking; and (7) radiofrequency ablation therapy for Wolff-Parkinson-White syndrome. Therapies considered economically attractive include (1) secondary prevention with statins in hyperlipidemia, (2) smoking cessation programs, (3) primary prevention in treatment of high blood pressure with diuretics and beta-blockers, (4) primary prevention with regular exercise programs, (5) secondary prevention with cardiac rehabilitation, and (6) postinfarction treatment with beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. A recent cost-minimization analysis has been performed showing aspirin to be a "best buy" therapy for secondary prevention of CVD. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease (TRANSCEND) program provide potential opportunities for both cost-minimization and cost-effectiveness analyses.
Rao, G., L. Fisch, et al. (2003). "Does this patient have Parkinson disease?" Jama 289(3): 347-53.
CONTEXT: Diagnosis of Parkinson disease (PD) remains challenging. An accurate diagnosis is important because effective symptomatic treatment for PD is available. OBJECTIVE: To systematically review the literature for information on the precision and accuracy of the clinical examination for diagnosing PD. DATA SOURCES: MEDLINE database was searched for all English-language articles related to the diagnosis of PD published from January 1966 through April 2001. The reference lists of all articles retrieved were searched for additional relevant sources. STUDY SELECTION: Studies in which patients presented with 1 or more typical features of PD were included if the final diagnosis was confirmed by a suitable criterion standard and data could be extracted to determine the accuracy of 1 or more symptoms or signs. Variability in descriptions of symptoms and signs made it impossible to combine data across existing studies for most findings. DATA SYNTHESIS: We identified 6 studies that met our criteria. The positive (presence) likelihood ratios (LRs) for tremor as a symptom of PD ranged from 1.3 to 17 (range of negative [absence] LRs, 0.24 to 0.60). Tremor as a sign of PD produced a range of positive LRs from 1.3 to 1.5 (negative LRs, 0.47 to 0.61). Clinical features useful in the diagnosis of PD include a history of the combination of symptoms of rigidity and bradykinesia (positive LR, 4.5; negative LR, 0.12); a history of loss of balance (range of positive LRs, 1.6 to 6.6; range of negative LRs, 0.29 to 0.35), symptoms of micrographia (range of positive LRs, 2.8 to 5.9; range of negative LRs, 0.30 to 0.44), and a history of shuffling gait (range of positive LRs, 3.3 to 15; range of negative LRs, 0.32 to 0.50). Trouble with certain tasks such as turning in bed (positive LR, 13; negative LR, 0.56), opening jars (positive LR, 6.1; negative LR, 0.26), and rising from a chair (range of positive LRs, 1.9 to 5.2; range of negative LRs, 0.39 to 0.58). Useful signs include the glabella tap test (positive LR, 4.5; negative LR, 0.13), difficulty walking heel-to-toe (positive LR, 2.9; negative LR, 0.32), and rigidity (range of positive LRs, 0.53 to 2.8; range of negative LRs, 0.38 to 1.6). Significant selection bias was detected in all studies included for review. CONCLUSIONS: Symptoms of tremor, rigidity, bradykinesia, micrographia, shuffling gait, and difficulty with the tasks of turning in bed, opening jars, and rising from a chair should be carefully reviewed in all patients with suspected PD. The glabella tap and heel-to-toe tests also should be assessed.
Rascol, O., P. Payoux, et al. (2003). "Limitations of current Parkinson's disease therapy." Ann Neurol 53 Suppl 3: S3-12; discussion S12-5.
Levodopa and other dopaminergic medications drastically improve the motor symptoms and quality of life of patients with Parkinson's disease in the early stages of the disease. However, once the "honeymoon" period has waned, usually after a few years of dopaminergic therapy, patients become progressively more disabled despite an ever more complex combination of available antiparkinsonian treatments. Sooner or later, they suffer from "dopa-resistant" motor symptoms (speech impairment, abnormal posture, gait and balance problems), "dopa-resistant" nonmotor signs (autonomic dysfunction, mood and cognitive impairment, sleep problems, pain) and/or drug-related side effects (especially psychosis, motor fluctuations, and dyskinesias). Therefore, the current antiparkinsonian therapy cannot be considered as ideal with regard to both efficacy and safety.
Rascol, O., C. Brefel-Courbon, et al. (2003). "The management of patients with early Parkinson's disease." Adv Neurol 91: 203-11.
Reich, S. G. and L. Marsh (2003). "Ten most commonly asked questions about the psychiatric aspects of Parkinson's disease." Neurolog 9(1): 50-6.
Remy, P. (2003). "[Is functional imaging useful in the clinical evaluation of Parkinson's disease?]." Rev Neurol (Paris) 159(5 Pt 2): 3S57-61.
Functional imaging is mainly used for clinical research. However, if available, this technique could help the clinical diagnosis. First, because it is possible to confirm the loss of nigrostriatal Dopaminergic neurons using [(18)F]-L-Dopa with PET or [(123)I]-FP-CIT with SPECT. Second, distinguishing idiopathic from atypical parkinsonism might be possible using the assessment of striatal Dopaminergic D2 receptors or the measurement of brain metabolism. However, there has been no prospective study to confirm this hypothesis and functional imaging is only performed to exclude patients with atypical parkinsonism from the waiting list for neurosurgical treatments.
Richy, F. and F. Megraud (2003). "[Helicobacter pylori infection as a cause of extra-digestive diseases: myth or reality?]." Gastroenterol Clin Biol 27(3 Pt 2): 459-66.
The persistent inflammation of the stomach induced by Helicobacter pylori infection can have consequences on the rest of the body. In the last few years, many studies have been performed on the implication of H. pylori in the pathogenesis of extra-gastric diseases attempting to establish if this association is real. Many diseases may be associated with H. pylori, e.g. vascular diseases, autoimmune diseases, skin diseases, sideropenic anemia, diabetes, Parkinson disease, and bronchiectasis. The number of important studies revealing such associations suggests that pathogenic mechanisms may link this infection with many diseases of unknown etiology. Unfortunately, the quality of the studies performed is not homogeneous, and more rigorous investigations are required to show whether a causal link exists between H. pylori infection and the pathogenic processes of these extra-digestive diseases.
Riess, O., D. Berg, et al. (2003). "Therapeutic strategies for Parkinson's disease based on data derived from genetic research." J Neurol 250 Suppl 1: I3-10.
Following the identification of mutations in alpha-synuclein as the cause of some rare forms of familial Parkinson's disease (PD), genetic research has uncovered numerous gene loci of PD. Meanwhile, several neurodegenerative diseases have been shown to accumulate a-synuclein in neuronal and glial cells summarizing this group of diseases as synucleinopathies. All currently known gene defects causing PD alter the ubiquitin-proteasomal pathway of protein degradation. Identification of these disease mutations allows studying the functional consequences which lead to cellular dysfunction and cell death in cell culture and transgenic animal models, to identify therapeutic targets and to test potential protective strategies in these models.
Rinne, J. O., I. Ulmanen, et al. (2003). "Catechol-O-methyl transferase (COMT) inhibitors in patients with Parkinson's disease: is COMT genotype a useful indicator of clinical efficacy?" Am J Pharmacogenomics 3(1): 11-5.
In clinical practice, two potent and selective catechol-O-methyl transferase (COMT) inhibitors are available for the control of motor fluctuation in patients with Parkinson's disease. However, because of the complexity of fluctuating motor symptoms, it is difficult to evaluate the clinical efficacy of COMT inhibitors in each individual. Therefore, an objective factor predicting the clinical efficacy of COMT inhibitors is needed. Individual variation in COMT activity is regulated by a single nucleotide of the COMT gene on the long arm of chromosome 22. Therefore, there could be a correlation between COMT genotype and the clinical efficacy of COMT inhibitors. Three double-blind studies evaluating the efficacy of a single or repeated doses of a COMT inhibitor failed to find significant difference in the improvement in the duration of daily 'on' time and degree of motor abilities between patients with different COMT genotypes. Furthermore, there were no significant differences in the severity and frequency of dopaminergic adverse effects between patients with different COMT genotypes. These data suggest that the COMT genotype is not a major factor in deciding the clinical efficacy of COMT inhibitors.
Romero, D. H. and G. E. Stelmach (2003). "Changes in postural control with aging and Parkinson's disease." IEEE Eng Med Biol Mag 22(2): 27-31.
Saint-Cyr, J. A. (2003). "Neuropsychology for movement disorders neurosurgery." Can J Neurol Sci 30 Suppl 1: S83-93.
The neuropsychologist plays a crucial role in three phases of the neurosurgical treatment of movement disorder patients, namely screening, outcome evaluation and research. In screening patients, the differential diagnosis of dementia, impact of depression or other psychiatric conditions, and the influence of disease and medication-induced symptoms on cognitive performance must be determined. Postoperatively, systematic evaluations elucidate the cognitive costs or benefits of the procedure. The neuropsychologist is then able to provide feedback and counselling to the professional staff, patient and family to inform management strategies. Neuropsychologists also study alteration of cognitive processing due to lesions or stimulation, which, in tandem with functional imaging, shed light on plasticity in cortical and subcortical processing.
Saint-Cyr, J. A. (2003). "Frontal-striatal circuit functions: context, sequence, and consequence." J Int Neuropsychol Soc 9(1): 103-27.
The exact role of the basal ganglia in both the motor and non-motor domains has proven elusive since it is virtually impossible to refer to its function in isolation of cortical, and especially frontal cortical circuits. The result is that we often speak of frontal-striatal circuits and functions but this still leaves us in the dark when trying to specify basal ganglia information processing. A critical review of the data from both basic science and clinical studies suggests that we should break down processing along a temporal continuum, including the domains of context, sequential information processing, and feedback or reinforcement (i.e., the consequences of action). This analysis would cut across other theoretical constructs, such as attention, central executive, memory, and learning functions, traditionally employed in the neuropsychological literature. Under specified behavioral constraint, the basal ganglia can then be seen to be involved in fundamental aspects of attentional control (often covert), in the guidance of the early stages of learning (especially reinforcement-based, but also encoding strategies in explicit paradigms), and in the associative binding of reward to cue salience and response sequences via dopaminergic mechanisms. Parkinson's disease is considered to offer only a limited view of basal ganglia function due to partial striatal depletion of dopamine and the potential involvement of other structures and transmitters in its pathology. It is hoped that the present formulation will suggest new heuristic research strategies for basal ganglia research, permitting a closer link to be established between neurophysiological, functional imaging and neuropsychological paradigms.
Saji, H. and Y. Iida (2003). "[Biomedical imaging in pharmacology with nuclear medical imaging methodologies: positron emission tomography (PET) and single photon emission computed tomography (SPECT)]." Nippon Yakurigaku Zasshi 121(3): 181-91.
The nuclear imaging technologies, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have the power to non-invasively obtain dynamic and real-time information on the in vivo behaviors of radiolabeled molecules not only in humans but also in experimental animals. Thus, PET and SPECT can image molecular interactions of biological processes in vivo directly and reveal biological phenomena that are hidden from view. Furthermore, these imaging procedures also can be repeatedly performed before and after interventions, thereby allowing each subject to be used as its own control. In these studies, the radiolabeled compounds used as imaging probes for non-invasive assays of biochemical processes should have defined in vivo behaviors that can provide valuable information on the physiological and pharmacological processes. This paper describes the principle of the nuclear medical imaging systems, rational design of radiolabeled imaging probes, and the application to in vivo investigation of the change of various neurotransmission systems under disease and drug treatment. The efficient utilization of these nuclear medical imaging technologies will accelerate biomedical studies and drug development.
Savoiardo, M. (2003). "Differential diagnosis of Parkinson's disease and atypical parkinsonian disorders by magnetic resonance imaging." Neurol Sci 24 Suppl 1: S35-7.
Magnetic resonance imaging (MRI) is not usually considered helpful for establishing the diagnosis of Parkinson's disease, but it is much more important to support the clinical diagnosis in atypical parkinsonian disorders. In multiple system atrophy with predominant parkinsonian features (MSA-P), MRI demonstrates putaminal abnormalities due to loss of neurons and gliosis and accumulation of iron in the posterior lateral part of the nucleus. When cerebellar features are present (MSA-C), pontine and cerebellar atrophy is seen with signal abnormalities that correspond to the distribution of the degenerative changes. In progressive supranuclear palsy, the main abnormality is atrophy of the midbrain. Mild-to-moderate cerebral atrophy may be present, but more-marked asymmetrical atrophy in the posterior frontal and parietal regions contralateral to the side of the clinical manifestations is characteristic of corticobasal degeneration.
Schapira, A. H. and C. W. Olanow (2003). "Rationale for the use of dopamine agonists as neuroprotective agents in Parkinson's disease." Ann Neurol 53 Suppl 3: S149-57; discussion S157-9.
Schiess, M. (2003). "Nonsteroidal anti-inflammatory drugs protect against Parkinson neurodegeneration: can an NSAID a day keep Parkinson disease away?" Arch Neurol 60(8): 1043-4.
Seibyl, J. P. (2003). "Imaging studies in movement disorders." Semin Nucl Med 33(2): 105-13.
Imaging presynaptic dopaminergic markers provides key insights into the pathophysiology of Parkinson's Disease (PD) and is becoming an important endpoint in clinical trials of potential disease-modifying therapies for PD. The further development of this area includes work to optimize targets for accurate and reliable measurement of disease progression. Ultimately, it may be possible to elaborate these markers to fine-tune our understanding of those patients who might be enrolled in a trial. For example, PD patients may be characterized as slow vs. fast progressors based on imaging measures, providing the opportunity to optimize the trial recruitment to demonstrate the greatest impact in Phase 2 evaluations of neuroprotective agents. Further, while dopamine degeneration is a crucial feature of PD, it is clear that there is widespread degeneration in the brain in PD and that many clinical manifestations of PD are likely not due to dopamine deficiency. It is reasonable to imagine that the characterization of additional targets outside the dopamine system could aid in both the molecular basis for disease characterization and ultimately optimization of therapeutics.
Shabnam, G. N., C. Th, et al. (2003). "Therapies for depression in Parkinson's disease." Cochrane Database Syst Rev(3): CD003465.
BACKGROUND: Depression is one of the most common neuropsychiatric disturbances in Parkinson's disease. 40% of observed variation in quality of life is due to depression. However, there is little hard evidence of the efficacy and safety of antidepressant therapies in Parkinson's disease. OBJECTIVES: To assess the efficacy and safety of antidepressant therapies in idiopathic Parkinson's disease. Safety refers to both the direct side-effects of the therapy and also the therapy's interactions with the symptoms of Parkinson's disease and with the antiparkinsonian medications. SEARCH STRATEGY: Relevant clinical trials were identified by electronic searches the Cochrane Controlled Trials Register (the Cochrane Library Issue 3, 2001), MEDLINE(1996-2001), EMBASE (1974-2001), PsychLit (1800's-2001), CINAHL (1982-2001) databases. The reference list of all trial reports and reviews were examined. Queries were sent out to all manufacturers and distributors of antidepressants within the UK requesting information on any relevant clinical trials. SELECTION CRITERIA: Randomised controlled trials (RCT) examining licensed oral antidepressants, electroconvulsive therapy (ECT) or behavioural therapy in the treatment of depression in idiopathic Parkinson's disease. DATA COLLECTION AND ANALYSIS: Data was extracted and assessed independently by three of the authors. Disagreements were resolved by discussion. MAIN RESULTS: Three randomised controlled trials were found examining oral antidepressant medications in Parkinson's disease in a total of 106 patients. No eligible trials of ECT or behavioural therapy were found. In the first arm of the crossover trial by Andersen 1980 (n=22) patients in the nortriptyline group showed a larger improvement than placebo group in median depression score in a self-made 31-item depression rating scale after 16 weeks of treatment but statistical significance was not calculated. A parallel group trial by Wermuth 1998 (n=37) did not show any statistically significant difference between the citalopram and placebo groups in the Hamilton Depression Scale after 52 weeks of treatment. The third study by Rabey 1996 (n=47) was a randomised open-label trial to compare fluvoxamine versus amitriptyline. Similar numbers of patients in amitriptyline and fluvoxamine groups (60% vs 55%) had a 50% reduction of Hamilton score after 16 months of treatment. However, further assessment of this trial was not possible because only summary results were available from an abstract and attempts to contact the authors failed. Visual hallucinations or confusion had been reported in patients with fluvoxamine and amitriptyline. Otherwise, no other major side effects were found in the other two trials. REVIEWER'S CONCLUSIONS: Insufficient data on the effectiveness and safety of any antidepressants therapies in Parkinson's disease are available on which to make recommendations for their use. Further large scale randomised controlled trials are urgently required in this area.
Shastry, B. S. (2003). "Neurodegenerative disorders of protein aggregation." Neurochem Int 43(1): 1-7.
In recent years, it has become increasingly clear that many neurodegenerative diseases involve aggregation and deposition of misfolded proteins such as amyloid beta, tau, alpha-synuclein and polyglutamine containing proteins. This abnormal deposition of misfolded proteins produce malfunctioning of a distinctive set of neurons. It may also induce oxidative and endoplasmic reticulum stress and proteosomal and mitochondrial dysfunction that ultimately leads to neuronal death. While hereditary forms of disorders are caused by genetic mutations, many sporadic cases are likely to be due to genetic and environmental factors. These disorders are progressive in nature. Therefore, treatment is difficult. However, for some diseases, a growing number of treatment options such as drugs, antioxidants, cell transplantation, surgery, rehabilitation procedures and preimplantation diagnosis is available. It should be noted that many of these treatments produce unacceptable risks or adverse effects and they are of only minimal benefit for patients. In future, an understanding of the causes of protein aggregation and genetic and environmental susceptibility factors of a specific individual (or specific individual determinants) may provide a better opportunity for an effective therapeutic intervention.
Siderowf, A. and M. Stern (2003). "Update on Parkinson disease." Ann Intern Med 138(8): 651-8.
This Update reviews developments in the pathophysiology and treatment of Parkinson disease during the past several years. In the area of pathophysiology, studies have addressed the contribution of environmental factors such as caffeine and pesticides. Large-scale epidemiologic studies have also expanded the role genetic factors are thought to play. Detailed studies of kindreds with familial Parkinson disease due to alpha-synuclein and parkin have catalyzed basic science investigations into the pathologic mechanisms of the disease. These studies have led to the development of a pathophysiologic model of Parkinson disease that emphasizes abnormal protein aggregation. Studies of treatment have clarified the relative roles of l-dopa and dopamine agonists in early Parkinson disease and shown the potential for surgical interventions, particularly deep-brain stimulation, to relieve the symptoms of advanced, medically refractory disease.
Silverdale, M. A., S. H. Fox, et al. (2003). "Potential nondopaminergic drugs for Parkinson's disease." Adv Neurol 91: 273-91.
Simpkins, N. and J. Jankovic (2003). "Neuroprotection in Parkinson disease." Arch Intern Med 163(14): 1650-4.
Treatment of Parkinson disease has improved dramatically over the past quarter of a century and promising therapies are emerging. Although treatment with levodopa results in marked symptomatic improvement, mortality rates of the disease have remained relatively unchanged. Recent findings of abnormal protein folding, coupled with oxidative stress, provide scientific rationale for novel therapeutic strategies designed to slow disease progression. To be effective, these disease-modifying and neuroprotective therapies must be instituted early in the course of the disease and early diagnosis therefore is critical. Consequently, primary care physicians will play an increasingly important role in early institution of such neuroprotective strategies. This review is designed to highlight some of the recent advances in our understanding of the mechanisms of neurodegeneration and to draw attention to the importance of early recognition and implementation of the new therapeutic interventions.
Siroky, M. B. (2003). "Neurological disorders cerebrovascular disease and parkinsonism." Urol Clin North Am 30(1): 27-47, v.
To store and expel urine at appropriate intervals, the lower urinary tract requires extensive input and control from the peripheral autonomic, somatic, and central nervous systems. Neurological disorders, such as cerebrovascular disease and Parkinson's disease, often cause functional disturbances of the lower urinary tract.
Smith, R., J. Lotharius, et al. (2003). "[Free radicals and ailing proteins--the culprits behind Parkinson disease?]." Lakartidningen 100(15): 1324-6, 1329-30.
Parkinson's disease is one of the most common neurodegenerative diseases, and affects approximately 1% of the population over 65 years of age. Many different insults appear to be involved in the etiology of the disease, among them environmental toxins and mitochondrial dysfunction. During the past five years, mutations in five different genes have been linked to rare, familial forms of Parkinson's disease. One of the mutated proteins, alpha-synuclein is normally implicated in synaptic plasticity and vesicle function. Dysfunction of this protein might lead to increased cytoplasmic dopamine levels. Since cytoplasmic dopamine is readily prone to autooxidation and enzymatic degradation--processes which generate reactive oxygen species--failure to properly store dopamine into vesicles might lead to oxidative stress. Indeed, nigral tissue from idiopathic Parkinson's disease patients shows signs of oxidative damage. In this article we propose that dopamine-induced oxidative stress might be a common final pathway in the pathogenesis of the disease.
Stewart, J. T. (2003). "Defining diffuse Lewy body disease. Tetrad of symptoms distinguishes illness from other dementias." Postgrad Med 113(5): 71-5; quiz 3.
It is an ageless principle in medicine that physicians cannot diagnose and treat an illness they do not recognize. In the past two decades, we have come to recognize the classic clinical picture of diffuse Lewy body disease. Once primary care physicians understand this challenging disorder, they are in an ideal position to identify and manage it. As with many dementing illnesses and other medical conditions, diffuse Lewy body disease is not curable, but much can be done to improve the quality of life of patients and their family.
Stilwell, J. L. and R. J. Samulski (2003). "Adeno-associated virus vectors for therapeutic gene transfer." Biotechniques 34(1): 148-50, 152, 154 passim.
Stocchi, F. and C. W. Olanow (2003). "Neuroprotection in Parkinson's disease: clinical trials." Ann Neurol 53 Suppl 3: S87-97; discussion S97-9.
Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.
Stocchi, F., L. Vacca, et al. (2003). "Are there clinically significant differences between dopamine agonists." Adv Neurol 91: 259-66.
Stoessl, A. J. and R. de la Fuente-Fernandez (2003). "Dopamine receptors in Parkinson's disease: imaging studies." Adv Neurol 91: 65-71.
Stowe, R. L., K. Wheatley, et al. (2003). "Surgery for Parkinson's disease: lack of reliable clinical trial evidence." J Neurol Neurosurg Psychiatry 74(4): 519-21.
There has been a striking resurgence of interest in surgery for Parkinson's disease (PD) with new targets identified and new procedures developed. This systematic review identified over 500 studies of surgery for PD published since 1990, including over 10 000 patients. However, the authors were unable to assess the value of PD surgery reliably because only seven randomised trials were identified including just 196 patients. Studies of surgery for PD have generally been of poor quality with too few patients, too short follow up, inappropriate choice of outcome measures, and lack of control groups. Much larger, randomised, controlled trials are needed to assess the longer term effects of surgery on patient rated quality of life and cost effectiveness.
Strelau, J. and K. Unsicker (2003). "Neuroregeneration." Adv Neurol 91: 95-100.
Sulkava, R. (2003). "Differential diagnosis between early Parkinson's disease and dementia with Lewy bodies." Adv Neurol 91: 411-3.
Surmeier, D. J. and M. D. Bevan (2003). ""The little engine that could": voltage-dependent Na(+) channels and the subthalamic nucleus." Neuron 39(1): 5-6.
The most effective treatment for late-stage Parkinson's disease is to electrically stimulate the subthalamic nucleus (STN) at high frequencies. Why this strategy works is unclear. The work by Do and Bean shows that the Na channels in STN neurons have distinctive features--like resurgence--that regulate their spiking behavior, providing new insights into the mechanism of DBS.
Sutoo, D. and K. Akiyama (2003). "Regulation of brain function by exercise." Neurobiol Dis 13(1): 1-14.
The effect of excercise on brain function was investigated through animal experiments. Exercise leads to increased serum calcium levels, and the calcium is transported to the brain. This in turn enhances brain dopamine synthesis through a calmodulin-dependent system, and increased dopamine levels regulate various brain functions. There are abnormally low levels of dopamine in the neostriatum and nucleus accumbens of epileptic mice (El mice strain) and spontaneously hypertensive rats (SHR). The low dopamine levels in those animals were improved following intracerebroventricular administration of calcium chloride. Dopamine levels and blood pressure in SHR were also normalized by exercise. In epileptic El mice, convulsions normalized dopamine levels and physiologic function. These findings suggest that exercise or convulsions affect brain function through calcium/calmodulin-dependent dopamine synthesis. This leads to the possibility that some symptoms of Parkinson's disease or senile dementia might be improved by exercise.
Takakusaki, K. (2003). "[Function of cortical basal nuclei: Pathophysiology of Parkinson's disease]." Nippon Seirigaku Zasshi 65(4-5): 113-29.
Takats, A. (2003). "[Diagnostic criteria and differential diagnosis of Parkinson disease]." Ideggyogy Sz 56(5-6): 144-54.
The clinical diagnosis of Parkinson's disease is based on the identification of some combination of the clinical motor signs of bradykinesia, rigidity, tremor and postural instability. Three levels of diagnostic confidence are differentiated: possible, probable, and definite. The diagnosis of possible and probable Parkinson's disease based on clinical criteria alone, while definite diagnosis requires neuropathologic confirmation. To differentiate Parkinson's disease (idiopathic Parkinsonian syndrome) and other Parkinsonian syndromes is of increasing importance considering the therapy and life expectancy of the patients. Recently the functional imaging technics have been more and more helpful in the early differential diagnosis of Parkinson's disease.
Tanner, C. M. (2003). "Is the cause of Parkinson's disease environmental or hereditary? Evidence from twin studies." Adv Neurol 91: 133-42.
Tatton, W., R. Chalmers-Redman, et al. (2003). "Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B." J Neural Transm 110(5): 509-15.
Deprenyl and other propargylamines are clinically beneficial in Parkinson's disease (PD). The benefits were thought to depend on monoamine oxidase B (MAO-B) inhibition. A large body of research has now shown that the propargylamines increase neuronal survival independently of MAO-B inhibition by interfering with apoptosis signaling pathways. The propargylamines bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH binding is associated with decreased synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH but increased synthesis of anti-apoptotic proteins like BCL-2, Cu-Zn superoxide dismutase and heat shock protein 70. Anti-apoptotic propargylamines that do not inhibit MAO-B are now in PD clinical trial.
Tatton, W. G., R. Chalmers-Redman, et al. (2003). "Apoptosis in Parkinson's disease: signals for neuronal degradation." Ann Neurol 53 Suppl 3: S61-70; discussion S70-2.
Controversy has surrounded a role for apoptosis in the loss of neurons in Parkinson's disease (PD). Although a variety of evidence has supported an apoptotic contribution to PD neuronal loss particularly in the nigra, two factors have weighed against general acceptance: (1) limitations in the use of in situ 3' end labeling techniques to demonstrate nuclear DNA cleavage; and (2) the insistence that a specific set of nuclear morphological features be present before apoptotic death could be declared. We first review the molecular events that underlie apoptotic nuclear degradation and the literature regarding the unreliability of 3' DNA end labeling as a marker of apoptotic nuclear degradation. Recent findings regarding the multiple caspase-dependent or caspase-independent signaling pathways that mediate apoptotic nuclear degradation and determine the morphological features of apoptotic nuclear degradation are presented. The evidence shows that a single nuclear morphology is not sufficient to identify apoptosis and that a cytochrome c, pro-caspase 9, and caspase 3 pathways is operative in PD nigral apoptosis. BAX-dependent increases in mitochondrial membrane permeability are responsible for the release of mitochondrial factors that signal for apoptotic degradation, and increased BAX levels have been found in a subset of PD nigral neurons. Studies using immunocytochemistry in PD postmortem nigra have begun to define the premitochondrial apoptosis signaling pathways in the disease. Two, possibly interdependent, pathways have been uncovered: (1) a p53-glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-BAX pathway; and (2) FAS receptor-FADD-caspase 8-BAX pathway. Based on the above, it seems unlikely that apoptosis does not contribute to PD neuronal loss, and the definition of the premitochondrial signaling pathways may allow for the development and testing of an apoptosis-based PD therapy.
Teismann, P., M. Vila, et al. (2003). "COX-2 and neurodegeneration in Parkinson's disease." Ann N Y Acad Sci 991: 272-7.
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Recent observations link cyclooxygenase type-2 (COX-2) to the progression of the disease. Consistent with this notion, studies with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) show that inhibition and ablation of COX-2 markedly reduce the deleterious effects of this toxin on the nigrostriatal pathway. The similarity between this experimental model and PD strongly supports the possibility that COX-2 expression is also pathogenic in PD.
Thomas, M., W. D. Le, et al. (2003). "Minocycline and other tetracycline derivatives: a neuroprotective strategy in Parkinson's disease and Huntington's disease." Clin Neuropharmacol 26(1): 18-23.
Tolosa, E. (2003). "Advances in the pharmacological management of Parkinson disease." J Neural Transm Suppl(64): 65-78.
Numerous advances have taken place in the pharmacological management of Parkinson disease (PD) in recent years. Some of the more clinically relevant will be discussed in the text that follows. New drugs have been developed to treat or prevent the motor fluctuations and dyskinesias that occur frequently with the continuous use of levodopa. Such drugs include the catechol-O-methyl-transferase (COMT) inhibitors, such as tolcapone and entecapone, and new dopamine (DA) agonists with long half lives such as cabergoline, pramipexole or ropirinole. Also new, atyical, antipsychotics have appeared which have revolutionized the treatment of PD since they allow us to control hallucinations and other psychotic behaviour without worsening of motor function. Finally preliminary reports suggest that cholinesterase inhibitors, such as rivastigmine, can be usefull in the management of cognitive impairment in PD, one of the most difficult clinical problems encountered in the management of this neurodegenerative disorder.
Tsui, J. K. (2003). "Treatment of dystonia in Parkinson's disease." Adv Neurol 91: 361-4.
Tuite, P. and J. Riss (2003). "Recent developments in the pharmacological treatment of Parkinson's disease." Expert Opin Investig Drugs 12(8): 1335-52.
Parkinson's disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.
Twelves, D., K. S. Perkins, et al. (2003). "Systematic review of incidence studies of Parkinson's disease." Mov Disord 18(1): 19-31.
Incidence studies of Parkinson's disease (PD) are important for both health-care planning and epidemiological research. This report reviews the methods and results of previous incidence studies of PD and makes recommendations for future studies. Original articles that described the incidence of PD were located using several strategies. The methods were summarised, and the results of studies with similar methodologies were compared on a standardised population. Twenty-five incidence studies were included. Each used different methods to identify incident patients, although most screened both primary care and hospital records. Only eight studies were prospective, and only two of these had any follow-up. The diagnostic criteria for PD varied (11 studies used two or more cardinal motor features, four used the UK Brain Bank criteria), as did the exclusion criteria and the definition of an incident case. In 16 studies, attempts were made to confirm the diagnosis by examination of patients by a specialist as part of the study. None of the studies used identical methods, but five were sufficiently similar to merit comparison. Four of these gave a similar incidence (16-19/100000/year), but one from Italy had a much lower incidence (8.4/100000), the reason for which was unclear. Five studies found significantly greater incidence in men. This review highlights the difficulties in performing good quality incidence studies of PD. Further incidence studies using standardised methods are required. A set of minimal scientific criteria has been devised to improve the quality and consistency of future studies.
Uitti, R. J. and Z. K. Wszolek (2003). "Dopamine agonists, sleep disorders, and driving in Parkinson's disease." Adv Neurol 91: 343-9.
Upadhya, S. C. and A. N. Hegde (2003). "A potential proteasome-interacting motif within the ubiquitin-like domain of parkin and other proteins." Trends Biochem Sci 28(6): 280-3.
Parkin and other unrelated proteins contain a ubiquitin-like domain (UbLD). This article describes a motif that might be important in the interaction of UbLD-containing proteins (UbLPs) with the proteasome. The proteasome-interacting motif, which is conserved in a subset of UbLPs, such as parkin, Rad23 and several transcription factors, is likely to enable the UbLPs to form a complex with the proteasome for proteolysis or the recently discovered non-proteolytic functions of the proteasome.
van Laar, T. (2003). "Levodopa-induced response fluctuations in patients with Parkinson's disease: strategies for management." CNS Drugs 17(7): 475-89.
Fluctuations in response to levodopa in patients in the advanced stages of idiopathic Parkinson's disease occur frequently and are a difficult problem to treat. Patients who are treated with levodopa have an additional 10% risk of experiencing response fluctuations with each year of treatment: 50% of patients have this problem after 5 years of receiving levodopa therapy and almost 100% of patients after 10 years.The mechanisms by which response fluctuations occur are only partially understood and can be divided into three main types: (i) presynaptic neuronal degeneration leading to a lack of buffering of released levodopa, which is mainly related to wearing-off phenomena; (ii) postsynaptic changes in dopamine receptor sensitivity and number, partially caused by the presynaptic changes, which are clinically related to at-random response fluctuations; and (iii) pharmacokinetic and pharmacodynamic influences of exogenously administered dopaminergic agents.Several oral and parenteral treatment strategies are recommended to manage response fluctuations, such as optimisation of dopamine receptor agonist therapy in combination with a reduction of the levodopa load; use of slow-release levodopa formulations; use of catechol-O-methyltransferase inhibitors; an increase of levodopa dose frequency; use of high-dose amantadine; and intermittent or continuous use of apomorphine and/or levodopa. Continuous stimulation of dopamine receptors with dopaminergic agents is one of the crucial basic steps in the treatment of patients at an advanced stage of Parkinson's disease, and the preferential use of dopamine receptor agonists has proven to be successful in the prevention and treatment of response fluctuations.
Vila, M. and S. Przedborski (2003). "Targeting programmed cell death in neurodegenerative diseases." Nat Rev Neurosci 4(5): 365-75.
Volles, M. J. and P. T. Lansbury, Jr. (2003). "Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease." Biochemistry 42(26): 7871-8.
Parkinson's disease (PD) is linked to mutations in the protein alpha-synuclein, which can exist in vitro in several aggregation states, including a natively unfolded monomer, a beta-sheet rich oligomer, or protofibril, and a stable amyloid fibril. This work reviews the current literature that is relevant to two linked questions: which of these species is pathogenic, and what is the mechanism of neurotoxicity? The amyloid fibril, fibrillar aggregates, Lewy bodies, and the alpha-synuclein monomer, which is normally expressed at high levels, are all unlikely to be pathogenic, for reasons discussed here. We therefore favor a toxic protofibril scenario, and propose that the pathogenic species is transiently populated during the process of fibrillization. Toxicity may arise from pore-like protofibrils that cause membrane permeabilization. An approach to testing this hypothesis is discussed.
Wang, J., H. Jiang, et al. (2003). "[The relationship between iron metabolism in central nervous system and Parkinson's disease]." Sheng Li Ke Xue Jin Zhan 34(1): 67-70.
Warner, T. T. and A. H. Schapira (2003). "Genetic and environmental factors in the cause of Parkinson's disease." Ann Neurol 53 Suppl 3: S16-23; discussion S23-5.
Despite being the subject of intense study, the pathogenesis of Parkinson's disease still remains unclear. In recent years, however, there has been increasing evidence to support a role for genetic factors in its cause. This has come from twin and family studies, the mapping and cloning of PARK genes that are associated with the development of PD, and analysis of potential susceptibility genes. There is also evidence indicating that environmental factors may play a role in the disease process. It is likely that for most cases, there is a complex interplay between these genetic and environmental influences in the causation of Parkinson's disease. This article reviews the evidence in support of genetic and environmental factors in the cause of PD.
Weimer, L. H. and O. Williams (2003). "Syncope and orthostatic intolerance." Med Clin North Am 87(4): 835-65.
Syncope and orthostatic intolerance remain common and significant clinical problems with many undocumented, misdiagnosed, or cryptogenic cases. Careful clinical assessment and application of advancing laboratory support can further improve diagnosis and treatment. Despite the depth of existing research into these common problems, many underlying mechanisms remain unproven.
Weinstock, M., E. Gorodetsky, et al. (2003). "A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease." Prog Neuropsychopharmacol Biol Psychiatry 27(4): 555-61.
Degeneration of cholinergic cortical neurons is one of the main reasons for the cognitive deficit in dementia of the Alzheimer type (AD) and in dementia with Lewy bodies (DLB). Many subjects with AD and DLB have extrapyramidal dysfunction and depression resulting from degeneration of dopaminergic, noradrenergic and serotoninergic neurons. We prepared a novel drug, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), with both cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity, as potential treatment of AD and DLB. TV-3326 inhibits brain acetyl and butyrylcholinesterase (BuChE) in rats after oral doses of 10-100 mg/kg. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain by more than 70% but has almost no effect on these enzymes in the small intestine in rats and rabbits. The brain selectivity results in minimal potentiation of the pressor response to oral tyramine. TV-3326 acts like other antidepressants in the forced swim test in rats, indicating a potential for antidepressant activity. Chronic treatment of mice with TV-3326 (26 mg/kg) prevents the destruction of nigrostriatal neurons by the neurotoxin MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In addition to ChE and MAO inhibition, the propargylamine moiety of TV-3326 confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells that results from prevention of the fall in mitochondrial membrane potential and antiapoptotic activity. These unique multiple actions of TV-3326 make it a potentially useful drug for the treatment of dementia with Parkinsonian-like symptoms and depression.
Wichmann, T. and M. R. DeLong (2003). "Pathophysiology of Parkinson's disease: the MPTP primate model of the human disorder." Ann N Y Acad Sci 991: 199-213.
The striatum is viewed as the principal input structure of the basal ganglia, while the internal pallidal segment (GPi) and the substantia nigra pars reticulata (SNr) are output structures. Input and output structures are linked via a monosynaptic "direct" pathway and a polysynaptic "indirect" pathway involving the external pallidal segment (GPe) and the subthalamic nucleus (STN). According to current schemes, striatal dopamine (DA) enhances transmission along the direct pathway (via D1 receptors), and reduces transmission over the indirect pathway (via D2 receptors). DA also acts on receptors in GPe, GPi, SNr, and STN. Electrophysiologic and other studies in primates rendered parkinsonian by treatment with the dopaminergic neurotoxin MPTP have demonstrated a reduction of neuronal activity of GPe and an increase of neuronal discharge in STN, GPi. and SNr. These findings are compatible with the view that striatal DA loss results in increased activity over the indirect pathway. Prominent bursting, oscillatory discharge patterns, and increased synchronization of neighboring neurons are found throughout the basal ganglia. These may result from changes in the activity of local circuits (e.g., the GPe-STN "pacemaker") or from more global abnormalities of the basal ganglia-thalamocortical network. These findings have been replicated in human patients undergoing microelectrode-guided stereotactic procedures targeted at GPi or STN. PET studies in patients with Parkinson's disease have lent further support to the proposed circuit abnormalities. The current models of basal ganglia function have recently been criticized. For instance, the strict separation of direct and indirect pathways and the segregation of D1 and D2 receptors have been questioned, and the almost complete absence of motor side effects of pallidal or thalamic lesions in human patients and animals is inconsistent. These results suggest that changes in discharge patterns and synchronization between basal ganglia neurons, abnormal network interactions, and compensatory mechanisms are at least as important in the pathophysiology of parkinsonism as changes in discharge rates in individual basal ganglia nuclei. Lesions of GPi or STN are effective in treating parkinsonism, because they reduce or abolish abnormal basal ganglia output, enabling remaining circuits to function more normally.
Wichmann, T. and M. R. DeLong (2003). "Functional neuroanatomy of the basal ganglia in Parkinson's disease." Adv Neurol 91: 9-18.
Widner, H. (2003). "Strategies to modify levodopa treatment." Adv Neurol 91: 229-36.
Wullner, U. and T. Klockgether (2003). "Inflammation in Parkinson's disease." J Neurol 250 Suppl 1: I35-8.
Several studies of Parkinson's disease (PD) patients and experimental models of PD indicate the presence of an inflammatory process in PD. Although the primary cellular mechanisms remain to be clarified, activation of resident microglia appears to aggravate or even maintain the disease process in PD. Modulation of inflammatory mechanisms could provide a new neuroprotective therapy in PD.
Young, C., M. Abercrombie, et al. (2003). "How a specialist nurse helps patients undergoing deep brain stimulation." Prof Nurse 18(6): 318-21.
Deep brain stimulation is becoming the most frequently used neurosurgical treatment for patients with complex Parkinson's disease. This paper reports on the creation of a clinical nurse specialist role in a Scottish hospital's movement disorder team to support patients going through this treatment and their families, working with the neuroscience nurses and multidisciplinary team.
Zesiewicz, T. A. and R. A. Hauser (2003). "Sleep attacks and dopamine agonists for Parkinson's disease: what is currently known?" CNS Drugs 17(8): 593-600.
The aetiology of sleep disturbances in patients with Parkinson's disease is multifactorial. Medications, the disease process and underlying sleep disorders may contribute to sleepiness in patients with the disease. Somnolence, excessive daytime sleepiness and sleep attacks appear to be more common in patients with Parkinson's disease who are treated with dopamine receptor agonists than in those who are treated with other antiparkinsonian agents, although virtually all dopaminergic antiparkinsonian medications may contribute to sleepiness. Somnolence caused by dopamine agonists may be dose related and occurs most frequently during the dose-escalation phase. Somnolence may also emerge or worsen after a period of time on a stable dose. Patients with Parkinson's disease and caregivers should be informed about the risk of sleepiness and sleep attacks associated with dopaminergic medications and the potential implications for driving safety.
Zhou, F. M., C. Wilson, et al. (2003). "Muscarinic and nicotinic cholinergic mechanisms in the mesostriatal dopamine systems." Neuroscientist 9(1): 23-36.
The striatum and its dense dopaminergic innervation originating in the midbrain, primarily from the substantia nigra pars compacta and the ventral tegmental area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system is involved mainly in motor coordination and in disorders such as Tourette's syndrome, Huntington's disease, and Parkinson's disease. The dopaminergic projections from the ventral tegmental area to the striatum participate more in the processes that shape behaviors leading to reward, and addictive drugs act upon this mesolimbic system. The midbrain DA areas receive cholinergic innervation from the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, whereas the striatum receives dense cholinergic innervation from local interneurons. The various neurons of the mesostriatal systems express multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA receptors. Especially in the striatum, the dense mingling of dopaminergic and cholinergic constituents enables potent interactions. Evidence indicates that cholinergic and dopaminergic systems work together to produce the coordinated functioning of the striatum. Loss of that cooperative activity contributes to the dysfunction underlying Parkinson's disease.