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.