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Parkinson's Disease Reviews: 2004

(212 References)

Abad, V. C. and C. Guilleminault (2004). "Review of rapid eye movement behavior sleep disorders." Curr Neurol Neurosci Rep 4(2): 157-63.

            The spectrum of rapid eye movement behavior disorders (RBD) spans various age groups, with the greatest prevalence in elderly men. Major diagnostic features include harmful or potentially harmful sleep behaviors that disrupt sleep continuity and dream enactment during rapid eye movement sleep. In RBD patients, the polysomnogram during rapid eye movement sleep demonstrates excessive augmentation of chin electromyogram or excessive chin or limb phasic electromyogram twitching. RBD may be associated with various neurodegenerative disorders, such as multiple system atrophy, Parkinson's disease, and dementia with Lewy bodies. Other co-morbid conditions may include narcolepsy, agrypnia excitata, sleepwalking, and sleep terrors. RBD is hypothesized to be caused by primary dysfunction of the pedunculo-pontine nucleus or other key brainstem structures associated with basal ganglia pathology or, alternatively, from abnormal afferent signals in the basal ganglia leading to dysfunction in the midbrain extrapyramidal area/ pedunculo-pontine nucleus regions.

Agorogiannis, E. I., G. I. Agorogiannis, et al. (2004). "Protein misfolding in neurodegenerative diseases." Neuropathol Appl Neurobiol 30(3): 215-24.

            A common pathogenic mechanism shared by diverse neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease and transmissible spongiform encephalopathies, may be altered protein homeostasis leading to protein misfolding and aggregation of a wide variety of different proteins in the form of insoluble fibrils. Mutations in the genes encoding protein constituents of these aggregates have been linked to the corresponding diseases, thus a reasonable scenario of pathogenesis was based on misfolding of a neurone-specific protein that forms insoluble fibrils that subsequently kill neuronal cells. However, during the past 5 years accumulating evidence has revealed the neurotoxic role of prefibrillar intermediate forms (soluble oligomers and protofibrils) produced during fibril formation. Many think these may be the predominant neurotoxic species, whereas microscopically visible fibrillar aggregates may not be toxic. Large protein aggregates may rather be simply inactive, or even represent a protective state that sequesters and inactivates toxic oligomers and protofibrils. Further understanding of the biochemical mechanisms involved in protein misfolding and fibrillization may optimize the planning of common therapeutic approaches for neurodegenerative diseases, directed towards reversal of protein misfolding, blockade of protein oligomerization and interference with the action of toxic proteins.

Alexopoulos, G. S., J. Streim, et al. (2004). "Using antipsychotic agents in older patients." J Clin Psychiatry 65 Suppl 2: 5-99; discussion 100-102; quiz 103-4.

            OBJECTIVES: Antipsychotics are widely used in geriatric psychiatric disorders. A growing number of atypical antipsychotics are available, expanding clinical options but complicating decision-making. Many questions about use of antipsychotics in older patients remain unanswered by available clinical literature. We therefore surveyed expert opinion on antipsychotic use in older patients (65 years of age or older) for recommendations concerning indications for antipsychotics, choice of antipsychotics for different conditions (e.g., delirium, dementia, schizophrenia, delusional disorder, psychotic mood disorders) and for patients with comorbid conditions or history of side effects, dosing strategies, duration of treatment, and medication combinations. METHOD: Based on a literature review, a 47-question survey with 1,411 options was developed. Approximately three quarters of the options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. For other options, experts were asked to write in answers. The survey was sent to 52 American experts on treatment of older adults (38 geriatric psychiatrists, 14 geriatric internists/family physicians), 48 (92%) of whom completed it. In analyzing responses to items rated on the 9-point scale, consensus was defined as a nonrandom distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred, second line/alternate, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean. Guidelines indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on 78% of options rated on the 9-point scale. The experts did not recommend using antipsychotics in panic disorder, generalized anxiety disorder, nonpsychotic major depression, hypochondriasis, neuropathic pain, severe nausea, motion sickness, or irritability, hostility, and sleep disturbance in the absence of a major psychiatric syndrome. However, antipsychotics were favored in several other disorders. For agitated dementia with delusions, the experts' first-line recommendation is an antipsychotic drug alone; they would also consider adding a mood stabilizer. Risperidone (0.5-2.0 mg/day) was first line followed by quetiapine (50-150 mg/day) and olanzapine (5.0-7.5 mg/day) as high second-line options. There was no first-line recommendation for agitated dementia without delusions; an antipsychotic alone was high second line (rated first line by 60% of the experts). The experts'first-line recommendation for late-life schizophrenia was risperidone (1.25-3.5 mg/day). Quetiapine (100-300 mg/day), olanzapine (7.5-15 mg/day), and aripiprazole (15-30 mg/day) were high second line. For older patients with delusional disorder, an antipsychotic was the only treatment recommended. For agitated nonpsychotic major depression in an older patient, the experts' first-line recommendation was an antidepressant alone (77% first line); second-line options were an antidepressant plus an antipsychotic, electroconvulsive therapy (ECT), an antidepressant plus a benzodiazepine, and an antidepressant plus a mood stabilizer. For nonpsychotic major depression with severe anxiety, the experts recommended an antidepressant alone (79% first line) and would also consider adding a benzodiazepine or mood stabilizer to the antidepressant. If an older patient with adequate dosages for adequate duration, there was limited support for adding an atypical antipsychotic to the antidepressant (36% first line after two failed antidepressant trials). Treatment of choice for geriatric psychotic major depression was an antipsychotic plus an antidepressant (98% first line), with ECT another first-line option (71% first line). For mild geriatric nonpsychotic mania, the first-line recommendation is a mood stabilizer alone; the experts would also consider discontinuing an antidepressant if the patient is receiving one. For severe nonpsychotic mania, the experts recommend a mood stabilizer alone; the experts would also consider discontinuing an antidepressant if the patient is receiving one. For severe nonpsychotic mania, the experts recommend a mood stabilizer plus an antipsychotic (57%; first line) or a mood stabilizer alone (48%; first line) and would discontinue any antidepressant the patient is receiving. For psychotic mania, treatment of choice is a mood stabilizer plus an antipsychotic (98%; first line). Risperidone (1.25-3.0 mg/day) and olanzapine (5-15 mg/day) were first-line options in combination with a mood stabilizer for mania with psychosis, with quetiapine (50-250 mg/day) high second line. If a patient has responded well, the experts recommended the following duration of treatment before attempting to taper and discontinue the antipsychotic: delirium, 1 week; agitated dementia, taper within 3-6 months to determine the lowest effective maintenance dose; schizophrenia, indefinite treatment at the lowest effective dose; delusional disorder, 6 months-indefinitely at the lowest effective dose; psychotic major depression, 6 months; and mania with psychosis, 3 months. For patients with diabetes, dyslipidemia, or obesity, the experts would avoid clozapine, olanzapine, and conventional antipsychotics (especially low- and mid-potency). Quetiapine is first line for a patient with Parkinson's disease. Clozapine, ziprasidone, and conventional antipsychotics (especially low- and mid-potency) should be avoided in patients with QTc prolongation or congestive heart failure. For patients with cognitive impairment, constipation, diabetes, diabetic neuropathy, dyslipidemia, xerophthalmia, and xerostomia, the experts prefer risperidone, with quetiapine high second line. More than a quarter of the experts considered these combinations contraindicated: clozapine + carbamazepine, ziprasidone + tricyclic antidepressant (TCA), and a low-potency conventional antipsychotic + fluoxetine. In combining antidepressants and antipsychotics, the experts would be much more cautious with selective serotonin reuptake inhibitors that are more potent inhibitors of the CYP 450 enzymes (i.e., fluoxetine, fluvoxamine, paroxetine) and with nefazodone, TCAs, and monoamine oxidase inhibitors. The experts recommended extra monitoring when combining any antipsychotic with lithium, carbamazepine, lamotrigine, or valproate (except aripiprazole, risperidone, or a high-potency conventional plus valproate) or with codeine, phenytoin, or tramadol. CONCLUSIONS: The experts reached a high level of consensus on many of the key treatment questions. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide direction for common clinical dilemmas in the use of antipsychotics in elderly patients. Clinicians should keep in mind that no guidelines can address the complexities of an individual patient and that sound clinical judgment based on clinical experience should be used in applying these recommendations.

Alm, P. A. (2004). "Stuttering and the basal ganglia circuits: a critical review of possible relations." J Commun Disord 37(4): 325-69.

            The possible relation between stuttering and the basal ganglia is discussed. Important clues to the pathophysiology of stuttering are given by conditions known to alleviate dysfluency, like the rhythm effect, chorus speech, and singing. Information regarding pharmacologic trials, lesion studies, brain imaging, genetics, and developmental changes of the nervous system is reviewed. The symptoms of stuttering are compared with basal ganglia motor disorders like Parkinson's disease and dystonia. It is proposed that the basal ganglia-thalamocortical motor circuits through the putamen are likely to play a key role in stuttering. The core dysfunction in stuttering is suggested to be impaired ability of the basal ganglia to produce timing cues for the initiation of the next motor segment in speech. Similarities between stuttering and dystonia are indicated, and possible relations to the dopamine system are discussed, as well as the interaction between the cerebral cortex and the basal ganglia. Behavioral and pharmacologic information suggests the existence of subtypes of stuttering. LEARNING OUTCOMES: As a result of this activity, the reader will (1) become familiar with the research regarding the basal ganglia system relating to speech motor control; (2) become familiar with the research on stuttering with indications of basal ganglia involvement; and (3) be able to discuss basal ganglia mechanisms with relevance for theory of stuttering.

Ando, K. (2004). "[Neuropsychopharmacological profile of nicotine]." Nihon Shinkei Seishin Yakurigaku Zasshi 24(2): 55-9.

            The reinforcing effects of nicotine have been investigated by intravenous self-administration methods using mice, rats, dogs, squirrel monkeys, rhesus monkeys, baboons, and humans. Based on accumulated data related to these effects, it is clear that subjects show moderate self-administration of nicotine with no marked manifestation in contrast to excessive self-administration of cocaine with hyperactivity and of morphine with withdrawal syndrome. The magnitude of reinforcing effects of nicotine was judged to be lower than that of cocaine and other abused drugs by the progressive ratio schedule method although persistent self-administration behavior for nicotine was maintained under the second-order schedule with conditioned stimulus in monkeys. The brain mechanism producing the reinforcing effects of nicotine is considered to involve nicotinic receptors at the nucleus accumbens, prefrontal cortex or other regions, as well as the mesolimbic dopaminergic system. It has been demonstrated by brain imaging techniques such as PET and fMRI that the relevant brain sites for producing craving for abused drugs such as cocaine include the amygdala, dorsolateral frontal cortex and anterior cingulated cortex. Further studies should elucidate the mechanism of craving for cigarettes by these imaging techniques. The actions of nicotine and its analogs have been studied for the purpose of developing therapeutic drugs for Alzheimer's disease, Parkinson's disease, Tourrette's syndrome and so on. Thus, studies on nicotine and its analogs with a wide variety of pharmacological profiles are interesting and important in the field of neuropsychopharmacology.

Ariga, H. (2004). "[Function of DJ]-1, a causative gene for familial Parkinson's disease]." Seikagaku 76(5): 456-9.

Asanuma, M., I. Miyazaki, et al. (2004). "Neuroprotective effects of nonsteroidal anti-inflammatory drugs on neurodegenerative diseases." Curr Pharm Des 10(6): 695-700.

            It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) possess anti-inflammatory, analgesic and antipyretic properties by inhibiting cyclooxygenase (COX), a prostaglandin-synthesizing enzyme. It has also been revealed that NSAIDs exert inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors which are related to inflammatory reactions including cytokine expression. Recently, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs, since it has been reported that inflammatory processes are associated with the pathogenesis of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In the experimental model of Parkinson's disease, NSAIDs have also exerted neuroprotective effects which are based not only on their COX-inhibiting effects but also on other properties: inhibitory effects on nitric oxide synthesis, action as agonists for peroxisome proliferator-activated receptor gamma, and some unknown pharmacological effects. In this article, various pharmacological effects of NSAIDs except their inhibitory action on COX are reviewed, and possible neuroprotective effects of NSAIDs have been discussed on neurodegenerative diseases, especially Parkinson's disease.

Ashkan, K., B. Wallace, et al. (2004). "Deep brain stimulation of the subthalamic nucleus in Parkinson's disease 1993-2003: where are we 10 years on?" Br J Neurosurg 18(1): 19-34.

            Since its advent in 1993, high frequency stimulation (HFS) of the subthalamic nucleus (STN) has rapidly developed into the most commonly practiced surgical procedure for the treatment of Parkinson's Disease (PD). Although its exact mechanism of action, be it through an inhibitory depolarization block, desynchronization of neuronal circuits or other means, is not clear, the efficacy and safety of the technique are now well established. HFS of the STN improves the motor function by at least 60%, drastically reduces the levodopa requirement and significantly improves the quality of life in PD. This review updates the recent concepts on the pathophysiology of PD and analyses the basic science principles underlying the clinical practice of the STN HFS. The evolution of the surgical technique and long-term patients' outcome are further discussed.

Ballard, C. G. (2004). "Definition and diagnosis of dementia with Lewy bodies." Dement Geriatr Cogn Disord 17 Suppl 1: 15-24.

            Significant advances have been made in neuropathologic identification procedures for dementia with Lewy bodies (DLB), but difficulties remain in clinical diagnosis. Consensus criteria state that the core features of DLB are fluctuating cognition with pronounced variation in attention and alertness, recurrent visual hallucinations and spontaneous motor features of parkinsonism. At least two of these features must be present for the diagnosis of probable DLB. Assessments of the validity of the consensus criteria against autopsy generally indicate high specificity but varying sensitivity. More detailed assessments of core diagnostic features or better operationalization, particularly of fluctuating cognition, may help improve the diagnostic guidelines. Greater utilization of some features described as supporting the diagnosis (such as auditory hallucinations) and the potential inclusion of additional symptoms (such as REM sleep behavioral disorder) also may be useful. In addition, the potential role of more detailed neuropsychology and neuroimaging in the diagnostic process needs to be evaluated, although it is important that changes to the diagnostic criteria are based on empirical evidence. Other key issues pertain to the classification of DLB patients with concurrent Alzheimer's disease and the differentiation of DLB and Parkinson's disease dementia based on less than a 1-year history of parkinsonism preceding the dementia.

Baptista, M. J., M. R. Cookson, et al. (2004). "Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease." Neuroscientist 10(1): 63-72.

            Dominant mutations in the gene for alpha-synuclein, a small presynaptic protein, can cause Parkinson's disease. Although there is still substantial debate about the precise mechanisms, alpha-synuclein is toxic to vulnerable neurons, probably as a result of its tendency to aggregate. Opposing this is another gene product that, when mutated, causes a recessive form of parkinsonism, parkin. Parkin has been recently shown to protect cells against alpha-synuclein toxicity. However, the precise details of the mechanism are unclear. This review will discuss the concept that there are multiple neuronal functions that are targeted by mutant alpha-synuclein, and in many cases, there is evidence that parkin can protect cells against damage to the same systems. The authors will also discuss ways in which to test some of these ideas, by using newly identified genes such as DJ-1 that cause similar phenotypes.

Barcia, C., M. E. Emborg, et al. (2004). "Blood vessels and parkinsonism." Front Biosci 9: 277-82.

            Blood vessels are the way for nutrients present outside the brain to gain access into the cerebral parenchyma. When neurons are diseased, for example by toxin exposure, reactive glial cells secrete local factors that induce microangiogenesis, probably as part of a spontaneous neuroprotective mechanism related to the increased metabolic demand. In Parkinson's disease (PD) and non human primate models of PD, nigral degeneration is associated with gliosis and microvascular proliferation. Interestingly, microangiogenesis also facilitates the entrance into the brain parenchyma of neurotoxins and harmful cytokine-releasing blood cells, both of which have been linked to neuronal cell death in PD. In the present review we discuss the potential implications of vascular-related phenomena with mechanisms of neuronal damage in PD.

Barcia Gonzalez, C. and M. T. Herrero Ezquerro (2004). "[Inflammation and Parkinson's disease]." Rev Neurol 38(6): 545-53.

            Parkinson's disease is a neurodegenerative disorder associated with aging characterized by a motor extrapiramidal alteration secondary to the progressive death of dopaminergic neurons of the substantia nigra pars compacta. The cause of this neuronal loss remains unknown but post mortem studies on brains of parkinsonian patients showed high index of inflammatory mechanism markers. This point has gone to open new lines of research in order to ascertain what role have these inflammatory process in neuronal degeneration and has opened new therapeutic possibilities to stop or at least to brake the neurodegenerative process.

Barker, R. A. and T. Foltynie (2004). "The future challenges in Parkinson's disease." J Neurol 251(3): 361-5.

Barnham, K. J., C. L. Masters, et al. (2004). "Neurodegenerative diseases and oxidative stress." Nat Rev Drug Discov 3(3): 205-14.

            Oxidative stress has been implicated in the progression of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxygen is vital for life but is also potentially dangerous, and a complex system of checks and balances exists for utilizing this essential element. Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. The systems in place to cope with the biochemistry of oxygen are complex, and many questions about the mechanisms of oxygen regulation remain unanswered. However, this same complexity provides a number of therapeutic targets, and different strategies, including novel metal-protein attenuating compounds, aimed at a variety of targets have shown promise in clinical studies.

Baskys, A. (2004). "Lewy body dementia: the litmus test for neuroleptic sensitivity and extrapyramidal symptoms." J Clin Psychiatry 65 Suppl 11: 16-22.

            Lewy body dementia, also referred to as dementia with Lewy bodies (DLB), is a neurodegenerative disorder now considered to be the second most common cause of dementia after Alzheimer's disease. Postmortem findings suggest that DLB accounts for 20% to 34% of all dementia cases and is often underdiagnosed. Salient features of DLB include fluctuations in cognition, perceptual abnormalities (e.g., visual hallucinations), and mild parkinsonism. Other symptoms include frequent falls, nighttime agitation, and depression. DLB symptomatology can be partly explained by the extensive destruction of dopaminergic and acetylcholinergic pathways caused by neurodegeneration. For this reason, DLB patients are especially vulnerable to the antidopaminergic and anticholinergic actions of most conventional antipsychotics, which makes treatment of the psychotic symptoms of DLB extremely difficult. Patients are particularly sensitive to developing extrapyramidal symptoms (EPS) and also to the potentially fatal complication of neuroleptic sensitivity, which affects approximately 50% of DLB patients. Therefore, a need exists for antipsychotic drugs with less propensity to induce EPS and reduced affinity for dopamine and acetylcholine receptors. Here we review studies evaluating the efficacy and tolerability of atypical antipsychotics for the treatment of psychoses associated with DLB. Olanzapine appears to be poorly tolerated, and risperidone has been associated with high risk of neuroleptic malignant syndrome. Clozapine use remains controversial because of its potent anticholinergic action and risk of agranulocytosis. Quetiapine has been shown to reduce psychiatric manifestations of DLB without causing neuroleptic sensitivity or increasing EPS. Hence, quetiapine is an attractive candidate for the treatment of psychoses in DLB and other dementias.

Bertoli-Avella, A. M., B. A. Oostra, et al. (2004). "Chasing genes in Alzheimer's and Parkinson's disease." Hum Genet 114(5): 413-38.

            Alzheimer's disease (AD), the most common type of dementia, and Parkinson's disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on "special" isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of "gene hunting" have evolved during the last few years and the significance of finding genes such as the presenilins, alpha- synuclein, parkin and DJ- 1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.

Blake, A. D., A. C. Badway, et al. (2004). "Delineating somatostatin's neuronal actions." Curr Drug Targets CNS Neurol Disord 3(2): 153-60.

            Somatostatin (somatotropin release inhibitory factor; SRIF) initiates its biological activity by interacting with a family of highly homologous integral membrane receptors (sst(1) -sst(5)). SRIF neuronal actions regulate protein phosphorylation levels, control second messenger production and modulate neuronal membrane potential. Recently, our understanding of SRIF neurobiology has been driven by new pharmacological and molecular biological tools. SRIF receptor subtype specific antibodies have identified a distinctive, yet overlapping, expression pattern for this receptor family, with multiple subtypes co-localizing in the central and peripheral nervous system. This complex expression profile has confounded efforts to establish each receptor's role in the nervous system in part by the possible homo- and heteroligomerization of the receptor proteins. However, the recent discovery of SRIF receptor subtype selective ligands, supplemented by in vitro and in vivo models with inactivated SRIF receptor genes, now provides opportunities to clearly delineate each receptor's neuronal role. The convergence of these pharmacologic, immunologic and molecular biologic approaches extend our understanding of SRIF neurobiology while promising new therapeutic avenues for SRIF research.

Boje, K. M. (2004). "Nitric oxide neurotoxicity in neurodegenerative diseases." Front Biosci 9: 763-76.

            Nitric oxide (nitrogen monoxide; NO) is a simple molecule with diverse biological functions. NO and related reactive nitrogen oxide species (RNOS) mediate intricate physiological and pathophysiological effects in the central nervous system. Depending on environmental conditions, NO and RNOS can initiate and mediate neuroprotection or neurotoxicity either exclusively or synergistically with other effectors. The focus of this review is limited to the neuroprotectant/neurotoxic role of NO in Acquired Immune Deficiency Syndrome (AIDS) Dementia Complex (aka HIV--Associated Dementia; HAD) Amyotrophic Lateral Sclerosis (aka Lou Gehrig's Disease), Alzheimer's Disease, Huntington's Disease, Multiple Sclerosis and Parkinson's Disease. This review will shed light on the question: "How important is NO in neurodegenerative diseases?"

Bosboom, J. L. and E. Wolters (2004). "Psychotic symptoms in Parkinson's disease: pathophysiology and management." Expert Opin Drug Saf 3(3): 209-20.

            Parkinson's disease (PD) is a chronic neurodegenerative disease, in which mainly dopaminergic neurons in the substantia nigra in the brain degenerate, leading to a depletion of dopamine (DA) in the striatum. The most important motor disturbances of the disease are bradykinesia (slowing down of movement), hypokinesia (poverty of movement), rigidity (muscle stiffness), tremor and postural instability. Besides these well-known motor symptoms, non-motor symptoms may develop, such as depression, cognitive impairment and psychosis. Psychotic symptoms constitute a relatively common but nevertheless serious complication, with visual hallucinations and paranoid delusions often being most prominent. These symptoms are important contributors to patient and caregiver distress and are often important risk factors for nursing home placement. Exogenous (related to therapeutic interventions) factors are of major importance but endogenous (related to the disease process itself) factors might also contribute to the development of psychotic symptoms in PD. Therapeutic strategies comprise reduction of antiparkinsonian treatment, cholinesterase inhibitors and atypical antipsychotics. As psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of strategies may be chosen.

Bowron, A. (2004). "Practical considerations in the use of apomorphine injectable." Neurology 62(6 Suppl 4): S32-6.

            This manuscript provides a practical summary of guidelines for institution of apomorphine subcutaneous injectable therapy, including patient education, pre-treatment issues, dosage titration and side-effect care. The timing of each injection is crucial if an impending "off" period is to be averted. Patients need to be aware of symptoms of an approaching "off" period, and the injection should be administered at the onset or ideally, in anticipation of an "off" episode. Patients being considered for apomorphine treatment should undergo pre-treatment assessment and optimization of ongoing oral therapy prior to initiation. Education and counseling regarding the benefits of apomorphine can often alleviate this. In addition, and where available, it is beneficial to provide the patient and caregiver(s) with additional written information and videos provided by the manufacturer demonstrating the operation of the pump or pen injection systems. Once a patient has been assessed as being a suitable candidate for apomorphine, an apomorphine challenge is performed to determine responsiveness and guide appropriate dosing, establish an individual dose, and to observe for side effects, such as nausea, postural hypotension, excessive somnolence, or dyskinesia. Three days prior to the challenge, domperidone 20 mg tid or trimethobenzamide (Tigan) 300 mg tid is recommended. Potential side effects include yawning, dopaminergic side effects, such as dyskinesias, nausea, orthostatic hypotension, confusion, hallucinations, somnolence and rarely, hypersexuality or other behavioral disturbances, and skin nodule formation.

Brooks, D. J. (2004). "Safety and tolerability of COMT inhibitors." Neurology 62(1 Suppl 1): S39-46.

            Combining levodopa with the catechol-O-methyltransferase (COMT) inhibitor entacapone has been shown to be an effective strategy in the management of Parkinson's disease (PD) patients experiencing motor fluctuations. Safety and tolerability information has come from postmarketing surveillance studies as well as several randomized, placebo-controlled trials with long-term open-label extension phases specifically investigating the safety and tolerability of levodopa plus entacapone. Results show the most common dopaminergic side effects to be dyskinesia and nausea, which result from the increased bioavailability of levodopa and can be readily managed. Non-dopaminergic side effects include diarrhea and harmless urine discoloration. There is no convincing evidence of hepatic injury with entacapone use, and therefore monitoring of liver enzymes is unnecessary. With over 300,000 patient-years of exposure, levodopa combined with entacapone can be considered safe and well tolerated.

Brotini, S. and G. L. Gigli (2004). "Epidemiology and clinical features of sleep disorders in extrapyramidal disease." Sleep Med 5(2): 169-79.

            Sleep disturbances are common in extrapyramidal diseases, including not only insomnia but excessive daytime sleepiness and parasomnias. In particular, complaints related to sleep are extremely common among patients affected by Parkinson's disease (PD). The underlying causes may include: patient age, associated illnesses, cognitive impairment, motor dysfunction caused by disease, neurochemical changes related to the disease, drugs, and secondary psychological responses to the disease. The exact prevalence of sleep disorders in PD is difficult to ascertain, due to the heterogeneity of patients as well as to the different criteria and methods used to diagnose and classify sleep disturbances. In this study, we will attempt to review the epidemiological data and to describe the various sleep disorders, which have been identified in extrapyramidal diseases, with particular reference to PD. There are no data available at present as to the role of gender in sleep disturbances. Finally, the benefit of sleep on extrapyramidal diseases will be addressed, taking into account that the above causes may modify the effects of sleep.

Brusa, A., R. Stoehr, et al. (2004). "Progressive supranuclear palsy: new disease or variant of postencephalitic parkinsonism?" Mov Disord 19(3): 247-52.

            We review the etiological importance of the epidemic encephalitis for progressive supranuclear palsy (PSP) and addresses the question of whether the explosion of PSP literature in the mid-20th century reflects the appearance of a new disease. We examined 2,000 studies on Parkinson's disease from 1861 to 1963 and found PSP-like cases in the past, before the epidemic encephalitis era. It can be assumed that PSP is neither a new disease nor a variant of postencephalitic parkinsonism.

Bryant, P. R., C. C. Geis, et al. (2004). "Stroke and neurodegenerative disorders. 4. Neurodegenerative disorders." Arch Phys Med Rehabil 85(3 Suppl 1): S21-33.

            This self-directed learning module highlights diagnosis, treatment, and rehabilitation issues in patients with neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease, and amyotrophic lateral sclerosis (ALS). It is part of the study guide on stroke and neurodegenerative disorders in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. This article specifically focuses on the differential diagnosis, diagnostic evaluation, medical management, and rehabilitation issues in MS. Similarly, the differential diagnosis treatment and rehabilitation in Parkinson's disease is discussed. Electrodiagnosis, pharmacologic treatment, and rehabilitation options for ALS are also discussed. OVERALL ARTICLE OBJECTIVES: To review the differential diagnosis, evaluation, medical treatment, and rehabilitation management of patients with MS, Parkinson's disease, and ALS.

Burke, R. E. (2004). "Recent advances in research on Parkinson disease: synuclein and parkin." Neurologist 10(2): 75-81.

            BACKGROUND: Until recently, most research effort on Parkinson disease (PD) was focused on possible environmental causes. With the discovery of mutations in two genes, synuclein and parkin, which are responsible for rare familial forms of the disease, there has been a major change in emphasis. REVIEW SUMMARY: The first genetic cause of PD to be identified was in the gene for synuclein, resulting in an alanine to threonine substitution at position 53. The likely pathogenetic significance of this mutation was supported by the discovery of a second mutation, and the presence of synuclein in Lewy bodies in sporadic PD cases. The synuclein protein has a tendency to self aggregate, and this tendency is increased in the mutants, and by oxidative injury to the protein. While there is growing evidence in animal models that overexpression of wildtype or mutant synuclein may lead to intracytoplasmic inclusions, and dysfunction of dopamine neurons, no animal models in rodents have yet replicated all important features of the disease. Deletions or point mutations in the gene for parkin cause an autosomal recessive, early onset form of parkinsonism. The parkin protein functions as an E3 ubiquitin-protein ligase, and it is involved in the degradation of cellular proteins by the proteasomal pathway. It is hypothesized that the loss of this function results in the toxic accumulation of its target proteins. CONCLUSIONS: Research on these inherited forms of PD is pointing towards a common theme, that disturbances of cellular protein handling can lead to the death of dopamine neurons in PD.

Burke, W. J., S. W. Li, et al. (2004). "Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases." Neurotoxicology 25(1-2): 101-15.

            The monoamine oxidase (MAO) metabolites of norepinephrine (NE) or epinephrine (EPI) and of dopamine (DA) are 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively. The toxicity of these catecholamine (CA) MAO metabolites was predicted over 50 years ago. However, until our recent chemical synthesis of these CA aldehyde metabolites, the hypothesis about their toxicity could not be tested. The present paper reviews recent knowledge gained about these compounds. Topics to be reviewed include: chemical synthesis and properties of DOPEGAL and DOPAL; in vitro and in vivo toxicity of CA aldehydes; subcellular mechanisms of toxicity; free radical formation by DOPEGAL versus DOPAL; mechanisms of accumulation of CA aldehydes in Alzheimer's disease (AD) and Parkinson's disease (PD) and potential therapeutic targets in Alzheimer's disease and Parkinson's disease.

Burton, D. A., G. Nicholson, et al. (2004). "Anaesthesia in elderly patients with neurodegenerative disorders: special considerations." Drugs Aging 21(4): 229-42.

            Neurodegenerative diseases are increasingly common in elderly patients, who present a particular anaesthetic challenge. The majority of people over the age of 70 years have some degree of cerebral atrophy. The pathogenesis of neurodegenerative diseases is due to alterations in the transport, degradation and aggregation of proteins. Alterations in physiology that occur with advancing age affect both the pharmacokinetics and pharmacodynamics of drugs used in the elderly. Changes in pharmacokinetics result in either increased or reduced drug concentrations depending on the variable contributions of absorption, metabolism and elimination. The distribution of a drug depends on its protein binding, cardiac output and blood volume, which are all altered in the elderly. Metabolism and excretion of drugs are also affected due to changes in hepatic and renal mass and blood flow in the elderly. A number of drugs are used in neurodegenerative disorders including antidepressants, benzodiazepines, antipsychotics, acetylcholinesterase inhibitors and levodopa. Polypharmacy is a common problem, which can lead to adverse drug interactions and an exacerbation of dementia. Levodopa, bromocriptine and tricyclic antidepressants are known to cause orthostatic hypotension in patients with neurodegenerative disease. Elderly patients are liable to excessive sedation from benzodiazepines in both the pre- and postoperative period; therefore these drugs should be prescribed in low doses. For induction of general anaesthesia propofol is a suitable agent in patients with neurodegenerative disease due to its rapid metabolism, but may not be suitable in patients with Parkinson's disease as it can induce spontaneous involuntary movements. Volatile inhalational agents should be administered carefully in the elderly, as they are more sensitive to the depressant cerebral and cardiovascular effects. Levodopa should be avoided in conjunction with halothane, which sensitises the heart to catecholamines. Co-administration of monoamine oxidase inhibitors and opioids should be avoided as it can cause agitation, muscular rigidity, sweating and hyperpyrexia. If an anticholinergic agent is required, then glycopyrronium bromide is the drug of choice in this group of patients, as it does not cross the blood brain barrier. Patients should continue to take their usual medications in hospital and do not let the change in routine alter the times at which treatments are administered. This is particularly relevant to the timing of levodopa in Parkinson's disease, as missed treatment can be detrimental. Regional anaesthesia may, however, have significant advantages in patients with Parkinson's disease, who can continue to take oral levodopa preoperatively, during surgery, if required, and early in the postoperative period. Anti-emetic drugs such as phenothiazines, butyrophenones and metoclopramide should be used carefully in the postoperative period in these patients as their antidopaminergic effects may induce or exacerbate parkinsonian effects.

Camicioli, R. and N. Fisher (2004). "Progress in clinical neurosciences: Parkinson's disease with dementia and dementia with Lewy bodies." Can J Neurol Sci 31(1): 7-21.

            Dementia occurs in up to 30% of people with Parkinson's disease and is a major cause of disability. Pathologically, Parkinson's dementia, where dementia follows the onset of parkinsonism by at least one year, overlaps with dementia with Lewy bodies. We review the functional impact, definitions, neuropsychology, epidemiology and pathophysiology of Parkinson's dementia, dementia with Lewy bodies and their overlap. Associated psychiatric and imaging findings are also considered. Lastly, current and emerging approaches to assessment and treatment in patients with these Lewy body associated dementias are presented.

Carini, M., G. Aldini, et al. (2004). "Mass spectrometry for detection of 4-hydroxy-trans-2-nonenal (HNE) adducts with peptides and proteins." Mass Spectrom Rev 23(4): 281-305.

            Despite the great technical advancement of mass spectrometry, this technique has contributed in a limited way to the discovery and quantitation of specific/precocious markers linked to free radical-mediated diseases. Unsaturated aldehydes generated by free radical-induced lipid peroxidation of polyunsaturated fatty acids, and in particular 4-hydroxy-trans-2 nonenal (HNE), are involved in the onset and progression of many pathologies such as cardiovascular (atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and cerebral ischemia). Most of the biological effects of HNE are attributed to the capacity of HNE to react with the nucleophilic sites of proteins and peptides (other than nucleic acids), to form covalently modified biomolecules that can disrupt important cellular functions and induce mutations. By considering the emerging role of HNE in several human diseases, an unequivocal analytical approach as mass spectrometry to detect/elucidate the structure of protein-HNE adducts in biological matrices is strictly needed not only to understand the reaction mechanism of HNE, but also to gain a deeper insight into the pathological role of HNE. This with the aim to provide intermediate diagnostic biomarkers for human diseases. This review sheds focus on the "state-of-the-art" of mass spectrometric applications in the field of HNE-protein adducts characterization, starting from the fundamental early studies and discussing the different MS-based approaches that can provide detailed information on the mechanistic aspects of HNE-protein interaction. In the last decade, the increases in the accessible mass ranges of modern instruments and advances in ionization methods have made possible a fundamental improvement in the analysis of protein-HNE adducts by mass spectrometry, and in particular by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) tandem mass spectrometry. The recent developments and uses of combined analytical approaches to detect and characterize the type/site of interaction have been highlighted, and several other aspects, including sample preparation methodologies, structure elucidation, and data analysis have also been considered.

Carreras, M. C., M. C. Franco, et al. (2004). "Nitric oxide, complex I, and the modulation of mitochondrial reactive species in biology and disease." Mol Aspects Med 25(1-2): 125-39.

            Mitochondria are the specialized organelles for energy metabolism but also participate in the production of O(2) active species, cell cycle regulation, apoptosis and thermogenesis. Classically, regulation of mitochondrial energy functions was based on the ADP/ATP ratio, which dynamically stimulates the transition between resting and maximal O(2) uptake. However, in the last years, NO was identified as a physiologic regulator of electron transfer and ATP synthesis by inhibiting cytochrome oxidase. Additionally, NO stimulates the mitochondrial production of O(2) active species, primarily O(2)(-) and H(2)O(2), and, depending on NO matrix concentration, of ONOO(-), which is responsible for the nitrosylation and nitration of mitochondrial components. By this means, alteration in mitochondrial complexes restricts energy output, further increases O(2) active species and changes cell signaling for proliferation and apoptosis through redox effects on specific pathways. These mechanisms are prototypically operating in prevalent generalized diseases like sepsis with multiorgan failure or limited neurodegenerative disorders like Parkinson's disease. Complex I appears to be highly susceptible to ONOO(-) effects and nitration, which defines an acquired group of mitochondrial disorders, in addition to the genetically induced syndromes. Increase of mitochondrial NO may follow over-expression of nNOS, induction and translocation of iNOS, and activation and/or increased content of the newly described mtNOS. Likewise, mtNOS is important in the modulation of O(2) uptake and cell signaling, and in mitochondrial pathology, including the effects of aging, dystrophin deficiency, hypoxia, inflammation and cancer.

Castagnoli, K. and T. Murugesan (2004). "Tobacco leaf, smoke and smoking, MAO inhibitors, Parkinson's disease and neuroprotection; are there links?" Neurotoxicology 25(1-2): 279-91.

            The potential neuroprotective properties of monoamine oxidase B (MAO-B) inhibitors have been of interest in part because of the role that this enzyme plays in the bioactivation of the parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Interestingly, tobacco smokers have lowered levels of brain and blood platelet MAO-B activity and a well documented lowered incidence of Parkinson's disease (PD) compared to non-smokers. This correlation has led to the intriguing question of whether there are possible relationships between smoking, MAO-B activity and PD. Recent studies have evaluated specific components of tobacco smoke for their MAO inhibiting and neuroprotective properties. This chapter summarizes the relevant literature relating to the basic questions in these areas. We have undertaken studies to identify possible inhibitors of MAO-B in the tobacco leaf and tobacco smoke and have evaluated one such compound in the MPTP PD mouse model. In this chapter we report on the results of these studies and present a discussion of potential avenues of research and their implication with respect to PD, smoking and monoamine oxidase.

Chan, D. K., D. Cordato, et al. (2004). "Comparison of environmental and genetic factors for Parkinson's disease between Chinese and Caucasians." Neuroepidemiology 23(1-2): 13-22.

            This review paper compares the differences in prevalence, and environmental and genetic risk factors for Parkinson's disease between Chinese and Caucasian subjects. Comparison of age-specific prevalence between Chinese people and Caucasians suggests that the prevalence is lower in the Chinese (at least in the past), although the prevalence rate in China appears to be rising. Distinctions in environmental risk factors and genetic factors are discussed. The difference in prevalence may be due to distinctions in environmental and genetic risk factors as well as the complex interaction between these environmental and genetic factors, although discrepancies in methodology for prevalence surveys can also be an explanation.

Chekhonin, V. P., V. P. Baklaushev, et al. (2004). "[Modeling Parkinson's disease and objectifying the nigro-striatum system dysfunction]." Zh Nevrol Psikhiatr Im S S Korsakova 104(1): 59-68.

Chen, L. W., K. K. Yung, et al. (2004). "Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease." Curr Drug Targets 5(2): 197-206.

            Parkinson's disease (PD) is a serious motor disorder and it is the second most common brain degenerative disease in human. PD is known to be caused by degeneration of dopamine neurons in the substantia nigra but the cause of cell death is largely unknown. Mammalian neurokinins [NKs] are a group of neuropeptides that include substance P (SP; neurokinin-1, NK-1), substance K (SK; NK-2; neurokinin A), and neuromedin K (NK; NK-3; neurokinin B). Their biological effects as neurotransmitters, neuromodulators, or neurotrophic-like factors are mediated by three distinct neurokinin receptors, namely SP receptor (SPR: NK-1 receptor, NK-1R), SKR (NK-2R), and NKR (NK-3R). Several lines of evidence have indicated that neurokinins are implicated in the pathogenesis of PD. First, decreases of SP level and SP-immunoreactivity have been found in nigral and striatal tissues of animals with PD and postmortem PD patients. Second, NKs exert neuroprotective effects on neurons. In addition, NK receptors, namely NK-1 and NK-3 receptors, are abundantly localized in dopaminergic and cholinergic neurons of the basal ganglia, indicating that these neurons are under the physiological regulation of NKs. Moreover, modulation in motor activity occurred in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, PD animal model, after systemic administration of NK receptor agonists. NKs and NK receptors, therefore, might be important molecules that are associated with functions and survival of neurons in the basal ganglia, in particular the dopamine neurons. Further studies should be devoted to elucidate the functional roles of NK systems in (a) the neuropathogenesis and neuroprotection during the course of PD, (b) the efficacy of NK receptor drugs towards PD, and (c) potential therapeutic intervention that targets at the prevention or treatment of PD.

Cheng, E. M., A. Siderowf, et al. (2004). "Development of quality of care indicators for Parkinson's disease." Mov Disord 19(2): 136-50.

            Parkinson's disease (PD) is a major cause of disability. To date, there have been no large-scale efforts to measure the quality of PD care because of a lack of quality indicators for conducting an explicit review of PD care processes. We present a set of quality indicators for PD care. Based on a structured review of the medical literature, 79 potential indicators were drafted. Through a two-round modified Delphi process, an expert panel of seven movement disorders specialists rated each indicator on criteria of validity, feasibility, impact on outcomes, room for improvement, and overall utility. Seventy-one quality indicators met validity and feasibility thresholds. Applying thresholds for impact on outcomes, room for improvement, and overall utility, a subset of 29 indicators was identified, spanning dopaminergic therapy, assessment of functional status, assessment and treatment of depression, coordination of care, and medication use. Multivariable analysis showed that overall utility ratings were driven by validity and impact on outcomes (P < 0.01). An expert panel can reach consensus on a set of highly rated quality indicators for PD care, which can be used to assess quality of PD care and guide the design of quality improvement projects.

Ciubotaru, V., Y. Poinsignon, et al. (2004). "[Severe pleuropericarditis induced by long-term bromocriptin therapy, report of a case and review of the literature]." Rev Med Interne 25(4): 310-4.

            INTRODUCTION: Bromocriptin, member of the class of ergolines, is commonly prescribed as treatment of Parkinson's disease. Apart from vascular, digestif, neurologic and psychic disorders, the authors report cases of retroperitoneal fibrosis and pleural effusion, as adverse reactions related to the bromocriptin. SYNTHESIS: About 40 cases of skin, pleural, lung and retroperitoneal attacks were described after long term and high doses of bromocriptin. More ten years ago, the first case of constrictive pericarditis was cited in the medical literature, and the bromocriptin was incriminated as responsible. Since then, two other cases were cited. Our observation is a constrictive pericarditis, found in a 72 years old patient treated with bromocriptin for Parkinson's disease since five years (cumulative dose intake 73 grams). Investigations aimed to establish etiology were negative. Bromocriptin is suspected and the treatment is discontinued. As in the three other cases, cardiac and neurologic conditions markedly improved after bromocriptin's withdrawal. A pericardic thickening persists at the echography. CONCLUSION: The responsibility of bromocriptin in the etiology of constrictive pericarditis is seldom discussed, because it remains an exclusion diagnosis. Periodic chest X-ray and echocardiography should be considered in patients with long-term bromocriptin treatment.

Collins, S. J., V. A. Lawson, et al. (2004). "Transmissible spongiform encephalopathies." Lancet 363(9402): 51-61.

            Nosologically, transmissible spongiform encephalopathies (TSE or prion diseases) should be grouped with other neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, which are all caused by toxic gain of function of an aberrant form of a constitutively expressed protein. Failure to clear these proteins from the brain induces neuronal dysfunction. Transmissibility is the property that separates TSE from other neurodegenerative diseases, and this property seems to reside within the structure of the abnormal protein. The human phenotypic range of these encephalopathies includes Creutzfeldt-Jakob disease and its variant form, kuru, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. Notwithstanding the generally low incidence of TSE and their limited infectiousness, major epidemics such as bovine spongiform encephalopathy and kuru arise in situations where intraspecies recycling of the abnormal protein is sustained. Moreover, evidence of chronic subclinical infection in animals offers insights into pathogenesis and prompts re-evaluation of the notion of species barriers and present infection control measures. Since case-to-case transmission is the only known mechanism underlying epidemics of TSE, potential reservoirs of infectivity in the tails of epidemics need continued vigilance.

Craft, S. and G. S. Watson (2004). "Insulin and neurodegenerative disease: shared and specific mechanisms." Lancet Neurol 3(3): 169-78.

            Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.

de la Fuente-Fernandez, R. and A. J. Stoessl (2004). "The biochemical bases of the placebo effect." Sci Eng Ethics 10(1): 143-50.

            A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson's disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral striatum of patients with Parkinson's disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson's disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson's disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively.

Defebvre, L. (2004). "[Motor complications in dopa treatment of parkinson disease: clinical description and evaluation]." Therapie 59(1): 93-6.

            The aim of this study was to present the clinical characteristics of and the evaluation methods for the motor complications sometimes observed in the early stages of Parkinson's disease, differentiating motor fluctuations and levodopa-induced dyskinesias. The most common forms of motor fluctuations are the predictable end-of-dose deterioration (wearing off), the early-morning akinesia, and the on-off phenomenon. Non-motor fluctuations are often associated with different symptoms: dysautonomia, pain, psychic or cognitive signs during off periods and sometimes also during on periods. Levodopa-induced dyskinesias are classified according to their temporal profile after drug administration, namely peak-dose dyskinesias (mainly choreic movements), biphasic dyskinesias--onset and end-of-dose--(mainly dystonic and ballic movements), and finally off-period dyskinesias (dystonic movements). Clinical evaluation of motor complications must be performed precisely to establish the best therapeutic strategy.

Dewey, R. B., Jr. (2004). "Management of motor complications in Parkinson's disease." Neurology 62(6 Suppl 4): S3-7.

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

Dlamini, Z., Z. Mbita, et al. (2004). "Genealogy, expression, and molecular mechanisms in apoptosis." Pharmacol Ther 101(1): 1-15.

            Apoptosis, known as programmed cell death, is a conserved, gene-directed mechanism for the elimination of unnecessary or unwanted cells from an organism. A retrospective look at the basis of human disease pathogenesis almost always reveals an apoptotic component that either contributes to disease progression or accounts for it. Modulating the expression of key molecular components of the cell death machinery is an attractive and obvious strategy for apoptosis-based therapeutics. Apoptosis is an important component of most developmental abnormalities and human diseases and in many cases the underlying cause of the resulting pathology. It has also become clear that many, if not all, viruses possess mechanisms to forestall apoptosis and provide a living host to enhance virus propagation. Diseases like AIDS involve excessive apoptosis, and suppression of apoptosis may restore functionality to the infected tissues. Although these are still early days, it is difficult not to get excited about the significant advances that have already been made. The true therapeutic benefits of apoptosis modulation for the treatment of many devastating human diseases remain to be discovered.

Dobson, J. (2004). "Magnetic iron compounds in neurological disorders." Ann N Y Acad Sci 1012: 183-92.

            Although iron plays an important role in many aspects of human neurophysiology, it also can be toxic under certain circumstances. Anomalous amounts of iron are known to be associated with most types of neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases. To date, little is known about the specific iron compounds present in this tissue and there is recent evidence to suggest that some forms are magnetic. This raises important questions with regard to the role of magnetic iron compounds in disease initiation and progression and, indeed, the origin of these compounds. This paper reviews recent work on the identification and analysis of magnetic iron compounds associated with neurological disorders.

Dobson, A. W., K. M. Erikson, et al. (2004). "Manganese neurotoxicity." Ann N Y Acad Sci 1012: 115-28.

            Manganese is an essential trace element and it is required for many ubiquitous enzymatic reactions. While manganese deficiency rarely occurs in humans, manganese toxicity is known to occur in certain occupational settings through inhalation of manganese-containing dust. The brain is particularly susceptible to this excess manganese, and accumulation there can cause a neurodegenerative disorder known as manganism. Characteristics of this disease are described as Parkinson-like symptoms. The similarities between the two disorders can be partially explained by the fact that the basal ganglia accumulate most of the excess manganese compared with other brain regions in manganism, and dysfunction in the basal ganglia is also the etiology of Parkinson's disease. It has been proposed that populations already at heightened risk for neurodegeneration may also be more susceptible to manganese neurotoxicity, which highlights the importance of investigating the human health effects of using the controversial compound, methylcyclopentadienyl manganese tricarbonyl (MMT), in gasoline to increase octane. The mechanisms by which increased manganese levels can cause neuronal dysfunction and death are yet to be elucidated. However, oxidative stress generated through mitochondrial perturbation may be a key event in the demise of the affected central nervous system cells. Our studies with primary astrocyte cultures have revealed that they are a critical component in the battery of defenses against manganese-induced neurotoxicity. Additionally, evidence for the role of oxidative stress in the progression of manganism is reviewed here.

Dogrukol-Ak, D., F. Tore, et al. (2004). "Passage of VIP/PACAP/secretin family across the blood-brain barrier: therapeutic effects." Curr Pharm Des 10(12): 1325-40.

            In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimer's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.

Doraiswamy, P. M. and A. E. Finefrock (2004). "Metals in our minds: therapeutic implications for neurodegenerative disorders." Lancet Neurol 3(7): 431-4.

            BACKGROUND: Abnormal interactions of copper or iron in the brain with metal-binding proteins (such as amyloid-beta peptide [Abeta] or neuromelanin) that lead to oxidative stress have emerged as important potential mechanisms in brain ageing and neurodegenerative disorders. Although a controlled study of desferrioxamine in Alzheimer's disease(AD) had some promising results, concerns about toxicity and brain delivery have limited trials of traditional chelators. The therapeutic significance of metal dysregulation in neurodegenerative disorders has remained difficult to test. RECENT DEVELOPMENTS: Clioquinol was identified as a prototype metal-protein-attenuating compound (MPAC). In a blinded and controlled 9 week study of a mouse model of AD, oral clioquinol decreased brain Abeta by 49% without systemic toxicity. The concentrations of copper and zinc in the brain rose by about 15% in mice treated with clioquinol. Two other studies in mice showed that the raising of brain copper concentrations through diet or genetics could lower amyloid load and increase survival. A recent placebo-controlled trial in 36 patients with AD showed that clioquinol (250-750 mg daily) reduced plasma concentrations of Abeta(1-42), raised plasma concentrations of zinc, and-in a subset with moderate dementia-slowed cognitive decline over 24 weeks. Two recent experiments also showed the neuroprotective effects of iron chelation in a mouse model of Parkinson's disease. WHERE NEXT?: The experimental and transgenic-animal studies of metal-protein interactions are convincing but do not provide conclusive answers either about causality or whether this strategy will protect against neurodegeneration in human beings. The finding that clioquinol could modulate plasma concentrations of amyloid and cognition in patients with AD needs to be interpreted cautiously, but is an important first step. Clioquinol was withdrawn because of concerns of its association with subacute myelo-optic neuropathy in Japan; therefore, any additional studies with this drug will likely be small and closely monitored proof-of-concept studies. The development of optimal second-generation MPACs is a desirable goal and may permit greater insights into the significance of metal-protein interactions across several neurodegenerative disorders.

Drucker-Colin, R. and L. Verdugo-Diaz (2004). "Cell transplantation for Parkinson's disease: present status." Cell Mol Neurobiol 24(3): 301-16.

            1. Parkinson's disease (PD) is a neurodegenerative disorder caused by the loss of neurons in the substantia nigra pars compacta and a striatal deficiency of dopamine. PD typically affects people in late middle age and progresses slowly. In the early stages of the disease, treatment targeting the dopaminergic network is effective. However, with disease progression, transplantation is an option for repairing and replacing missing dopaminergic neurons. 2. In this review, we evaluate the tissue grafts and cellular therapies that have and are being considered. Clinical trials were originally derived from transplants of adrenal medullary chromaffin cells and embryonic nigral dopaminergic neurons in patients with PD. 3. Recently, novel molecular and cellular treatments are being utilized in animals and these include embryonic stem cells, fetal cells from pigs, or transfected cells. In spite of new molecular techniques and some 20 years of experience, the transplantation therapy for PD has today the same problems and results as the first reports which used neural fetal tissue or adrenal grafts.

Duda, J. E. (2004). "Pathology and neurotransmitter abnormalities of dementia with Lewy bodies." Dement Geriatr Cogn Disord 17 Suppl 1: 3-14.

            The neuropathology of dementia with Lewy bodies (DLB) is characterized by the presence of Lewy bodies (LBs) and Lewy neurites (LNs) in specific systems throughout the brainstem, diencephalon, basal ganglia and neocortex. DLB shares many features with Parkinson's disease (PD) with respect to LB distribution in the brainstem, and there is recent evidence that Lewy pathology (LP), which consists of LBs and LNs, may progress in a systematic fashion through the brain regardless of clinical phenotype. Increasing evidence supports a central role for LNs in Lewy neurodegeneration and engenders a 'neuritic dystrophy hypothesis' described herein. LP formation also occurs in Alzheimer's disease (AD) and other dementias, and it is unclear whether there is a common underlying pathophysiology in these diseases or if the LP merely represents a common final pathway. Cholinergic deficits are evident in both DLB and AD, with reductions in acetylcholine and abnormalities in nicotinic and muscarinic receptor expression in both diseases. Cholinergic deficits are greater in DLB than in AD, although generally there is less brain atrophy in DLB. The lower neurodegeneration and preservation of cholinergic receptors in DLB has important therapeutic implications because patients with DLB (vs. AD) may receive greater benefits from cholinergic pharmacologic therapy. Patients with DLB who display parkinsonian signs have severe dopamine neurotransmitter deficiencies similar to those in patients with PD, although the manifestation of these deficiencies is different. Both groups have striatal dopamine transporter deficiencies, but the striatal dopamine D2 receptors are reduced in DLB patients compared with PD and control subjects. D2 receptor deficiencies in DLB may be the cause of the relative lack of response to levodopa treatment and the severe adverse reaction to neuroleptics in these patients.

Eckert, T. and D. Eidelberg (2004). "The role of functional neuroimaging in the differential diagnosis of idiopathic Parkinson's disease and multiple system atrophy." Clin Auton Res 14(2): 84-91.

            Parkinsonism is a symptom of a number of neurodegenerative disorders in the elderly. Even though clinical criteria for various parkinsonian disorders have been developed recently, the differential diagnosis of parkinsonian disorders based on clinical symptoms remains unsatisfactory, particularly in early disease stages. Early differential diagnosis on the other hand is important as prognosis and treatment options differ substantially. Multiple system atrophy (MSA) is one of the major differential diagnoses of idiopathic Parkinson's disease (PD). Radiotracer-based imaging methods such as positron emission tomography (PET) remain the established method for differential diagnosis of parkinsonian disorders. The following paper provides a review of different PET imaging methods for the differential diagnosis of PD and MSA patients.

Ekshyyan, O. and T. Y. Aw (2004). "Apoptosis in acute and chronic neurological disorders." Front Biosci 9: 1567-76.

            Programmed cell death or apoptosis is a physiologically important process in neurogenesis wherein approximately 50% of the neurons apoptose during maturation of the nervous system. However, premature apoptosis and/or aberrations in apoptosis control contribute to the pathogenesis of a variety of neurological disorders including acute brain injury such as trauma, spinal cord injury, ischemic stroke and ischemia/reperfusion as well as chronic disease states such as Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, spinal muscular atrophy, and diabetic neuropathy. The current review will focus on two major topics, namely, the general concepts of our current understanding of the apoptosis death machinery, its mediators and regulation, and the relationship between aberrant apoptosis and genesis of neurodegenerative disorders. This knowledge of apoptosis mechanisms will underpin the basis for development of novel therapeutic strategies and treatment modalities that are directed at control of the neuronal apoptotic death program.

Factor, S. A. (2004). "Literature review: intermittent subcutaneous apomorphine therapy in Parkinson's disease." Neurology 62(6 Suppl 4): S12-7.

            Apomorphine injectable has been used in Europe for more than a decade as a rescue therapy for intractable "off" periods in Parkinson's disease (PD). Some studies were performed as early as the 1970's. This article reviews double-blind and open studies with apomorphine for PD prior to the year 2000. Most were performed in Europe. Double-blind studies with injection doses of 1-5 mg have demonstrated that onset of clinical benefit typically occurs within 10 minutes, and lasts for up to two hours. The magnitude of benefit rivals that of levodopa. Long-term, open-label studies have demonstrated the persistent response to apomorphine injectable as a rescue therapy for as long as five years. Duration of benefit and dose of a single injection remains the same, but a need for increased number of doses per day is reported in keeping with disease progression. For many patients, the need for concomitant domperidone administration for antiemesis wanes over time. Apomorphine has also been shown in smaller studies to be effective for a variety of non-motor "off" phenomena, including pain, panic attacks, and a variety of gastrointestinal symptoms. Subutaneous intermittent bolus injects are also useful in patients post operatively who are unable to take oral medications.

Fendyur, A., I. Kaiserman, et al. (2004). "The burst of mitochondrial diseases: neurons and calcium." Isr Med Assoc J 6(6): 356-9.

Fernandez-Espejo, E. (2004). "Pathogenesis of Parkinson's disease: prospects of neuroprotective and restorative therapies." Mol Neurobiol 29(1): 15-30.

            Parkinson's disease (PD) is caused by the degeneration of dopaminergic neurons of substantia nigra projecting to striatum. The cause of idiopathic PD is obscure, and most cases are sporadic. It is widely accepted that there is a genetic component of the disease, and the earlier the age of onset, the greater the likelihood that genetic factors play a dominant role. Oxidative stress of the substantia nigra seems to contain the driving force for neurodegeneration, leading to a destructive "toxic cycle." The most prevalent therapy is levodopa administration, but it is not efficacious after several years of treatment. Several alternative therapies are currently being explored, such as neuroprotective approaches. Compounds with potentially neuroprotective efficacy such as selegiline, dopamine agonists, riluzole, creatine, and coenzyme Q10 are currently being tested. Trophic factors represent another class of neuroprotective compounds, but their intracerebral administration is difficult to achieve. In this respect, a potentially useful therapeutic approach is grafting cell vectors that release trophic molecules that stimulate regeneration in the damaged nigrostriatal system. Promising results have been obtained with fibroblasts engineered to secrete glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) or viral vectors expressing GDNF. We have tested the suitability of intrastriatal grafts of chromaffin cells obtained from the Zuckerkandl's organ, which exert beneficial effects in parkinsonian rats, and release trophic factors such as GDNF and transforming growth factor-beta1 (TGF-beta1).

Finley, J. W. (2004). "Does environmental exposure to manganese pose a health risk to healthy adults?" Nutr Rev 62(4): 148-53.

            Manganese is an essential nutrient that also may be toxic at high concentrations. Subjects chronically exposed to manganese-laden dust in industrial settings develop neuropsychological changes that resemble Parkinson's disease. Manganese has been proposed as an additive to gasoline (as a replacement for the catalytic properties of lead), which has generated increased research interest in the possible deleterious effects of environmental exposure to manganese. Low-level exposure to manganese has been implicated in neurologic changes, decreased learning ability in school-aged children, and increased propensity for violence in adults. However, a thorough review of the literature shows very weak cause-and-effect relationships that do not justify concern about environmental exposure to manganese for most of the North American population.

Fisone, G., A. Borgkvist, et al. (2004). "Caffeine as a psychomotor stimulant: mechanism of action." Cell Mol Life Sci 61(7-8): 857-72.

            The popularity of caffeine as a psychoactive drug is due to its stimulant properties, which depend on its ability to reduce adenosine transmission in the brain. Adenosine A(1) and A(2A) receptors are expressed in the basal ganglia, a group of structures involved in various aspects of motor control. Caffeine acts as an antagonist to both types of receptors. Increasing evidence indicates that the psychomotor stimulant effect of caffeine is generated by affecting a particular group of projection neurons located in the striatum, the main receiving area of the basal ganglia. These cells express high levels of adenosine A(2A) receptors, which are involved in various intracellular processes, including the expression of immediate early genes and regulation of the dopamine- and cyclic AMP-regulated 32-kDa phosphoprotein DARPP-32. The present review focuses on the effects of caffeine on striatal signal transduction and on their involvement in caffeine-mediated motor stimulation.

Fiszer, U. (2004). "[Selected aspects of immunological disorders in Parkinson disease]." Neurol Neurochir Pol 38(1 Suppl 1): S63-6.

            Numerous factors are involved in the pathogenesis of Parkinson's disease, including inflammation in certain regions of the brain. Studies suggest a significant role of microglia in dopaminergic cell injury. Cytokines and apoptosis-related proteins were elevated in the brain and cerebrospinal fluid. The occurrence of autoantibodies against neuronal structures has been found in Parkinson's disease. Disturbed cellular and humoral immune functions in peripheral blood and cerebrospinal fluid of patients have been also reported. An infectious cause of Parkinson's disease has been also discussed for years.

Fraix, V. (2004). "[Gene therapy for Parkinson's disease]." Rev Med Interne 25(7): 524-7.

            INTRODUCTION: Parkinson's disease is a progressive neurodegenerative disorder whose main histopathological feature is the loss of dopaminergic neurons in the pars compacta of the substantia nigra with secondary striatal dopaminergic insufficiency. Treatment relies on medical therapy, using levodopa and dopaminergic agonists. However, the development of treatment complications, including motor fluctuations and levodopa-induced dyskinesia, led to the development of alternative therapeutical strategies such as deep brain stimulation and gene therapy. EXEGESIS: Current gene therapy models for Parkinson's disease have focused on two strategies. The first one is the replacement of biosynthetic enzymes for dopamine synthesis and the second consists in the addition of neurotrophic factors for protection and restoration of dopaminergic neurons. CONCLUSION: Neuroprotection and restoration of the nigrostriatal pathway are important issues for future genetic treatment strategies for Parkinson's disease and could include, in addition to neurotrophic factors, genes to prevent apoptosis or detoxify free radical species.

Friedman, J. H. and K. L. Chou (2004). "Sleep and fatigue in Parkinson's disease." Parkinsonism Relat Disord 10 Suppl 1: S27-35.

            Sleep disorders and fatigue are common problems in Parkinson's disease (PD). Although they frequently appear together, they are often distinct symptoms that must be understood separately. Fatigue has been reported to be the most bothersome aspect of PD in about one-third of patients, yet it is poorly understood and not clearly treatable. Sleep disorders, while more common, are less bothersome to the patients and often responsive to therapy. An overview of sleep disorders in PD and an approach to therapy will also be outlined. The little that is known about fatigue in PD will be reviewed.

Frucht, S. J. (2004). "Movement disorder emergencies in the perioperative period." Neurol Clin 22(2): 379-87.

            Movement disorder emergencies are uncommon in the perioperative period; however, when they occur, then carry significant morbidity. By paying attention to the phenomenology of the movement disorder, the effects of medications administered in the operating room, and unusual sequelae of surgery, neurologists can have a positive impact on the outcome of these patients.

Galvez-Jimenez, N. and A. E. Lang (2004). "The perioperative management of Parkinson's disease revisited." Neurol Clin 22(2): 367-77.

            The perioperative management of patients who have PD requires knowledge of the potential complications of various types of surgery. Neurologists should be able to balance patient comfort against the potential complications of antiparkinsonian therapy. The authors believe that the approach outlined in the Appendix increases patient comfort, facilitates nursing care, and can potentially reduce some of the complications seen in the postoperative period.

Gekht, A. B. (2004). "[Treatment of Parkinson's disease: use of piribedil]." Zh Nevrol Psikhiatr Im S S Korsakova 104(1): 54-6.

Giroud Benitez, J. L. (2004). "[Early-onset Parkinson's disease]." Rev Neurol 38(7): 698-9.

Glanzer, J. G., P. G. Haydon, et al. (2004). "Expression profile analysis of neurodegenerative disease: advances in specificity and resolution." Neurochem Res 29(6): 1161-8.

            Microarray technology has become a common tool for developing expression profiles. Initially used in the analysis of cells lines and homogeneous tissues, this platform has been applied to more diverse tissues, such as the brain. Several neural disorders have already been profiled by microarrays using relatively large amounts of tissue. This data has unveiled many genes with differential expression between normal and diseased tissue that could potentially be used as gene markers for these afflictions. Because of the heterogeneity of the CNS, it is likely that small differences between gene expression in these studies would be enhanced by the sampling of a subset of cells based on these newly characterized gene markers. Subtraction of normal, unaffected cells from the sample may also result in a more accurate profile of a diseased cell. Expression profile studies from several neuropathological states are presented, with emphasis placed on those studies using small samples of cellular material and those using specialized methods of cell isolation and RNA amplification.

Gotz, M. E., K. Double, et al. (2004). "The relevance of iron in the pathogenesis of Parkinson's disease." Ann N Y Acad Sci 1012: 193-208.

            Investigations that revealed increased levels of iron in postmortem brains from patients with Parkinson's disease (PD) as compared to those from individuals not suffering from neurological disorders are reported. The chemical natures in which iron predominates in the brain and the relevance of neuromelanin for neuronal iron binding are discussed. Major findings have been that iron levels increase with the severity of neuropathological changes in PD, presumably due to increased transport through the blood-brain barrier in late stages of parkinsonism. Glial iron is mainly stored as ferric iron in ferritin, while neuronal iron is predominantly bound to neuromelanin. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of reactive biological intermediates, including reactive oxygen species, and the formation of cytotoxic protein aggregates. There are indications that iron-mediated neuronal death in PD proceeds retrogradely. These results are also discussed with respect to their relevance for disease progression in relation to cytotoxic alpha-synuclein protofibril formation.

Grunblatt, E. (2004). "The benefits of microarrays as tools for studying neuropsychiatric disorders." Drugs Today (Barc) 40(2): 147-56.

            DNA microarray technology is currently an area of great interest. These microarray or "gene chip" technologies, which arose out of the development of large-scale sequencing approaches, are now coming increasingly into use, generating a far greater volume of data than the data representing the sequences themselves. This technology is a powerful tool for the analysis of the organization and regulation of the brain in both diseased and healthy subjects. It can provide new insights into gene function, disease pathophysiology, disease classification and drug development. In this review, the basic theory of microarray technology and its analysis methods are presented, and technical problems are discussed. Additionally, some current results from microarray technology conducted in neuropsychiatry are presented.

Gupta, A. K. and R. Bluhm (2004). "Seborrheic dermatitis." J Eur Acad Dermatol Venereol 18(1): 13-26; quiz 19-20.

            Seborrheic dermatitis is a common inflammation of the skin, occurring most often on the face, scalp and chest. It is closely related to infantile seborrheic dermatitis, or diaper rash. Seborrheic dermatitis is particularly common in patients with Parkinson's disease or with HIV/AIDS. The recent resurgence of interest in Malassezia yeasts has revived the old hypothesis that seborrheic dermatitis is caused by an altered relationship between these skin commensals and the host. Moreover, the success of antifungal medications in treating seborrheic dermatitis provides new evidence for this view. LEARNING OBJECTIVE: Upon completing this paper, the reader should be aware of the clinical presentation of seborrheic dermatitis and which populations are at particular risk of developing this disorder. In addition, s/he will be aware of the role of Malassezia yeasts in seborrheic dermatitis and the way in which knowledge of the importance of these yeasts has altered the treatment of this disorder.

Halberstadt, C., D. F. Emerich, et al. (2004). "Use of Sertoli cell transplants to provide local immunoprotection for tissue grafts." Expert Opin Biol Ther 4(6): 813-25.

            The recent success of allogeneic islet transplantation for the treatment of type I diabetes has renewed interest in cell therapy for diseases of secretory cell dysfunction. Unfortunately, widespread clinical use of cell transplantation is limited by tissue availability and the need for long-term immunosuppresion. Testicular Sertoli cells can confer local immunoprotection for co-transplanted cells and may provide a means of overcoming the obstacles associated with cell transplantation. Sertoli cell grafts protect islets in animal models of diabetes and can be transplanted into the brain to enhance regeneration and promote the survival of co-grafted tissues. This review describes the role that Sertoli cells normally play in testicular immunology, details the preclinical data using transplanted Sertoli cells in models of diabetes and Parkinson's disease and discusses some of the possible mechanisms involved in this phenomena, as well as the future of this technology.

HaMai, D. and S. C. Bondy (2004). "Oxidative basis of manganese neurotoxicity." Ann N Y Acad Sci 1012: 129-41.

            Exposure to excessive levels of manganese, an essential trace element, can evoke severe psychiatric and extrapyramidal motor dysfunction closely resembling Parkinson's disease. The clinical manifestations of manganese toxicity arise from focal injury to the basal ganglia. This region, characterized by intense consumption of oxygen and significant dopamine content, can incur mitochondrial dysfunction, depletion of levels of peroxidase and catalase, and catecholamine biochemical imbalances following manganese exposure. The site specificity of the pathology and the nature of the cellular damage caused by manganese have been attributed to its capacity to produce cytotoxic levels of free radicals. However, support for such a pro-oxidant role for manganese has been largely limited to inferences drawn from histopathological observations. More recently, research efforts into the molecular details of manganese toxicity have provided evidence of an etiological relationship between oxidative stress and manganese-related neurodegeneration. This review focuses on studies that evaluate the redox chemistry of manganese during the neurodegenerative process and its molecular consequences.

Hamani, C., J. A. Saint-Cyr, et al. (2004). "The subthalamic nucleus in the context of movement disorders." Brain 127(Pt 1): 4-20.

            The subthalamic nucleus (STN) has been regarded as an important modulator of basal ganglia output. It receives its major afferents from the cerebral cortex, thalamus, globus pallidus externus and brainstem, and projects mainly to both segments of the globus pallidus, substantia nigra, striatum and brainstem. The STN is essentially composed of projection glutamatergic neurons. Lesions of the STN induce choreiform abnormal movements and ballism on the contralateral side of the body. In animal models of Parkinson's disease this nucleus may be dysfunctional and neurons may fire in oscillatory patterns that can be closely related to tremor. Both STN lesions and high frequency stimulation ameliorate the major motor symptoms of parkinsonism in humans and animal models of Parkinson's disease and reverse certain electrophysiological and metabolic consequences of dopamine depletion. These new findings have led to a renewed interest in the STN. The aim of the present article is to review briefly the major anatomical, pharmacological and physiological aspects of the STN, as well as its involvement in the pathophysiology and treatment of Parkinson's disease.

Harrower, T. P. and R. A. Barker (2004). "Is there a future for neural transplantation?" BioDrugs 18(3): 141-53.

            Traditionally neural transplantation has had as its central tenet the replacement of missing neurons that have been lost because of neurodegenerative processes, as exemplified by diseases such as Parkinson disease (PD). However, the effectiveness and widespread application of this approach clinically has been limited, primarily because of the poor donor supply of human fetal neural tissue and the incomplete neurobiological understanding of the circuit reconstruction required to normalize function in these diseases. So, in PD the progress from promising neural transplantation in animal models to proof-of-principle, open-labeled clinical transplants, to randomized, placebo-controlled studies of neural transplantation has not been straightforward. The emergence of previously undescribed adverse effects and lack of significant functional advantage in recent clinical studies has been disappointing and has served to cast a new, and perhaps more realistic, perspective on this treatment approach. In fact, there have been calls by some involved in neural transplantation to return to the drawing board before pressing on with further clinical trials, and the return to basic experimentation. This therefore precipitates the question - is there a future for neural transplantation? It is important to remember that there are a number of possible explanations for the disappointing results from the recent clinical trials in PD, ranging from the mode of transplantation to patient selection. Nevertheless, almost irrespective of these reasons for the current trial results, there have always been significant practical and ethical problems with using human fetal tissue, and so a number of alternative cell sources have been investigated. These alternative sources include stem cells, which are attractive for cell-based therapies because of their potential ease of isolation, propagation and manipulation, and their ability in some cases to migrate to areas of pathology and differentiate into specific and appropriate cell types. Furthermore, the availability of stem cells derived from non-embryonic sources (e.g. adult stem cells derived from the sub-ventricular zone) has removed some of the ethical limitations associated with the use of embryonic human tissue. These potentially beneficial aspects of stem cells means that there is a future for neural transplantation as a means of treating patients with a range of neurological disorders, although whether this will ever translate into a truly effective, widely available therapy remains unknown.

Harrower, T. P. and R. A. Barker (2004). "The emerging technologies of neural xenografting and stem cell transplantation for treating neurodegenerative disorders." Drugs Today (Barc) 40(2): 171-89.

            Neural transplantation has normally been considered in the context of the neurodegenerative disorders, Parkinson's and Huntington's disease, which are characterized pathologically by the predominant loss of specific cells in the basal ganglia. This approach has now emerged from the experimental arena into the level of clinical trial, at least with respect to fetal human allografts. However the ethical and practical problems with using such tissue has led to the search for alternative sources of cells of which two of the most promising are cells from another species, such as the pig (xenografts), and stem cells. Neural transplantation using cells derived from the developing pig brain offers many advantages. Firstly, time-mated litters will overcome the issue of donor tissue supply. Secondly, advances in genetic technology have led to the development of pigs which have a reduced rejection potential. Thirdly, xenografted neural fiber outgrowth may be superior to that from neural grafts derived from the same species (allografts) which may increase the potential for circuit reconstruction. Disadvantages with this tissue source include concerns about transmission of zoonotic infections and the immunological rejection of the xenograft. Stem cells are defined as cells capable of division (self-renewal) and differentiation into a range of different cell types (differentiation). A variety of such cells exist including embryonic stem cells, neural stem cells derived from the developing fetal brain (neural progenitor cells), adult neural stem cells and adult stem cells originating from outside of the central nervous system. Each of these different types of stem cell have their own unique benefits but also disadvantages, and access to each type is constrained by a number of limiting factors. All of this means that the translation of these cell therapies into practice is not straightforward and must be done at a pace dictated by laboratory-based research rather than corporate share price.

Hashimoto, T. (2004). "[Microrecording: a guide to stereotactic brain operations]." No Shinkei Geka 32(3): 297-303.

Heales, S. J., A. A. Lam, et al. (2004). "Neurodegeneration or neuroprotection: the pivotal role of astrocytes." Neurochem Res 29(3): 513-9.

            Formation of nitric oxide (NO), by astrocytes, has been suggested to contribute, via impairment of mitochondrial function, to the neurodegnerative process. Thus co-culture of neuronal cells with NO-generating astrocytes leads to a loss of mitochondrial function, as reflected by diminished activities of complexes IV and II+III. However, such damage may in the first instance be limited due to upregulation of neuronal glutathione metabolism as a result of metabolic trafficking of glutathione from the astrocyte to neurone. Furthermore, exposure of astrocytes to NO leads to increased glutathione metabolism resulting in the preservation of glutathione precursors for neuronal utilization. Failure of glutathione trafficking could render neuronal cells particularly susceptible to NO, leading to cell death. In addition, depletion with time of the nitric oxide synthase cofactor, tetrahydrobiopterin, may result in the astrocytic generation of more potent oxidizing species, which could contribute to the neurodegenerative process.

Heiss, W. D. and R. Hilker (2004). "The sensitivity of 18-fluorodopa positron emission tomography and magnetic resonance imaging in Parkinson's disease." Eur J Neurol 11(1): 5-12.

            Parkinson's disease (PD) as the most important movement disorder is characterized by a progressive loss of nigral dopamine neurons and a subsequent degeneration within several other transmitter systems. Functional brain imaging with positron emission tomography (PET) and the radiotracer 18-fluorodopa (FDOPA) is capable to quantify the deficiency of dopamine synthesis and storage within pre-synaptic striatal nerve terminals. Therefore, FDOPA-PET allows the diagnosis of PD in early disease stages and the differentiation of clinically unclear cases from other movement disorders, e.g. essential tremor. Additionally, FDOPA-PET imaging permits the follow-up of disease progression, the assessment of medical and surgical PD therapy strategies with possible neuroprotective properties and the detection of pre-clinical disease in subjects at risk for the disorder. The classical domain of morphological magnetic resonance imaging (MRI) is the differentiation of symptomatic Parkinsonism from PD. However, recent advances in MRI data acquisition and analysis techniques demonstrated MRI to be also a valuable tool for detection of nigral pathology in PD and for differentiation of neurodegenerative disorders with atypical Parkinsonism.

Hening, W. A., R. P. Allen, et al. (2004). "An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder." Sleep 27(3): 560-83.

            This paper reviews evidence from April, 1998 through April 2002 for the dopaminergic treatment of the restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). There has been increased study of dopaminergic agents for the treatment of these conditions since publication of a review paper and practice parameters that covered all types of medical treatment of RLS and PLMD in 1999. For this reason, the Restless Legs Syndrome Task Force and the Standards of Practice Committee decided to update the evidence on dopaminergic treatment of these conditions. This paper reviews the literature on levodopa, dopaminergic agonists (pergolide, pramipexole, ropinirole, talipexole, cabergoline, piribidel, DHEC), and other dopaminergic agents (amantadine, selegiline).

Hermann, A., M. Gerlach, et al. (2004). "Neurorestoration in Parkinson's disease by cell replacement and endogenous regeneration." Expert Opin Biol Ther 4(2): 131-43.

            Parkinson's disease (PD) is characterised by a continuous and selective loss of dopaminergic neurons in the substantia nigra pars compacta with a subsequent reduction of the neurotransmitter dopamine. Thus, the prospect of replacing the missing or damaged dopaminergic cells is very attractive. Possible regenerative therapies include transplanting developing neural tissue or neural stem cells into the degenerated host brain and inducing proliferation of endogenous stem cells by pharmacological manipulations. Neural stem cells, with the capacity to self renew and produce the major cell types of the brain, exist in the developing and adult CNS. These cells can be generated and expanded in vitro while retaining the potential to differentiate into nervous tissue. However, one major problem is the control of growth and differentiation of these cells. This review discusses new data on stem cell technology in cell replacement strategies in PD as well as endogenous dopaminergic regeneration.

Hogg, R. C. and D. Bertrand (2004). "Nicotinic acetylcholine receptors as drug targets." Curr Drug Targets CNS Neurol Disord 3(2): 123-30.

            While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems it has also been observed that this alkaloid can have beneficial effects. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states we review the possibility to design new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.

Ikemoto, K. (2004). "Significance of human striatal D-neurons: implications in neuropsychiatric functions." Prog Neuropsychopharmacol Biol Psychiatry 28(3): 429-34.

            The human striatum, especially its ventral part, the nucleus accumbens (Acc), contains numerous nonmonoaminergic aromatic L-amino acid decarboxylase (AADC) [=dopa decarboxylase (DDC)] neurons (D-neurons). AADC is the second-step synthesizing enzyme for monoamines and is also the rate-limiting enzyme of phenylethylamine (PEA) synthesis. D-neurons may participate in the manifestation of efficacy of pharmacotherapy for Parkinson's disease by taking up monoamine precursors including L-dopa or droxidopa (L-threo-DOPS) and by converting them to dopamine or noradrenaline, respectively. Although previous studies have shown that AADC activity was elevated in the striatum of drug-naive schizophrenia, the number of striatal D-neurons was reduced in autopsy brains of schizophrenia. It is unclear whether or not such reduction of striatal D-neurons implies downregulation. Possible pluripotentiality of D-neurons, including compensatory functions against aging and degeneration, was discussed based on recent published works.

Imai, Y. and R. Takahashi (2004). "[Dopaminergic neuronal death in Parkinson's disease: is accumulation of unfolded proteins a cause or effect?]." Tanpakushitsu Kakusan Koso 49(7 Suppl): 1113-7.

Ismail, M. S. and I. H. Richard (2004). "A reality test: How well do we understand psychosis in Parkinson's disease?" J Neuropsychiatry Clin Neurosci 16(1): 8-18.

            Psychosis in Parkinson's disease (PD) is a major source of distress to patients and caregivers. Although the advent of atypical antipsychotic agents has, to some extent, resolved a clinical dilemma by preserving motor function while treating psychosis, our understanding of psychosis in PD remains in a nascent state. In this article the authors address several issues relating to psychosis in PD including the following: 1) prevalence, 2) possible etiologies and risk factors and 3) treatment. They also identify limitations in our understanding of this complex phenomenon and conclude that, despite availability of reasonable treatments for psychosis in PD, the search for a better understanding of the phenomenon must continue.

Jayakar, S. S. and M. Dikshit (2004). "AMPA receptor regulation mechanisms: future target for safer neuroprotective drugs." Int J Neurosci 114(6): 695-734.

            The post-synaptic AMPA receptors play an important role in mediating fast excitatory transmission in the mammalian brain. Over-activated AMPA receptors induce excitotoxicity, implicated in a number of Chronic neurodegenerative disorders such as Parkinson's disease, Huntington's disease, and AIDS encephalitis. AMPA receptor antagonists offer protection against neurodegeneration in the experimental models even if they are given 24 h after the injury. Because AMPA receptors seem to be involved in the neurodegenerative diseases, modulating the activity of the AMPA receptors could be an attractive approach to reduce or prevent excitotoxicity. Studies conducted recently have exhibited a number of new mechanisms for AMPA receptor regulation. Modulations of these were found to have protective implications. AMPA receptor depolarization and desensitization are protective to the neurons. Receptor desensitization depends on the receptor subunit composition. The R/G editing site and the flip/flop cassettes in AMPA receptor subunits contribute to a great extent in receptor desensitization and recovery rates. Molecules that could quicken receptor desensitization or delay recovery could be of use. AMPA receptors limit neuronal entry of Ca2+ ions by regulating Ca2+-permeability. Ca2+-permeable receptor channels are made up of GluR1, GluR3, or GluR4 subunits, whereas presence of the GluR2 subunit restricts Ca2+ entry and renders the receptor Ca2+-impermeable. GluR2 levels, however, experience a fall after neuronal insult rendering the AMPA receptors Ca2+-permeable, thus factors that could interfere with this event might prove to be very beneficial against excitotoxicity. AMPA receptor clusters are stabilized by PSD-95, which requires palmitoylation at two sites. Targeting palmitoylation of the PSD-95 can also be a useful approach to disperse AMPA clusters at the synapse. In the perisynaptic region, mGluRs are present a little away from the synapse and are among the glutamate transporters, which require high-frequency firing for activation. On activation they might enhance the activity of NMDA receptors at the synapse to increase the levels of AMPA receptors. AMPA receptors surfaced at this juncture can contribute to heavy Ca2+ influx. Thus, blocking this pathway could be of considerable importance in preventing the excitotoxicity. A number of proteins such as the GRIP, PICK, and NSF also modulate the functions of AMPA receptors. Polyamines also block Ca2+ permeable AMPA receptors and thus are protective. NO and cGMP also play an important role in negatively regulating AMPA receptors and thus could offer protection. Modulation of AMPA receptor by different mechanisms has been discussed in the present review to implicate importance of these targets/pathways for safer and future neuroprotective drugs.

Jenner, P. (2004). "Avoidance of dyskinesia: preclinical evidence for continuous dopaminergic stimulation." Neurology 62(1 Suppl 1): S47-55.

            Current concepts suggest that avoidance of pulsatile stimulation of dopamine receptors in Parkinson's disease (PD) can prevent the onset of dyskinesia. In MPTP-treated primates, repeated administration of levodopa or other short-acting dopamine agonist drugs leads to the onset of marked involuntary movements. In contrast, treatment with long-acting dopamine agonists leads to a much lower level of dyskinesia. Similar results have been obtained in PD patients, although the introduction of levodopa is a requirement in virtually all patients and this leads to further increases in motor complications. The concept of continuous dopaminergic stimulation should also apply to levodopa, such that reduced dyskinesia would be expected if it could be administered in a manner that avoids pulsatile receptor stimulation. In MPTP monkeys, administration of multiple small doses of levodopa in conjunction with the peripheral COMT inhibitor entacapone removes much of the pulsatility of motor function seen with standard levodopa treatment regimens and, at the same time, results in a lower incidence and intensity of dyskinesia. Furthermore, the addition of multiple small doses of levodopa plus entacapone to dopamine agonist treatment also avoids dyskinesia induction in MPTP-treated primates. These results suggest that administering of levodopa with entacapone as either initial or supplemental therapy for PD patients might reduce the risk for motor complications. Clinical trials to assess this hypothesis and determine if the results in MPTP monkeys can be duplicated in PD patients are warranted.

Kalia, S. K., J. E. Nash, et al. (2004). "To serve and protect? Interventions in the subthalamic nucleus for Parkinson's disease. Commentary on "Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease"." Exp Neurol 185(2): 201-3.

Kang, G. A. and J. M. Bronstein (2004). "Psychosis in nursing home patients with Parkinson's disease." J Am Med Dir Assoc 5(3): 167-73.

            Psychosis in patients with Parkinson's disease (PD) is a common and important problem. It is a frequent cause of nursing home placement and is associated with a high mortality. The cause of psychosis in PD is usually multi-factorial but often involves the agents used to treat the motor symptoms of the disease. Treatment strategies should include ruling out other causes of cognitive decline, reducing anti-PD medications, and judicious use of atypical neuroleptic medications. Cholinesterase inhibitors can also be useful as an adjunctive agent in patients with psychosis and cognitive decline. Careful management of PD patients with psychosis can often result in good control of hallucinations and delusions without significant decline in motor function.

Kim, D. W. (2004). "Efficient induction of dopaminergic neurons from embryonic stem cells for application to Parkinson's disease." Yonsei Med J 45 Suppl: 23-7.

            For cell replacement therapy of neurodegenerative diseases such as Parkinson's disease (PD), methods for efficiently generating midbrain dopaminergic (DA) neurons from embryonic stem (ES) cells have been investigated. Two aspects of DA neuron generation are considered: genetic modification and manipulation of culture conditions. A transcription factor known as critical for development of DA neurons, Nurr1, was introduced into ES cells to see how they facilitate the generation of DA neurons from ES cells. Also, two culture procedures, the 5-stage method and stromal cell-derived inducing activity (SDIA) method, were used for ES cell differentiation. Using the 5-stage method, we and others previously demonstrated that Nurr1-overexpressing ES cells, under treatment of signaling molecules such as SHH and FGF8 followed by treatment of ascorbic acid, can differentiate into DA neurons with a high efficiency (> 60% of TH+/Tuj1+ neurons). Furthermore, using the SDIA method with treatment of signaling molecules, we found that Nurr1-overexpressing ES cells can differentiate to DA neurons with the highest efficiency ever reported (approximately 90% of TH+/Tuj1+ neurons). Importantly, our semi-quantitative and real-time PCR analyses demonstrate that all known DA marker genes (e.g., TH, AADC and DAT) were up-regulated in Nurr1- overexpressing ES cells when compared to the na ve ES cells. These cells produced increased dopamine compared to na ve D3 cells after differentiation. In the in vivo context after transplantation, the genetically modified ES cells also showed the highly increased dopaminergic neuronal phenotypes. Thus, the combination of genetic engineering and appropriate culture conditions provides a useful tool to generate a good cell source from ES cells for cell replacement therapy of degenerative diseases such as PD.

Kim, S. I., H. Voshol, et al. (2004). "Neuroproteomics: expression profiling of the brain's proteomes in health and disease." Neurochem Res 29(6): 1317-31.

            The term "proteome" describes the protein complement of a genome. Proteomes of cells are dynamic and are directly affected by environmental factors, such as stress and/or drug treatment, or as a result of aging and disease. One of the distinct advantages of proteomic analysis, not attainable with RNA expression data, is the ability to fractionate the cell's proteins into various subpopulations. In neuroscience, "neuromics" (proteomics in the central nervous system) is in its infancy, with a paucity of studies in the context of the brain. One of the objectives of this review is to illustrate the potential of neuromics to profile differences in the distribution of thousands of proteins as a function of disease markers. We have previously used this approach to determine the effects of varied postmortem interval in examining human brain tissue and to identify biomarkers. Here we review proteomic studies of schizophrenia, Alzheimer's disease, and Parkinson's disease. Experimental results regarding Parkinson's disease are presented to illustrate the potential of neuromics to identify pathways of pathogenesis and novel therapeutic targets.

Kim, S., J. H. Seo, et al. (2004). "Alpha-synuclein, Parkinson's disease, and Alzheimer's disease." Parkinsonism Relat Disord 10 Suppl 1: S9-13.

            Alpha synuclein (alpha-SN) is a ubiquitous protein that is especially abundant in the brain and has been postulated to play a central role in the pathogenesis of Parkinson's disease (PD), Alzheimer's disease, and other neurodegenerative disorders. Here, we show that alpha-SN plays dual role of neuroprotection and neurotoxicity depending on its concentration or level of expression. In addition, our study shows that alpha-synuclein is differentially expressed in human peripheral blood mononuclear cells. PD patients expressed more alpha-synuclein than healthy controls. Thus, the alpha-synuclein expression in the peripheral immune system might be one of the primary causes of immune abnormalities in PD patients.

Kinkead, B. and C. B. Nemeroff (2004). "Neurotensin, schizophrenia, and antipsychotic drug action." Int Rev Neurobiol 59: 327-49.

            The search for the underlying pathophysiology of schizophrenia has been an active avenue of investigation since the disease was first recognized more than 100 years ago. Although a great deal of the research has been driven by the known pharmacology of effective antipsychotic drugs, i.e., overactivity of the dopamine system, recent advances in neurobiology provide evidence that reduced synaptic connectivity/neurotransmission may play a substantial role in this disorder. One neuropeptide long posited to play a role in the biology of schizophrenia is neurotensin (NT). Central nervous system administration of NT has been shown to produce a wide variety of effects. Because of its close association with the dopamine (DA) system, the role of the NT system in clinical disorders hypothesized to involve DA circuits such as schizophrenia, Parkinson's disease, and drug abuse has been closely scrutinized. In addition, NT neurotransmission has been implicated in regulation of the stress response, stress-induced gastric ulcers, temperature regulation, food consumption, and analgesia. NT also acts as a growth factor in a variety of human cancer cell lines derived from lung, colon, prostate, and pancreas. This review first provides a background of the NT system. Second, data indicating that NT may mediate the effects of antipsychotic drugs are summarized. Third, data implicating NT in the pathophysiology of schizophrenia are described. Finally, evidence suggesting the use of NTergic compounds as novel antipsychotic drugs are presented.

Kirik, D., B. Georgievska, et al. (2004). "Localized striatal delivery of GDNF as a treatment for Parkinson disease." Nat Neurosci 7(2): 105-10.

Kohno, Y. and S. Takeuchi (2004). "[Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole]." Nippon Yakurigaku Zasshi 123(6): 429-40.

            Pramipexole hydrochloride (pramipexole) is a nonergot dopamine D(2) agonist, and the S(-)enantiomer is used for the treatment of Parkinson's disease (PD). Pramipexole possessed the highest affinity with the D(3) subtype among the D(2) receptor subfamily members (D(2), D(3), D(4)), lacking affinity with the D(1) and D(5) subtype. Pramipexole ameliorated the motor disturbances in PD animal models, induced contralateral rotational behavior reflecting post-synaptic D(2) receptor stimulation in the striatum, and showed a variety of neuroprotective effects in vitro and in vivo experimental systems. The neuroprotective effects of pramipexole seemed to be derived from several mechanisms: stimulation of D(2) autoreceptor, stimulation of D(3) receptor, inhibition of oxidative reaction and following radical production, increase of Bcl-2 protein and inhibition of apoptotic cell death, and production of neurotrophic factor. Clinical efficacy of pramipexole both in monotherapy and combined use with L-DOPA were confirmed evaluating by UPDRS (Unified Parkinson's Disease Rating Scale) II (Activities of daily living) and III (Motor), in the results of clinical studies mainly performed in USA and European countries and partly in Japan. In addition, patients initially treated with pramipexole demonstrated reduction in problematic symptoms and in loss of striatal [(123)I]2beta-carboxymethoxy-3beta-(4-idodophenyl)tropan uptake, a marker of dopamine neuron degeneration, compared with those initially treated with L-DOPA.

Koller, W. and M. Stacy (2004). "Other formulations and future considerations for apomorphine for subcutaneous injection therapy." Neurology 62(6 Suppl 4): S22-6.

            This manuscript reviews apomorphine administration in formulations other than intermittent bolus injection, and comments on other potential uses for this unique compound. Continuous sc apomorphine therapy has been shown to alter peak-dose dyskinesia thresholds in advancing patients, and in some instances may replace all other anti-parkinson therapies. In general continuous infusion of sc apomorphine at a rate of 4 mg/h is well tolerated, and has been postulated to be equivalent to approximately 600 mg levodopa/day. This therapy is associated with skin complications, particularly nodule formation, and focal panniculitis is seen in more than 50% of subjects. Optimal dosages for intranasal apomorphine range from 2 to 5 mg per inhalation with benefit seen at 7.5 minutes and duration of effect of 45 to 55 minutes. Side effects included nasal irritation, vestibulitis, dyskinesias, yawning, and nausea. Comparison of 3 mg sc and 30 mg sublingual apomorphine in 9 Parkinson's disease subjects in a blinded cross-over trial found that the time to peak benefit was beyond 40 minutes with sl apomorphine, compared to 21 minutes in the sc preparation. Chronic use of the sublingual formulation was associated with severe stomatitis in half the subjects, and markedly limited the treatment. Rectal administration of apomorphine has been evaluated in limited, usually post-operative settings. Administration of a 200 mg apomorphine rectal suppository resulted in an average time to benefit of 32 minutes with an average duration of 195 minutes. Sedation, nausea and faintness were reported as side effects. Although the diagnostic confirmation potential of this agent has been questioned, the drug may have an important role in evaluating the potential for benefit in the deep brain stimulation surgical setting.

Koller, W. C. and W. Tse (2004). "Unmet medical needs in Parkinson's disease." Neurology 62(1 Suppl 1): S1-8.

            Levodopa, introduced in the late 1960s, was the first highly effective drug for the symptomatic treatment of Parkinson's disease (PD) and remains the mainstay of pharmacologic treatment. However, long-term treatment has important limitations. The disease continues to progress despite treatment with levodopa, and a neuroprotective therapy is urgently required. In addition, motor complications associated with chronic levodopa therapy are an important source of disability. Treatment of these complications forms a major focus of modern PD management, and it is in this area that recent advances in our knowledge offer the best opportunity for therapeutic gain. In the search for improved therapies, suitable outcome measures to better assess overall disability in PD and disease progression are essential.

Kondo, T. (2004). "[Parkinson's disease, familial Parkinson's disease]." Nippon Rinsho 62 Suppl: 97-101.

Kostic, V. S. (2004). "Comt inhibition in the treatment of Parkinson's disease: neuroprotection and future perspectives." Adv Exp Med Biol 541: 75-90.

Lang, A. E. and J. A. Obeso (2004). "Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough." Lancet Neurol 3(5): 309-16.

            Levodopa remains the most effective treatment for Parkinson's disease (PD). However, the drug is complicated by a wide range of adverse effects, most notably motor fluctuations and dyskinesias. Long-acting dopamine agonists are associated with a reduced incidence of these complications and modern surgical approaches and pharmacological methods of providing more continuous dopaminergic stimulation have a substantial ameliorative effect on these problems. Despite these advances, disease progression remains unaffected. For this reason there has been much enthusiasm for cellular therapies designed to replace degenerating nigrostriatal dopaminergic neurons. However, recent fetal transplant trials have failed to show expected benefit and have been complicated by medication dyskinesias". Even if successful, such treatment may be predestined to provide no better outcome than available treatments given current medical and surgical experience that emphasises the increasingly critical role of "non-dopaminergic" symptoms to quality of life in late-stage PD. Knowledge of the widespread, multisystem nature of the neurodegeneration that accounts for these problems suggests that restoration of the nigrostriatal dopamine system should not be the ultimate goal of future research.

Le, W. and S. H. Appel (2004). "Mutant genes responsible for Parkinson's disease." Curr Opin Pharmacol 4(1): 79-84.

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

Leon, J., D. Acuna-Castroviejo, et al. (2004). "Melatonin and mitochondrial function." Life Sci 75(7): 765-90.

            Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.

LeWitt, P. A. (2004). "Subcutaneously administered apomorphine: pharmacokinetics and metabolism." Neurology 62(6 Suppl 4): S8-11.

            Apomorphine is a non-narcotic morphine derivative that acts as a potent dopaminergic agonist. Its high first-pass hepatic metabolism prevents effectiveness by the oral route; instead, subcutaneous injection is the usual route, and intranasal, sublingual, rectal, and iontophoretic transdermal delivery has been investigated for the treatment of Parkinson's disease (PD). The rate of uptake after subcutaneous injection is influenced by factors such as location, temperature, depth of injection, and body fat. Studies have shown the latency of onset to clinical effect after s.c. injection ranged from 7.3 to 14 minutes. Cerebrospinal fluid T(max)lags behind plasma T(max) by 10 to 20 minutes. Considerable intersubject variability is found with pharmacokinetic variables; in some studies there are five- to tenfold differences in C(max)and area-under-the-concentration-time-curve seen in PD patients. Apomorphine metabolism occurs through several enzymatic pathways, including N-demethylation, sulfation, glucuronidation, and catechol-O-methyltransferase as well as by nonenzymatic oxidation. The complexities of apomorphine uptake, distribution, and clearance probably contribute to its variability of clinical actions.

LeWitt, P. A. and D. Nyholm (2004). "New developments in levodopa therapy." Neurology 62(1 Suppl 1): S9-16.

            More than 30 years after its development, levodopa is still the most effective treatment for the symptomatic control of Parkinson's disease (PD). Although a number of therapies have been developed in an attempt to improve PD management, such as dopaminergic agonists and inhibitors of COMT and MAO-B, most patients still depend on levodopa alone because of its superior ability to control PD symptoms. The issue of toxicity has been raised by in vitro studies suggesting that levodopa might be toxic to dopaminergic neurons, but this has since been answered by in vivo studies finding no evidence of toxicity and possibly even neurotrophic-like effects. A more pressing concern regarding levodopa is its association with the development of motor complications after long-term use. Pulsatile dopaminergic stimulation as a result of erratic absorption and the short half-life of levodopa have been central issues in attempts to explain this occurrence. Evidence suggests that altering the delivery of levodopa to provide a more continuous supply of this drug to the brain may result in improved control of PD symptoms.

Linazaroso, G., N. van Blercom, et al. (2004). "[Hypothesis: Parkinson's disease, reward deficiency syndrome and addictive effects of levodopa]." Neurologia 19(3): 117-27.

            Since Parkinson's disease (PD) patients could suffer from a reward deficiency syndrome, they are particularly prone to develop addictive behaviours. Dopamine is involved in reward processing and in addiction. Pulsatile administration of antiparkinsonian drugs may lead to the development of dyskinesias and addictive behaviours. However, this phenomenon occurs in very few cases. Indeed, both processes share molecular mechanisms although with some differences such as the topography of the changes (it predominates in motor regions in PD with dyskinesias and in limbic regions in addictions). Nevertheless, investigations conducted to know the physiopathology of levodopa-induced dyskinesias may lead to important cues for understanding the underlying mechanisms responsible for addiction. Thus, this may have important implications for the discovery of new therapeutic strategies.

Linnebur, S. A. (2004). "What's new about old drugs." J Gerontol Nurs 30(1): 4-11.

            Every month new clinical trials are published that provide relevant insight into medical care. Health care professionals are expected to review the results of these trials to update their knowledge and clinical practice. Although it is impossible to review every clinical trial, it is important to evaluate study findings in one's area of interest or practice. For nurses and other practitioners in the field of geriatrics, clinical trials involving drug therapy can be particularly valuable. This article is a review of clinical trials published in the past year that provide new information about drug therapy used by elderly patients. It reviews recent clinical trials in the areas of cardiology (hypertension, dyslipidemia, antioxidants for cardiovascular disease, hormone replacement therapy, atrial fibrillation, systolic heart failure), hematology (venous thromboembolic disease), neurology (Parkinson's disease, post-herpetic neuralgia), and rheumatology (osteoarthritis). Major findings and implications for geriatric clinical practice are included.

Low, S. J. and C. L. Roland (2004). "Review of NMDA antagonist-induced neurotoxicity and implications for clinical development." Int J Clin Pharmacol Ther 42(1): 1-14.

            NMDA receptor antagonists have been investigated for many years as therapeutic agents for the treatment of neurological disorders such as stroke, epilepsy, pain and Parkinson's disease. It has been discovered, however, that many of these compounds cause adverse behavioral (psychotomimetic) effects and can produce neurotoxicity characterized by neuronal vacuolization, induction of heat-shock protein, neuronal/axonal degeneration and regional brain cell death in several animal species. It is unknown whether NMDA antagonists induce neurotoxicity in humans. The mechanism of NMDA antagonist-induced neurotoxicity is not completely known, but some evidence suggests disinhibition of GABAergic inputs to the affected neurons. Several classes of compounds have been shown to prevent NMDA antagonist-induced neurotoxicity. The extent of neurotoxicity produced by NMDA antagonists is affected by many factors, including type of antagonist, dose, length of exposure, age, sex and species. While there are no published regulatory guidelines regarding how NMDA antagonist compounds should be evaluated, sponsors and investigators of these compounds should make every effort to assess the potential for neurotoxicity. NMDA receptor antagonists, as well as other CNS-active compounds need to be analyzed for neurotoxicity through careful experimental design, adequate tissue sampling and through the use of a sensitive method of detection.

Lozano, A. M. and N. Mahant (2004). "Deep brain stimulation surgery for Parkinson's disease: mechanisms and consequences." Parkinsonism Relat Disord 10 Suppl 1: S49-57.

            Despite the introduction of new medications, motor fluctuations and dyskinesias disable a significant proportion of Parkinson's disease patients. This has lead to renewed interest in stereotactic neurosurgery. A skilled team is needed to ensure that patient assessment and selection, operative technique, intraoperative monitoring, and post-operative management are optimised. High frequency stimulation has similar effects to ablative surgery, and is generally preferred. The clinical effects and possible mechanisms of action of deep brain stimulation of the subthalamic nucleus and globus pallidus are reviewed.

Lu, Y. (2004). "Recombinant adeno-associated virus as delivery vector for gene therapy--a review." Stem Cells Dev 13(1): 133-45.

            Recombinant adeno-associated virus (rAAV) is one of the most promising delivery vectors for gene therapy, due to its nonpathogenic property, nonimmunogenecity to host, and broad cell and tissue tropisms. This article summarizes the biological characteristics of AAV; the procedures to prepare, purify, and characterize the rAAV for gene therapy applications; and some of the clinical trials utilizing rAAV as delivery vehicles. Also discussed are the current efforts to modify rAAV to change its tropism, the application of different promoters to accommodate specific transgene expression, and the strategy to expand its capacity.

Magyar, K. and B. Szende (2004). "(-)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties." Neurotoxicology 25(1-2): 233-42.

            (-)-Deprenyl (selegiline) is an irreversible inhibitor of monoamine oxidase (MAO) B, which was discovered in 1962 and become the "golden standard" of MAO research. Like the other MAO-B inhibitors, it was synthesized as an antidepressant, but in a selective MAO-B inhibitory dose it does not act in depression. It is used in the treatment of Parkinson's disease. (-)-Deprenyl potentiates the effect of dopamine, it has antioxidant activity and prevents the toxicity of the dopaminergic (6-OH-dopamine; 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)), the noradrenergic (DSP-4) and cholinergic (AF64A) neurotoxins after pre-treatment. When (-)-deprenyl was administered with levodopa in a long-term treatment of Parkinsonian patients, it induces adverse events (nausea, dizziness, confusion, hallucination, insomnia and cardiovascular changes), which could be due to dopamine potentiation in dopaminergic systems (limbic system), other than the nigrostriatal pathway. (-)-Deprenyl in much lower concentrations needed to induce MAO-B inhibition (10(-9) to 10(-13) M) potently inhibits MPTP or serum withdrawal induced apoptosis in tissue cultures of neuro-ectodermal origin (PC12, M1, M2058). The (+)-enantiomer of deprenyl lacks of this property. The anti-apoptotic activity of (-)-deprenyl can be prevented by inhibiting the metabolism of the drug with SKF-525A pre-treatment, which suggests that some of the presently unknown metabolites could be responsible for the anti-apoptotic activity. In high concentration (10(-3) M), (-)-deprenyl and its metabolites induce apoptosis in tissue cultures without serum withdrawal (biphasic action). Our findings support the view that 100, or even 1000 times lower dose of (-)-deprenyl can be offered in human therapy to protect, or slow down neuronal degeneration, than it is presently used. With low dose of the drug the dopaminergic adverse events could be avoided, while anti-apoptotic activity might be preserved.

Marien, M. R., F. C. Colpaert, et al. (2004). "Noradrenergic mechanisms in neurodegenerative diseases: a theory." Brain Res Brain Res Rev 45(1): 38-78.

            A deficiency in the noradrenergic system of the brain, originating largely from cells in the locus coeruleus (LC), is theorized to play a critical role in the progression of a family of neurodegenerative disorders that includes Parkinson's disease (PD) and Alzheimer's disease (AD). Consideration is given here to evidence that several neurodegenerative diseases and syndromes share common elements, including profound LC cell loss, and may in fact be different manifestations of a common pathophysiological process. Findings in animal models of PD indicate that the modification of LC-noradrenergic activity alters electrophysiological, neurochemical and behavioral indices of neurotransmission in the nigrostriatal dopaminergic system, and influences the response of this system to experimental lesions. In models related to AD, noradrenergic mechanisms appear to play important roles in modulating the activity of the basalocortical cholinergic system and its response to injury, and to modify cognitive functions including memory and attention. Mechanisms by which noradrenaline may protect or promote recovery from neural damage are reviewed, including effects on neuroplasticity, neurotrophic factors, neurogenesis, inflammation, cellular energy metabolism and excitotoxicity, and oxidative stress. Based on evidence for facilitatory effects on transmitter release, motor function, memory, neuroprotection and recovery of function after brain injury, a rationale for the potential of noradrenergic-based approaches, specifically alpha2-adrenoceptor antagonists, in the treatment of central neurodegenerative diseases is presented.

Marin, I., J. I. Lucas, et al. (2004). "Parkin and relatives: the RBR family of ubiquitin ligases." Physiol Genomics 17(3): 253-63.

            Mutations in the parkin gene cause autosomal-recessive juvenile parkinsonism. Parkin encodes a ubiquitin-protein ligase characterized by having the RBR domain, composed of two RING fingers plus an IBR/DRIL domain. The RBR family is defined as the group of genes whose products contain an RBR domain. RBR family members exist in all eukaryotic species for which significant sequence data is available, including animals, plants, fungi, and several protists. The integration of comparative genomics with structural and functional data allows us to conclude that RBR proteins have multiple roles, not only in protein quality control mechanisms, but also as indirect regulators of transcription. A recently formulated hypothesis, based on a case of gene fusion, suggested that RBR proteins may be often part of cullin-containing ubiquitin ligase complexes. Recent data on Parkin protein agrees with that hypothesis. We discuss the involvement of RBR proteins in several neurodegenerative diseases and cancer.

Marino, G. and C. Lopez-Otin (2004). "Autophagy: molecular mechanisms, physiological functions and relevance in human pathology." Cell Mol Life Sci 61(12): 1439-54.

            Autophagy is a degradative mechanism mainly involved in the recycling and turnover of cytoplasmic constituents from eukaryotic cells. Over the last years, yeast genetic screens have considerably increased our knowledge about the molecular mechanisms of autophagy, and a number of genes involved in fundamental steps of the autophagic pathway have been identified. Most of these autophagy genes are present in higher eukaryotes indicating that this process has been evolutionarily conserved. In yeast, autophagy is mainly involved in adaptation to starvation, but in multicellular organisms this route has emerged as a multifunctional pathway involved in a variety of additional processes such as programmed cell death, removal of damaged organelles and development of different tissue-specific functions. Furthermore, autophagy is associated with a growing number of pathological conditions, including cancer, myopathies and neurodegenerative disorders. The physiological and pathological roles of autophagy, as well as the molecular mechanisms underlying this multifunctional pathway, are discussed in this review.

Marshall, V. L. and D. G. Grosset (2004). "GPI-1485 (Guilford)." Curr Opin Investig Drugs 5(1): 107-12.

            GPI-1485 is a neuroimmunophilin ligand that binds to FK-506-binding proteins and is under development by Guilford for the potential treatment of erectile dysfunction following nerve injury during prostate resection and Parkinson's disease. In August 2002, phase II clinical trials investigating GPI-1485 for Parkinson's disease commenced, and in November 2003, further phase II trials commenced for post-prostatectomy erectile dysfunction.

Marzolini, C., E. Paus, et al. (2004). "Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance." Clin Pharmacol Ther 75(1): 13-33.

            Drug transporters are increasingly recognized to be important to drug disposition and response. P-glycoprotein, the encoded product of the human MDR1 (ABCB1) gene, is of particular clinical relevance in that this transporter has broad substrate specificity, including a variety of structurally divergent drugs in clinical use today. Moreover, expression of this efflux transporter in certain tissue compartments such as the gastrointestinal tract and brain capillary endothelial cells limits oral absorption and central nervous system entry of many drugs. Recently, a number of single-nucleotide polymorphisms (SNPs) in MDR1 have been identified. An increasing number of studies have also implicated certain commonly occurring SNPs in MDR1 in problems including altered drug levels and host susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and CD4 cell recovery during human immunodeficiency virus therapy. However, in many such cases, the reported effects of MDR1 SNPs have been inconsistent and, in some cases, conflicting. In this review SNPs in MDR1 in relation to population frequencies, drug levels, and phenotypes are outlined. In addition, issues relating to MDR1 haplotypes, environmental factors, and study design, as potential confounding factors of the observed MDR1 polymorphism effect in vivo, are also discussed.

Mattson, M. P. (2004). "Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders." Ann N Y Acad Sci 1012: 37-50.

            Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.

McClure, S. M., M. K. York, et al. (2004). "The neural substrates of reward processing in humans: the modern role of FMRI." Neuroscientist 10(3): 260-8.

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

McGeer, P. L. and E. G. McGeer (2004). "Inflammation and neurodegeneration in Parkinson's disease." Parkinsonism Relat Disord 10 Suppl 1: S3-7.

            The immunohistochemical demonstration of reactive microglia and activated complement components suggests that chronic inflammation occurs in affected brain regions in Parkinson's disease (PD). Evidence from humans and monkeys exposed to MPTP indicates this inflammation may persist many years after the initial stimulus has disappeared. Chronic inflammation can damage host cells. Reports in the literature indicate that antiinflammatory agents inhibit dopaminergic cell death in animal models of PD, and there is one epidemiological report that their use significantly diminishes the risk of PD in humans. There is a marked elevation in the mRNA levels for complement proteins and markers of activated microglia in affected regions in PD. The upregulation appears greater than that found in inflamed arthritic joints. These data support the hypothesis that chronic inflammation may play an important role, if secondary, in the pathogenesis of PD.

McInerney-Leo, A., K. Gwinn-Hardy, et al. (2004). "Prevalence of Parkinson's disease in populations of African ancestry: a review." J Natl Med Assoc 96(7): 974-9.

            There have been a number of studies looking at the prevalence of Parkinson's disease (PD) in different racial and geographical populations. Some of the earliest studies suggested a difference in the prevalence of PD in African Americans as compared with Caucasians. As such a difference would have important implications for healthcare and research into the etiology of PD, we undertook a review of published studies to determine whether evidence suggested that such a difference exists. We reviewed 20 studies that looked at incidence, prevalence, and percentages of neurology patients with PD and Parkinsonism in Africa and in African-American populations. Two of these were door-to-door studies that relied on questionnaires for initial ascertainment, another was performed by review of outpatient records of a large health maintenance organization, while the remainder were based on hospital admissions, diagnosis in the community, or death certificate reports. In the aggregate, these studies suggest PD may be less frequent among Africans and African Americans than among Caucasians, although the most well-designed study showed only a statistically insignificant reduction in the prevalence of PD among African Americans. Although an apparently lower disease frequency among people of African origin may have a basis in the pathobiology of the disease, nearly all of these studies were vulnerable to a variety of ascertainment biases, and many lacked stringent application of diagnostic criteria applied by specialists trained in movement disorders. We conclude that a difference in the prevalence of PD and Parkinsonism between black and other populations is unproven and will require additional well-designed studies to determine if previously reported ethnic differences in disease prevalence are real.

McIntyre, C. C., M. Savasta, et al. (2004). "How does deep brain stimulation work? Present understanding and future questions." J Clin Neurophysiol 21(1): 40-50.

            High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been vaulted forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address the present knowledge of the effects of high frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathologic network activity. Using the results from microdialysis, neural recording, functional imaging, and neural modeling experiments, the authors address the main hypotheses and attempt to reconcile what have been considered conflicting results from different research modalities.

McKeith, I. G. and U. P. Mosimann (2004). "Dementia with Lewy bodies and Parkinson's disease." Parkinsonism Relat Disord 10 Suppl 1: S15-8.

            Lewy bodies (LB) in the central nervous system are associated with several different clinical syndromes including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Long term follow up of PD patients finds up to 78% eventually develop dementia, most of these patients exhibiting fluctuating cognition and visual hallucinations similar to DLB and with extensive cortical LB at autopsy. alpha-Synuclein positive, neuritic pathology, in the putamen of DLB and Parkinson's disease dementia (PDD), may contribute to postural-instability gait difficulty, parkinsonism, diminished levodopa responsiveness and increased neuroleptic sensitivity. Cognitive and neuropsychiatric symptoms improve with cholinesterase inhibitor treatment in both patient groups. DLB and PDD should be seen as different points on a spectrum of LB disease. Distinguishing them as separate disorders may be useful in clinical practice, but may be of limited value in terms of investigating and treating the underlying neurobiology.

McKeith, I., J. Mintzer, et al. (2004). "Dementia with Lewy bodies." Lancet Neurol 3(1): 19-28.

            Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Meissner, W., M. P. Hill, et al. (2004). "Neuroprotective strategies for Parkinson's disease: conceptual limits of animal models and clinical trials." Trends Pharmacol Sci 25(5): 249-53.

            Parkinson's disease (PD) is a progressive neurodegenerative disorder. Although therapies that treat the symptoms of the disease have proven efficacy, strategies that slow or stop the neurodegenerative process are currently not available. Recently, the National Institute of Neurological Disorders and Stroke (NINDS) conducted a systematic assessment of candidate pharmacological agents with putative neuroprotective properties. Twelve agents have been selected as potential candidates for upcoming clinical trials. However, the data resulting from the use of these agents in animal models of PD using a clinically driven design have not been published. Furthermore, the selection of interesting candidates should be based on the soundest clinically driven preclinical validation. This lack of published data, associated with the conceptual limits of the current way of testing drugs in clinical trials, prompts us to argue for further preclinical validation of the 12 candidates.

Meredith, G. E., G. M. Halliday, et al. (2004). "A critical review of the development and importance of proteinaceous aggregates in animal models of Parkinson's disease: new insights into Lewy body formation." Parkinsonism Relat Disord 10(4): 191-202.

            The pace of development of new animal models of Parkinson's disease (PD) has increased dramatically in the recent past, primarily because of the identification of the protein, alpha-synuclein, in Lewy bodies in both idiopathic and familial PD. This discovery has allowed the production of transgenic models that incorporate a form of human, mutant alpha-synuclein from rare familial cases, and has enabled the search for Lewy-body-like aggregations of this protein in toxin-induced models. Indeed, alpha-synuclein-positive inclusions, some of which bear strong resemblance to Lewy bodies, have now been recognized and their formation investigated in several different, environmentally-induced and transgenic models. Nevertheless, these data have yet to provide a uniform theory of inclusion pathogenesis for PD. The aim of this review is not only to summarize the findings to date on alpha-synuclein-immunopositive inclusion bodies, including some new information on Lewy bodies, but also provide a concise viewpoint on their origin and formation in animal models. We will provide evidence for a predicted series of intracellular events that underlie inclusion formation. Triggered by oxidative and metabolic stress, chronic, toxin-treated animals, rather than transgenic models transfected with human alpha-synuclein, eventually produce inclusion bodies that most closely resemble early stages of Lewy bodies. Elucidating the common mechanisms in animal models is a first step towards understanding the role of Lewy bodies and their formation in Parkinson's disease.

Miller, F. G. (2004). "Sham surgery: an ethical analysis." Sci Eng Ethics 10(1): 157-66.

            Surgical clinical trials have seldom used a "sham" or placebo surgical procedure as a control, owing to ethical concerns. Recently, several ethical commentators have argued that sham surgery is either inherently or presumptively unethical. In this article I contend that these arguments are mistaken, and that there are no sound ethical reasons for an absolute prohibition of sham surgery in clinical trials. Reflecting on three cases of sham surgery, especially on the recently reported results of a sham-controlled trial of arthroscopic surgery for arthritis of the knee, I present an ethical analysis that focuses on the methodological rationale for use of sham surgery, risk-benefit assessment, and informed consent.

Minagar, A. and R. E. Kelley (2004). "Movement disorders." Prim Care 31(1): 111-27.

Montgomery, E. B., Jr. (2004). "Rehabilitative approaches to Parkinson's disease." Parkinsonism Relat Disord 10 Suppl 1: S43-7.

            Many sources of disability impact on quality of life and some are likely to remain relatively refractory to pharmacological or surgical treatment. Rehabilitative approaches may help despite the paucity of randomized control studies. There is increasing evidence from neuroscience, reviewed here, that supports current rehabilitative approaches and most importantly, can be the basis for future rehabilitative approaches. Parkinson's disease is complex and the disabilities not absolute but relative. These disabilities can be affected by the environment or context in which the motor activities occur. These observations can be exploited and argue for the potential of rehabilitative approaches.

Montine, K. S., J. F. Quinn, et al. (2004). "Isoprostanes and related products of lipid peroxidation in neurodegenerative diseases." Chem Phys Lipids 128(1-2): 117-24.

            Lipid peroxidation is a major outcome of free radical-mediated injury to brain, where it directly damages membranes and generates a number of oxidized products. Some of the chemically and metabolically stable oxidation products are useful in vivo biomarkers of lipid peroxidation. These include the isoprostanes (IsoPs) and isofurans (IsoFs), derived from arachidonic acid (AA), and neuroprostanes (NeuroPs), derived from docosahexaenoic acid (DHA). We have shown increased levels of IsoPs, NeuroPs, and IsoFs in diseased regions of brain from patients who died from advanced Alzheimer's disease (AD) or Parkinson's disease (PD). Increased cerebrospinal fluid (CSF) levels of IsoPs are present in patients with AD or Huntington's disease (HD) early in the course of their illness, and CSF IsoPs may improve the laboratory diagnostic accuracy for AD. In contrast, quantification of IsoPs in plasma and urine of AD patients has yielded inconsistent results. These results indicate that brain lipid peroxidation is a potential therapeutic target early in the course of AD and HD, that CSF IsoPs may aid in the assessment of anti-oxidant experimental therapeutics and laboratory diagnosis of AD.

Moos, T. and E. H. Morgan (2004). "The metabolism of neuronal iron and its pathogenic role in neurological disease: review." Ann N Y Acad Sci 1012: 14-26.

            Neurons need iron, which is reflected in their expression of the transferrin receptor. The concurrent expression of the ferrous iron transporter, divalent metal transporter I (DMT1), in neurons suggests that the internalization of transferrin is followed by detachment of iron within recycling endosomes and transport into the cytosol via DMT1. To enable DMT1-mediated export of iron from the endosome to the cytosol, ferric iron must be reduced to its ferrous form, which could be mediated by a ferric reductase. The presence of nontransferrin-bound iron in brain extracellular fluids suggests that neurons can also take up iron in a transferrin-free form. Neurons are thought to be devoid of ferritin in many brain regions in which there is an association between iron accumulation and cellular damage, for example, neurons of the substantia nigra pars compacta. The general lack of ferritin together with the prevailing expression of the transferrin receptor indicates that iron acquired by activity of transferrin receptors is directed toward immediate use in relevant metabolic processes, is exported, or is incorporated into complexes other than ferritin. Iron has long been considered to play a significant role in exacerbating degradation processes in brain tissue subjected to acute damage and neurodegenerative disorders. In brain ischemia, the damaging role of iron may depend on the inhibition of detoxifying enzymes responsible for catalyzing the oxidation of ferrous iron. Brain ischemia may also lead to an increase in iron supply to neurons as transferrin receptor expression by brain capillary endothelial cells is increased. Pharmacological blockage of the transferrin receptor/DMT1-mediated uptake could be a target to prevent further iron uptake. In chronic neurodegenerative settings, a deleterious role of iron is suggested since cases of Alzheimer's disease, Parkinson's disease, and Huntington's disease have a significantly higher accumulation of iron in affected regions. Dopaminergic neurons are rich in neuromelanin, shown to be more redox-active in Parkinson's disease cases. Iron-containing inflammatory cells may, however, account for the main portion of iron present in neurodegenerative disorders. More knowledge about iron metabolism in normal and diseased neurons is warranted as this may identify pharmaceutical targets to improve neuronal iron management.

Moran, L. B. and M. B. Graeber (2004). "The facial nerve axotomy model." Brain Res Brain Res Rev 44(2-3): 154-78.

            Experimental models such as the facial nerve axotomy paradigm in rodents allow the systematic and detailed study of the response of neurones and their microenvironment to various types of challenges. Well-studied experimental examples include peripheral nerve trauma, the retrograde axonal transport of neurotoxins and locally enhanced inflammation following the induction of experimental autoimmune encephalomyelitis in combination with axotomy. These studies have led to novel insights into the regeneration programme of the motoneurone, the role of microglia and astrocytes in synaptic plasticity and the biology of glial cells. Importantly, many of the findings obtained have proven to be valid in other functional systems and even across species barriers. In particular, microglial expression of major histocompatibility complex molecules has been found to occur in response to various types of neuronal damage and is now regarded as a characteristic component of "glial inflammation". It is found in the context of numerous neurodegenerative disorders including Parkinson's and Alzheimer's disease. The detachment of afferent axonal endings from the surface membrane of regenerating motoneurones and their subsequent displacement by microglia ("synaptic stripping") and long-lasting insulation by astrocytes have also been confirmed in humans. The medical implications of these findings are significant. Also, the facial nerve system of rats and mice has become the best studied and most widely used test system for the evaluation of neurotrophic factors.

Murakami, N. (2004). "[Parkinsonism-dementia complex on Guam]." Nippon Rinsho 62 Suppl: 118-21.

Murata, M. (2004). "Novel therapeutic effects of the anti-convulsant, zonisamide, on Parkinson's disease." Curr Pharm Des 10(6): 687-93.

            We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg/day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca(++) channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

Nagata, K. (2004). "[Cigarette smoking and neurological disease]." No To Shinkei 56(3): 205-23.

Nagatsu, T. (2004). "Progress in monoamine oxidase (MAO) research in relation to genetic engineering." Neurotoxicology 25(1-2): 11-20.

            Monoamine oxidase (MAO) is an enzyme that oxidizes various physiologically and pathologically important monoamine neurotransmitters and hormones such as dopamine, noradrenaline, adrenaline, and serotonin. Two types of MAO, i.e. type A (MAO-A) and type B (MAO-B), were first discovered pharmacologically. MAO-A is inhibited by clorgyline; and MAO-B, by deprenyl. cDNAs MAO-A and MAO-B were cloned and their structures determined. MAO-A and MAO-B are made of similar but different polypeptides and encoded by different nuclear genes located on the X chromosome (Xp11.23). MAO-A and MAO-B genes consist of 15 exons with identical intron-exon organization, suggesting that they were derived from a common ancestral gene. Both enzymes require a flavin cofactor, flavin adenine dinucleotide (FAD), which binds to the cysteine residue of a pentapeptide sequence (Ser-Gly-Gly-Cys-Tyr). Both enzymes exist on the outer membrane of mitochondria of various types of cells in various tissues including the brain. In humans, MAO-A is abundant in the brain and liver, whereas the liver, lungs and intestine are rich in MAO-B. MAO-A oxidizes noradrenaline and serotonin; and MAO-B, mainly beta-phenylethylamine. In the human brain, MAO-A exists in catecholaminergic neurons, but MAO-B is found in serotonergic neurons and glial cells. MAO-A knockout mice exhibit increased serotonin levels and aggressive behavior, whereas MAO-B knockout mice show little behavioral change. The gene knockout mice of MAO-A or MAO-B, together with the observation that some humans lack MAO-A, MAO-B, or both have contributed to our understanding of the function of MAO-A and MAO-B in health and disease. MAO-A and MAO-B may be closely related to various neuropsychiatric disorders such as depression and Parkinson's disease, and inhibitors of them are the subject of drug development for such diseases.

Naoi, M., W. Maruyama, et al. (2004). "Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains." Neurotoxicology 25(1-2): 193-204.

            Salsolinol, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, is an endogenous catechol isoquinoline detected in humans by M. Sandler. In human brain, a series of catechol isoquinolines were identified as the condensation products of dopamine or other monoamines with aldehydes or keto-acids. Recently selective occurrence of the (R)enantiomers of salsolinol derivatives was confirmed in human brain, and they are synthesized by enzymes in situ, but not by the non-enzymatic Pictet-Spengler reaction. A (R)salsolinol synthase catalyzes the enantio-specific synthesis of (R)salsolinol from dopamine and acetaldehyde, and (R)salsolinol N-methyltransferase synthesizes N-methyl(R)salsolinol, which is further oxidized into 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion by non-enzymatic and enzymatic oxidation. The step-wise reactions, N-methylation and oxidation, induce the specified distribution of the N-methylated and oxidized derivatives in the human nigro-striatum, suggesting that these derivatives may be involved in the function of dopamine neurons under physiological and pathological conditions. As shown by in vivo and in vitro experiments, salsolinol derivatives affect the levels of monoamine neurotransmitters though the inhibition of enzymes related in the metabolism of catechol- and indoleamines. In addition, the selective neurotoxicity of N-methyl(R)salsolinol to dopamine neurons was confirmed by preparation of an animal model of Parkinson's disease in rats. The involvement of N-methyl(R)salsolinol in the pathogenesis of Parkinson's disease was further indicated by the increase in the N-methyl(R)salsolinol levels in the cerebrospinal fluid and that in the activity of its synthesizing enzyme, a neural (R)salsolinol N-methyltransferase, in the lymphocytes prepared from parkinsonian patients. N-methyl(R)salsolinol induces apoptosis in dopamine neurons, which is mediated by death signal transduction in mitochondria. In addition, salsolinol was found to function as a signal transmitter for the prolactin release in the neuro-intermediate lobe of the brain. These results are discussed in relation to role of dopamine-derived endogenous salsolinol derivatives as the regulators of neurotransmission, dopaminergic neurotoxins and neuro-hormonal transmitters in the human brain.

Naumann, M. and W. Jost (2004). "Botulinum toxin treatment of secretory disorders." Mov Disord 19 Suppl 8: S137-41.

            Botulinum neurotoxin serotype A (BoNT/A) has revolutionised the treatment of a variety of autonomic hypersecretory disorders. Several open and controlled studies indicate that BoNT/A is a safe and effective treatment for focal hyperhidrosis of the axillae and palms, for gustatory sweating, and for some other rare conditions associated with focal hyperhidrosis. There is class I evidence for the efficacy of botulinum toxin in axillary hyperhidrosis and class II evidence for palmar hyperhidrosis and gustatory sweating. BoNT/A has the potential to replace current invasive and surgical techniques and should at least be considered as a viable alternative. The results of pilot studies to treat sialorrhea are encouraging. However, the optimal dose, best mode of application, side effects, and duration of BoNT/A action in this condition remain uncertain. We need further formal clinical trials to evaluate risks and benefits of BoNT/A for palliative treatment in of sialorrhea in Parkinson's disease and in bulbar amyotrophic lateral sclerosis. Based on the few reports published, BoNT/A injections into the lacrimal gland for hyperlacrimation may be an elegant method to treat this sometimes disabling condition. Again, larger studies are needed to evaluate the risks and long-term benefits of this treatment option.

Nelson, R. L. (2004). "Epidemiology of fecal incontinence." Gastroenterology 126(1 Suppl 1): S3-7.

            Nursing home residence is by far the most prominent association with fecal incontinence, with a prevalence approaching 50%. In one major survey, urinary incontinence was the greatest risk factor for developing fecal incontinence, and fecal incontinence was the greatest risk factor for developing urinary incontinence. Immobility, dementia, and the use of physical restraints were also important risk factors. Specific diseases associated with fecal incontinence include diabetes, multiple sclerosis, Parkinson's disease, stroke, and spinal cord injury. The surgical procedures lateral internal sphincterotomy for anal fissure, fistulotomy, and ileal pouch reconstruction can result in fecal incontinence. Children who are born with congenital abnormalities, such as imperforate anus, often experience soiling for many years. Future studies to determine the prevalence and etiology of fecal and urinary incontinence will need to first define these conditions and eliminate referral bias. Epidemiologic investigations of both disorders should be performed jointly because the conditions are so often comorbid.

Newhouse, P. A., A. Potter, et al. (2004). "Effects of nicotinic stimulation on cognitive performance." Curr Opin Pharmacol 4(1): 36-46.

            Recent advances in studies of nicotinic agents in humans have begun to more carefully define cognitive operations that can be influenced by nicotinic stimulation and/or blockade. Careful separation of the cognitive domains affected by nicotinic stimulation has identified attentional performance as the most likely candidate to be positively influenced by nicotinic receptor activation. Studies of the effects of nicotinic systems and/or nicotinic receptor stimulation in pathological disease states such as Alzheimer's disease, Parkinson's disease, attention deficit/hyperactivity disorder and schizophrenia show the potential for therapeutic utility of nicotinic drugs. In contrast to studies in pathological states, studies of nicotine in normal-non-smokers tend to show deleterious effects. This contradiction can be resolved by consideration of cognitive and biological baseline dependency differences between study populations in terms of the relationship of optimal cognitive performance to nicotinic receptor activity. Although normal individuals are unlikely to show cognitive benefits after nicotinic stimulation except under extreme task conditions, individuals with a variety of disease states can benefit from nicotinic drugs. Attentional function/dysfunction may serve as an endophenotypic therapeutic target for nicotinic drug development.

Newhouse, P., A. Singh, et al. (2004). "Nicotine and nicotinic receptor involvement in neuropsychiatric disorders." Curr Top Med Chem 4(3): 267-82.

            Advances in the understanding of the neurobiology of the nicotinic receptor have started to be matched by an appreciation of the potential role of these receptors in a variety of neuropsychiatric disorders. While alterations in nicotinic receptor number and/or function have been associated with such conditions as Alzheimer's disease for several years, there is increasing evidence that nicotinic receptor function may play a significant role in other disorders as well including schizophrenia, Parkinson's disease, anxiety disorders, and attention deficit-hyperactivity disorder (ADHD). Research in our laboratory and those of other investigators have utilized sophisticated psychopharmacological, cognitive, electrophysiological, neuroimaging and other techniques to assess the impact of nicotinic receptor modulation on the clinical expression of these disorders. This manuscript reviews data, both experimental and clinical, relating to the role of nicotine and/or nicotinic receptor function in a variety of neuropsychiatric disorders with the perspective of developing appropriate targets for therapeutic drug development.

Newman, M. B., C. D. Davis, et al. (2004). "Transplantation of human umbilical cord blood cells in the repair of CNS diseases." Expert Opin Biol Ther 4(2): 121-30.

            Cell transplantation therapies have been used to treat certain neurodegenerative diseases such as Parkinson's and Huntington's disease. However, ethical concerns over the use of fetal tissues, and the inherent complexities of standardising the procurement, processing and transplantation methods of this tissue, have prompted the search for a source of cells that have less ethical stigmatisations, are readily available and can be easily standardised. Several sources of human cells that meet these principles have been under investigation. Cells from human umbilical cord blood (HUCB) are one source that is consistent with these principles; therefore, they have become of great interest in the field of cellular repair/replacement for the treatment of CNS diseases and injury. This review will focus on the advantages of HUCB cells as a source for cellular transplantation therapies, recent studies that have examined the potential of these cells in vitro to be directed towards neural phenotypes, and in vivo studies that have investigated the functional recovery of animals in a number of models of CNS injury and disease following administration of HUCB cells.

Nguyen, N., V. Pradel, et al. (2004). "[Drug-induced parkinson syndromes]." Therapie 59(1): 105-12.

            Parkinsonism is defined by the association of akinesia with one of the following symptoms: extrapyramidal rigidity, tremor at rest, or postural instability. A drug-induced aetiology must always be suspected when parkinsonian symptoms appear, or increase in a patient receiving drug treatment. Indeed drug-induced is the more frequent aetiology of secondary parkinsonism. The main treatments involved are antipsychotic and other neuroleptic drugs (accounting for up to two-thirds of drug-induced parkinsonism), and calcium-channel entry blockers. The risk associated with antipsychotics is often dose dependent and related to dopamine D2 striatal receptor occupancy induced by the antipsychotic drug. This risk is inferior for the second generation antipsychotics. The other treatments more rarely involved are antidepressants (tricyclic and selective serotonin reuptake inhibitors), lithium, valproic acid, and others. The main criterium for imputability is chronological, regression of symptoms being observed in 40-74% of cases, after a mean delay of 3 months from cessation of treatment. However, 15% of cases persist after drug withdrawal, leading to a diagnosis of underlying idiopathic Parkinson's disease.

Nikolaus, S., M. Beu, et al. (2004). "The contribution of small animal positron emission tomography to the neurosciences--a critical evaluation." Rev Neurosci 15(2): 131-56.

            This article presents an overview of those animal studies which so far have been performed with dedicated small animal positron emission tomographs in the field of the neurosciences. In vivo investigations focus on energy metabolism, perfusion and receptor/transporter binding in rat models of reinforcement, learning and memory, traumatic brain injury, epilepsy, depression, cardiovascular diseases--such as ischemia and focal stroke--and neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. In the majority of studies, important novel aspects arise from the fact that the investigators made use of an option inherent to in vivo studies, namely to conduct longitudinal investigations on the same animals. Relevant findings pertain to the relationship of brain metabolism/perfusion and the cholinergic system, the regulation state of dopamine receptors upon cocaine administration and withdrawal, the regulation state of dopamine receptors and transporters in animal models of Parkinson's and Huntington's disease, and potential treatments of progressive dopaminergic depletion with adenoviral vectors, embryonic grafts, stem cells and nerve growth factors.

Norris, E. H., B. I. Giasson, et al. (2004). "Alpha-synuclein: normal function and role in neurodegenerative diseases." Curr Top Dev Biol 60: 17-54.

            Synucleins are a family of small, highly charged proteins expressed predominantly in neurons. Since their discovery and characterization during the last decade, much has been learned about their structure, potential functions, interactions with other proteins, and roles in disease. One of these proteins, alpha-synuclein (alpha-syn), is the major building block of pathological inclusions that characterize many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation type 1 (NBIA-1), which collectively are termed synucleinopathies. Furthermore, genetic and biological studies support a role for alpha-syn in the pathophysiology of these diseases. Therefore, research must be continued in order to better understand the functions of the synuclein proteins under normal physiological conditions as well as their role in diseases.

O'Neill, M. J., D. Bleakman, et al. (2004). "AMPA receptor potentiators for the treatment of CNS disorders." Curr Drug Targets CNS Neurol Disord 3(3): 181-94.

            Glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission in the mammalian central nervous system and also participate in forms of synaptic plasticity thought to underlie memory and learning, and the formation of neural networks during development. Molecular cloning techniques have shown that the AMPA receptor family is composed of four different subunits named GluR1-4 or GluRA-D (newly termed as Glu(A1)-Glu(A4)) and native AMPA receptors are most likely tetramers generated by the assembly of one or more of these subunits, yielding homomeric or heteromeric receptors. Additional complexity among AMPA receptors is conferred by alternative splicing of RNA for each subunit giving rise to flip and flop variants. Clinical and experimental data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. Several classes of AMPA receptor potentiators have been reported, including pyrroliddones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and more recently biarylpropylsulfonamides (LY392098, LY404187 and LY503430). These molecules enhance cognitive function in rodents, which appears to correlate with increased hippocampal activity. In addition, clinical studies have suggested that AMPA receptor modulators enhance cognitive function in elderly subjects, as well as patients suffering from neurological and psychiatric disorders. Several independent studies have suggested that AMPA receptors can increase BDNF expression by both calcium-dependent and independent pathways. For example, recent studies have shown that AMPA receptors interact with the protein tyrosine kinase, Lyn. Activation of Lyn can recruit the mitogen-activated protein kinase (MAPK) signalling pathway and increase the expression of BDNF. Therefore, in addition to directly enhancing glutamatergic synaptic transmission, AMPA receptor activation can increase the expression of BDNF in vitro and in vivo. This may account for activity of AMPA receptor potentiators in rodent models predictive of antidepressant activity (forced swim and tail suspension tests). The increase in neurotrophin expression also may contribute to the functional, neuroprotective and neurotrophic actions of LY404187 and LY503430 after infusion of 6-OHDA into the substantia nigra. In conclusion, several potent, selective and systemically active AMPA receptor potentiators have been reported. Data indicate that these molecules modulate glutamatergic transmission, enhance synaptic transmission, long-term potentiation (LTP) and increase neurotrophin expression. Therefore, these AMPA receptor potentiators offer an exciting new class of drugs with potential for treating (1) cognitive impairment associated with Alzheimer's disease and schizophrenia, (2) depression, (3) slowing the progression and potentially enhancing recovery from Parkinson's disease.

Obeso, J. A., M. Rodriguez-Oroz, et al. (2004). "The origin of motor fluctuations in Parkinson's disease: importance of dopaminergic innervation and basal ganglia circuits." Neurology 62(1 Suppl 1): S17-30.

            The severity of dopamine depletion and the consequent pathophysiologic changes that occur in basal ganglia circuits determine the severity of parkinsonian signs. Restoring the dopamine deficit or the downstream physiologic abnormalities improves Parkinson's Disease (PD) main motor features and as a result, attenuates the short-duration response (SDR). Therefore, both the magnitude and duration of the motor response are a function of the degree of motor severity, which is primarily governed by the loss of tonic dopaminergic activity and disruption of basal ganglia homeostatic mechanisms among which the STN-GPe/GPi circuits play a fundamental role. As neurodegeneration advances, standard levodopa administration give rises to wider oscillations in striatal dopamine availability and "pulsatile" stimulation of striatal dopamine receptors becomes predominant. This induces molecular and physiologic changes that further accentuate and aggravate the SDR that sustains motor fluctuations. Treatments capable of providing and restoring more tonic and physiologic dopaminergic stimulation may avoid many of these abnormalities and lead to better clinical outcomes.

Ochiai, T., J. Regis, et al. (2004). "[Three dimensional stereotactic functional neurosurgical planning]." Nippon Rinsho 62(4): 669-76.

            In order to arrive the small area in the deep brain with minimum invasion, stereotactic technique is useful. Subthalamic nucleus stimulation with this technique has been common for Parkinson disease. Recently some papers reported the cognitive performance change after implantation and there were some discussion about the electrode trajectory. Though we didn't have the answer until now, three-dimensional target included the trajectory seems to be important. Another way, stereotactic technique was used the epilepsy evaluation. The point of this procedure was based on the clinical aspect, the well-known neural network and the anatomical understanding for each patient. Three-dimensional anatomical target provides us the best treatment for stereotactic neurosurgery.

Okun, M. S. and J. L. Vitek (2004). "Lesion therapy for Parkinson's disease and other movement disorders: update and controversies." Mov Disord 19(4): 375-89.

            An analysis of the international literature on lesioning for movement disorders was undertaken to review lesion therapy for Parkinson's disease (PD) and other movement disorders and to highlight important controversies surrounding this surgical technique. Lesions have been placed throughout the neuraxis with varying approaches and success. Our understanding of the pathophysiological basis underlying the development of PD and other movement disorders has led to a better understanding of why lesioning certain portions of the nervous system should improve motor function. Advances in imaging technology and electrophysiological techniques used for localization of brain structures, such as microelectrode mapping, have improved the ability to accurately identify and lesion target structures deep in the brain. This improvement has led to an increase in the degree and consistency of clinical benefit. The major controversies in lesion therapy include: (1) which target for which disorder; (2) determination of the optimal lesion site and whether the external globus pallidus (GPe) should be included in the pallidotomy lesion for PD; (3) determination of the size of the lesion; (4) whether bilateral lesions can be placed without the high incidence of side effects reported by some investigators; (5) whether microelectrodes aid in the ability to improve clinical outcomes or increase the risk of side effects by making multiple microelectrode penetrations; (6) whether the subthalamic nucleus (STN) should be explored further as a lesioning target; and (7) whether lesioning should be abandoned entirely in favor of deep brain stimulation (DBS). Many important questions and controversies regarding lesion therapy remain unanswered. It is unlikely given the pro-DBS environment that these questions will be answered in the near future. We should, however, be careful not to abandon an effective therapy before fully exploring through randomized trials the relative effect of different surgical approaches for the treatment of patients with movement disorders.

Olanow, C. W. (2004). "Manganese-induced parkinsonism and Parkinson's disease." Ann N Y Acad Sci 1012: 209-23.

            It has long been appreciated that manganese exposure can cause neurotoxicity and a neurologic syndrome that resembles Parkinson's disease (PD). Current evidence indicates that manganese-induced parkinsonism can be differentiated from PD because of its predilection to accumulate in and damage the pallidum and striatum rather than the SNc. The clinical syndrome, response to levodopa, imaging studies with MRI and PET, and pathologic features all help to distinguish these two conditions and permit the correct diagnosis to be established. This is of particular relevance in differentiating patients with parkinsonism due to manganese intoxication from patients with idiopathic PD who have incidental manganese exposure.

Olanow, C. W. (2004). "The scientific basis for the current treatment of Parkinson's disease." Annu Rev Med 55: 41-60.

            Parkinson's disease (PD) is an age-related neurodegenerative disease that affects approximately one million people in the United States. The introduction of levodopa revolutionized the treatment for this disorder, but the long-term utility of the drug is limited by motor complications, the development of features such as postural instability and dementia that do not respond to treatment, and continued disease progression. Insights into the organization of the basal ganglia in the normal and PD conditions has permitted the design of new treatment strategies that reduce the risk of developing motor complications. Additionally, increased knowledge of the mechanisms responsible for cell death in PD has permitted the development of putative neuroprotective drugs that might slow or stop disease progression. No drug has yet been established to alter the rate of disease progression, but the rapid pace of research offers reason for optimism.

Olanow, C. W. and F. Stocchi (2004). "COMT inhibitors in Parkinson's disease: can they prevent and/or reverse levodopa-induced motor complications?" Neurology 62(1 Suppl 1): S72-81.

            COMT inhibitors have historically been used as adjuncts to levodopa in fluctuating PD patients to increase "on" time and reduce "off" time. Evidence that motor complications are related to intermittent or pulsatile stimulation of striatal dopamine receptors has led to the use of long-acting dopaminergic therapies that provide more continuous dopaminergic stimulation (CDS). CDS-based therapies are associated with the prevention and reversal of levodopa-related motor complications in MPTP-lesioned primates and PD patients. However, levodopa remains the most effective and widely used anti-parkinsonian agent and is eventually required in all PD patients. The standard oral formulation of levodopa has a relatively short half-life and is associated with the development of motor complications when used as either initial or supplemental therapy. The CDS concept raises the possibility that administration of levodopa in combination with a COMT inhibitor to extend its half-life might reduce the risk of inducing motor complications. This article considers the possibility that combining levodopa with entacapone may prevent or reverse motor complications.

Oliveira, E., A. Michel, et al. (2004). "The pulmonary consultation in the perioperative management of patients with neurologic diseases." Neurol Clin 22(2): v, 277-91.

            Postoperative pulmonary complications greatly contribute to peri-operative morbidity and mortality. Parkinson's disease, sleep apnea, stroke and neuromuscular disorders significantly increase the risk for pulmonary postoperative complications that result from associated changes in respiratory function. This article discusses perioperative pulmonary evaluation and management of the surgical patient who has neurologic disease.

Ollinet, C., D. Bedague, et al. (2004). "[Functional surgery for movement disorders: implications for anaesthesia]." Ann Fr Anesth Reanim 23(4): 428-32.

            Functional surgery for movement disorders is a recent stereotactic neurosurgical operation, restricted yet to patients with advanced Parkinson's disease or with generalized primary dystonia. One or two electrodes are implanted in the basal ganglia, namely in the globus pallidus pars interna or in the subthalamic nucleus, to realize a deep brain stimulation at high frequency. While this approach needs additional data to demonstrate clinical benefits, first results observed after short and long-term follow up are encouraging. Perioperative problems in patients with Parkinson's disease are possible respiratory disorders, a postoperative miss in medication doses and potential drug interactions with anaesthesia. The objectives of anaesthesia will be to allow stereotactic neurosurgical procedure, to maintain the upper airway patency and to be quickly reversible.

Ozelius, L. J. (2004). "Update on the genetics of primary torsion dystonia loci DYT6, DYT7, and DYT13 and the dystonia-plus locus DYT12." Adv Neurol 94: 109-12.

Paolini, M., A. Sapone, et al. (2004). "Parkinson's disease, pesticides and individual vulnerability." Trends Pharmacol Sci 25(3): 124-9.

Paviour, D. C., R. A. Surtees, et al. (2004). "Diagnostic considerations in juvenile parkinsonism." Mov Disord 19(2): 123-35.

            Juvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.

Perez, R. G. and T. G. Hastings (2004). "Could a loss of alpha-synuclein function put dopaminergic neurons at risk?" J Neurochem 89(6): 1318-24.

            The alpha-synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of alpha-synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Soluble alpha-synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by alpha-synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional alpha-synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal alpha-synuclein function may contribute to the dopamine-related loss of substantia nigra neurons during Parkinson's disease pathogenesis.

Peschanski, M., A. C. Bachoud-Levi, et al. (2004). "Integrating fetal neural transplants into a therapeutic strategy: the example of Huntington's disease." Brain 127(Pt 6): 1219-28.

            Fetal neural transplants have become clinically relevant over the past 15 years for two major neurodegenerative diseases, namely Parkinson's disease and Huntington's disease. It is therefore timely to consider how this neurosurgical procedure can integrate the therapeutic armamentarium, what can be expected of it, and what cannot. We use here the example of Huntington's disease to show what fetal neural transplants may uniquely offer for that disease. Up to very recent times, Huntington's disease has been one special example of those neurodegenerative diseases against which neurologists feel totally helpless. This has all changed today and, although results are essentially still to come, one can foresee the mobilization of very large scientific and medical forces against this disease, with definite steps forward in terms of physiopathology and a better view of the therapeutic challenges. While defining the role that fetal neural transplantation may play in meeting these challenges, we also try to show rationales and developments for all types of treatments attempted or suggested so far, as well as their limits and, when relevant, informative failures. The date of writing this review needs to be noted, because the rapid accumulation of data on molecular mechanisms of Huntington's disease pathogenesis and the increasing numbers of clinical trials do not allow much time for the ink of a review to dry.

Pezzoli, G., M. Canesi, et al. (2004). "An overview of parkinsonian syndromes: data from the literature and from an Italian data-base." Sleep Med 5(2): 181-7.

            Recent molecular biology research on neurodegenerative diseases, including parkinsonisms, has identified mutations in the genes that code for the proteins alpha-synuclein and tau, which have been used to classify them into synucleinopathies and tauopathies. The synucleinopathies include, besides the most common and well studied Parkinson's disease (PD), dementia with Lewy bodies, which accounts for approximately 20% of all cases of dementia in the elderly, and multiple system atrophy, whereas the tauopathies include rare and rapidly progressive syndromes, such as progressive supranuclear palsy and corticobasal degeneration. Data we collected at our center in over 2900 parkinsonian patients show that PD accounts for no more than 70% of parkinsonisms. The various syndromes have many features in common that make the differential diagnosis difficult in the early stages of disease. Our data are consistent with the findings reported in the international literature and provide additional information useful for differential diagnosis.

Phillips, B. (2004). "Movement disorders: a sleep specialist's perspective." Neurology 62(5 Suppl 2): S9-16.

            This review focuses on restless legs syndrome (RLS) and Parkinson's disease (PD). These conditions are frequently encountered in clinical sleep medicine and are among the most important of the "nonapnea" sleep disorders. RLS and PD share many features, including derangement of central dopaminergic systems as the putative cause, akathisia, and nocturnal motor fluctuations. In addition, both conditions increase in prevalence with aging, exhibit a beneficial response to dopaminergic therapy, and cause marked sleep disturbances. They frequently overlap, with about 20% of patients with PD having symptoms of RLS. Both conditions appear to have a genetic predisposition that is "turned on" by environmental factors. Adverse responses to levodopa occur in both RLS and PD, manifested as rebound and augmentation in RLS and as fluctuations in motor response and dyskinesias in PD. Newer dopaminergic agents are helpful in the management of both conditions.

Piccini, P. and A. Whone (2004). "Functional brain imaging in the differential diagnosis of Parkinson's disease." Lancet Neurol 3(5): 284-90.

            The accurate diagnosis of idiopathic Parkinson's disease (IPD) is not only important for deciding on treatment strategies and providing a prognosis, but also crucial for studies designed to investigate the aetiology and pathogenesis of parkinsonian disorders. Over recent decades, improvements in the characterisation of the parkinsonian syndromes have led to improvements in clinical diagnostic accuracy; however, clinical criteria alone are not always sufficient to distinguish between IPD and other parkinsonian syndromes, particularly in the early stages of disease and in atypical presentations. Therefore, in addition to the development and implementation of diagnostic clinical assessments, there is a need for available objective markers to aid the physician in the differential diagnosis of IPD. Functional neuroimaging holds the promise of improved diagnosis and allows assessment in early disease. In this review, the use of PET and single photon emission CT in the differential diagnosis of IPD are discussed.

Pirtosek, Z. and D. Flisar (2004). "Neuroprotection and dopamine agonists." Adv Exp Med Biol 541: 55-74.

Poewe, W. (2004). "The role of COMT inhibition in the treatment of Parkinson's disease." Neurology 62(1 Suppl 1): S31-8.

            Several prospective double-blind, placebo-controlled trials have demonstrated that combining levodopa with the COMT inhibitor entacapone is efficacious in reducing motor fluctuations. Compared with levodopa alone, mean daily "on" time was increased by 1-1.7 hours, with a corresponding decrease in daily "off" time. In addition, some studies have shown that these benefits are associated with significant improvements in both UPDRS motor and ADL scores. These benefits have been shown to persist in long-term clinical trials with follow-up for up to 3 years. Recent studies have also examined the value of combining levodopa with entacapone in stable patients who do not experience motor response fluctuations. Here, too, benefits have been reported, especially in health-related quality of life measures. Studies to determine if administering levodopa in combination with entacapone will delay the development of dyskinesia and motor fluctuations are eagerly awaited.

Pollak, P. (2004). "Movement disorders: Parkinson's disease dominates." Lancet Neurol 3(1): 15.

Przuntek, H., T. Muller, et al. (2004). "Diagnostic staging of Parkinson's disease: conceptual aspects." J Neural Transm 111(2): 201-16.

            Insidious onset of mild, unspecific, sensitive, vegetative, psychopathological, cognitive and perceptive disturbances, i.e. visual and olfactory dysfunction, with a resulting change of personal behaviour, i.e. reduced stress tolerance, precede the initially intermittently occurring motor symptoms in patients with Parkinson's disease (PD). Novel neuropathological findings suggest an expansion pattern of the neurodegenerative process beyond the nigral dopaminergic neurons with the initial event located outside the brain. We related these clinical observations of premotor symptoms of PD to this novel neuropathological concept of emerging neurodegeneration, which starts in the enteric system and then rises via spinal cord and brainstem to nigral and subsequent cortical neurons. We describe an initial premotor phase, which starts in non dopaminergic areas, and subdivide it according to the onset of gastrointestinal and brainstem associated and sensory deficits. Then motor symptoms occur and increase in the further course of PD similar to the Hoehn and Yahr stages. Our proposed diagnostic concept aims to an earlier diagnosis of PD. In addition, attention should be given to diseases of the gastrointestinal tract and psychosomatic disorders, all of which, if not or ineffectively treated, may contribute to an enhanced vulnerability for PD. The concept takes into account, that an as far unknown pathogen, e.g. viral infection or nutritional component, that meets a genetically predisposed person with a long lasting disturbed enteric nervous system, may be at risk for PD. Earlier premotor diagnosis of PD will enable more convincing future results on the therapeutic efficacy of neuroprotective compounds.

Rajendra, W., A. Armugam, et al. (2004). "Neuroprotection and peptide toxins." Brain Res Brain Res Rev 45(2): 125-41.

            Neurodegeneration induced by excitatory neurotransmitter glutamate is considered to be of particular relevance in several types of acute and chronic neurological impairments ranging from cerebral ischaemia to neuropathological conditions such as motor neuron disease, Alzheimer's, Parkinson's disease and epilepsy. The hyperexcitation of glutamate receptors coupled with calcium overload can be prevented or modulated by using well-established competitive and non-competitive antagonists targeting ion/receptor channels. The exponentially increasing body of pharmacological evidence over the years indicates potential applications of peptide toxins, due to their exquisite subtype selectivity on ion channels and receptors, as lead structures for the development of drugs for the treatment of wide variety of neurological disorders. This review comprehensively highlights the overview of the diversity in the molecular as well as neurobiological mechanisms of different peptide toxins derived from venomous animals with particular reference to neuroprotection. In addition, the potential applications of peptide toxins in the diagnosis and treatment of neurological disorders such as neuromuscular disorders, epilepsy, Alzheimer's and Parkinson's diseases, gliomas and ischaemic stroke and their future prospects in the diagnosis as well as in the therapy are addressed.

Recchia, A., P. Debetto, et al. (2004). "Alpha-synuclein and Parkinson's disease." Faseb J 18(6): 617-26.

            Alpha-synuclein (alpha-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system. Interest in alpha-syn has increased dramatically after the discovery of a relationship between its dysfunction and several neurodegenerative diseases, including Parkinson's disease (PD). The physiological functions of alpha-syn remain to be fully defined, although recent data suggest a role in regulating membrane stability and neuronal plasticity. Various trigger factors, either environmental or genetic, can lead to a cascade of events involving misfolding or loss of normal function of alpha-syn. In dopaminergic neurons, this may promote a vicious cycle in which elevation in cytoplasmic dopamine, oxidative stress, alpha-syn dysfunction, and disruption of vesicle function lead to dopaminergic cell loss and PD. Alpha-syn dysfunction appears to be a common feature of all forms of PD. The mechanism by which alpha-syn induces neuronal cell toxicity may invoke multiple pathways, such as aggregation or interaction with other proteins and molecules, including synphilin-1, chaperone 14-3-3 protein, and dopamine itself. This complexity has hindered the development of models to study PD. The available animal models of PD, each present distinct advantages and limits. Findings to date suggest that alpha-syn-based models represent a paradigm, which is closest to the human pathology.

Reniewska, B., M. Mulak, et al. (2004). "[Coexistence of Alzheimer's disease with pseudoexfoliation syndrome PEX]." Klin Oczna 106(1-2): 107-9.

            Alzheimer disease is a type of cerebral amyloidosis, which is most frequently recognized after the age of 80. In pathophysiology of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and age-related cataract changes in protein aggregation play important role, for that reason they form common group of diseases, called conformational diseases. Patients with Alzheimer disease have more common pseudoexfoliation syndrome (PEX), characterized by the accumulation of an abnormal pathognomonic material in the anterior segment of the eye. Regarding common feature of the structure of fibrillar pseudoexfoliation and amyloid material, it is considered that eye examination could be useful in the early diagnosis of Alzheimer disease.

Richardson, D. R. (2004). "Novel chelators for central nervous system disorders that involve alterations in the metabolism of iron and other metal ions." Ann N Y Acad Sci 1012: 326-41.

            Recent evidence suggests that iron (Fe) and other metals play a role in a number of neurodegenerative diseases including Friedreich's ataxia, Alzheimer's disease, Huntington's disease, and Parkinson's disease. In this review, the role of Fe and other metals in the pathology of these conditions is assessed and the potential of Fe chelators for treatment is discussed. Lipophilic chelators have been designed that may be capable of crossing the blood-brain barrier, a property lacking in desferrioxamine (DFO), a chelator in widespread clinical use. A far less commonly used chelator, clioquinol, has already shown activity in vivo in animal models and also in Alzheimer's disease patients. Considering that there is no effective treatment for many neurological diseases, the therapeutic use of lipophilic Fe chelators remains a potential strategy that requires investigation. In particular, we discuss the development of several series of aroylhydrazone chelators that could have high potential in the treatment of these diseases.

Riederer, P., W. Danielczyk, et al. (2004). "Monoamine oxidase-B inhibition in Alzheimer's disease." Neurotoxicology 25(1-2): 271-7.

            Alzheimer's disease (AD) is the most common cause of dementia in late life. There is still no clear-cut consensus whether this disease involves genetic or environmental factors or both. There is a great need to find a way to delay the disease, as delaying the onset of the disease will bring a great relieve on social and medical resources. The monoamine oxidase-B (MAO-B) inhibitors were shown to be effective in treating Parkinson's disease and possibly AD, with concomitant extension of life span. This article gives a short review on MAO-B inhibitors and their mechanism for neuroprotective effects in AD.

Ringheim, G. E. and K. Conant (2004). "Neurodegenerative disease and the neuroimmune axis (Alzheimer's and Parkinson's disease, and viral infections)." J Neuroimmunol 147(1-2): 43-9.

            The appearance of activated immune cells and the accumulation of inflammation-associated proteins are common phenomena associated with neurodegenerative diseases. These inflammatory components of central nervous system (CNS) diseases have most often been described in the context of an immune response to damage and cell loss already occurring in the affected brain area. There has, however, been a renewed interest in how the neuroimmune axis might itself be involved in the etiology of these neurodegenerative diseases, particularly in cases involving slow, chronic, progressive neuropathology. This review addresses immune activation in Alzheimer's, Parkinson's, and brain viral infections that may be causative of, rather than responsive to, the observed neuronal loss in these pathologies.

Roitberg, B., K. Urbaniak, et al. (2004). "Cell transplantation for Parkinson's disease." Neurol Res 26(4): 355-62.

            Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of the dopamine producing neurons projecting from the substantia nigra into the corpus striatum. Current medical therapy is limited and cannot stop or reverse the degeneration. Over the past 30 years, attempts were made to change the course of the disease by replacing the lost neurons with grafts from various sources. Recent controlled clinical trials of fetal cell transplantation for PD have had disappointing results. These events present an opportunity to examine the past developments and future direction of cell transplantation for PD.

Roitberg, B. (2004). "Transplantation for stroke." Neurol Res 26(3): 256-64.

            Stroke is the most common cause of disability in the United States, and one of the leading causes of mortality and disability in the world. The hope that damage to the CNS can be reversed or at least ameliorated is the central idea behind the research into neural repair. The ultimate repair for the brain should restore the entire lost structure and it's function. However, partial benefit is possible from addressing some of the needs of the injured brain. These partial solutions are the basis of current research into brain repair after stroke. An opportunity arises for two kinds of intervention: (1) replacement of neurons; (2) support of existing neurons, to prevent excessive degeneration and promote rewiring and plasticity. Transplantation for stroke in the rat model was regularly reported starting in 1992, demonstrating graft survival and even evidence of connection with the host brain. These studies determined several parameters for future work in stroke models, but ultimately had limited efficacy and did not progress to clinical experiments. A variety of cell types have been tried for restoration of brain function after stroke, mostly in rodent models. Human fetal cells had shown some promise in clinical studies for the treatment of Parkinson's disease. The technical and ethical difficulties associated with these cells promoted a search for alternatives. These include porcine fetal cells, human cultured stem cells, immortalized cell lines, marrow stromal cells, Sertoli cells pineal cells, and other sources. Human clonal cell lines have few ethical limitations, but some questions remain regarding their safety and efficacy. Autologous somatic stem cells are a very attractive source--there are no ethical concerns and graft rejection is not an issue. However, it is not clear that somatic cells can are plastic enough and can be safely induced to a neural fate. Restorative treatment for stroke is a new field of study. Naturally, new ideas abound and many strategies have been suggested and tried. Methods and controversies abound, and include: local delivery of cells to the area of the stroke versus grafting to an area of the brain far removed form the stroke; cell therapy for reconstitution of structure and function versus use of cell grafts to support intrinsic repair and recovery mechanisms; intravascular administration of bone marrow or other stem cells; and combination grafts, or co-grafting of several cell types or cells and other substances. The various strategies address the issue of restorative treatments form different perspectives. Some interventions occur early after stroke, or are intended to preserve existing neural structures. For example, treatment strategies that aim to provide trophic support may demonstrate early beneficial results. Other strategies aim for growth and integration of new neurons to replace those lost after stroke. In this case, early beneficial results are not likely. Functional integration of grafted neurons, if it can ever happen, is likely to require training and exercise of the appropriate capacities. Further advances in preclinical studies of neural transplantation will require improved animal models with increased sensitivity to subtle behavioral and imaging changes. Non-human primate models have been established and may increase in importance as a phase before clinical trials. The future of brain repair for stroke is likely to require some form of combination therapy designed to replace the lost cells and supporting structure, attract new blood supply, support and enhance intrinsic repair and plasticity mechanisms.

Rossi, L., M. F. Lombardo, et al. (2004). "Mitochondrial dysfunction in neurodegenerative diseases associated with copper imbalance." Neurochem Res 29(3): 493-504.

            Copper is an essential transition metal ion for the function of key metabolic enzymes, but its uncontrolled redox reactivity is source of reactive oxygen species. Therefore a network of transporters strictly controls the trafficking of copper in living systems. Deficit, excess, or aberrant coordination of copper are conditions that may be detrimental, especially for neuronal cells, which are particularly sensitive to oxidative stress. Indeed, the genetic disturbances of copper homeostasis, Menkes' and Wilson's diseases, are associated with neurodegeneration. Furthermore, copper interacts with the proteins that are the hallmarks of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion diseases, and familial amyotrophic lateral sclerosis. In all cases, copper-mediated oxidative stress is linked to mitochondrial dysfunction, which is a common feature of neurodegeneration. In particular we recently demonstrated that in copper deficiency, mitochondrial function is impaired due to decreased activity of cytochrome c oxidase, leading to production of reactive oxygen species, which in turn triggers mitochondria-mediated apoptotic neurodegeneration.

Sachdev, P. (2004). "[Homocysteine and neuropsychiatric disorders]." Rev Bras Psiquiatr 26(1): 50-6.

            The author presents an overview of the current literature on homocysteine as a risk factor for neuropsychiatric disorders. The databases MEDLINE, Current Contents and EMBASE were searched (between 1966 and 2002) for English language publications with the key words 'Homocysteine' and 'Stroke'; 'Alzheimer Disease'; 'Cognitive Impairment'; 'Epilepsy'; 'Depression'; or 'Parkinson's disease'. Individual articles were hand searched for relevant cross-references. It is biologically plausible that high homocysteine levels may cause brain injury and neuropsychiatric disorders. Homocysteine is proatherogenic and prothrombotic, thereby increasing the risk of cerebrovascular disease, and may have a direct neurotoxic effect. Evidence for homocysteine as a risk factor for cerebral microvascular disease is conflicting but warrants further study. Cross-sectional and some longitudinal studies support increased prevalence of stroke and vascular dementia in hyperhomocysteinemic individuals. The evidence of increased neurodegeneration is accumulating. The relationship with depression is still tentative, as it is with epilepsy. Currently, treatment studies are necessary to place the evidence on a stronger footing, and maybe high-risk patients should be screened for hyperhomocysteinemia and this should be treated with folic acid. More research evidence is necessary before population screening can be recommended.

Samii, A., J. G. Nutt, et al. (2004). "Parkinson's disease." Lancet 363(9423): 1783-93.

            Parkinson's disease is the most common serious movement disorder in the world, affecting about 1% of adults older than 60 years. The disease is attributed to selective loss of neurons in the substantia nigra, and its cause is enigmatic in most individuals. Symptoms of Parkinson's disease respond in varying degrees to drugs, and surgery offers hope for patients no longer adequately controlled in this manner. The high prevalence of the disease, and important advances in its management, mean that generalists need to have a working knowledge of this disorder. This Seminar covers the basics, from terminology to aspects of diagnosis, treatment, and pathogenesis.

Sawabini, K. A. and R. L. Watts (2004). "Treatment of depression in Parkinson's disease." Parkinsonism Relat Disord 10 Suppl 1: S37-41.

            Depression is an important and common nonmotor feature of Parkinson's disease (PD) that is associated with significant disability and a negative impact on quality of life. The physician should remain vigilant for symptoms of depression as they may be mistaken for the progression of Parkinson's disease itself. Transient dysphoria that occurs during 'off' periods in fluctuating PD patients must be distinguished from true depression. Antidepressant therapy should be instituted if depression is interfering with the patient's daily function. The use of serotonin reuptake inhibitors and tricyclic antidepressants in the treatment of depression in PD is widespread in clinical practice. Dopamine agonists may be effective in the treatment of milder depression as well. Individual or family counseling may be helpful. In patients with severe depression who are refractory to antidepressant medications, a series of electroconvulsive treatments can be lifesaving. Nonconventional therapies such as transcranial magnetic stimulation are being investigated.

Schapira, A. H. (2004). "Disease modification in Parkinson's disease." Lancet Neurol 3(6): 362-8.

            Several separate gene mutations have now been identified in familial Parkinson's disease and important environmental influences modulating risk for the idiopathic form of the disease have also been recognised. These insights have provided important clues in the development of disease modifying therapies. Some compounds have already been shown to potentially delay disease progression in early clinical trials. The most important challenge, particularly for those drugs that might have a symptomatic effect, is defining appropriate markers that will confirm a neuroprotective effect.

Schapira, A. H. and C. W. Olanow (2004). "Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions." Jama 291(3): 358-64.

            Parkinson disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the United States. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment, and features develop such as postural instability, falling, and dementia that are not adequately controlled with existing medications. Accordingly, neuroprotective therapy that might slow, stop, or reverse disease progression is urgently needed. While many agents appear to be promising based on laboratory studies, selecting clinical end points for clinical trials that are not confounded by symptomatic effects of the study intervention has been difficult. More recently, neuroimaging end points have been used as biomarkers of disease progression, but again there are concerns that they may be influenced by regulatory effects of the drugs used. We review clinical trials aimed at detecting neuroprotection in Parkinson disease and address the controversies surrounding the interpretation of these studies.

Scherzer, C. R. and M. B. Feany (2004). "Yeast genetics targets lipids in Parkinson's disease." Trends Genet 20(7): 273-7.

Schipper, H. M. (2004). "Heme oxygenase-1: transducer of pathological brain iron sequestration under oxidative stress." Ann N Y Acad Sci 1012: 84-93.

            Mechanisms responsible for the pathological deposition of redox-active brain iron in human neurological disorders remain incompletely understood. Heme oxygenase-1 (HO-1) is a 32-kDa stress protein that degrades heme to biliverdin, free iron, and carbon monoxide. In this chapter, we review evidence that (1) HO-1 is overexpressed in CNS tissues affected by Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and other degenerative and nondegenerative CNS diseases; (2) the pro-oxidant effects of dopamine, hydrogen peroxide, beta-amyloid, and proinflammatory cytokines stimulate HO-1 expression in some of these conditions; and (3) upregulation of HO-1 in astrocytes exacerbates intracellular oxidative stress and promotes sequestration of nontransferrin-derived iron by the mitochondrial compartment. A model is presented implicating glial HO-1 induction as a "final common pathway" leading to pathological iron sequestration and mitochondrial insufficiency in a host of human CNS disorders.

Sharma, S., M. Kheradpezhou, et al. (2004). "Neuroprotective actions of coenzyme Q10 in Parkinson's disease." Methods Enzymol 382: 488-509.

Shibasaki, H., H. Fukuyama, et al. (2004). "Neural control mechanisms for normal versus parkinsonian gait." Prog Brain Res 143: 199-205.

            The non-invasive methods which can be applied to the study of the cerebral control mechanisms for human gait are limited because of technical constraints. In particular, the subject's head has to be fixed for most measurements. Despite this problem, SPECT-detected, rCBF activation studies have shown that the cerebral cortex participates in the control of the normal volitional walking of healthy human subjects. The active brain areas include the foot and trunk regions of the primary sensorimotor cortex, and the supplementary motor area (SMA), lateral premotor cortex, and cingulated gyrus. Selected subcortical structures also exhibit walking-related activity, including the dorsal brainstem and cerebellum. These same regions are active in patients with Parkinson's disease (PD), but significantly less so in the right SMA, left precuneus, and right cerebellar hemisphere. For the "kinesie paradoxale" of PD patients, the right lateral premotor area plays an important role in the visually induced gait improvement brought on by adding transverse lines to the walking path.

Shimazu, S. and I. Miklya (2004). "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives." Prog Neuropsychopharmacol Biol Psychiatry 28(3): 421-7.

            The discovery of enhancer regulation in the mesencephalon and the concept that it plays a key role in the operation of innate and acquired drives [Neurochem. Res. 28 (2003) 1187] sets the trace amines (TAs) in their true physiological perspective. The regulation is defined as the existence of enhancer-sensitive neurons in the brain capable of working in a split-second on a high activity level due to endogenous enhancer substances. For the time being, only beta-phenylethylamine (PEA) and tryptamine are the experimentally analyzed examples. (-)-Deprenyl (selegiline), widely used in Parkinson's disease and Alzheimer's disease today, and known as the first selective monoamine oxidase (MAO) type-B inhibitor for decades, was identified as a PEA-derived synthetic mesencephalic enhancer substance. An important and convincing confirmation of the enhancer concept was the recent development of a highly specific and potent tryptamine-derived synthetic mesencephalic enhancer substance, (-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP]. This substance, which is specific and hundreds of times more potent than selegiline, is now the best experimental tool to study the enhancer regulation in the mesencephalon and a promising candidate to significantly surpass the therapeutic efficiency of selegiline in depression, Parkinson's disease, and Alzheimer's disease.

Sibon, I. and F. Tison (2004). "Vascular parkinsonism." Curr Opin Neurol 17(1): 49-54.

            PURPOSE OF REVIEW: Vascular parkinsonism is a highly controversial concept since its first description by Critchley in 1929. There is no doubt that cerebrovascular disease can cause elements of parkinsonism. However, the extent of the spectrum of vascular parkinsonism remains quite imprecise. Here we review recent epidemiological, clinical, electrophysiological, morphological and functional brain imaging and pathological studies on 'vascular parkinsonism'. RECENT FINDINGS: Epidemiological studies have demonstrated that vascular parkinsonism represents 3-5% of all cases of parkinsonism. The more specific clinical features are a history of stroke, lower body parkinsonism and poor levodopa response. Vascular risk factors are dominated by arterial hypertension, whereas others have been less evaluated. Vascular lesions within or outside the basal ganglia, unique and multiple, lacunae or territorial infarcts can be demonstrated by magnetic resonance imaging. Functional imaging of the dopaminergic pathway helps to differentiate vascular parkinsonism from idiopathic Parkinson's disease. However, none of these clinical or imaging criteria taken alone are specific for the diagnosis. A combination of convergent clinical and imaging clues are therefore necessary to improve the accuracy of the diagnosis, which is only certain when the pathology excludes underlying idiopathic Parkinson's disease. SUMMARY: At present it remains unexplained why some patients develop vascular parkinsonism and others do not with the same apparent vascular lesion load. This will need further research along with the need to develop criteria to improve the accuracy of diagnosis of vascular parkinsonism. Vascular parkinsonism is also a research field on the relationships between vascular brain lesions and neurodegenerative disorders.

Sidhu, A., C. Wersinger, et al. (2004). "alpha-Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease." FEBS Lett 565(1-3): 1-5.

            Parkinson's disease (PD) is a slow progressive neurodegenerative disorder. Recent evidence suggests a central role for alpha-synuclein, a protein of unknown function, in the genesis of PD. The phenomenon of selective degeneration of dopaminergic neurons in PD may be linked to the potential toxicity of dopamine itself and aberrations in the processes which regulate dopamine content may underlie the pathogenesis of this disease. Here, we review a vital role of alpha-synuclein in the modulation of dopamine transporter (DAT) function, and describe how disruption of this modulatory process permits increased re-uptake of high levels of intracellular dopamine by DAT, causing profound neurotoxicity.

Sidhu, A., C. Wersinger, et al. (2004). "Does alpha-synuclein modulate dopaminergic synaptic content and tone at the synapse?" Faseb J 18(6): 637-47.

            alpha-Synuclein is a key component of the pathological process of neurodegeneration in Parkinson's disease. Although its contributions to normal physiological conditions remain elusive, converging observations suggest that a primary function of this protein in dopaminergic neurons may be the regulation of dopamine content and synaptic tone at the synapse. We review here cumulative evidence that demonstrates the participation of alpha-synuclein in the life cycle of dopamine from its synthesis, storage, release, and reuptake. The regulatory role of alpha-synuclein on dopamine metabolism is assessed by discussing the experimental evidence supporting each of these observations in the healthy physiological maintenance of dopaminergic neurons, as well as showing how disruption of these events can initiate the observed neurotoxicity of alpha-synuclein and the genesis of the degenerative processes associated with Parkinson's disease.

Small, G. W. (2004). "Neuroimaging as a diagnostic tool in dementia with Lewy bodies." Dement Geriatr Cogn Disord 17 Suppl 1: 25-31.

            Due to similar presenting symptoms, many physicians find it difficult to distinguish cases of dementia with Lewy bodies (DLB) from Alzheimer's disease or Parkinson's disease with dementia. The pathologic diagnosis of DLB has improved because of the discovery of probes for alpha-synuclein, a protein found in Lewy bodies. However, pathologic diagnosis can be employed postmortem only, and therefore diagnostic techniques that can be employed to guide patient management are still needed. Consensus criteria have been developed for establishing a clinical diagnosis of DLB, but they lack sensitivity. Therefore, a review of the recent literature was conducted to establish whether neuroimaging studies are useful diagnostic tools to help differentiate these syndromes. At least six types of tests can be used to image the brain of patients with dementia. Structural studies (x-ray, magnetic resonance imaging and computerized tomography) can disclose the presence of stroke sequelae and other lesions, whereas functional studies (magnetic resonance spectroscopy, positron emission tomography and single-photon emission computed tomography) can disclose metabolic and blood flow alterations that may be characteristic for different types of dementia. Although more formal studies are needed to confirm that these imaging techniques are reliable diagnostic tools for DLB and permit the establishment of guidelines for their use, neuroimaging techniques currently are being employed in practice to differentiate dementia types as a guide to treatment.

Sohn, Y. H. and M. Hallett (2004). "Motor evoked potentials." Phys Med Rehabil Clin N Am 15(1): 117-31, vii.

            Noninvasive electrical stimulation of the human brain first was attempted in the 1950s. In the early 1980s, the first clinical application method of transcranial electrical stimulation was developed. Investigators in the mid-1980s showed that it was possible to stimulate the nerve and the brain using external magnetic stimulation (transcranial magnetic stimulation [TMS]), with little or no pain. TMS now is used commonly in clinical neurology to study central motor conduction time. Depending on the stimulation techniques and parameters, TMS can excite or inhibit brain activity, allowing functional mapping of cortical regions and creation of transient functional lesions. It now is used widely as a research tool to study aspects of human brain physiology, including motor function and the pathophysiology of various brain disorders.

Stacy, M. (2004). "Apomorphine: North American clinical experience." Neurology 62(6 Suppl 4): S18-21.

            This manuscript reviews North American clinical trials examining subcutaneous injection of apomorphine in Parkinson's disease (PD) patients, and the available, cumulative apomorphine safety data for the US. These data provide strong documentation concerning dosing range (2-6 mg/injection), dosing frequency (1-10 injections/day), therapeutic response, and duration and onset of benefit. The US pivotal trial for subcutaneously injected apomorphine demonstrated robust and statistically significant benefit from drug administration when compared to subjects receiving placebo. Interestingly, these changes closely mirrored the response to levodopa in the same population, as measured by Unified Parkinson's Disease Rating Scale and Webster Step Seconds, and suggests that apomorphine may have greater potency than other agonists. A study of subjects ranging from early to advanced disease, conducted at the NIH, demonstrated a decline in duration of response and increased time to response in the advanced group when compared to levodopa naive subjects, despite the observation that threshold and optimal response dosages did not differ. Pharmacodynamic responses from a single average-dosage administration of 4.2 mg apomorphine in several studies demonstrated a benefit as early as 7.5 minutes with a duration of benefit as long as 90 minutes. Serious adverse events occurred in 16% of the subjects in these studies with the most common adverse events including dyskinesias (21%), hallucinations (11%), and orthostatic hypotension (9%).

Steele, P. E., P. H. Tang, et al. (2004). "Clinical laboratory monitoring of coenzyme Q10 use in neurologic and muscular diseases." Am J Clin Pathol 121 Suppl: S113-20.

            Coenzyme Q10 (Q10) is available as an over-the-counter dietary supplement in the United States. While its use could be considered a form of alternative therapy, the medical profession has embraced the use of Q10 in specific disease states, including a series of neurologic and muscular diseases. Clinical laboratory monitoring is available for measurement of total Q10 in plasma and tissue and for measurement of redox status, ie, the ratio of reduced and oxidized forms of Q10. Many published studies have been anecdotal, in part owing to the rarity of some diseases involved. Unfortunately, many studies do not report Q10 levels, and, thus, the relationship of clinical response to Q10 concentration in plasma frequently is not discernible. Consistent laboratory monitoring of patients treated with this compound would help ease interpretation of the results of the treatment, especially because so many formulations of Q10 exist in the marketplace, each with its own bioavailability characteristics. Q10 has an enviable safety profile and, thus, is ideal to study as an adjunct to more conventional therapy. Defining patient subpopulations and characteristics that predict benefit from exogenous Q10 and defining therapeutic ranges for those particular applications are major challenges in this field.

Stewart, D., E. Morgan, et al. (2004). "Dopamine agonist switching in Parkinson's disease." Hosp Med 65(4): 215-9.

            There are a number of situations for patients with Parkinson's disease in which a safe and efficacious switch from treatment with one dopamine agonist to another may be required. This article explores reasons for making such a switch, and provides practical guidance on performing it.

Stieglitz, T., M. Schuettler, et al. (2004). "Neural prostheses in clinical applications--trends from precision mechanics towards biomedical microsystems in neurological rehabilitation." Biomed Tech (Berl) 49(4): 72-7.

            Neural prostheses partially restore body functions by technical nerve excitation after trauma or neurological diseases. External devices and implants have been developed since the early 1960s for many applications. Several systems have reached nowadays clinical practice: Cochlea implants help the deaf to hear, micturition is induced by bladder stimulators in paralyzed persons and deep brain stimulation helps patients with Parkinson's disease to participate in daily life again. So far, clinical neural prostheses are fabricated with means of precision mechanics. Since microsystem technology opens the opportunity to design and develop complex systems with a high number of electrodes to interface with the nervous systems, the opportunity for selective stimulation and complex implant scenarios seems to be feasible in the near future. The potentials and limitations with regard to biomedical microdevices are introduced and discussed in this paper. Target specifications are derived from existing implants and are discussed on selected applications that has been investigated in experimental research: a micromachined implant to interface a nerve stump with a sieve electrode, cuff electrodes with integrated electronics, and an epiretinal vision prosthesis.

Stocchi, F. and C. W. Olanow (2004). "Continuous dopaminergic stimulation in early and advanced Parkinson's disease." Neurology 62(1 Suppl 1): S56-63.

            Evidence from preclinical and clinical studies indicates that pulsatile stimulation of striatal dopamine receptors is a key factor in the development of levodopa-associated motor complications. Therefore, in the de novo patient it is believed that providing a more continuous dopaminergic stimulation from the start of antiparkinson therapy may prevent priming for motor fluctuations and dyskinesia. Conversely, in the more advanced patient who is already suffering from motor complications, it is believed that providing a more continuous stimulation may reverse the development of motor complications, enabling the patient to enjoy more stable benefits from therapy. All PD patients eventually require levodopa therapy during the course of their disease, and the benefits of providing continuous dopaminergic stimulation with levodopa have been clearly demonstrated in a number of studies. However, these studies have included the use of approaches such as SC infusion or intra-intestinal infusion. Because these are relatively difficult to handle and not very practical for the patient, compliance is generally low. Therefore, the development of a simple treatment regimen using an oral formulation of levodopa to provide a more continuous dopaminergic stimulation will represent a significant advance in antiparkinsonian pharmacotherapy.

Strickland, D. and J. M. Bertoni (2004). "Parkinson's prevalence estimated by a state registry." Mov Disord 19(3): 318-23.

            A solid understanding of the descriptive epidemiology of a disease is essential in etiologic investigations; this includes prevalence and incidence, as well as groups within the larger community who may have noticeably lower or higher rates. We ascertained the usefulness of a non-traditional registry in describing Parkinson's disease (PD) patterns in a community. A passive surveillance PD registry in Nebraska began data collection on 1 January 1997. All physicians were required to report PD diagnosis, pharmacists reported new prescriptions of anti-PD drugs (PD cases were confirmed later with the prescribing physician), and there was a patient self-report mechanism. The overlap of reporting by the sources allowed estimation of the number not reported by any source, using the statistical technique "capture-recapture." As of January 2000, the Nebraska PD Registry had reports of 5,062 PD patients. The number not reported by any Registry reporting source was calculated to be 117, leading to an estimated total of 5,179 cases and a prevalence of 329.3 per 100,000 population. Tabulations of age- and gender-specific prevalence rates, as well as county-level estimates, allow examination of areas of elevated or lowered prevalence. The combination of a passive surveillance system and capture-recapture technique presents a useful method for epidemiologic description, and more traditional survey methods could benefit by including capture-recapture capability.

Swope, D. M. (2004). "Rapid treatment of "wearing off" in Parkinson's disease." Neurology 62(6 Suppl 4): S27-31.

            Patients with advanced Parkinson's disease (PD) may develop a variety of motor complications associated with levodopa therapy. Motor fluctuations, such as early morning akinesia and "wearing-off," may respond to individualized medical management with titrated combinations of levodopa, dopamine agonists, COMT inhibitors and amantadine. Often with disease progression, dyskinesias and unpredictable, rapid "off" periods will also emerge. These motor complications are less amenable to traditional anti-parkinson therapy manipulation. This manuscript reviews approaches for "rescue" therapy in PD patients with "wearing off," sudden "offs," early morning akinesia, and variable response to individual doses of oral medications. Strategies for preparing and administering liquid levodopa are discussed within the context of gastric emptying, intestinal absorption, and active transport across the blood brain barrier. In addition other levodopa preparations in early development, including the orally administered levodopa methyl ester and the potential for a subcutaneously administered levodopa ethyl ester are reviewed. Furthermore, practical guidelines regarding the dosing, administration, use of the antiemetic trimethobenzamide (Tigan), time to "on," duration of benefit, and potential side effects associated with subcutaneously injected apomorphine are provided.

Takuma, K., A. Baba, et al. (2004). "Astrocyte apoptosis: implications for neuroprotection." Prog Neurobiol 72(2): 111-27.

            Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.

Tambur, A. R. (2004). "Transplantation immunology and the central nervous system." Neurol Res 26(3): 243-55.

            Controlled clinical trials of cell transplantation for Parkinson's disease yielded disappointing results. Significant long-term functional improvement was not observed and cell survival was low. Although the brain was traditionally considered as "immunologically privileged" recent findings demonstrated late increase in the number of microglia around the grafts, therefore implying an involvement of immune mechanisms. The immunology of organ and cell transplantation to other body locations is scrupulously investigated and significant stepping-stones have been achieved. Ample evidence regarding the role of antigen-presenting cells in graft rejection has been documented. However, this knowledge did not benefit the discipline of cell transplantation to the central nervous system, and the minimal consideration of potential immune responses remain empirical in nature. In this review we summarize current knowledge of the major histo-compatibility complex and its role in transplant immunology. Resident cells of the brain that take part in immune responses are also discussed. Based on this information we hypothesize that the immune mechanisms involved with the long-term graft failure of cell transplantation to the central nervous system are likely to be chronic, and not acute, rejection. This, in turn, should have significant importance in the choice of anti-rejection drugs to be used.

Tanaka, K. and N. Ogawa (2004). "Possibility of non-immunosuppressive immunophilin ligands as potential therapeutic agents for Parkinson's disease." Curr Pharm Des 10(6): 669-77.

            Non-immunosuppressive immunophilin ligands (NI-IPLs) are attracting attention as new candidate drugs for neuroprotection and/or neurorestoration, particularly since they do not have the adverse effects of immunosuppressants. However, it is not yet enough to understand that NI-IPLs are useful drugs for treating neurological disorders. In particular, the molecular mechanism of NI-IPL activity in target cells in the brain remains obscure. In this review, we focused on the molecular basis of the neuroprotective properties of IPLs. Our findings suggest that IPLs have neuroprotective effects mediated by multiple beneficial properties such as a glutathione (GSH)-activating effect, a neurotrophic factor (NTF)-activating effect, and an anti-apoptotic effect, but not by an immunosuppressive effect, both in cell cultures and in vivo. In particular, the GSH-activating effect and the NTF-activating effect of NI-IPLs may be essential to the expression of their neuroprotective properties. Thus, NI-IPLs might have a potentially beneficial effect by ameliorating neurological disorders, since they do not cause serious side effects such as immune deficiency.

Tapia-Nunez, J. and P. Chana-Cuevas (2004). "[Diagnosis of Parkinson's disease]." Rev Neurol 38(1): 61-7.

            INTRODUCTION: Presently article carried out an up-to-date revision of the literature on the diagnosis of the Parkinson's disease, considering the clinical aspects, those of neuroradiology and the genetic diagnosis. DEVELOPMENT: The Parkinson's disease is the second most common neurodegenerative disorder and despite of the important development that has taken place in the last years as much in molecular genetics and neuroradiology, the diagnosis of this disease continuous being eminently clinical, the appropriate knowledge of the calls 'cardinal signs' and its application in the diagnosis increases the possibility that this it is guessed right, regrettably the definitive approach is only obtained in the autopsy. The genetic studies and of neuroradiology mainly are presented as tools for a more reliable differential diagnosis with other parkinsonism forms and the knowledge of these techniques can be useful in the taking of therapeutic decisions or of the affected patient's integral treatment. They have also been different monogenic forms in origin to the sporadic form of the illness. CONCLUSION: The knowledge and search of the preponderant clinical signs increases the capacity of diagnostic of the illness, in the same way the appropriate use of additional methods of investigation, mainly in the differential diagnosis.

Thomas, S. and D. MacMahon (2004). "Parkinson's disease, palliative care and older people: Part 2." Nurs Older People 16(2): 22-6; quiz 28.

            In the second of two articles on palliative care for people with Parkinson's disease, the authors consider other aspects of care relevant to this complex stage. They conclude that better understanding of its complexity, its innate variability and the roles extended team members can play help to improve the care given to patients.

Thomas, S. (2004). "The role of health professionals in supporting expert patients schemes." Prof Nurse 19(8): 442-5.

            A diagnosis of chronic disease can be devastating. Health-care professionals are one part of the team centred on supporting the person through that illness. Lay-led-self-management programmes are another strand. This paper focuses on expert patients programmes and the importance of integrating self-management into current health-care provision.

Thomas, S. and D. MacMahon (2004). "Parkinson's disease, palliative care and older people: Part 1." Nurs Older People 16(1): 22-6.

            In the first of two articles on palliative care for people with Parkinson's disease, the authors revise the common features of the disease, its different stages and the nature of palliative care for people who suffer from it. Next month, they consider management of common problems in late-stage Parkinson's and various ethical issues that nurses may encounter.

Thomas, M. and W. D. Le (2004). "Minocycline: neuroprotective mechanisms in Parkinson's disease." Curr Pharm Des 10(6): 679-86.

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

Thorpy, M. J. (2004). "Sleep disorders in Parkinson's disease." Clin Cornerstone 6 Suppl 1A: S7-15.

            Depression, dementia, and physiologic changes contribute to the high prevalence of sleep disturbances in patients with Parkinson's disease (PD). Antiparkinsonian drugs also play a role in insomnia by increasing daytime sleepiness and affecting motor symptoms and depression. Common types of sleep disturbances in PD patients include nocturnal sleep disruption and excessive daytime sleepiness, restless legs syndrome, rapid eye movement sleep behavior disorder, sleep apnea, sleep walking and sleep talking, nightmares, sleep terrors, and panic attacks. A thorough assessment should include complete medical and psychiatric histories, sleep history, and a 1- to 2-week sleep diary or Epworth Sleepiness Scale evaluation. Polysomnography or actigraphy may also be indicated. Treatment should address underlying factors such as depression or anxiety. Hypnotic therapy for sleep disturbances in PD patients should be approached with care because of the risks of falling, agitation, drowsiness, and hypotension. Behavioral interventions may also be useful.

Tinsley, R. and P. Eriksson (2004). "Use of gene therapy in central nervous system repair." Acta Neurol Scand 109(1): 1-8.

            Recent advances have increased our molecular understanding of the central nervous system (CNS), in both health and disease. In order to realize the clinical benefits of these findings, new molecular-based therapies need to be developed, such as CNS gene therapy. Although the field has suffered setbacks, it remains an attractive technology for providing new therapies in the post-genomic world. The development of new vectors, and their extensive application in animal models of CNS disease, provides evidence suggesting that gene therapy will eventually become an accepted clinical option. In fact, the first gene therapy clinical trial for Parkinson's disease has recently begun. This review discusses how gene therapy has been applied in animal models, and how it may be used to repair the damage caused by CNS diseases and trauma in human beings. Furthermore, it explores how such treatments may be combined with, and augment, more conventional therapeutic approaches.

Toft, M. and J. Aasly (2004). "[The genetics of Parkinson disease]." Tidsskr Nor Laegeforen 124(7): 922-4.

            BACKGROUND: Parkinson's disease, PD, is the second most common neurodegenerative disorder. A genetic component in Parkinson's disease was long thought to be unlikely, but recent genetic studies have identified several genes associated with the disease. MATERIAL AND METHODS: A review of the literature and personal experiences from genetic studies in central Norway are presented. RESULTS: Nine loci on the human genome have been linked to Parkinson's disease. Mutations in the alfa-synuclein, parkin, DJ-1, and arguably UCH-L1 genes are identified for familial PD. Recently a locus on chromosome 1 was linked to common late-onset PD in the Icelandic population. Iceland's population is primarily of Norse descent. This locus may be of significant importance to Norwegian PD patients. INTERPRETATION: The genes and loci identified have improved our understanding of the pathogenesis in PD significantly. This knowledge may help to create new treatment strategies for PD.

Tretter, L., I. Sipos, et al. (2004). "Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease." Neurochem Res 29(3): 569-77.

            Oxidative stress and partial deficiencies of mitochondrial complex I appear to be key factors in the pathogenesis of Parkinson's disease. They are interconnected; complex I inhibition results in an enhanced production of reactive oxygen species (ROS), which in turn will inhibit complex I. Partial inhibition of complex I in nerve terminals is sufficient for in situ mitochondria to generate more ROS. H2O2 plays a major role in inhibiting complex I as well as a key metabolic enzyme, alpha-ketoglutarate dehydrogenase. The vicious cycle resulting from partial inhibition of complex I and/or an inherently higher ROS production in dopaminergic neurons leads over time to excessive oxidative stress and ATP deficit that eventually will result in cell death in the nigro-striatal pathway.

Trzesniewska, K., M. Brzyska, et al. (2004). "Neurodegenerative aspects of protein aggregation." Acta Neurobiol Exp (Wars) 64(1): 41-52.

            Protein aggregation and amyloid fibril deposits are characteristic features of more than twenty pathologic conditions characterized by plaque deposition in the central nervous system. Recent studies point out relationships between protein misfolding and numerous serious diseases. Despite different origins (sporadic, familial or transmissible), they are sometimes called conformational diseases to emphasize aberrant conformations as the putative cause of deposits that precede or accompany the clinical manifestation of the disease. Neurological disorders such as Alzheimer's disease (AD), Prion disorders (PrD), Parkinson's disease (PD), and Huntington's disease (HD) are the most typical examples of protein-based dementias, characterized by protein conformational transitions (alpha-helix/random coil to beta-sheet) that cause aggregation followed by fibrillization. Although it is very tempting to postulate a common mechanism of toxicity based on conformational and structural analogies, it should be noted that the factors responsible for conformational transition, oligomerization, aggregation, and plaque formation, are still subject of speculation and additional data is required to test the amyloid fibril hypothesis.

Vermel, A. E. (2004). "[Stem cells: general characteristics and perspectives of their clinical use]." Klin Med (Mosk) 82(1): 5-11.

            Culturing of embryonic and adult stem cells (SC) is characterized. Animal experiments on models of human pathology (diabetes mellitus, acute myocardial unfarction, cerebral stroke, Parkinson's disease, etc.) have shown that use of SC is associated with good effects on the diseases. Pilot results of SC treatment of acute myocardial infarction, parkinsonism, hemoblastoses, systemic lupus erythematosus, rheumatoid arthritis and others are reviewed.

Volkmann, J. (2004). "Deep brain stimulation for the treatment of Parkinson's disease." J Clin Neurophysiol 21(1): 6-17.

            Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.

Wang, L. H., C. G. Besirli, et al. (2004). "Mixed-lineage kinases: a target for the prevention of neurodegeneration." Annu Rev Pharmacol Toxicol 44: 451-74.

            The activation of the c-Jun N-terminal kinase (JNK) pathway is critical for naturally occurring neuronal cell death during development and may be important for the pathological neuronal cell death of neurodegenerative diseases. The small molecule inhibitor of the mixed-lineage kinase (MLK) family of kinases, CEP-1347, inhibits the activation of the JNK pathway and, consequently, the cell death in many cell culture and animal models of neuronal death. CEP-1347 has the ability not only to inhibit cell death but also to maintain the trophic status of neurons in culture. The possible importance of the JNK pathway in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases provides a rationale for the use of CEP-1347 for the treatment of these diseases. CEP-1347 has the potential of not only retarding disease progression but also reversing the severity of symptoms by improving the function of surviving neurons.

West, A. B. and N. T. Maidment (2004). "Genetics of parkin-linked disease." Hum Genet 114(4): 327-36.

            Research into Parkinson's disease (PD), once considered the archetypical non-genetic neurodegenerative disorder, has been revolutionized by the identification of a number of genes, mutations of which underlie various familial forms of the disease. Whereas such mutations appear to exist in a relatively small number of individuals from a few families, the study of the function of these genes promises to reveal the fundamental disease pathogenesis, not only of familial forms of the disease, but also of the much more common sporadic PD. The observation that mutations in the second identified PD locus (parkin) are common in juvenile- and early-onset PD and increasing evidence supporting a direct role for parkin in late-onset disease make this gene a particularly compelling candidate for intensified investigation. The determination of the frequency and effect of parkin mutations in various subsets of PD will be crucial for understanding the way in which parkin is related to neurodegenerative mechanisms, and whether these subsets might be effectively identified and treated. In addition, many aspects of parkin-linked disease, originally thought to be well defined, have now been obscured both by genetic studies that preclude a simple model of disease transmission and by clinical and pathological studies that demonstrate broad variability in cases with parkin mutations. Future studies that address the issues in question should have a far-reaching impact in downstream biochemical studies and our understanding of parkin's role in PD.

Willis, G. L. and G. A. Kennedy (2004). "The implementation of acute versus chronic animal models for treatment discovery in Parkinson's disease." Rev Neurosci 15(1): 75-87.

            Animal models for neuropsychiatric disorders are implemented for the purpose of investigating a single or multiple aspects of a specific disease entity. In Parkinson's disease (PD) several models have been utilised to study the biochemical and behavioural consequences of dopamine (DA) neurone degeneration with the intent of further understanding the aetiology of this disease and improving its treatment. While the bilateral 6-hydroxydopamine (6-OHDA) model has been used to produce a broad spectrum of neurochemical and behavioural deficits characterising DA degeneration in humans, this model is traumatic, labour intensive and is associated with high mortality due to the acute effects of the neurotoxin. Consequently, the unilateral 6-OHDA model was developed and implemented. In this model damage to the ascending DA system is produced on one side of the brain thereby inducing postural rotation. This movement is exaggerated by activating the remaining DA systems with apomorphine or amphetamine thereby making it more quantifiable. In view of the less traumatic effects on homeostasis and relative ease with which this model can be implemented it has been used routinely for the purpose of screening potential anti-Parkinsonian drugs for clinical use. However, like any model, the use of the unilateral rotation model has its limitations. It is proposed that the process of exaggerating DA function using this paradigm limits the discovery of potential anti-PD drugs to those which are effective in counteracting an exaggerated DA response. This factor may account for the high incidence of unwanted side effects including involuntary movement, tardive dyskinaesia (TD) and psychosis which are commonly observed in DA replacement therapy. Secondly, this approach limits potential drug candidates to those acting exclusively on brain DA systems. This too is a problem in the sense that PD is known to be a disease involving numerous systems in the human brain and potential therapies acting via other neurochemical systems are being excluded when this model is used exclusively. The object of the present paper is to report the discovery of a non-DA drug possessing potent anti-Parkinsonian qualities which were revealed using the bilateral 6-OHDA model of PD as a screening tool. When the same drug was retested in the traditional unilateral screening model no effect was observed, while more advanced models confirmed its efficacy. These results illustrate that the implementation of appropriate models for revealing new treatment strategies for PD should be broadly based so that single treatment entities are not exclusively pursued for diseases whose aetiologies are multifaceted. Premature extrapolation of findings from a single, early stage model to its clinical counterpart can be detrimental to advancing new treatment strategies, induce false hope, and increase morbidity in PD patients.

Wu, G., Y. Z. Fang, et al. (2004). "Glutathione metabolism and its implications for health." J Nutr 134(3): 489-92.

            Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.

Xu, X., S. Pin, et al. (2004). "Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis." Ann N Y Acad Sci 1012: 299-305.

            In 1987, Miyajima et al. first characterized an autosomal recessive, adult-onset neurodegenerative disorder resembling Parkinson's disease associated with near-absent circulating serum ceruloplasmin levels. Coined "familial apoceruloplasmin deficiency", they described a patient with a presenting triad of diabetes mellitus, retinal degeneration, and neurodegeneration with blepharospasm. Neuropathological evaluation revealed abundant iron deposition in selected neurons of the basal ganglia and substantia nigra with associated neuronal dropout and spongioform degeneration without evidence of reactive gliosis. Subsequently, mutations in the ceruloplasmin gene have been determined to result in the excessive iron accumulation seen in the pancreas, retina, and brain. Elevated serum ferritin suggests a systemic iron overload syndrome, yet affected patients had low transferrin saturation and a mild anemia. This new disease, "aceruloplasminemia", reveals a role for ceruloplasmin as an essential ferroxidase critical for iron homeostasis. This multicopper oxidase promotes efficient iron efflux such that individuals lacking ceruloplasmin develop a presumed oxidative injury secondary to iron accumulation and significant neuronal damage. Aceruloplasminemic mice provide a valuable model to further study the mechanisms by which ceruloplasmin regulates iron trafficking and the role of iron in oxidative injury. Despite the dependence of ceruloplasmin on copper for its function, aceruloplasminemia represents an iron storage disease and not a defect in copper metabolism. However, recent evidence in Saccharomyces cerevisiae indicates that Fet3, the yeast homologue of ceruloplasmin, functions as an essential cuprous oxidase. Further investigation into the mechanisms by which ceruloplasmin regulates iron and copper homeostasis will provide valuable insight into the pathogenesis of metallo-mediated diseases and elucidate mechanisms for transition metal (copper, iron) neuropathology.

Yamada, M. and H. Yasuhara (2004). "Clinical pharmacology of MAO inhibitors: safety and future." Neurotoxicology 25(1-2): 215-21.

            In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called "cheese effect." Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.

Zhu, B. T. (2004). "CNS dopamine oxidation and catechol-O-methyltransferase: importance in the etiology, pharmacotherapy, and dietary prevention of Parkinson's disease." Int J Mol Med 13(3): 343-53.

            In this article, a particular emphasis has been placed on the conceptual development and understanding of the unique pathogenic changes that are indigenous to the striatal dopaminergic neurons as an important etiological factor in human Parkinson's disease (PD) as well as on the understanding of their clinical implications. Specifically, I have discussed the etiological roles of central nervous system dopamine oxidation in PD, along with a critical review of the available evidence in support of the proposed hypotheses. The chemically-reactive dopamine quinone/semiquinone intermediates are known to be highly neurotoxic and potentially genotoxic. There is considerable evidence for the suggestion that the long-term use of levodopa accelerates the progression of PD. In comparison, centrally-acting non-catechol dopamine receptor agonists would be an excellent alternative to levodopa for the treatment of PD (particularly for late-stage PD) because these agents would not undergo redox cycling to cause oxidative neuronal damage. Catechol-O-methyltransferase (COMT)-mediated methylation metabolism of catecholamine neurotransmitters is a crucial first-line detoxification pathway, and its role in the causation and prevention of PD is also discussed. On the basis of the modulation of COMT-mediated methylation of catecholamines, it is mechanistically explained that hyperhomocysteinemia would be a pathogenic factor in PD whereas vitamins B6, B12, and folate would be a protective factor. Lastly, according to the mechanistic understanding developed here, a novel dietary strategy is proposed that is specifically tailored toward lowering the risk of human PD, which includes eating a nutritionally-balanced diet that contains adequate (but not excessive) amounts of fruits and vegetables, along with adequate dietary supplementation of S-adenosyl-L-methionine, vitamins C, B6, B12, and folate. It is believed that these conceptual developments would also aid in our better understanding of other age-related neurodegenerative disorders, such as Alzheimer's and Huntington's diseases.

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