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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