Parkinson Disease: California

Martin JL, Ancoli-Israel S. · Veteran's Affairs Greater Los Angeles Healthcare System, Geriatric Research, Education and Clinical Center, 16111 Plummer Street, North Hills, CA 91343, USA. · Clin Geriatr Med. · Pubmed #18035230 links to  free full text

Abstract: Nighttime sleep disruption is characteristic of long-term care residents, is typically accompanied by daytime sleepiness, and may be caused by a multitude of factors. Causal factors include medical and psychiatric illness, medications, circadian rhythm abnormalities, sleep disordered breathing and other primary sleep disorders, environmental factors, and lifestyle habits. There is some suggestion that these factors are amenable to treatment; however, further research on the implementation of treatments within the long-term care setting is needed. Additional work is also needed to understand the administrative and policy factors that might lead to systemic changes in how sleep is viewed and sleep problems are addressed in long-term care settings.

Chen JJ, Swope DM, Dashtipour K. · Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Loma Linda University, Loma Linda, California 92350, USA. · Clin Ther. · Pubmed #18035186 No free full text.

Abstract: BACKGROUND: Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B (MAO-B) prolong the duration of action of both endogenously and exogenously derived dopamine. Rasagiline [N-propargyl-l(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits brain MAO-B and is specifically designed for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to review the pharmacology, tolerability, and clinical efficacy of rasagiline in the treatment of PD. METHODS: MEDLINE (1966-April 2007), the Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts (1970-April 2007) were searched for original research and review articles published in English. The search terms were monoamine oxidase, neuroprotection, Parkinson disease, propargylamine, rasagiline, and selegiline. The reference lists of articles were also consulted, as was information provided by the manufacturer of rasagiline. RESULTS: Data from 63 clinical and laboratory studies were analyzed. Based on the results from those studies, we concluded that rasagiline PO QD, at the therapeutic dosage range of 0.5 to 1 rag/d, is effective and well tolerated and completely, selectively, and specifically inhibited MAO-B. Pharmacologically, rasagiline was found to be < or =10-fold more potent than selegiline and was not metabolized to amphetamine derivatives. Rasagiline was effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provided modest yet clinically meaningful benefit. A randomized, double-blind, placebo-controlled study found that, after 26 weeks of treatment, the adjusted effect size for total Unified Parkinson's Disease Rating Scale score was -4.20 (95% CI, -5.66 to -2.73) for rasagiline 1 mg/d versus placebo (P < 0.001). Preliminary long-term data from an open-label study suggest a sustained therapeutic advantage when rasagiline is initiated early (before the need for dopaminergic agents) rather than later. In patients with more advanced disease who received treatment with dopaminergic agents, rasagiline and entacapone were associated with reductions of "off" time significantly greater than placebo (-1.18 and -1.2 vs 0.4 hour; both, P < or = 0.001). Rasagiline was well tolerated in younger (aged <;70 years) and older (aged > or =70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of diet-derived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. CONCLUSIONS: Based on this review, rasagiline has been found to be well tolerated and effective in the treatment of early PD and as adjunctive treatment in motor fluctuations. Whether rasagiline is associated with clinically significant neuroprotection (ie, disease modification) in PD is the subject of ongoing clinical trials.

Cummings J, Winblad B. · UCLA Alzheimer's Center, 10911 Weyburn Avenue, Suite 200, Los Angeles, CA 90095-7226, USA. · Expert Rev Neurother. · Pubmed #17997695 No free full text.

Abstract: Rivastigmine patch is the first transdermal treatment to be approved for Alzheimer's disease (AD) and Parkinson's disease dementia in the USA and for AD in Europe. It provides smooth, continuous drug delivery, and has the potential to maintain rivastigmine concentrations within an optimal therapeutic window while avoiding the peaks and troughs associated with oral drug delivery. The target dose, rivastigmine 9.5 mg/24 h patch (a 10 cm(2) patch), is given once daily and requires a simple one-step dose titration to the therapeutic dose. In a 24-week study in 1195 AD patients, the rivastigmine 9.5 mg/24 h patch provided similar efficacy to the highest dose range of capsules, with approximately three-times fewer reports of nausea and vomiting. Patients in the 9.5 mg/24 h patch and 12 mg/day capsule groups evidenced significant improvements versus placebo on both primary outcome measures: the Alzheimer's Disease Assessment Scale-Cognitive subscale; and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change; in addition to the following secondary outcome measures: Alzheimer's Disease Cooperative Study-Activities of Daily Living scale; Mini-Mental State Examination; and Trail Making Test Part A for assessment of attention, visual tracking and motor processing speed. Treatment differences on the Neuropsychiatric Inventory and Ten Point Clock-drawing Test did not reach statistical significance in this study. The patch may be the optimal way to treat dementia patients with rivastigmine.

Chesselet MF. · Department of Neurology and Neurobiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. · Exp Neurol. · Pubmed #17949715 links to  free full text

Abstract: Mutations in alpha-synuclein were the first genetic defect linked to Parkinson's disease (PD). The relevance of alpha-synuclein to sporadic PD is strongly supported by the presence of alpha-synuclein aggregates in neurons of patients. This has prompted the development of numerous animal models based on alpha-synuclein overexpression, primarily through genetic methods in mice and viral transduction in rats. In mice, different promoters and transgenes lead to a wide variety of phenotypes accompanied by non-existent, late onset, or non-specific neurodegeneration. Rapid neurodegeneration, in contrast, is observed after viral transduction but is limited to the targeted region and does not mimic the broad pathology observed in the disease. Overall, each model reproduces a subset of features of PD and can be used to identify therapeutic targets and test disease-modifying therapies. The predictive value of all models of the disease, however, remains speculative in the absence of effective neuroprotective treatments for PD in humans.

Fiandaca M, Forsayeth J, Bankiewicz K. · Department of Neurological Surgery, Movement Disorder Research Program, University of California, Mission Center Building, San Francisco, CA 94103, USA. · Exp Neurol. · Pubmed #17920059 No free full text.

Abstract: The incidence of Parkinson's disease (PD) increases greatly with age, and the baby-boomer population can expect to generate a large number of individuals with the disease, all of whom will have significantly increased medical care needs over periods of 20 years or more. This emerging healthcare burden to our society calls for accelerated efforts to understand this disease better and treat it more effectively. The growing interest in gene therapy grew out of a recognition that new medicines may be needed to combat the relentless progression of the disease in the face of conventional pharmaco-therapies and surgical interventions that have so far failed to offer more than palliative relief. The potential of gene therapy to alter dramatically the course of the disease lies very much with the challenge of converting a research tool into a medical option, a process that clearly requires a unique combination of rigor and flexibility. In this review, we examine the unique aspects of gene therapy that make its use in PD attractive, but also analyze the difficulties of employing a medicine that acts for the rest of the patient's life.

Bhidayasiri R, Truong DD. · Chulalongkorn Comprehensive Movement Disorders Center, Division of Neurology, Chulalongkorn University Hospital, Bangkok 10330, Thailand. · J Neurol Sci. · Pubmed #17897677 No free full text.

Abstract: Long-term dopaminomimetic therapy, not limited to levodopa, is complicated by the emergence of variations of motor response in a majority of Parkinson disease (PD) patients. These variations can occur in different forms, as early wearing off during the initial stage of motor complications, dyskinesias in the intermediate stage, and complex fluctuations in the advanced stage. Considered to be a major source of disability in advanced PD patients, recognition of these complications is critical in order to develop different strategies designed not only to treat these problems when they develop, but also to prevent troublesome complications associated with potential risk factors. In this article, authors classify a wide clinical spectrum of motor complications into different stages as the disease progresses through the treatment. A number of strategies are proposed in order to manage these complications as well as to avoid them. Better understanding of these potential complications will result in better management of these problems and lessen the disability associated with advanced PD.

Henderson VW. · Department of Health Research and Policy, Stanford University, Stanford, California 94305-5405, United States. · Climacteric. · Pubmed #17882682 No free full text.

Abstract: Menopausal status and estrogen-containing hormone therapy may influence several neurological disorders, including Alzheimer's disease, epilepsy, migraine headache, multiple sclerosis, Parkinson's disease, sleep disorders, and stroke. For most of these illnesses, evidence on hormone therapy is insufficient to guide practice decisions. For stroke, clinical trial evidence indicates that hormone therapy increases risk of cerebral infarction. For women with Alzheimer's disease, estrogen treatment trials have tended to be small and of short duration. Most suggest that estrogen started after the onset of dementia symptoms does not meaningfully improve cognition or slow disease progression. Hormone therapy initiated after age 64 increased all-cause dementia in the Women's Health Initiative Memory Study. Many observational studies, however, report protective associations between hormone use and Alzheimer risk. Apparent risk reduction may represent a bias toward hormone therapy, since hormones are more often prescribed to healthier women. However, when compared to the Women's Health Initiative Memory Study, estrogen exposures in many observational studies reflect hormone initiation at a younger age, closer to the time of menopause. One intriguing hypothesis is that hormone therapy initiated or used during an early critical window may reduce later Alzheimer incidence. Public health implications of this hypothesis are important, but current data are inadequate to decide the issue.

Rockenstein E, Crews L, Masliah E. · Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA. · Adv Drug Deliv Rev. · Pubmed #17869376 No free full text.

Abstract: Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.

Truong DD, Bhidayasiri R, Wolters E. · The Parkinson's and Movement Disorder Institute, 9940 Talbert Avenue, Fountain Valley, CA 92708, USA. · J Neurol Sci. · Pubmed #17804018 No free full text.

Abstract: Progress in pharmacology has markedly improved the treatment of early Parkinson's disease. The management of advanced Parkinson's symptoms, however, remains a challenge. These symptoms are divided into motor and non-motor symptoms. Non-motor symptoms may appear early or late in the disease and sometimes even before the onset of the first motor symptoms confirming the diagnosis. The spectrum of non-motor symptoms encompasses autonomic dysfunctions, sleep disorders, mood disorders, impulse control disorders, cognitive dysfunction, dementia, paranoia and hallucinations. They are often less appreciated than motor symptoms but are important sources of disability for many PD patients. This review describes these non-motor symptoms and their managements.

Chen JJ, Fernandez HH. · Movement Disorders Center, Schools of Medicine and Pharmacy, Loma Linda University, Loma Linda, California 92350, USA. · Drugs Aging. · Pubmed #17702535 No free full text.

Abstract: Parkinson's disease affects up to 1 million people in the US, most of them elderly. Motor and non-motor symptoms can be significantly disabling to the point of necessitating institutionalisation. Age-related changes in drug absorption, distribution, metabolism and excretion complicate the treatment of elderly patients with Parkinson's disease. General management principles include initiation of medication at low doses with gradual titration based on clinical effects, avoidance of certain classes of drugs (e.g. anticholinergics), and attention to polypharmacy and its risk for potentially toxic drug interactions. Levodopa remains the most efficacious anti-Parkinson's disease medication and should be the cornerstone of therapy in the elderly Parkinson's disease patient. Use of dopamine receptor agonists, amantadine and anticholinergic drugs in the elderly is limited by high risk for psychotoxicity. Catechol-O-methyltransferase inhibitors may be used to augment levodopa in the setting of 'wearing off' (i.e. motor fluctuations). Monoamine oxidase type B (MAO-B) inhibitors can be used across the spectrum of disease severity, but selegiline (deprenyl), the prototype in this class, is characterised by low and erratic bioavailability of the parent drug and conversion to amphetamine metabolites that may increase the risk of adverse events. A new orally disintegrating tablet formulation overcomes some of these limitations. Rasagiline is a new, selective, second-generation MAO-B inhibitor that is chemically and metabolically distinct from selegiline. The favourable safety profile of rasagiline in the elderly and its once-daily formulation may maximise drug adherence and improve outcomes.

Lipton SA, Gu Z, Nakamura T. · Neuroscience and Aging Center, Burnham Institute for Medical Research, La Jolla, California 92037, USA. · Int Rev Neurobiol. · Pubmed #17678953 No free full text.

Abstract: Inflammatory mediators, including free radicals such as nitric oxide (NO) and reactive oxygen species (ROS), can contribute to neurodegenerative diseases in part by triggering protein misfolding. In this chapter, we will discuss a newly discovered pathway for this phenomenon and possible novel treatments. Excitotoxicity, defined as overstimulation of glutamate receptors, has been implicated in a final common pathway contributing to neuronal injury and death in a wide range of acute and chronic neurological disorders, ranging from Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD) to stroke and trauma. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, leading to excessive Ca(2+) influx through the receptor's associated ion channel and subsequent free radical production, including NO and ROS. These free radicals can trigger a variety of injurious pathways, but newly discovered evidence suggests that some proteins are S-nitrosylated (transfer of NO to a critical thiol group), and this reaction can mimic the effect of rare genetic mutations. This posttranslational modification can contribute to protein misfolding, triggering neurodegenerative diseases. One such molecule affected is protein disulfide isomerase (PDI), an enzyme responsible for normal protein folding in the endoplasmic reticulum (ER). We found that when PDI is S-nitrosylation (forming SNO-PDI), the function of the enzyme is compromised, leading to misfolded proteins and contributing to neuronal cell injury and loss. Moreover, SNO-PDI occurs at pathological levels in several human diseases, including AD and PD. This discovery thus links protein misfolding to excitotoxicity and free radical formation in a number of neurodegenerative disorders. Another molecule whose S-nitrosylation can lead to abnormal protein accumulation is the E3 ubiquitin ligase, parkin, which contributes to the pathogenesis of PD. One way to ameliorate excessive NO production and hence abnormal S-nitrosylations would be to inhibit NMDA receptors. In fact, blockade of excessive NMDA receptor activity can in large measure protect neurons from this type of injury and death. However, inhibition of the NMDA receptor by high-affinity antagonists also blocks the receptor's normal function in synaptic transmission and leads to unacceptable side effects. For this reason, many NMDA receptor antagonists have disappointingly failed in advanced clinical trials. Our group was the first to demonstrate that gentle blockade of NMDA receptors by memantine, via a mechanism of uncompetitive open-channel block with a rapid "off-rate," can prevent this type of damage in a clinically efficacious manner without substantial side effects. For these Uncompetitive/Fast Off-rate therapeutics, we use the term "UFO drugs" because like Unidentified Flying Objects, they leave very quickly as soon as their job is finished. As a result, memantine blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this by preferentially entering the receptor-associated ion channel when it is excessively open, and, most importantly, when its off-rate from the channel is relatively fast so that it does not accumulate to interfere with normal synaptic transmission. Hence, memantine is clinically well tolerated, has been used in Europe for PD for many years, and recently passed multiple phase III trials for dementia, leading to its approval by the FDA and European Union for moderate-to-severe AD. Clinical studies of memantine for additional neurological disorders, including other dementias, neuropathic pain, and glaucoma, are underway. We have also developed a series of second-generation drugs that display greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, including critical thiol groups that are S-nitrosylated. In this case, in contrast to PDI or parkin, S-nitrosylation proves to be neuroprotective by decreasing excessive NMDA receptor activity. Targeted S-nitrosylation of the NMDA receptor can be achieved by coupling NO to memantine, yielding second-generation "UFO drugs" known as NitroMemantines.

Cummings J, Lefèvre G, Small G, Appel-Dingemanse S. · UCLA Alzheimer's Center, Los Angeles, CA 90095-7226, USA. · Neurology. · Pubmed #17646618 No free full text.

Abstract: The dual cholinesterase inhibitor rivastigmine is approved in capsule form in many countries for the symptomatic treatment of dementia associated with Alzheimer disease (AD) and Parkinson disease (PD). All orally administered cholinesterase inhibitors are associated with central cholinergic gastrointestinal side effects, particularly during the titration phase, which are believed to be caused by a rapid increase in brain acetylcholine levels after effective inhibition of the target enzymes. A recently developed rivastigmine transdermal patch may have the potential to reduce such side effects. Pharmacokinetic studies have shown that transdermal administration of rivastigmine prolongs t(max), lowers C(max), and reduces fluctuations in plasma concentration. The 10-cm(2) rivastigmine patch provides comparable exposure (area under the curve, AUC) to the highest capsule dose (6-mg BID) and may be the target maintenance dose for most patients, delivering optimal rivastigmine exposure to produce a therapeutic effect. The potential of a patch to improve the tolerability of rivastigmine (e.g., nausea and vomiting) while permitting similar exposure to the highest doses of capsules may, in turn, lead to improved efficacy and compliance.

Quik M, Bordia T, O'Leary K. · The Parkinson's Institute, Sunnyvale, CA 94089, USA. · Biochem Pharmacol. · Pubmed #17631864 links to  free full text

Abstract: Parkinson's disease is a debilitating neurodegenerative movement disorder characterized by damage to the nigrostriatal dopaminergic system. Current therapies are symptomatic only and may be accompanied by serious side effects. There is therefore a continual search for novel compounds for the treatment of Parkinson's disease symptoms, as well as to reduce or halt disease progression. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in parkinsonian animals and in Parkinson's disease. In addition, nicotine protects against nigrostriatal damage in experimental models, findings that have led to the suggestion that the reduced incidence of Parkinson's disease in smokers may be due to the nicotine in tobacco. Altogether, these observations suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Work to identify the subtypes affected in Parkinson's disease is therefore critical for the development of targeted therapies. Results show that striatal alpha6beta2-containing nAChRs are particularly susceptible to nigrostriatal damage, with a decline in receptor levels that closely parallels losses in striatal dopamine. In contrast, alpha4beta2-containing nAChRs are decreased to a much smaller extent under the same conditions. These observations suggest that development of nAChR agonists or antagonists targeted to alpha6beta2-containing nAChRs may represent a particularly relevant target for Parkinson's disease therapeutics.

Khandhar SM, Marks WJ. · Northern California Kaiser Permanente, Surgical Movement Disorders Program, San Francisco, California, USA. · Dis Mon. · Pubmed #17586326 No free full text.

This publication has no abstract.

Wu AD. · Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles (UCLA) and Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Rev Neurol Dis. · Pubmed #17514152 No free full text.

Abstract: Functional neuroimaging provides insights into the pathogenesis of motor symptoms in Parkinson's disease (PD) and improves our understanding of both established neuromodulatory therapies such as deep brain stimulation (DBS) and potential ones such as repetitive transcranial magnetic stimulation (rTMS). Functional imaging studies can reveal the consequences of the dopaminergic lesion in PD among a widespread network of subcortical-cortical regions. Characteristic patterns of normal cortical brain activation for motor tasks are systematically altered in PD. Recent work has emphasized the task dependence of these changes and their gradual evolution over the course of the disease. Clinically relevant PD treatment with medications or DBS tends to normalize these patterns. In this context, rTMS is discussed as a potential noninvasive alternative for neuromodulation of cortical function. Although rTMS is not a current treatment, we review recent rTMS studies in PD that suggest its promise, illustrate how functional imaging can guide application of rTMS, and suggest that subcortical dopamine release could be an rTMS mechanism of action. The combination of rTMS and functional neuroimaging broadens our knowledge of functional cortical networks in PD, which can eventually provide physicians with pathophysiologic information about different PD treatment options and rationales for neuromodulatory interventions.

Dodson MW, Guo M. · Department of Neurology and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. · Curr Opin Neurobiol. · Pubmed #17499497 No free full text.

Abstract: Mutations in PARKIN, PTEN-induced kinase 1 (PINK1) and DJ-1 are found in autosomal recessive forms and some sporadic cases of Parkinson's disease. Recent work on these genes underscores the central importance of mitochondrial dysfunction and oxidative stress in Parkinson's disease. In particular, pink1 and parkin loss-of-function mutants in Drosophila show similar phenotypes, and pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial function. DJ-1 has a role in oxidative stress protection, but a direct role of DJ-1 in mitochondrial function has not been fully established. Importantly, defects in mitochondrial function have also been identified in patients who carry both PINK1 and PARKIN mutations, and in those who have sporadic Parkinson's disease. Future studies of the biochemical interactions between Pink1 and Parkin, and identification of other components in this pathway, are likely to provide insight into Parkinson's disease pathogenesis, and might identify new therapeutic targets.

Liao S, Arnold RM. · University of California-Irvine, Orange, California 92868, USA. · J Palliat Med. · Pubmed #17472515 No free full text.

This publication has no abstract.

Manning-Bog AB, Langston JW. · The Parkinson's Institute, 1170 Morse Ave., Sunnyvale, CA 94089, USA. · Neurotox Res. · Pubmed #17449461 No free full text.

Abstract: Within the past 25 years, discoveries of environmental and monogenetic forms of parkinsonism have shaped the direction of Parkinson's disease (PD) research and development of experimental systems to study PD. In this review, we outline a remarkable array of in vivo models available, with particular emphasis on their benefits and pitfalls and the contribution each has made to enhance our understanding of pathological mechanisms involved in PD. Further, we discuss the increasingly popular approach of "model fusion" to create a new generation of animal systems in which to study gene-environment interactions, and the usefulness of such models in capturing the most common events underlying PD.

Tetrud JW. · Movement Disorders Center, The Parkinson's Institute, Sunnyvale, CA 94089, USA. · CNS Spectr. · Pubmed #17426665 links to  free full text

Abstract: Levodopa has played a central role in the treatment of Parkinson's disease for nearly 40 years and remains the single most effective symptomatic treatment for the disease. However, the response to levodopa therapy changes over time, and its long-term use is commonly associated with disabling motor complications. For this reason, the appropriate role of levodopa in the treatment of Parkinson's disease-in particular, the question of when to initiate therapy with the drug-has been a matter of controversy. Because levodopa is the most effective treatment for Parkinson's disease, the management of this disease becomes a matter of balancing short-term symptom control with long-term functional outcomes. This article provides an overview of the basis for levodopa-associated motor complications and their impact on patients' clinical function and quality of life, followed by a discussion of strategies for managing these complications to achieve optimum symptom control while minimizing the adverse effects of long-term therapy.

Quik M, O'Neill M, Perez XA. · The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA. · Trends Pharmacol Sci. · Pubmed #17412429 No free full text.

Abstract: Parkinson's disease is a neurodegenerative movement disorder that is characterized by a loss of nigrostriatal dopamine-containing neurons. Unexpectedly, there is a reduced incidence of Parkinson's disease in tobacco users. This finding is important because the identification of the component(s) responsible for this effect could lead to therapeutic strategies to slow down or halt the progression of Parkinson's disease. Results from cell culture models consistently show that nicotine protects against neurotoxicity. However, data from animal models of nigrostriatal damage are conflicting, thus raising questions about a neuroprotective role of nicotine. Accumulating evidence indicates that discrepancies are observed primarily in mouse models of the disease. By contrast, reproducible protection occurs in rat models and in a nonhuman primate parkinsonian model that closely resembles the human disease. These findings highlight the need to use the appropriate animal model and treatment conditions when testing putative neuroprotective agents.

Hermanowicz N. · Department of Neurology, Movement Disorders Program, University of California-Irvine 92697-4275, USA. · Semin Neurol. · Pubmed #17390254 No free full text.

Abstract: The fundamental concepts of the medical treatment of Parkinson's disease are simple, and remain based on the enhancement of dopaminergic transmission by means of levodopa and dopamine agonists. Recently published practice parameters from the American Academy of Neurology and an evidence-based review under the auspices of the Movement Disorder Society provide guidance on motor complications and also cognitive and psychiatric issues associated with Parkinson's disease. The choices of medications are increasing as are the routes of administration, with the arrival of injectable and transdermal dopamine agonists and a monoamine inhibitor absorbed via the buccal mucosa. Although simple conceptually, the actual care of patients with Parkinson's disease is often complex, requiring consideration of potential future complications and individualized medication regimens, and minimizing the adverse effects of medications that range from unpleasant to seriously disturbing.

Salmon DP, Filoteo JV. · Department of Neurosciences (0948), University of California, San Diego9500 Gilman Drive, La Jolla, CA 92093-0948, USA. · Semin Neurol. · Pubmed #17226737 No free full text.

Abstract: Neuropsychological studies have shown that there are several prominent differences in the patterns of cognitive deficits that occur in neurodegenerative disorders that have their primary etiology in either cortical or subcortical brain dysfunction. Quantitative and qualitative differences are apparent across many cognitive domains, including memory (in all its aspects), attention, executive functions, language and semantic knowledge, and visuospatial abilities. These distinct patterns of deficits have been broadly characterized as forming cortical and subcortical dementia syndromes. Differentiating between cortical and subcortical dementia provides a heuristically useful model for understanding brain-behavior relationships in neurodegenerative diseases and may improve the ability to clinically distinguish among various dementing disorders.

Greenberg DA, Jin K. · Buck Institute for Age Research, Novato, California 94945, USA. · Int Rev Neurobiol. · Pubmed #17178470 No free full text.

This publication has no abstract.

Chade AR, Kasten M, Tanner CM. · Department of Clinical Research, Parkinson's Institute, Sunnyvale, CA 94089-1605, USA. · J Neural Transm Suppl. · Pubmed #17017522 No free full text.

Abstract: Study of the nongenetic causes of Parkinson's disease (PD) was encouraged by discovery of a cluster of parkinsonism produced by neurotoxic pyridine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the 1980s. Since that time, epidemiologic investigations have suggested risk factors, though their results do not establish causality. Pesticide exposure has been associated with increased risk in many studies. Other proposed risks include rural residence and certain occupations. Cigarette smoking, use of coffee/caffeine, and non-steroidal antiinflammatory drugs (NSAIDs) all appear to lower risk of PD, while dietary lipid and milk consumption, high caloric intake, and head trauma may increase risk. The cause of PD is likely multifactorial. Underlying genetic susceptibility and combinations of risk and protective factors likely all contribute. The combined research effort by epidemiologists, geneticists, and basic scientists will be needed to clarify the cause(s) of PD.

Fink AL. · Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA. · Acc Chem Res. · Pubmed #16981679 No free full text.

Abstract: alpha-Synuclein is a small (14 kDa), abundant, intrinsically disordered presynaptic protein, whose aggregation is believed to be a critical step in Parkinson's disease (PD). The kinetics of alpha-synuclein fibrillation are consistent with a nucleation-dependent mechanism, in which the critical early stage of the structural transformation involves a partially folded intermediate. Although the basis for the toxic effects of aggregated alpha-synuclein are unknown, it has been proposed that transient oligomers are responsible, possibly by forming pores in membranes. In this Account, I discuss our investigations into the molecular basis for alpha-synuclein aggregation/fibrillation, including factors that either accelerate or inhibit fibrillation, effects of molecular crowding, oxidation, point mutations, and lipid membranes, as well as the variety of conformational and oligomeric states that alpha-synuclein can adopt. It is apparent that neuronal cells must have a very fine balance of factors that control the levels and potential aggregation of alpha-synuclein.