Parkinson Disease: New York

Gong B, Leznik E. · Taub Institute for Research on Alzheimer's disease and the Aging Brain, Department of Pathology, Columbia University, New York, New York, USA. · Drug News Perspect. · Pubmed #17925890 No free full text.

Abstract: Impairment of the ubiquitin-proteasome system (UPS) results in the failure to remove and degrade misfolded proteins and consequently causes the accumulation of misfolded proteins in the cell. The aberrant interactions between misfolded proteins and normal intracellular proteins are thought to underlie the pathogenesis in many neurodegenerative diseases. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is an important component of the UPS. Its major function is related to mono-ubiquitin recycling and thereby, sustaining protein degradation. Mutations of the UCH-L1 gene and alterations of its proteins' activity have been found to associate with several neurodegenerative disorders. In this review, we will discuss a link between UCH-L1 and Parkinson's, Huntington's and Alzheimer's diseases. We will also present a potential strategy for the treatment of Alzheimer's disease by boosting endogenous UCH-L1 activity.

Thomas B, Beal MF. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street, A-501, New York, NY 10021, USA. · Hum Mol Genet. · Pubmed #17911161 links to  free full text

Abstract: Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding alpha-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness.

Olanow CW, Watkins PB. · Department of Neurology, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA. · Clin Neuropharmacol. · Pubmed #17909307 No free full text.

Abstract: Tolcapone (Tasmar), an inhibitor of catechol-O-methyltransferase, is an effective antiparkinsonian agent when used as an adjunct to levodopa in patients with Parkinson disease who have end-of-dose motor fluctuations. In clinical trials, tolcapone significantly reduced "off" time and levodopa requirements. The drug is generally well tolerated, with the most common adverse events being dopaminergic related. However, clinical trials demonstrated dose-related increases in liver enzymes, and postmarketing surveillance noted 4 cases of acute hepatotoxicity with 3 fatalities that were attributed to tolcapone. For this reason, the drug was withdrawn from the market in some countries, and its use was severely restricted in the United States. An analysis of safety data indicates that, since the labeling restrictions in 1998, there have been more than 40,000 patient-years of tolcapone treatment worldwide, with only 3 reports of severe, but reversible, liver injury and no reports of hepatic fatality. It can be concluded that severe liver injury due to tolcapone is a rare event. Based on these data, the drug has been reintroduced to the market in several European countries, and the Food and Drug Administration in the United States has modified monitoring requirements. The new labeling recommends monitoring of liver function every 2 to 4 weeks for 6 months and at the physician's discretion thereafter. In addition, patients must be taken off the drug if blood tests show enzyme elevation of greater than twice the upper limit of normal. This article reviews the data pertaining to the safety and efficacy of tolcapone.

Eckert T, Tang C, Eidelberg D. · Center for Neurosciences, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA. · Lancet Neurol. · Pubmed #17884682 No free full text.

Abstract: BACKGROUND: Clinical research into Parkinson's disease has focused increasingly on the development of interventions that slow the neurodegeneration underlying this disorder. These investigations have stimulated interest in finding objective biomarkers that show changes in the rate of disease progression with treatment. Through radiotracer-based imaging of nigrostriatal dopaminergic function, a specific class of biomarkers to monitor the progression of Parkinson's disease has been identified, and these biomarkers were used in the clinical trials of drugs with the potential to modify the course of the disease. However, in some of these studies there was discordance between the imaging outcome measures and blinded clinical ratings of disease severity. Research is underway to identify and validate alternative ways to image brain metabolism, through which the efficacy of new therapies for Parkinson's disease and related disorders can be assessed. RECENT DEVELOPMENTS: During recent years, spatial covariance analysis has been used with (18)F-fluorodeoxyglucose PET to detect abnormal patterns of brain metabolism in patients with neurodegenerative disorders. Rapid, automated, voxel-based algorithms have been used with metabolic imaging to quantify the activity of disease-specific networks. This approach has helped to characterise the unique metabolic patterns associated with the motor and cognitive features of Parkinson's disease. The results of several studies have shown correction of abnormal motor, but not cognitive, network activity by treatment with dopaminergic therapy and deep brain stimulation. The authors of a longitudinal imaging study of early-stage Parkinson's disease reported substantial differences in the development of these metabolic networks over a follow-up of 4 years. WHERE NEXT?: Developments in network imaging have provided the basis for several new applications of metabolic imaging in the study of Parkinson's disease. A washout study is currently underway to determine the long-duration effects of dopaminergic therapy on the network activity related to Parkinson's disease, which will be useful to plan future trials of disease-modifying drugs. Network approaches are also being applied to the study of atypical parkinsonian syndromes. The characterisation of specific patterns associated with atypical parkinsonian syndromes and classic Parkinson's disease will be the basis for a fully automated imaging-based procedure for early differential diagnosis. Efforts are underway to quantify the networks related to Parkinson's disease with less invasive imaging methods. Assessments of network activity with perfusion-weighted MRI show excellent concordance with measurements done with established radiotracer techniques. This approach will ultimately enable the assessment of abnormal network activity in people who are genetically at risk of Parkinson's disease.

Perl DP, Olanow CW. · Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029-6574, USA. · J Neuropathol Exp Neurol. · Pubmed #17882011 No free full text.

Abstract: Manganese is an essential trace metal that is widely used in industry, particularly in the manufacture of steel. Exposure to high levels of manganese can cause neurotoxicity with the development of a form of parkinsonism known as manganism. It has recently been hypothesized that manganese exposure might also cause or accelerate the development of Parkinson disease (PD). This article is a review of the pathologic studies that have been reported in patients with manganism and in primates experimentally intoxicated with manganese. They demonstrate a consistent pattern characterized by damage to the globus pallidus (particularly the internal segment) with sparing of the substantia nigra pars compacta and the absence of Lewy bodies. This finding contrasts with what is seen in PD, in which there is preferential degeneration of dopamine neurons in the substantia nigra pars compacta coupled with Lewy bodies and preservation of the pallidum. These pathologic findings do not support the notion that manganese causes PD but rather argues that manganese-induced parkinsonism and PD are distinct and separate disease entities.

Levy G. · Department of Biostatistics, Columbia University, 722 W 168th St, Sixth Floor, New York, NY 10032, USA. · Arch Neurol. · Pubmed #17846263 links to  free full text

Abstract: Twentieth-century hypotheses attributing a substantive role to aging in Parkinson disease (PD) pathogenesis have been countered by evidence from clinical, pathological, and biochemical investigations. However, age influences the clinical progression of PD. Several studies have demonstrated that advancing age is associated with a faster rate of motor progression, decreased levodopa responsiveness, more severe gait and postural impairment, and more severe cognitive impairment and the development of dementia in patients with PD. A model for the relationship between PD and aging is proposed that incorporates the following 3 elements: (1) There occurs a superposition of a topographic gradient of neuronal loss in brainstem and basal forebrain structures related to the disease process and an aging-related temporal gradient. (2) While PD is a chronic progressive disorder, the most important determinant of clinical progression is advancing age rather than disease duration. (3) The effects of the disease process and aging on nondopaminergic structures involve a biologic interaction. The model implies that understanding the degenerative process in nondopaminergic structures in PD as it relates to molecular mechanisms accompanying the aging of the nervous system may create opportunities for interventions affecting the clinical progression of the disease.

Ventruti A, Cuervo AM. · Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. · Curr Neurol Neurosci Rep. · Pubmed #17764636 No free full text.

Abstract: All cellular components are subjected to continuous surveillance by intracellular quality control systems. The major players involved in this quality control are molecular chaperones, which detect the abnormal components, and proteases, which eliminate them from the cell. Malfunctioning of the cellular surveillance systems inexorably leads to cell toxicity, and often cell death, due to the accumulation of unwanted nonfunctional components inside cells. In this work, we review the contribution of the autophagic system to cellular quality control and the consequences that autophagy malfunction has on cellular function. Special emphasis is made on the recently identified role of this system in maintenance of neuronal homeostasis and in the links currently established between alterations in the autophagic system and major neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Goldman SA. · Division of Cell and Gene Therapy, Departments of Neurology and Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA. · Clin Pharmacol Ther. · Pubmed #17713467 No free full text.

Abstract: Neural stem cells, able to self-renew and give rise to both neurons and glia, line the cerebral ventricles of the adult human brain. Humans also harbor lineage-restricted neuronal progenitors in the hippocampus and glial progenitor cells in both the gray and white matter of the forebrain. These various stem and progenitor cell types may provide targets for pharmacotherapy for a variety of disorders of the central nervous system. Each resident progenitor phenotype may be mobilized and induced to differentiate in vivo by the actions of both exogenous growth factors and small molecule modulators of progenitor-selective signaling pathways. This strategy may be particularly efficacious in neurodegenerations such as Huntington's disease, in which lost neurons may be replenished through the directed induction of progenitor cells lining the ventricular wall of the affected striatum. Similarly, the mobilization of glial progenitor cells may permit the introduction of new oligodendrocytes to demyelinated regions of adult white matter. Our rapidly increasing understanding of the molecular control of progenitor cell mobilization and differentiation should provide a wealth of new opportunities for recruiting endogenous progenitors as a means of treating neurological disease.

Richard IH. · Department of Neurology, University of Rochester School of Medicine, Mt. Hope Professional Building, 1351 Mt. Hope Avenue, Suite 100, Rochester, NY 14620-3917, USA. · Curr Neurol Neurosci Rep. · Pubmed #17618535 No free full text.

Abstract: This article provides an update on depression and apathy in Parkinson's disease (PD), both of which are common but often misunderstood. The diagnosis of depression in PD can be challenging and we still do not have solid evidence on which to base our treatment decisions. Apathy is most commonly seen in the setting of dementia or depression but emerging evidence suggests that it may be a core feature of PD. There are conflicting reports about the effects of deep brain stimulation (DBS) on mood and apathy, but studies suggest that at least some patients may develop depression and apathy after the procedure. Although we are making strides toward a better understanding of depression and apathy in PD, it is clear that more research is needed about these non-motor features.

Kieburtz K, Ravina B. · University of Rochester Medical Center, Rochester, NY, USA. · Nat Clin Pract Neurol. · Pubmed #17479072 No free full text.

This publication has no abstract.

Fahn S. · Columbia University, New York, USA. · J Neural Transm Suppl. · Pubmed #17447410 No free full text.

Abstract: Levodopa is the most efficacious drug to treat the symptoms of Parkinson's disease (PD) and is widely considered the "gold standard" by which to compare other therapies, including surgical therapy. Response to levodopa is one of the criteria for the clinical diagnosis of PD. A major limiting factor in levodopa therapy is the development of motor complications, namely dyskinesias and motor fluctuations. The ELLDOPA study was designed to determine if levodopa affected the progression of PD. This double-blind randomized study showed that the subjects treated with levodopa for 40 weeks had less severe parkinsonism than the placebo treated subjects even after a 2-week washout of medications, with the highest dose group showing the greatest benefit. Thus, levodopa may actually have neuroprotective value, but the result was not conclusive of slowing disease progression, because the same result could have arisen from a very long-lasting symptomatic benefit of levodopa.

Sulzer D. · Department of Neurology, Black 309, 650 West, 168th Street, Columbia University, New York State Psychiatric Institute, New York City, NY 10032, USA. · Trends Neurosci. · Pubmed #17418429 No free full text.

Abstract: Parkinson's disease arises from genetic and possibly neurotoxic causes that produce massive cell death of the neuromelanin-containing dopaminergic neurons of the substantia nigra. Loss of these neurons is essential for the diagnostic parkinsonian features. Although many genetic mutations have been suggested as causes or risk factors for Parkinson's disease, the low penetrance of some mutations and the low disease concordance in relatives suggests that there must be interactions between multiple factors. We suggest that 'multiple hits' that combine toxic stress, for example, from dopamine oxidation or mitochondrial dysfunction, with an inhibition of a neuroprotective response, such as loss of function of parkin or stress-induced autophagic degradation, underlie selective neuronal death. We discuss the properties of substantia nigra dopamine neurons that might make them particular targets of such multiple hits.

Biglan KM, Ravina B. · Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620, USA. · Semin Neurol. · Pubmed #17390255 No free full text.

Abstract: Despite increases in our understanding of the pathophysiology and environmental and genetic influences of illness in Parkinson's disease, neuroprotection remains an elusive goal. No interventions are widely accepted as disease modifying in Parkinson's disease. Continued research identifying novel therapeutic targets is likely to result in several putative neuroprotective agents. Assimilating lessons from previous neuroprotection trials will be critical in developing future trials aimed at efficiently identifying neuroprotective treatments. Ultimately, overcoming the unique challenges of a heterogenous, slowly progressive disorder with multiple potential outcome measures will be necessary to identify treatments that have meaningful effects.

Ma Y, Eidelberg D. · Center for Neurosciences, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, New York University School of Medicine, Manhasset, NY, USA. · Mol Imaging Biol. · Pubmed #17334854 No free full text.

Abstract: Brain imaging of cerebral blood flow and glucose metabolism has been playing key roles in describing pathophysiology of Parkinson's disease (PD) and Huntington's disease (HD), respectively. Many biomarkers have been developed in recent years to investigate the abnormality in molecular substrate, track the time course of disease progression, and evaluate the efficacy of novel experimental therapeutics. A growing body of literature has emerged on neurobiology of these two movement disorders in resting states and in response to brain activation tasks. In this paper, we review the latest applications of these approaches in patients and normal volunteers at rest conditions. The discussions focus on brain mapping studies with univariate and multivariate statistical analyses on a voxel basis. In particular, we present data to validate the reproducibility and reliability of unique spatial covariance patterns related with PD and HD.

Messer A, McLear J. · Wadsworth Center, New York State Department of Health, Albany, New York 12201-2002, USA. messer@wadsworth-org · BioDrugs. · Pubmed #17176119 No free full text.

Abstract: Single-chain Fv and single-domain antibodies retain the binding specificity of full-length antibodies but they can be cloned, selected, engineered, and manipulated as genes. When expressed intracellularly in mammalian cells these intracellular antibodies, or intrabodies, have the potential to alter the folding, interactions, modifications, or subcellular localization of their targets. These reagents have previously been developed as therapeutics against cancer and HIV. Since misfolded and accumulated intracellular proteins characterize several major neurodegenerative disorders, including Huntington disease (HD) and Parkinson disease, these disorders are prime candidates for intrabody therapy. In this article we review the extension of intrabody technology to the nervous system. Studies of HD have been used to develop the approach and anti-synuclein strategies are in the early stages of development. Such neurodegenerative diseases are therefore poised for engineered antibody approaches, which can provide a pipeline of novel therapeutics and new drug discovery tools.

Duff K. · Taub Institute, Columbia University, New York State Psychiatric Institute, 650 W168th St, New York, NY 10032, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132962 No free full text.

This publication has no abstract.

Feng J. · Department of Physiology and Biophysics, State University of New York, Buffalo, NY 14214, USA. · Neuroscientist. · Pubmed #17079513 No free full text.

Abstract: Parkinson's disease (PD) is characterized by the selective loss of nigral dopaminergic (DA) neurons, which have long axons enriched with microtubules. Depolymerization of microtubules by PD toxins such as rotenone disrupts vesicular transport. The ensuing accumulation of vesicles in the cell body leads to increased cytosolic concentration of dopamine due to leakage of the vesicles. Elevated oxidative stress induced by dopamine oxidation may thus trigger the selective demise of DA neurons. Many strategies have been developed to protect DA neurons by stabilizing microtubules either directly or through intracellular signaling cascades. On the other hand, parkin, one of the most frequently mutated genes in PD, encodes for a protein-ubiquitin E3 ligase that strongly binds to microtubules. Parkin stabilizes microtubules through three domains that provide strong and independent interactions with tubulin and microtubules. These interactions anchor parkin on microtubules and may facilitate its E3 ligase activity on misfolded proteins transported along microtubules. Thus, parkin and rotenone, two prominent genetic and environmental factors linked to PD, act in an opposing manner on the same molecular target in the cell, microtubules, whose destruction underlies the selective vulnerability of dopaminergic neurons.

Leegwater-Kim J, Waters C. · Columbia University Medical Center, Department of Neurology, Division of Movement Disorders, 710 W. 168th Street, New York, NY 10032, USA. · Expert Opin Pharmacother. · Pubmed #17059382 No free full text.

Abstract: Although levodopa remains the gold standard treatment for Parkinson's disease, many patients develop motor complications with chronic levodopa exposure. Tolcapone is a catechol-O-methyltransferase inhibitor that extends the action of levodopa. When used in conjunction with levodopa, tolcapone has been shown to be effective in improving motor fluctuations and reducing levodopa requirements in Parkinson's disease patients. However, rare reports of severe hepatotoxicity have limited its use. A recent review of the data on tolcapone-treated patients suggests that, with proper monitoring of liver function, the potential for hepatotoxicity with tolcapone use is negligibly small.

Szeto HH. · Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA. · AAPS J. · Pubmed #17025271 links to  free full text

Abstract: Increasing evidence suggests that mitochondrial dysfunction and oxidative stress play a crucial role in the majority of neurodegenerative diseases. Mitochondria are a major source of intracellular reactive oxygen species (ROS) and are particularly vulnerable to oxidative stress. Oxidative damage to mitochondria has been shown to impair mitochondrial function and lead to cell death via apoptosis and necrosis. Because dysfunctional mitochondria will produce more ROS, a feed-forward loop is set up whereby ROS-mediated oxidative damage to mitochondria favors more ROS generation, resulting in a vicious cycle. It is now appreciated that reduction of mitochondrial oxidative stress may prevent or slow down the progression of these neurodegenerative disorders. However, if mitochondria are the major source of intracellular ROS and mitochondria are most vulnerable to oxidative damage, then it would be ideal to deliver the antioxidant therapy to mitochondria. This review will summarize the development of a novel class of mitochondria-targeted antioxidants that can protect mitochondria against oxidative stress and prevent neuronal cell death in animal models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis.

Garruto RM. · Laboratory of Biomedical Anthropology and Neurosciences, State University of New York at Binghamton, Binghamton, New York 13902-6000, USA. · Curr Alzheimer Res. · Pubmed #17017870 No free full text.

Abstract: The Twentieth Century witnessed tremendous advances in our understanding of neurodegenerative diseases. Not least among them were the contributions from hyperendemic foci of neurodegenerative disorders in isolated human groups worldwide, with the knowledge gained applicable to our understanding of related neurodegenerative diseases globally.

Kaufmann H. · Mount Sinai School of Medicine, New York, NY 10029, USA. · J Neural Transm Suppl. · Pubmed #17017570 No free full text.

Abstract: In the 1950s it was found that an artificial aminoacid, 3,4-threo-dihydroxyphenylserine (DOPS), was converted to norepinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxylase (AADC), bypassing the need for the rate limiting enzyme dopamine beta hydroxylase. Trying to replicate the success of dihydroxyphenylalanine (DOPA) in the treatment of Parkinson disease, treatment with DOPS was attempted in patients with autonomic failure who have impaired NE release. DOPS improved orthostatic hypotension in patients with familial amyloid polyneuropathy, congenital deficiency of dopamine beta hydroxylase, pure autonomic failure and multiple system atrophy. DOPS pressor effect is due to its conversion to NE outside the central nervous system because concomitant administration of carbidopa, an inhibitor of AADC that does not cross the blood-brain barrier, blunted both the increase in plasma NE and the pressor response. DOPS pressor response is not dependent on intact sympathetic terminals because its conversion to NE also occurs in non-neuronal tissues.

Fahn S. · Department of Neurology, Columbia University, New York, NY, USA. · J Neural Transm Suppl. · Pubmed #17017562 No free full text.

Abstract: Levodopa has been the gold standard for Parkinson's disease (PD) therapy since it was successfully introduced in 1967. But in the years since then, after recognizing that levodopa often leads to the motor complications of wearing-off and dyskinesias, there have been debates among clinicians as to when levodopa therapy should be started. Delaying therapy was advocated for the purpose of delaying the development of these motor complications. This became more popular as the dopamine agonists became available. Although less potent than levodopa in ameliorating the symptoms of PD, they were much less likely to produce the unwanted motor complications, even though they had their own adverse effects. When it was recognized that dopamine, itself, might be a factor leading to the death of dopaminergic neurons through its contributing to the formation of oxyradicals, a new concern arose, namely that levodopa, through its conversion to brain dopamine, might add to the existing oxidative stress and possibly enhance neurodegeneration of dopaminergic neurons. Though widely debated and without definite evidence, this possibility was sufficient to make some clinicians have further reason to delay the start of levodopa therapy. The ELLDOPA study was created to test this hypothesis. The clinical component of the study failed to find an enhancement of PD symptoms after levodopa was withdrawn following 40 weeks of levodopa therapy. Rather, the clinical results indicated that the symptoms had progressed much less than placebo, and in a dose-response manner. This suggests that levodopa may actually have neuroprotective properties. The uncertainty that a 2-week withdrawal of levodopa may not have entirely eliminated its symptomatic benefit and the discordant results of the neuroimaging component of the ELLDOPA study have created even more uncertainty that levodopa is neuroprotective. A survey of neurologists who treat PD patients showed that the vast majority of these clinicians do not believe levodopa is neuroprotective, and they remain concerned about the drug's likelihood of inducing motor complications. Thus, the ELLDOPA study failed to change the treating pattern of PD, and the clinicians require more convincing evidence of either neuroprotection or neurotoxicity of levodopa before they would alter their treatment approach.

Bodis-Wollner I, Jo MY. · Department of Neurology, SUNY Downstate Medical Center, Brooklyn, NY, USA. · J Neural Transm Suppl. · Pubmed #17017549 No free full text.

Abstract: Vision in PD. In PD an impairment of dopaminergic neurons of the preganglionic retina and a defect of the retinal nerve fibers (axons of the retinal ganglion cells) has been demonstrated and a correlation of loss of spatial contrast sensitivity, with the progression of motor impairment in PD has been described. These low level visual deficits contribute but do not directly explain behavioural visual deficits in PD involving spatial cognition, internal representation, space navigation and visual categorization. Language deficits in non-demented PD patients can include impairments in comprehension, verbal fluency, and naming. Comprehension deficits become evident when patients are required to process sentences with non-canonical, irregular grammatical structures. Semantic memory deficits may result in the impairments in category fluency and confrontational naming. Selective language deficits may be due to impaired dynamics of the "phonological loop" connecting the pre-frontal cortex and the basal ganglia. A more encompassing linguistic and functional model of PD specific language impairments would be useful for evaluating language deficits in the context of motor dysfunction.

Costa e Silva JA. · The International Center for Mental Health Policy and Research, New York University-School of Medicine, New York NY, USA. · Metabolism. · Pubmed #16979426 No free full text.

Abstract: Sleep is an active state that is critical for our physical, mental, and emotional well-being. Sleep is also important for optimal cognitive functioning, and sleep disruption results in functional impairment. Insomnia is the most common sleep disorder in psychiatry. At any given time, 50% of adults are affected with 1 or more sleep problems such as difficulty in falling or staying asleep, in staying awake, or in adhering to a consistent sleep/wake schedule. Narcolepsy affects as many individuals as does multiple sclerosis or Parkinson disease. Sleep problems are especially prevalent in schizophrenia, depression, and other mental illnesses, and every year, sleep disorders, sleep deprivation, and sleepiness add billions to the national health care bill in industrialized countries. Although psychiatrists often treat patients with insomnia secondary to depression, most patients discuss their insomnia with general care physicians, making it important to provide this group with clear guidelines for the diagnosis and management of insomnia. Once the specific medical, behavioral, or psychiatric causes of the sleep problem have been identified, appropriate treatment can be undertaken. Chronic insomnia has multiple causes arising from medical disorders, psychiatric disorders, primary sleep disorders, circadian rhythm disorders, social or therapeutic use of drugs, or maladaptive behaviors. The emerging concepts of sleep neurophysiology are consistent with the cholinergic-aminergic imbalance hypothesis of mood disorders, which proposes that depression is associated with an increased ratio of central cholinergic to aminergic neurotransmission. The characteristic sleep abnormalities of depression may reflect a relative predominance of cholinergic activity. Antidepressant medications presumably reduce rapid eye movement (REM) sleep either by their anticholinergic properties or by enhancing aminergic neurotransmission. Intense and prolonged dreams often accompany abrupt withdrawal from antidepressant drugs, a reflection of an REM rebound after drug-induced REM deprivation. The postulated link between sleep and psychiatric disorders has been reinforced by the findings of modern neurobiology.

Olanow CW, McNaught KS. · Department of Neurology, Mount Sinai School of Medicine, New York, New York10029, USA. · Mov Disord. · Pubmed #16972273 No free full text.

Abstract: Increasing genetic, pathological, and experimental evidence suggest that neurodegeneration in both familial and sporadic forms of Parkinson's disease (PD) may be related to a defect in the capacity of the ubiquitin-proteasome system (UPS) to clear unwanted proteins, resulting in protein accumulation, aggregation, and cytotoxicity. This concept is supported by in vitro and in vivo laboratory experiments which show that inhibition of UPS function can cause neurodegeneration coupled with the formation of Lewy body-like inclusions. This hypothesis could account for the presence of protein aggregates and Lewy bodies in PD, the other biochemical features seen in the disorder, and the age-related vulnerability of the substantia nigra pars compacta. It also suggests novel targets for putative neuroprotective therapies for PD.