Parkinson Disease: Georgia

Morgan JC, Sethi KD. · Medical College of Georgia, Movement Disorders Program, Department of Neurology, 1429 Harper Street, HF-1121, Augusta, GA 30912, USA. · Expert Opin Emerg Drugs. · Pubmed #16939381 No free full text.

Abstract: Parkinson's disease (PD) afflicts millions of people worldwide. There are numerous drugs available for PD; however, levodopa remains the gold standard of pharmacotherapy to which all other therapies are compared. Levodopa is quite effective for many motor symptoms (bradykinesia, tremor, rigidity) of PD; however, non-levodopa-responsive motor symptoms (postural instability) and nonmotor symptoms are frequently the most troublesome in middle and later stages of disease. Although motor symptoms remain an important focus for emerging drugs, current research is largely geared to identify and develop disease-slowing therapies. Another important area of focus has become treatment of the nonmotor symptoms of PD (especially depression and dementia). This review discusses emerging drugs in the management of the motor and nonmotor symptoms of PD and drugs under study as disease-slowing/neuroprotective agents.

Cáceda R, Kinkead B, Nemeroff CB. · Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Suite 4000 WMRB, 101 Woodruff Circle, Atlanta, GA 30322 4990, USA. · Peptides. · Pubmed #16891042 No free full text.

Abstract: Neurotensin (NT), an endogenous brain-gut peptide, has a close anatomical and functional relationship with the mesocorticolimbic and neostriatal dopamine system. Dysregulation of NT neurotransmission in this system has been hypothesized to be involved in the pathogenesis of schizophrenia. Additionally, NT containing circuits have been demonstrated to mediate some of the mechanisms of action of antipsychotic drugs, as well as the rewarding and/or sensitizing properties of drugs of abuse. NT receptors have been suggested to be novel targets for the treatment of psychoses or drug addiction.

Gatev P, Darbin O, Wichmann T. · Yerkes National Primate Center, Emory University, Atlanta, Georgia 30322, USA. · Mov Disord. · Pubmed #16830313 No free full text.

Abstract: A substantial body of work within the last decade has demonstrated that there is a variety of oscillatory phenomena that occur in the basal ganglia and in associated regions of the thalamus and cortex. Most of the earlier studies focused on recordings in rodents and primates. More recently, significant advances have been made in this field of research through the analysis of basal ganglia field potentials recorded from implanted deep brain stimulation electrodes in the basal ganglia of human patients with Parkinson's disease and other disorders. It now appears that oscillatory activity may play a significant role in the pathogenesis of these diseases. The most significant finding is that in Parkinson's disease synchronized oscillatory activity in the 10- to 35-Hz band (often termed "beta-band") is prevalent in the basal ganglia-thalamocortical circuits, and that such activity can be reduced by dopaminergic treatments. The entrainment of large portions of these circuits may disrupt information processing in them and may lead to parkinsonian akinesia (and perhaps tremor). Although less firmly established than the role of oscillations in movement disorders, oscillatory activities at higher frequencies may also be a component of normal basal ganglia physiology.

Gross RE, Krack P, Rodriguez-Oroz MC, Rezai AR, Benabid AL. · Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA. · Mov Disord. · Pubmed #16810720 No free full text.

Abstract: The vast majority of centers use electrophysiological mapping techniques to finalize target selection during the implantation of deep brain stimulation (DBS) leads for the treatment of Parkinson's disease and tremor. This review discusses the techniques used for physiological mapping and addresses the questions of how various mapping strategies modify target selection and outcome following subthalamic nucleus (STN), globus pallidus internus (GPi), and ventralis intermedius (Vim) deep brain stimulation. Mapping strategies vary greatly across centers, but can be broadly categorized into those that use microelectrode or semimicroelectrode techniques to optimize position prior to implantation and macrostimulation through a macroelectrode or the DBS lead, and those that rely solely on macrostimulation and its threshold for clinical effects (benefits and side effects). Microelectrode criteria for implantation into the STN or GPi include length of the nucleus recorded, presence of movement-responsive neurons, and/or distance from the borders with adjacent structures. However, the threshold for the production of clinical benefits relative to side effects is, in most centers, the final, and sometimes only, determinant of DBS electrode position. Macrostimulation techniques for mapping, the utility of microelectrode mapping is reflected in its modification of electrode position in 17% to 87% of patients undergoing STN DBS, with average target adjustments of 1 to 4 mm. Nevertheless, with the absence of class I data, and in consideration of the large number of variables that impact clinical outcome, it is not possible to conclude that one technique is superior to the other in so far as motor Unified Parkinson's Disease Rating Scale outcome is concerned. Moreover, mapping technique is only one out of many variables that determine the outcome. The increase in surgical risk of intracranial hemorrhage correlated to the number of microelectrode trajectories must be considered against the risk of suboptimal benefits related to omission of this technique.

Greene JG. · Emory University School of Medicine, 505 Whitehead Biomedical Research Building, 615 Michael Street, Atlanta, GA 30322, USA. · J Physiol. · Pubmed #16740610 links to  free full text

Abstract: Dysfunction of dopamine neurons has been implicated in several neuropsychiatric disorders, including Parkinson's disease, addiction, bipolar disorder and depression. Recent elucidation of gene expression profiles in dopamine neuron subpopulations has shed light on the function of different groups of dopamine neurons in the CNS and on their dysfunction in disease states. In particular, concerted differences in gene expression appear to underlie the unique properties of distinct dopamine neurons. Specifically, dopamine neurons in the substantia nigra (SN), which are prone to degenerate in Parkinson's disease, express high levels of transcripts related to energy metabolism, mitochondria and phosphate signalling pathways. In contrast, ventral tegmental area (VTA) dopamine neurons prominently express genes related to synaptic plasticity and neuropeptides, suggesting intriguing mechanisms for the involvement of VTA dysfunction in addiction and mood disorders. As new functions of dopaminergic neurotransmission become clearer, continued exploration of the transcriptional neuroanatomy of these unique neurons will be vital for producing targeted, selective, and effective therapeutic agents.

Rye DB. · Department of Neurology, Emory University School of Medicine, 101 Woodruff Circle, WMRB-Suite 6000, PO Drawer V, Atlanta, GA 30322, USA. · Curr Neurol Neurosci Rep. · Pubmed #16522272 No free full text.

Abstract: Patients with Parkinson's disease and parkinsonian syndromes (eg, dementia with Lewy body disease, multisystem atrophy, and Shy-Drager syndrome) suffer from daytime sleepiness. This sleepiness is common and very real, often approaching levels observed in the prototypical disorder of sudden-onset sleep, namely narcolepsy/cataplexy. Physicians need to be vigilant in assessing parkinsonian patients for sleepiness because treatment can dramatically enhance quality of life and prevent the significant morbidity and mortality that attends daytime sleepiness. Male patients with advanced disease, cognitive impairment, drug-induced psychosis, and orthostatic hypotension are most at risk for developing pathologic sleepiness. Because primary sleep disorders can coexist with parkinsonism (eg, sleep apnea, insufficient or interrupted sleep), these potential causes should be carefully assessed with polysomnography and treated appropriately. Dopaminomimetics exacerbate sleepiness in a small subset of patients in a dose-dependent fashion. Nonetheless, the primary pathologies involved in parkinsonism appear to be the greatest contributors to daytime sleepiness. Sleepiness in parkinsonism, especially a narcolepsy-like phenotype, may necessitate treatment with wake-promoting agents such as bupropion, modafinil, or traditional psychostimulants.

Lauterbach EC. · Division of Adult and Geriatric Psychiatry, Mercer University School of Medicine, Macon, GA 31201, USA. · Minerva Med. · Pubmed #16175159 No free full text.

Abstract: The neuropsychiatry of Parkinson's disease (PD) and its correlates are reviewed. Dementia occurs in up to 30% and can be treated with cholinesterase inhibitors. Cognitive impairments involve executive, visuospatial, attentional, and memory dysfunctions. Apathy may respond to dopamine agonists or cholines-terase inhibitors. Cognitive impairment, psychosis, and depression predict quality of life. Visual hallucinations and paranoia are common, and respond to low dose clozapine. Depression is common and predicts caregiver burden and depression. The best data suggest the efficacy of nortriptyline and the safety of SSRIs. Anxiety disorders occur in 40% of patients, especially off-period panic attacks and specific phobias. Bromazepam has proven useful for anxiety in PD, but buspirone has only diminished drug-induced dyskinesias to date. Sleep disorders occur in up to 94% of patients. Insomnia is common and is treated by dopaminergic agent dose reduction, nocturnal dosing, treatment of depression, or use of short half-lived hypnotics, depending on etiology. Parasomnias include REM behavior disorder and vivid dreams and nightmares. Excessive daytime somnolence occurs in at least 15% of patients. Sleep attacks are common and patients should be warned about driving when taking dopamine agonists. Sexual disorders occur in most patients. Paraphilias are associated with dopamine agonists, and clozapine may be useful in their treatment. Surgical therapies are associated with a wide variety of neuropsychiatric features, and vigilance for suicide attempts with subthalamic nucleus stimulation seems warranted. Neuropsychiatric disorders are important determinants of quality of life and caregiver burden in PD. More clinical research is needed to establish effective treatments.

Betarbet R, Sherer TB, Greenamyre JT. · Center for Neurodegenerative Disease, Department of Neurology, Emory University, Atlanta, GA 30322, USA. · Exp Neurol. · Pubmed #15629758 No free full text.

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by nigrostriatal dopaminergic degeneration and development of cytoplasmic inclusions known as Lewy bodies. To date, the mechanisms involved in PD pathogenesis are not clearly understood. Clues from genetic studies including identification of mutations in genes for alpha-synuclein, parkin, and ubiquitin carboxy hydrolase L1 associated with familial PD and the presence of proteinaceous cytoplasmic inclusions in spared dopaminergic nigral neurons in sporadic cases of PD have suggested an important role for ubiquitin-proteasome system (UPS) and aberrant protein degradation. In vivo and in vitro studies have linked parkin, alpha-synuclein, and oxidative stress to a compromised UPS and PD pathogenesis suggesting novel therapeutic targets.

Lauterbach EC. · Division of Adult and Geriatric Psychiatry, Mercer University School of Medicine, 655 First Street, Macon, GA 31201, USA. · Psychiatr Clin North Am. · Pubmed #15550293 No free full text.

Abstract: Parkinson's disease is associated with classical Parkinsonian features that respond to dopaminergic therapy. Neuropsychiatric sequelae include dementia, major depression, dysthymia, anxiety disorders, sleep disorders, and sexual disorders. Panic attacks are particularly common. With treatment, visual hallucinations, paranoid delusions, mania, or delirium may evolve. Psychosis is a key factor in nursing home placement, and depression is the most significant predictor of quality of life. Clozapine may be the safest treatment for psychotic features, but more research is needed to establish the efficacy of antidepressant treatments. Dementia with Lewy bodies, the second most common dementia in the elderly, may present in association with systematized delusions, depression, or RBD. Early evidence suggests the utility of rivastigmine, donepezil, low-dose olanzapine, and quetiapine in treating DLB. Parkinson-plus syndromes generally lack a good response to dopaminergic treatment and evidence additional features, including dysautonomia, cerebellar and pontine features, eye signs, and other movement disorders. MSA is associated with dysautonomia and RBD. SND (MSA-P) is associated with frontal cognitive impairments, but dementia, psychosis, and mood disorders have not been strikingly apparent unless additional pathological findings are present. In SDS (MSA-A), impotence is almost ubiquitous; urinary incontinence is frequent; depression is occasional, and sleep apnea should be treated to avoid sudden death during sleep. OPCA neuropsychiatric correlates await further definition. Progressive supranuclear palsy neuropsychiatric features include apathy, subcortical dementia, pathological emotionality, mild depression and anxiety, and lack of appreciable response to donepezil. CBD usually is recognized by early frontal dementia with ideomotor apraxia, often in the right upper extremity, attended later by poorly responsive unilateral Parkinsonism, with additional signs including cortical reflex myoclonus, limb dystonia, alien limb, oculomotor apraxia when asked to look horizontally, depression, personality changes, and, occasionally, Kluver-Bucy syndrome. The neuropsychiatry of FTDP-17 involves apraxia, executive impairment, personality changes, hyperorality, and occasional psychosis. Future research in these Parkinsonian disorders should target the characterization of neuropsychiatric sequelae and their treatment.

Rye DB. · Department of Neurology, Emory Healthcare Program in Sleep Medicine, Emory University School of Medicine, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA. · Neurology. · Pubmed #15505137 No free full text.

Abstract: In Parkinson's disease (PD), waking is frequently punctuated by sleep episodes, including rapid eye movement (REM) (i.e., dream) sleep, and sleep is interrupted by motor activities such as periodic limb movements and REM sleep behavior disorder. Because these pathologic behaviors are unaccounted for by contemporary models, this review summarizes the complex effects of dopamine (DA) on normal and pathological waking-sleeping. Maintenance of wakefulness is probably promoted by mesocorticolimbic DA circuits, and suppression of nocturnal movement appears to be influenced by indirect pathways linking midbrain DA neurons with pre-motor structures in the mesopontine tegmentum and ventromedial medulla. A diencephalospinal DA system may have an additional important role in mediating state-specific sensorimotor activity that is relevant to periodic limb movements and restless legs syndrome.

Borlongan CV, Wang Y, Su TP. · Department of Neurology and Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta GA 30912-3200, USA. · Front Biosci. · Pubmed #15353366 No free full text.

Abstract: Hibernation is a potential protective strategy for the peripheral, as well as for the central nervous system. A protein factor termed hibernation induction trigger (HIT) was found to induce hibernation in summer-active ground squirrels. Purification of HIT yielded an 88-kD peptide that is enriched in winter hibernators. Partial sequence of the 88-kD protein indicates that it may be related to the inhibitor of metalloproteinase. Using opioid receptor antagonists to elucidate the mechanisms of HIT, it was found that HIT targeted the delta opioid receptors. Indeed, delta opioid (D-Ala 2, D-Leu 5) enkephalin (DADLE) was shown to induce hibernation. Specifically, HIT and DADLE were found to prolong survival of peripheral organs, such as the lung, the heart, liver, and kidney preserved en bloc or as a single preparation. In addition, DADLE has been recently demonstrated to promote survival of neurons in the central nervous system. Exposure to DADLE dose-dependently enhanced cell viability of cultured primary rat fetal dopaminergic cells. Subsequent transplantation of these DADLE-treated dopaminergic cells into the Parkinsonian rat brain resulted in a two-fold increase in surviving grafted cells. Interestingly, delivery of DADLE alone protected against dopaminergic depletion in a rodent model of Parkinson s disease. Similarly, DADLE blocked and reversed the dopaminergic terminal damage induced by methamphetamine (METH). Such neuroprotective effects of DADLE against METH neurotoxicity was accompanied by attenuation of mRNA expressions of a tumor necrosis factor p53 and an immediate early gene c-fos. In parallel to these beneficial effects of DADLE on the dopaminergic system, DADLE also ameliorated the neuronal damage induced by ischemia-reperfusion following a transient middle cerebral artery occlusion. In vitro replication of this ischemia cell death by serum-deprivation of PC12 cells revealed that DADLE exerted neuroprotection in a naltrexone-sensitive manner. These results taken together suggest that DADLE stands as a novel therapeutic agent. In this review paper, we present laboratory evidence supporting the use of DADLE for protection of peripheral and central nervous system.

Rye DB. · Program in Sleep Medicine, Emory University School of Medicine WMRB-101 Woodruff Circle-Suite 6000, Atlanta, GA 30322, USA. · Sleep Med. · Pubmed #15165542 No free full text.

Abstract: Dopamine is a neurotransmitter that modulates diverse waking behaviors including movement, motivation, cognition, reward, and feeding. Interest in dopamine's additional contributions to normal and pathologic sleep-wake states has experienced a recent rebirth originating from two clinical disorders: Parkinson's disease and Restless Legs Syndrome. The former, the prototypical disorder of brain dopamine cell loss, is accompanied by marked sleep disruption and impairments in daytime alertness. The latter is exquisitively responsive to pharmacologic agents that act upon dopamine receptors. The potential neurobiological substrates underlying these observations are reviewed here. Converging lines of evidence suggest that mesocorticolimbic dopamine circuits are involved in promoting wakefulness, while a less studied diencephalospinal dopamine system might underly the sensorimotor dysfunction of Restless Legs Syndrome.

Watts RL, Raiser CD, Stover NP, Cornfeldt ML, Schweikert AW, Allen RC, Subramanian T, Doudet D, Honey CR, Bakay RA. · Department of Neurology, Emory University, Atlanta, GA, USA. · J Neural Transm Suppl. · Pubmed #12946059 No free full text.

Abstract: Human retinal pigment epithelial (hRPE) cells are dopaminergic support cells in the neural retina. Stereotaxic intrastriatal implantation of hRPE cells attached to gelatin microcarriers (Spheramine) in rodent and non-human primate models of Parkinson's disease (PD) produces long term amelioration of motor and behavioral deficits, with histological and PET evidence of cell survival without immunosuppression. Long-term safety in cynomologous monkeys has also been demonstrated. Six H&Y stage III/IV PD patients were enrolled in a one-year, open-label, single center study to evaluate the safety and efficacy of Spheramine (approximately 325,000 cells) implanted in the most affected post-commissural putamen. All patients tolerated the implantation of Spheramine well and demonstrated improvement. At 6, 9, and 12 months post-operatively, the mean UPDRS-Motor score "off", the primary outcome measure, improved 33%, (n = 6), 42% (n = 6), and 48% (n = 3), respectively. No "off-state" dyskinesias have been observed. Based on these preliminary results, Spheramine appears to show promise in treating late stage PD patients.

McDonald WM, Richard IH, DeLong MR. · Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA. · Biol Psychiatry. · Pubmed #12893111 No free full text.

Abstract: Parkinson's disease (PD) is primarily a disease of elderly individuals with a peak age at onset of 55 to 66 years. It is characterized by bradykinesia, rigidity, tremor, and postural instability; and affects approximately 1 million individuals in the US and is the second most common neurodegenerative disease next to Alzheimer's disease. The motor symptoms of PD are the focus of pharmacotherapy, yet the nonmotor symptoms (e.g., dementia, psychosis, anxiety, insomnia, autonomic dysfunction, and mood disturbances) can be the most disturbing, disabling, and misunderstood aspects of the disease. Depressive symptoms occur in approximately half of PD patients and are a significant cause of functional impairment for PD patients. There is accumulating evidence suggesting that depression in PD is secondary to the underlying neuroanatomical degeneration, rather than simply a reaction to the psychosocial stress and disability. The incidence of depression is correlated with changes in central serotonergic function and neurodegeneration of specific cortical and subcortical pathways. Understanding comorbid depression in PD may therefore add to the understanding of the neuroanatomical basis of melancholia.

Sethi KD. · Medical College of Georgia, Augusta, GA 30912, USA. · Curr Opin Neurol. · Pubmed #12869807 No free full text.

Abstract: PURPOSE OF REVIEW: Tremors can be encountered in a variety of disease states but the most common causes are Parkinson disease and essential tremor. This review was undertaken to highlight advances in the field during the last 12 months. RECENT FINDINGS: Kinetic tremor may be more prominent in essential tremor than postural tremor. Clinically Parkinson disease and essential tremor may be confused with each other but it may be possible to distinguish between these two nitrites using sophisticated electrophysiology. Monosymptomatic rest tremor has recently been shown to be associated with decreased fluorodopa uptake on the positron emission tomography scan suggesting its relationship to Parkinson disease. SUMMARY: Significant advances have been made in the understanding of the pathophysiology, genetics and therapy of tremor disorders during the last 12 months. This review will consider Parkinson disease, essential tremor and other tremors and highlight advances in the field.

Wichmann T, DeLong MR. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. · Ann N Y Acad Sci. · Pubmed #12846988 No free full text.

Abstract: The striatum is viewed as the principal input structure of the basal ganglia, while the internal pallidal segment (GPi) and the substantia nigra pars reticulata (SNr) are output structures. Input and output structures are linked via a monosynaptic "direct" pathway and a polysynaptic "indirect" pathway involving the external pallidal segment (GPe) and the subthalamic nucleus (STN). According to current schemes, striatal dopamine (DA) enhances transmission along the direct pathway (via D1 receptors), and reduces transmission over the indirect pathway (via D2 receptors). DA also acts on receptors in GPe, GPi, SNr, and STN. Electrophysiologic and other studies in primates rendered parkinsonian by treatment with the dopaminergic neurotoxin MPTP have demonstrated a reduction of neuronal activity of GPe and an increase of neuronal discharge in STN, GPi. and SNr. These findings are compatible with the view that striatal DA loss results in increased activity over the indirect pathway. Prominent bursting, oscillatory discharge patterns, and increased synchronization of neighboring neurons are found throughout the basal ganglia. These may result from changes in the activity of local circuits (e.g., the GPe-STN "pacemaker") or from more global abnormalities of the basal ganglia-thalamocortical network. These findings have been replicated in human patients undergoing microelectrode-guided stereotactic procedures targeted at GPi or STN. PET studies in patients with Parkinson's disease have lent further support to the proposed circuit abnormalities. The current models of basal ganglia function have recently been criticized. For instance, the strict separation of direct and indirect pathways and the segregation of D1 and D2 receptors have been questioned, and the almost complete absence of motor side effects of pallidal or thalamic lesions in human patients and animals is inconsistent. These results suggest that changes in discharge patterns and synchronization between basal ganglia neurons, abnormal network interactions, and compensatory mechanisms are at least as important in the pathophysiology of parkinsonism as changes in discharge rates in individual basal ganglia nuclei. Lesions of GPi or STN are effective in treating parkinsonism, because they reduce or abolish abnormal basal ganglia output, enabling remaining circuits to function more normally.

Sherer TB, Betarbet R, Greenamyre JT. · Department of Neurology, Emory University, Atlanta, GA 30322, USA. · ScientificWorldJournal. · Pubmed #12805673 No free full text.

Abstract: Parkinson's disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear.

Abosch A, Lozano A. · Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA. · Can J Neurol Sci. · Pubmed #12691480 No free full text.

Abstract: Stereotactic neurosurgery for the treatment of movement disorders focuses primarily on the treatment of Parkinson's disease (PD), essential tremor (ET), and dystonia. The surgical targets in use are the subthalamic nucleus (STN) and the globus pallidus internus (GPi) for PD, GPi for dystonia, and ventralis intermedius (Vim) nucleus of the thalamus for ET. Following target selection, procedures include the generation of lesions or the placement of deep brain stimulating electrodes in the selected target. Additionally, transplantation has been used in the treatment of PD. The indications, outcomes, and risks of the various procedures are reviewed.

Vitek JL. · Department of Neurology, Emory University School of Medicine, Atlanta, Ga 30322, USA. · Stereotact Funct Neurosurg. · Pubmed #12652037 No free full text.

Abstract: Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) is increasingly being used for the treatment of advanced Parkinson's disease (PD). Although both targets have demonstrated clinical efficacy in the treatment of the cardinal motor signs of PD, the STN has gained greater popularity and is now considered the site of choice by most centers performing these procedures. This preference stems predominately from the belief that STN DBS provides greater improvement in reducing the motor manifestations of PD and allows a reduction in dopaminergic medication not permitted with GPi DBS. There are, however, a number of issues that must be considered before abandoning GPi in favor of STN as the surgical target of choice for DBS. The maximal benefit reported for GPi stimulation is not significantly different than that reported for the STN, 67 versus 71%, and while reductions in medication are required with STN stimulation to avoid inducing dyskinesia, GPi stimulation may directly suppress dyskinesia obviating any need to reduce medication. As such, many centers may not attempt to reduce antiparkinsonian medication with GPi DBS. In addition, there are significantly more reports of changes in mood, behavior and a higher incidence of adverse events reported for STN stimulation. Most studies of DBS are nonrandomized, assessment protocols are not standardized, and lead locations are not reported. Thus, before drawing conclusions regarding the optimal site for DBS for advanced PD we must take a critical eye to the present data and address the outstanding questions that remain with well-designed clinical trials that evaluate motor, nonmotor and adverse events and address the above clinical variables by randomizing patients, using standardized methods of assessment and defining the lead location.

Wichmann T, DeLong MR. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Adv Neurol. · Pubmed #12442660 No free full text.

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Betarbet R, Sherer TB, Di Monte DA, Greenamyre JT. · Center for Neurodegenerative Disease and Department of Neurology, Emory University, Atlanta, GA 30322, USA. · Brain Pathol. · Pubmed #12408237 No free full text.

Abstract: Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms responsible for PD are not completely understood, many clues have come from biochemical, epidemiological, and genetic studies. Mutations in certain genes found in rare, familial cases of PD, such as alpha-synuclein and parkin, suggest a role for the ubiquitin-proteosome system and aberrant protein aggregation. Biochemical analyses have implicated mitochondrial dysfunction in PD. Epidemiological and animal model studies point to a role for environmental toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction, resulting from either genetic defects, environmental exposures or an interaction between the two, may cause alpha-synuclein aggregation or neurodegeneration through oxidative stress or excitotoxicity. A better understanding of the mechanisms underlying PD should reveal novel therapeutic targets.

Dhandapani KM, Brann DW. · Institute of Molecular Medicine and Genetics, Program in Neurobiology, and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912, USA. · Biol Reprod. · Pubmed #12390866 links to  free full text

Abstract: Within the last few years, there has been a growing interest in the neuroprotective effects of estrogen and the possible beneficial effects of estrogen in neurodegenerative diseases such as stroke, Alzheimer disease, and Parkinson disease. Here, we review the progress in this field, with a particular focus upon estrogen-induced protection from stroke-induced ischemic damage. The important issue of whether clinically relevant selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene and estrogen replacement therapy can exert neuroprotection is also addressed. Although the mechanism of estrogen and SERM neuroprotection is not clearly resolved, we summarize the leading possibilities, including 1) a genomic estrogen receptor-mediated pathway that involves gene transcription, 2) a nongenomic signaling pathway involving activation of cell signalers such as mitogen-activated protein kinases and/or phosphatidylinositol-3-kinase /protein kinase B, and 3) a nonreceptor antioxidant free-radical scavenging pathway that is primarily observed with pharmacological doses of estrogen. The role of other potential mediatory factors such as growth factors and the possibility of an astrocyte role in neuroprotection is also discussed.

Marino MJ, Awad H, Poisik O, Wittmann M, Conn PJ. · Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA. · Amino Acids. · Pubmed #12373536 No free full text.

Abstract: Our current understanding of the circuitry of the basal ganglia, and the pathophysiology of Parkinson's disease has led to major breakthroughs in the treatment of this debilitating movement disorder. Unfortunately, there are significant problems with the currently available pharmacological therapies that focus on dopamine replacement or dopaminergic agonists. Because of this, much effort has been focused on developing novel targets for the treatment of Parkinson's disease. The metabotropic glutamate receptors are a family of G-protein coupled receptors activated by glutamate. These receptors are differentially distributed throughout the basal ganglia in a manner suggesting that they may provide novel targets for the treatment of movement disorders. In this review we summarize anatomical and physiological data from our work and the work of other laboratories describing the distribution and physiological roles of metabotropic glutamate receptors in the basal ganglia with emphasis on possible therapeutic targets.

Sethi KD. · Department of Neurology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. · Curr Opin Neurol. · Pubmed #12151843 No free full text.

Abstract: Parkinson disease is a slowly progressive neurodegenerative disorder with a varied clinical picture and a variable rate of progression. Recently, there have been some studies conducted to assess the diagnostic accuracy and other clinical aspects of the disease. In the absence of a biomarker the clinical diagnosis is imprecise. This leads to a significant number of misdiagnoses, especially in early disease. Assessment of the clinical features suggests that an accuracy of 90% may be the highest that can be expected using current diagnostic criteria. In addition to bradykinesia, which is a core symptom, different types of tremors occur. Whereas the rest tremor is characteristic, action tremor, re-emergent tremor and orthostatic tremor may occur in Parkinson disease. Symptomatic treatments are quite effective in early disease but clinical course is complicated by the appearance of motor fluctuations and dyskinesias in more advanced disease. Non-motor complications, such as cognitive, psychiatric and autonomic problems, become bothersome and disabling in some patients.

Borlongan CV, Sanberg PR. · Department of Neurobiology and Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, 30912, USA. · Drug Discov Today. · Pubmed #12110244 No free full text.

Abstract: Neural transplantation has emerged as an efficacious experimental treatment for CNS disorders, especially Parkinson's disease. However, logistical and ethical issues impede large-scale clinical trials. To this end, alternatives to human fetal cells as donor cell grafts have been examined, including xenografts, stem cells, genetically engineered cells, immortalized cell lines, or paraneural cells that secrete specific neurotrophic or growth factors. Accumulating evidence also suggests that exogenous treatment with neurotrophic or growth factors, immunosuppressants, free radical scavengers, and anti-apoptotic agents can enhance survival and functional effects of the grafts. This article will review recent studies demonstrating the potential of these alternative cell graft sources and novel drugs for treating Parkinson's disease.