Parkinson Disease: Illinois

Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L, Anonymous00253. · Rush University Medical Center, 1725 W. Harrison Street, Chicago, IL 60612, USA. · Mov Disord. · Pubmed #15372591 links to  free full text

Abstract: The Movement Disorder Society Task Force for Rating Scales for Parkinson's disease (PD) prepared a critique of the Hoehn and Yahr scale (HY). Strengths of the HY scale include its wide utilization and acceptance. Progressively higher stages correlate with neuroimaging studies of dopaminergic loss, and high correlations exist between the HY scale and some standardized scales of motor impairment, disability, and quality of life. Weaknesses include the scale's mixing of impairment and disability and its non-linearity. Because the HY scale is weighted heavily toward postural instability as the primary index of disease severity, it does not capture completely impairments or disability from other motor features of PD and gives no information on nonmotor problems. Direct clinimetric testing of the HY scale has been very limited, but the scale fulfills at least some criteria for reliability and validity, especially for the midranges of the scale (Stages 2-4). Although a "modified HY scale" that includes 0.5 increments has been adopted widely, no clinimetric data are available on this adaptation. The Task Force recommends that: (1) the HY scale be used in its original form for demographic presentation of patient groups; (2) when the HY scale is used for group description, medians and ranges should be reported and analysis of changes should use nonparametric methods; (3) in research settings, the HY scale is useful primarily for defining inclusion/exclusion criteria; (4) to retain simplicity, clinicians should "rate what you see" and therefore incorporate comorbidities when assigning a HY stage; and (5) because of the wide usage of the modified HY scale with 0.5 increments, this adaptation warrants clinimetric testing. Without such testing, however, the original five-point scales should be maintained.

Prodoehl J, Corcos DM, Vaillancourt DE. · Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA. · Neurosci Biobehav Rev. · Pubmed #19428499 No free full text.

Abstract: The classic grasping network has been well studied but thus far the focus has been on cortical regions in the control of grasping. Sub-cortically, specific nuclei of the basal ganglia have been shown to be important in different aspects of precision grip force control but these findings have not been well integrated. In this review, we outline the evidence to support the hypothesis that key basal ganglia nuclei are involved in parameterizing specific properties of precision grip force. We review literature from different areas of human and animal work that converges to build a case for basal ganglia involvement in the control of precision gripping. Following on from literature showing anatomical connectivity between the basal ganglia nuclei and key nodes in the cortical grasping network, we suggest a conceptual framework for how the basal ganglia could function within the grasping network, particularly as it relates to the control of precision grip force.

Chan CS, Gertler TS, Surmeier DJ. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. · Trends Neurosci. · Pubmed #19307031 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder of which the core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Recent work has revealed that the engagement of L-type Ca(2+) channels during autonomous pacemaking renders SNc DA neurons susceptible to mitochondrial toxins used to create animal models of PD, indicating that homeostatic Ca(2+) stress could be a determinant of their selective vulnerability. This view is buttressed by the central role of mitochondria and the endoplasmic reticulum (linchpins of current theories about the origins of PD) in Ca(2+) homeostasis. Here, we summarize this evidence and suggest the dual roles had by these organelles could compromise their function, leading to accelerated aging of SNc DA neurons, particularly in the face of genetic or environmental stress. We conclude with a discussion of potential therapeutic strategies for slowing the progression of PD.

Simuni T, Lyons KE, Pahwa R, Hauser RA, Comella C, Elmer L, Weintraub D. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Ill, USA. · Eur Neurol. · Pubmed #19176961 links to  free full text

Abstract: The management of early Parkinson's disease (PD) involves the treatment of motor symptoms, and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews efficacy and safety data for the newest PD treatment options, as well as for established therapies. Part 2 of the article, presented here, reviews key data relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

Simuni T, Lyons KE, Pahwa R, Hauser RA, Comella C, Elmer L, Weintraub D. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Ill 60611, USA. · Eur Neurol. · Pubmed #19176960 links to  free full text

Abstract: The management of early Parkinson's disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

Simuni T, Sethi K. · Department of Neurology, Northwestern University, Chicago, IL, USA. · Ann Neurol. · Pubmed #19127582 No free full text.

Abstract: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Traditionally, attention has focused on the motor symptomatology of PD, but it is now appreciated that the nonmotor symptoms affecting neuropsychiatric, sleep, autonomic, and sensory domains occur in up to 88% of PD patients and can be an important source of disability. Nonmotor manifestations of PD play a significant role in the impairment of disease-related quality of life. The cause of nonmotor manifestations of PD is multifactorial, but to a large extent, these manifestations are related to the nature of the neurodegenerative process and the widespread nondopaminergic neuropathological changes associated with the disease. Recognition of nonmotor disability is essential not only for ascertaining the functional status of patients but also for better appreciating the nature of the neurodegenerative process in PD. In addition, a number of nonmotor manifestations can precede the onset of motor symptoms in PD and can be used as screening tools allowing for early disease identification and for trials of possible disease-modifying interventions. This article reviews depression, sleep, and autonomic dysfunction in PD.

Reilly JL, Lencer R, Bishop JR, Keedy S, Sweeney JA. · Center for Cognitive Medicine, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA. · Brain Cogn. · Pubmed #19028266 No free full text.

Abstract: The increasing use of eye movement paradigms to assess the functional integrity of brain systems involved in sensorimotor and cognitive processing in clinical disorders requires greater attention to effects of pharmacological treatments on these systems. This is needed to better differentiate disease and medication effects in clinical samples, to learn about neurochemical systems relevant for identified disturbances, and to facilitate identification of oculomotor biomarkers of pharmacological effects. In this review, studies of pharmacologic treatment effects on eye movements in healthy individuals are summarized and the sensitivity of eye movements to a variety of pharmacological manipulations is established. Primary findings from these studies of healthy individuals involving mainly acute effects indicate that: (i) the most consistent finding across several classes of drugs, including benzodiazepines, first- and second- generation antipsychotics, anticholinergic agents, and anticonvulsant/mood stabilizing medications is a decrease in saccade and smooth pursuit velocity (or increase in saccades during pursuit); (ii) these oculomotor effects largely reflect the general sedating effects of these medications on central nervous system functioning and are often dose-dependent; (iii) in many cases changes in oculomotor functioning are more sensitive indicators of pharmacological effects than other measures; and (iv) other agents, including the antidepressant class of serotonergic reuptake inhibitors, direct serotonergic agonists, and stimulants including amphetamine and nicotine, do not appear to adversely impact oculomotor functions in healthy individuals and may well enhance aspects of saccade and pursuit performance. Pharmacological treatment effects on eye movements across several clinical disorders including schizophrenia, affective disorders, attention deficit hyperactivity disorder, Parkinson's disease, and Huntington's disease are also reviewed. While greater recognition and investigation into pharmacological treatment effects in these disorders is needed, both beneficial and adverse drug effects are identified. This raises the important caveat for oculomotor studies of neuropsychiatric disorders that performance differences from healthy individuals cannot be attributed to illness effects alone. In final sections of this review, studies are presented that illustrate the utility of eye movements for use as potential biomarkers in pharmacodynamic and pharmacogenetic studies. While more systematic studies are needed, we conclude that eye movement measurements hold significant promise as tools to investigate treatment effects on cognitive and sensorimotor processes in clinical populations and that their use may be helpful in speeding the drug development pathway for drugs targeting specific neural systems and in individualizing pharmacological treatments.

Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA. · Parkinsonism Relat Disord. · Pubmed #18585085 links to  free full text

Abstract: Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are formed and inflammation is chronic. Nevertheless, isradipine, an L-type calcium-channel blocker, attenuates the degeneration. These data support the validity of the MPTP/p model for unravelling the degenerative processes in PD and testing therapies that slow their progress.

Monahan AJ, Warren M, Carvey PM. · Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA. · Cell Transplant. · Pubmed #18522239 No free full text.

Abstract: Despite decades of research and the development of a large group of animal models, our understanding of the mechanisms responsible for the progressive loss of dopamine neurons in Parkinson's disease (PD) is unknown. So-called neuroprotective studies demonstrate that a vast group of molecules readily attenuate the dopamine (DA) neuron loss produced by DA neurotoxin insult. Despite these successes, these neuroprotective strategies have been surprisingly ineffective in patients. This may reflect the fact that the initial pathogenic event and the subsequent disease progression is a consequence of different mechanisms. As we began to think about this disconnect, we discovered that animals exposed to DA neurotoxins exhibited blood-brain barrier (BBB) dysfunction. If the BBB in PD patients is disrupted, then the barrier that normally segregates peripheral vascular factors from brain parenchyma is no longer present. Immune cells could then enter brain and produce a self-perpetuating (progressive) degenerative process. In this review, we propose that peripheral immunity contributes to the degenerative process of PD and may be responsible for the progressive nature of the disease. This hypothesis is supported by a broad and diverse literature that is just beginning to come together to suggest that PD is, in part, an autoimmune disease. In order to understand this hypothesis, the reader must question the conventional wisdom that the BBB is intact in PD, the brain is an immune privileged area, and that pathogenic insult and disease progression may reflect different mechanisms.

Newman MB, Bakay RA. · Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois 60612, USA. · Neurotherapeutics. · Pubmed #18394566 No free full text.

Abstract: The loss of dopaminergic neurons of the substantia nigra is the pathological hallmark characteristic of Parkinson's disease (PD). The strategy of replacing these degenerating neurons with other cells that produce dopamine has been the main approach in the cell transplantation field for PD research. The isolation, differentiation, and long-term cultivation of human embryonic stem cells and the therapeutic research discovery made in relation to the beneficial properties of neurotrophic and neural growth factors has advanced the transplantation field beyond dopamine-producing cells. The present review addresses recent advances in human embryonic stem cell experimentation in relation to treating PD, as well as cell transplantation techniques in conjunction with alternative therapeutics.

Meredith GE, Sonsalla PK, Chesselet MF. · Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA. · Acta Neuropathol. · Pubmed #18273623 links to  free full text

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder whose etiology is not understood. This disease occurs both sporadically and through inheritance of single genes, although the familial types are rare. Over the past decade or so, experimental and clinical data suggest that PD could be a multifactorial, neurodegenerative disease that involves strong interactions between the environment and genetic predisposition. Our understanding of the pathophysiology and motor deficits of the disease relies heavily on fundamental research on animal models and the last few years have seen an explosion of toxin-, inflammation-induced and genetically manipulated models. The insight gained from the use of such models has strongly advanced our understanding of the progression and stages of the disease. The models have also aided the development of novel therapies to improve symptomatic management, and they are critical for the development of neuroprotective strategies. This review critically evaluates these in vivo models and the roles they play in mimicking the progression of PD.

Xie X, Ramkumar V, Toth LA. · Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA. · Comp Med. · Pubmed #18246865 No free full text.

Abstract: This review will examine how dopamine, a monoamine neurotransmitter, and adenosine, a neuromodulator, regulate behavioral activation, primarily as reflected by locomotor activity, in rodents. Complex interactions among 2 major types of adenosine receptors (A1AR and A2AAR) and 2 dopamine receptors (D1R and D2R) occur due to physical interactions that alter their ligand-binding properties and subsequent effects on common postreceptor signaling molecules. The output from these interactions in striatum modulates neurotransmission and subsequently influences spontaneous locomotor activity. Caffeine is a nonselective adenosine receptor antagonist that blocks 2 major types of adenosine receptors, A1AR and A2AAR, in the brain. Pharmacologic manipulation of these receptors with drugs such as caffeine offers potential therapeutic benefit for treatment of Parkinson disease.

Comella CL. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. · Mov Disord. · Pubmed #18175398 No free full text.

Abstract: Sleep disturbances are one of the most common of the nonmotor complications of Parkinson's disease (PD), and increase in frequency with advancing disease. The causes of sleep disturbance in PD are numerous, and many patients may have several factors that contribute. These disorders can be broadly categorized into those that involve nocturnal sleep and daytime manifestations such as excessive daytime sleepiness. Some sleep disorders, in particular REM sleep behavior disorder (RBD) and excessive daytime sleepiness (EDS) may arise as a primary manifestation of PD, reflecting the anatomic areas affected by the neurodegenerative process. Appropriate diagnosis of the sleep disturbance affecting a PD patient can lead to specific treatments that can consolidate nocturnal sleep and enhance daytime alertness.

Kordower JH, Olanow CW. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Exp Neurol. · Pubmed #17888424 No free full text.

Abstract: Gene therapy for Parkinson's disease has become a clinical reality with three different approaches currently being tested in patients. All three trials employ an adeno-associated virus with a type two serotype (AAV2). To date, no serious adverse events related to the injections of therapeutic vectors have been reported in any patient. This safety profile was predicted based upon, in some cases, exhaustive preclinical testing in both rodent and primate species. Still some argue that regulatable promoters are required so that expression of the transgene can be halted should untoward side effects arise. We argue that given the current empirical data base of AAV2, the lack of regulatable promoters that have been proven to be safe and effective, and the pressing clinical needs of PD patients, the mandatory use of regulatable vectors is not only unnecessary but, in some instances, misguided and potentially dangerous. This commentary will outline the issues related to the use of regulatable promoters for gene therapy for PD and express our opinion as to why mandating the use of such promoters might result in outcomes that are unsafe, unproductive, and counter to the progress of scientifically sound, clinical research.

Surmeier DJ. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. · Lancet Neurol. · Pubmed #17884683 No free full text.

Abstract: Parkinson's disease is a common neurodegenerative disorder of unknown cause. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of Parkinson's disease are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is their increasing reliance on Ca(2+) channels to maintain autonomous activity with age. This reliance could pose a sustained metabolic stress on mitochondria, accelerating cellular ageing and death. The Ca(2+) channels underlying autonomous activity in dopaminergic neurons are closely related to the L-type channels found in the heart and smooth muscle. Systemic administration of isradipine, a dihydropyridine blocker of L-type channels, forces dopaminergic neurons in rodents to revert to a juvenile, Ca(2+)-independent mechanism to generate autonomous activity. More importantly, reversion confers protection against toxins that produce experimental parkinsonism, pointing to a potential neuroprotective strategy for Parkinson's disease with a drug class that has been used safely in human beings for decades. These studies also suggest that, although genetic and environmental factors can hasten its onset, Parkinson's disease stems from a distinctive neuronal design common to all human beings, making its appearance simply a matter of time.

Grujic Z. · Center for Alzheimer's, Cognitive and Memory Disorders, Evanston Northwestern Healthcare, Glenview, Illinois, USA. · Dis Mon. · Pubmed #17656192 No free full text.

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Mercury MG, Tschan W, Kehoe R, Kuechler A. · Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. · Dis Mon. · Pubmed #17656191 No free full text.

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Reese SL. · American Parkinson Association, National Young Onset and Illinois Information and Referral Centers, Glenbrook Hospital, Glenvew, Illinois, USA. · Dis Mon. · Pubmed #17656190 No free full text.

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Freedom T. · Sleep Disorders Center, Evanston Nothwestern Healthcare, Evanston Hospital, Evanston, Illinois, USA. · Dis Mon. · Pubmed #17656189 No free full text.

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Dubow JS. · Movement Disorders Center, Evanston Northwestern Healthcare, Glenbrook Hospital, Glenview, Illinois, USA. · Dis Mon. · Pubmed #17656188 No free full text.

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Boelen M. · Evanston Northwestern Healthcare, Glenbrook Hospital, Glenview, Illinois, USA. · Dis Mon. · Pubmed #17656187 No free full text.

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Cozzens JW. · Northwestern University Feinberg School of Medicine, Movement Disorders Functional Neurosurgical Program, Evanston Northwestern Healthcare, Illinois, USA. · Dis Mon. · Pubmed #17586330 No free full text.

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Rezak M. · Northwestern University, Feinberg School of Medicine, Movement Disorders Program, Evanston Northwestern Healthcare, Evanston and Glenbrook Hospitals, Evanston and Glenview, Illinois, USA. · Dis Mon. · Pubmed #17586328 No free full text.

Abstract: Treatment options for Parkinson's disease have greatly expanded in recent years. Pharmacological treatments, such as levodopa, dopamine receptor agonists, anticholinergic medications, monoamine oxidase B inhibitors, and the catechol-O-methyl transferase inhibitors, remain the mainstay of therapeutic intervention and are reviewed. Additionally, the traditional and new roles for amantadine are explained. Despite the great efficacy of levodopa, "levodopa-sparing strategies" in early Parkinson's disease are emphasized in order to delay the development of difficult-to-manage motor fluctuations and dyskinesias.

Rubin SM. · Women's Neurology Center, Glenbrook Hospital, Glenview, Illinois, USA. · Dis Mon. · Pubmed #17586327 No free full text.

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Reynolds MR, Berry RW, Binder LI. · Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. · Biochemistry. · Pubmed #17542619 No free full text.

Abstract: Recent literature has ushered in a new awareness of the diverse post-translational events that can influence protein folding and function. Among these modifications, protein nitration is thought to play a critical role in the onset and progression of several neurodegenerative diseases. While previously considered a late-stage epiphenomenon, nitration of protein tyrosine residues appears to be an early event in the lesions of amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The advent of highly specific biochemical and immunological detection methods reveals that nitration occurs in vivo with biological selectively and site specificity. In fact, nitration of only a single Tyr residue is often sufficient to induce profound changes in the activity of catalytic proteins and the three-dimensional conformation of structural proteins. Presumably, nitration modifies protein function by altering the hydrophobicity, hydrogen bonding, and electrostatic properties within the targeted protein. Most importantly, however, nitrative injury may represent a unifying mechanism that explains how genetic and environmental causes of neurological disease manifest a singular phenotype. In this review and synthesis, we first examine the pathways of protein nitration in biological systems and the factors that influence site-directed nitration. Subsequently, we turn our attention to the structural implications of site-specific nitration and how it affects the function of several neurodegeneration-related proteins. These proteins include Mn superoxide dismutase and neurofilament light subunit in amyotrophic lateral sclerosis, alpha-synuclein and tyrosine hydroxylase in Parkinson's disease, and tau in Alzheimer's disease.