C Warren Olanow

Icahn School of Medicine at Mount Sinai, Borough of Manhattan, New York, United States

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Publications (287)2366.56 Total impact

  • C Warren Olanow, Matthew B Stern
    Annals of Neurology 12/2009; 64 Suppl 2(6):S1-2. DOI:10.1002/ana.21442 · 11.91 Impact Factor
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    ABSTRACT: The pathophysiology of Parkinson's disease is reviewed in light of recent advances in the understanding of the functional organization of the basal ganglia (BG). Current emphasis is placed on the parallel interactions between corticostriatal and corticosubthalamic afferents on the one hand, and internal feedback circuits modulating BG output through the globus pallidus pars interna and substantia nigra pars reticulata on the other. In the normal BG network, the globus pallidus pars externa emerges as a main regulatory station of output activity. In the parkinsonian state, dopamine depletion shifts the BG toward inhibiting cortically generated movements by increasing the gain in the globus pallidus pars externa-subthalamic nucleus-globus pallidus pars interna network and reducing activity in "direct" cortico-putaminal-globus pallidus pars interna projections. Standard pharmacological treatments do not mimic the normal physiology of the dopaminergic system and, therefore, fail to restore a functional balance between corticostriatal afferents in the so-called direct and indirect pathways, leading to the development of motor complications. This review emphasizes the concept that the BG can no longer be understood as a "go-through" station in the control of movement, behavior, and emotions. The growing understanding of the complexity of the normal BG and the changes induced by DA depletion should guide the development of more efficacious therapies for Parkinson's disease.
    Annals of Neurology 12/2009; 64 Suppl 2(6):S30-46. DOI:10.1002/ana.21481 · 11.91 Impact Factor
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    ABSTRACT: Cell-based therapies that involve transplantation into the striatum of dopaminergic cells have attracted considerable interest as possible treatments for Parkinson's disease (PD). However, all double-blind, sham-controlled, studies have failed to meet their primary endpoints, and transplantation of dopamine cells derived from the fetal mesencephalon is associated with a potentially disabling form of dyskinesia that persists even after withdrawal of levodopa (off-medication dyskinesia). In addition, disability in advanced patients primarily results from features such as gait dysfunction, freezing, falling, and dementia, which are likely due to nondopaminergic pathology. These features are not adequately controlled with dopaminergic therapies and are thus unlikely to respond to dopaminergic grafts. More recently, implanted dopamine neurons have been found to contain Lewy bodies, suggesting that they are dysfunctional and may have been affected by the PD pathological process. Collectively, these findings do not bode well for the short-term future of cell-based dopaminergic therapies in PD.
    Annals of Neurology 11/2009; 66(5):591-6. DOI:10.1002/ana.21778 · 11.91 Impact Factor
  • C Warren Olanow, Jeffrey H Kordower
    Annals of Neurology 10/2009; 66(4):432-6. DOI:10.1002/ana.21832 · 11.91 Impact Factor
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    ABSTRACT: A therapy that slows disease progression is the major unmet need in Parkinson's disease. In this double-blind trial, we examined the possibility that rasagiline has disease-modifying effects in Parkinson's disease. A total of 1176 subjects with untreated Parkinson's disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72. Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (+/-SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09+/-0.02 points per week in the early-start group vs. 0.14+/-0.01 points per week in the placebo group, P=0.01), less worsening in the score between baseline and week 72 (2.82+/-0.53 points in the early-start group vs. 4.52+/-0.56 points in the delayed-start group, P=0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085+/-0.02 points per week in the early-start group vs. 0.085+/-0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47+/-0.50 points in the early-start group and 3.11+/-0.50 points in the delayed-start group, P=0.60). Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials.gov number, NCT00256204.)
    New England Journal of Medicine 09/2009; 361(13):1268-78. DOI:10.1056/NEJMoa0809335 · 54.42 Impact Factor
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    C Warren Olanow, Stanley B Prusiner
    Proceedings of the National Academy of Sciences 09/2009; 106(31):12571-2. DOI:10.1073/pnas.0906759106 · 9.81 Impact Factor
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    ABSTRACT: Rotigotine is a novel, non-ergoline dopamine D(3)/D(2)/D(1)-receptor agonist for the treatment of Parkinson's disease that can be continuously delivered by the transdermal route to provide stable plasma levels. Continuous drug delivery should reduce the risk of dyskinesia induction in comparison to pulsatile dopaminergic treatment. Thus the aim of the study was to compare the reversal of motor disability and induction of dyskinesia produced by continuous compared to pulsatile rotigotine administration in MPTP-treated common marmosets. The study also investigated whether pulsatile or continuous rotigotine administration in combination with l-DOPA prevented l-DOPA-induced dyskinesia. Animals were treated for 28 days with vehicle or pulsatile (twice daily) or continuous delivery of rotigotine (via an osmotic minipump). Subsequently, l-DOPA was then co-administered for a further 28 days. Animals were assessed for locomotor activity, motor disability and dyskinesia induction. The study showed that both continuous and pulsatile administration of rotigotine improved motor deficits and normalized motor function in MPTP-treated monkeys. However, continuous rotigotine delivery reduced dyskinesia expression compared to pulsatile treatment. Both pulsatile and continuous rotigotine administration produced less dyskinesia than administration of l-DOPA alone. The addition of l-DOPA to either pulsatile or continuous rotigotine treatment resulted in the induction of marked dyskinesia similar to that produced by treatment with l-DOPA alone. These data further support the hypothesis that continuous delivery of a dopaminergic agent reduces the risk of dyskinesia induction. However, continuous rotigotine administration did not prevent l-DOPA from inducing dyskinesia suggesting that l-DOPA may induce dyskinesia by mechanisms different from dopamine agonist drugs.
    Experimental Neurology 08/2009; 219(2):533-42. DOI:10.1016/j.expneurol.2009.07.011 · 4.62 Impact Factor
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    ABSTRACT: We explored the relationship between ubiquitin proteasome system (UPS) and lysosomal markers and the formation of alpha-synuclein (alpha-syn) inclusions in nigral neurons in Parkinson disease (PD). Lysosome Associated Membrane Protein 1(LAMP1), Cathepsin D (CatD), and Heat Shock Protein73 (HSP73) immunoreactivity were significantly decreased within PD nigral neurons when compared to age-matched controls. This decrease was significantly greater in nigral neurons that contained alpha-syn inclusions. Immunoreactivity for 20S proteasome was similarly reduced in PD nigral neurons, but only in cells that contained inclusions. In aged control brains, there is staining for alpha-syn protein, but it is non-aggregated and there is no difference in LAMP1, CatD, HSP73 or 20S proteasome immunoreactivity between alpha-syn positive or negative neuromelanin-laden nigral neurons. Targeting over-expression of mutant human alpha-syn in the rat substantia nigra using viral vectors revealed that lysosomal and proteasomal markers were significantly decreased in the neurons that displayed alpha-syn-ir inclusions. These findings suggest that alpha-syn aggregation is a key feature associated with decline of proteasome and lysosome and support the hypothesis that cell degeneration in PD involves proteosomal and lysosomal dysfunction, impaired protein clearance, and protein accumulation and aggregation leading to cell death.
    Neurobiology of Disease 07/2009; 35(3):385-98. DOI:10.1016/j.nbd.2009.05.023 · 5.20 Impact Factor
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    C Warren Olanow, Matthew B Stern, Kapil Sethi
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    ABSTRACT: Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches.
    Neurology 06/2009; 72(21 Suppl 4):S1-136. DOI:10.1212/WNL.0b013e3181a1d44c · 8.30 Impact Factor
  • Jose A. Obeso, C. Warren Olanow
    Annals of Neurology 05/2009; 65(5):618-619. DOI:10.1002/ana.21727 · 11.91 Impact Factor
  • Article: Reply.
    Anthony H Schapira, C Warren Olanow
    Annals of Neurology 05/2009; 65(4):481. DOI:10.1002/ana.21690 · 11.91 Impact Factor
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    ABSTRACT: Experimental studies suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) induces impulsivity in patients with Parkinson's disease (PD). The purpose of this study was to assess various measures of impulse control in PD patients with STN DBS in comparison to patients receiving medical therapy. In a cross-sectional evaluation, 53 consecutively eligible patients were assessed for impulsivity with the Barratt Impulsiveness Scale, for impulse control disorders (ICDs) using the Minnesota Impulsive Disorders Interview, and for obsessive-compulsive symptoms using the Maudsley Obsessional-Compulsive Inventory. Independent samples t-tests revealed that compulsivity scores were not different between DBS patients and patients without DBS. However, impulsivity scores were significantly higher in DBS patients. Additionally, ICDs were observed in 3 of 16 (19%) DBS patients and in 3 of 37 (8%) medically treated patients. No association was found between the use of dopamine agonists and impulsivity in DBS patients. Our data suggest that screening for impulsivity and ICDs should be performed prior to DBS, and that patients should be monitored for these problems during follow-up. Prospective trials are needed to confirm the findings of this exploratory study and to elucidate the reasons of a possible induction of impulsivity by STN DBS.
    European Journal of Neurology 03/2009; 16(4):493-7. DOI:10.1111/j.1468-1331.2008.02509.x · 3.85 Impact Factor
  • C Warren Olanow
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    ABSTRACT: A disease-modifying therapy is the most important unmet medical need in the treatment of Parkinson disease (PD). Laboratory studies have identified many promising candidate agents, but none has been proven to be neuroprotective in PD. A major limitation has been the development of an endpoint that accurately reflects the underlying disease state. This dramatically limits the potential for a new drug being approved as a disease-modifying agent in PD. For the present, the best opportunity to provide patients with PD with a disease-modifying effect is with agents that have been approved for their symptomatic effects. This article reviews currently available drugs for PD and considers the evidence that they might have neuroprotective effects in PD.
    Neurology 03/2009; 72(7 Suppl):S59-64. DOI:10.1212/WNL.0b013e318199068b · 8.30 Impact Factor
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    ABSTRACT: The objective of this study is to assess dyskinesias in 34 Parkinson's disease patients randomized to receive bilateral fetal nigral transplantation with 4 donors per side (12), 1 donor per side (11), or placebo (11). Videotape recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits during the “practically defined off” (12 hours after last evening dopaminergic therapy) and “best on” (best response following morning dopaminergic therapy) states. Videotapes were analyzed in random order by a blinded investigator. Dyskinesias during “best on” (on-medication dyskinesia) were observed in all, but 1 patient at baseline, and in all patients at each subsequent visit. There were no differences between groups. No patient had dyskinesia at baseline in “practically-defined off” (“off-medication” dyskinesia). Following transplantation, off-medication dyskinesia was observed in 13 of 23 patients, but not in any patient in the placebo group (P = 0.019). There was no difference in dyskinesia score between patients in the 1 and 4 donor groups. On-medication dyskinesias were typically generalized and choreiform, whereas off-medication dyskinesias were usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off-medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias. © 2008 Movement Disorder Society
    Movement Disorders 02/2009; 24(3):336 - 343. DOI:10.1002/mds.22208 · 5.63 Impact Factor
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    ABSTRACT: This report describes pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term.
    Movement Disorders 12/2008; 23(16):2303-6. DOI:10.1002/mds.22369 · 5.63 Impact Factor
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    ABSTRACT: A neuroprotective therapy is the single most important unmet medical need in Parkinson's disease. Several promising agents in the laboratory have been tested in the clinic, but none has been established in clinical trials to have a disease modifying effect despite positive results because of potential confounding symptomatic or pharmacologic effects. The delayed start design was developed to try to avoid a symptomatic confound when testing a putative neuroprotective therapy. In this study design, patients are randomly assigned to study drug or placebo in the first phase of the study, and both groups receive the active drug in the second phase. If benefits seen at the end of phase I persist through the end of phase II, they cannot be readily explained by a symptomatic effect (as patients in both groups are receiving the same medication) and benefits in the early start group must relate to the early initiation of the treatment. Although the precise mechanism responsible for such an effect can be debated, positive results in a delayed start study indicate that patients who receive early treatment have a better outcome than those where the treatment is delayed. We are using the delayed start design to assess the potential disease modifying effects of rasagiline in a prospective double blind controlled trial (the ADAGIO study). We here describe the rationale for the study and baseline characteristics of the 1,176 patients who have been enrolled into the trial. © 2008 Movement Disorder Society
    Movement Disorders 11/2008; 23(15):2194 - 2201. DOI:10.1002/mds.22218 · 5.63 Impact Factor
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    ABSTRACT: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.
    Movement Disorders 11/2008; 23(15):2129-70. DOI:10.1002/mds.22340 · 5.63 Impact Factor
  • Aktuelle Neurologie - AKTUEL NEUROL; 09/2008
  • Venugopalan D Nair, C Warren Olanow
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    ABSTRACT: We have previously reported that specific dopamine agonists mediate protection against apoptosis induced by oxidative stress by activating the D2 receptor-coupled phosphoinositide 3-kinase (PI-3K)/Akt pathway. In the present study we examined the downstream effectors of PI-3K/Akt signaling and their role in cell death after oxidative stress and protection provided by ropinirole, a D2 receptor agonist in PC12 cells and primary cultures of dopamine neurons. Ropinirole treatment was associated with rapid translocation and phosphorylation of the PI-3K substrate Akt and phosphorylation of Akt substrates. One of these Akt downstream substrates was identified as the pro-apoptotic factor glycogen synthase kinase-3beta (GSK-3beta). Ropinirole-induced protection was associated with phosphorylation of GSK-3beta (inactivation). In contrast, inhibition of PI-3K blocked the phosphorylation of Akt and GSK-3beta (activation) and prevented the protection mediated by ropinirole. Suppression of Akt with specific short hairpin RNA in normal PC12 cells caused cell death, which was associated with reduced phosphorylation of GSK-3beta and reduced levels of beta-catenin, a transcriptional activator that is regulated by GSK-3beta. Knock-out of GSK-3beta expression with a short hairpin RNA alone was itself sufficient to cause cell death. We further demonstrated that oxidative stress induced by hydrogen peroxide (H2O2) dephosphorylates Akt and GSK-3beta, increases GSK-3beta activity, and promotes an interaction with beta-catenin and its degradation. Inhibition of GSK-3beta activity by inhibitor VIII protects cells from H2O2 similar to ropinirole. These results indicate that GSK-3beta downstream of Akt plays a critical role in cell death and survival in these models.
    Journal of Biological Chemistry 06/2008; 283(22):15469-78. DOI:10.1074/jbc.M707238200 · 4.60 Impact Factor
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    ABSTRACT: Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body-like inclusions that stained positively for alpha-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.
    Nature medicine 06/2008; 14(5):504-6. DOI:10.1038/nm1747 · 28.05 Impact Factor

Publication Stats

23k Citations
2,366.56 Total Impact Points

Institutions

  • 1996–2015
    • Icahn School of Medicine at Mount Sinai
      • • Department of Neurology
      • • Department of Neuroscience
      Borough of Manhattan, New York, United States
  • 2014
    • Mount Sinai Hospital
      New York City, New York, United States
  • 2010
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, CA, United States
  • 2009
    • University College London Hospitals NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2006–2008
    • Rush University Medical Center
      • Department of Neurological Sciences
      Chicago, IL, United States
  • 1994–2008
    • Mount Sinai Medical Center
      New York, New York, United States
  • 2007
    • University Center Rochester
      • Department of Neurology
      Rochester, Minnesota, United States
  • 1997–2006
    • King's College London
      • MRC Centre for Neurodegeneration Research
      London, ENG, United Kingdom
  • 2002
    • Gracie Square Hospital, New York, NY
      New York City, New York, United States
  • 2001
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2000
    • CUNY Graduate Center
      New York City, New York, United States
    • Universidad de Navarra
      • Department of Neurology and Neurosurgery
      Pamplona, Navarre, Spain
    • University College London
      • Institute of Neurology
      London, ENG, United Kingdom
  • 1989–2000
    • University of South Florida
      • • Parkinson's Disease and Movement Disorders Center
      • • Department of Neurology
      Tampa, FL, United States
  • 1992–1994
    • Louisiana State University in Shreveport
      Shreveport, Louisiana, United States
  • 1991
    • Honolulu University
      Honolulu, Hawaii, United States
    • Cornell University
      • Department of Neurology and Neuroscience
      Ithaca, NY, United States