<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03043768</url>
  </required_header>
  <id_info>
    <org_study_id>CAPTURE PD,Vs.02.0,06/29/2015</org_study_id>
    <nct_id>NCT03043768</nct_id>
  </id_info>
  <brief_title>Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson's Disease</brief_title>
  <acronym>CAPTURE-PD</acronym>
  <official_title>Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson's Disease (CAPTURE PD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GWT-TUD GmbH</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Michael J. Fox Foundation for Parkinson's Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Prothena Biosciences Limited</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>GWT-TUD GmbH</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In Parkinson's disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor&#xD;
      and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in&#xD;
      the early stages of the disease. The investigators recently introduced a non-invasive&#xD;
      technique to assess autonomic adrenergic fiber function using the quantitative pilomotor&#xD;
      axon-reflex test (QPART). In the present study the investigators aim to assess the&#xD;
      association between alpha-synuclein mediated structural autonomic nerve fiber damage and&#xD;
      nerve function in PD, elucidate the role of neuropathy progression during the early disease&#xD;
      stages, and test reproducibility and external validity of pilomotor function assessment using&#xD;
      quantitative pilomotor axon-reflex test (QPART) and sudomotor function via quantitative&#xD;
      direct and indirect test of sudomotor function (QDIRT).&#xD;
&#xD;
      A prospective controlled study will be conducted in four sites (Dresden, Germany; Berlin,&#xD;
      Germany; Budapest, Hungary; Boston, USA). A total of 52 male and female patients with&#xD;
      idiopathic PD (Hoehn&amp;Yahr 1-2) and 52 age- and sex-matched healthy controls will be&#xD;
      recruited. Pilomotor function will be evaluated after iontophoresis of phenylephrine on the&#xD;
      dorsal forearm to elicit a cutaneous axon-reflex mediated response (goosebumps). Silicone&#xD;
      impressions of the stimulated area will be obtained, scanned and quantified for pilomotor&#xD;
      muscle impressions by number, impression size and area of axon-reflex pilomotor erection&#xD;
      spread. Sudomotor function will be evaluated after axon-reflex stimulation via iontophoresis&#xD;
      of acetylcholine on the dorsal forearm. Stained sweat droplets will be captured using&#xD;
      repeated digital photography and will be quantified over time for droplet number and&#xD;
      axon-reflex spread. Sympathetic skin responses following deep inspiration will be analyzed&#xD;
      using skin conductance quantification. Testing and evaluation of autonomic and motor symptoms&#xD;
      will be performed at baseline, after 2 weeks, 1 year, 2 years and 3 years. Skin biopsies will&#xD;
      be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and&#xD;
      alpha-synuclein accumulation.&#xD;
&#xD;
      The investigators expect that this study will unveil whether progression of autonomic nerve&#xD;
      dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression&#xD;
      of autonomic symptom severity and alpha-synuclein deposition in PD. Additionally, potential&#xD;
      applications of the used techniques include interventional studies evaluating&#xD;
      disease-modifying approaches and clinical assessment of autonomic dysfunction in patients&#xD;
      with PD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PURPOSE OF THE PROTOCOL With the goal of developing novel endpoints for early stage trials of&#xD;
      disease modifying therapies in Parkinson's disease (PD) the objective of this study is to a)&#xD;
      assess reproducibility b) external validity and reliability c) to perform a longitudinal&#xD;
      assessment of sudomotor (QDIRT) and pilomotor (QPART) responses in early PD patients.&#xD;
&#xD;
      Moreover, this study aims to assess the hypothesis that functional impairment in pilomotor&#xD;
      and sudomotor nerve fibers in early PD correlates with a-synuclein deposition mediated&#xD;
      structural fiber damage and may therefore constitute a potential non- invasive biomarker for&#xD;
      autonomic involvement in PD.&#xD;
&#xD;
      BACKGROUND In skin biopsy studies of PD, alpha-synuclein accumulation in cutaneous autonomic&#xD;
      nerve fibers has been linked to autonomic nervous system disturbances even in the early&#xD;
      stages of the disease. (1) The investigators recently introduced a non-invasive technique to&#xD;
      assess autonomic adrenergic fiber function using the quantitative pilomotor axon-reflex test&#xD;
      (QPART). (2)&#xD;
&#xD;
      OBJECTIVES Demonstrating generalizability and reliability of the QPART technique, the&#xD;
      anticipated positive results of this protocol might lend support to the utility of QPART as a&#xD;
      diagnostic tool. This might be of particular interest in clinical practice as the QPART&#xD;
      technique has been shown to assess small fiber function with low variability and&#xD;
      comparatively low technical effort whereas vasomotor assessment is limited by high&#xD;
      variability and sudomotor assessment requires technical demanding settings. (3) Moreover, the&#xD;
      anticipated positive correlation between functional and structural pilomotor nerve fiber&#xD;
      impairment might support the capacity of the QPART technique to assess specific fiber damage&#xD;
      and thus provide a non-invasive tool to 1.) study pilomotor nerve damage in research studies&#xD;
      and 2.) allow for longitudinal clinical assessment in PD patients to monitor disease&#xD;
      progression.&#xD;
&#xD;
      ETHICAL STANDARD The study protocol has been approved by the institutional review board of&#xD;
      Technische Universität Dresden (IRB study reference: EK349082015) as well as by the&#xD;
      institutional review board of each participating site (Berlin accepted the protocol based on&#xD;
      Technische Universität Dresden IRB approval; Budapest IRB number: 004513-004/2016/OTIG;&#xD;
      Boston IRB number: 2016P000141)&#xD;
&#xD;
      This study will be conducted according to the principles expressed in the Declaration of&#xD;
      Helsinki. Written informed consent will be obtained from each study participant. The consent&#xD;
      will be reviewed with the subject by one of the study physicians. The subject will sign the&#xD;
      informed consent before any procedures pertaining to the study are initiated. A copy of the&#xD;
      signed informed consent will be given to the participant and another copy kept on file.&#xD;
      Conduction of this study will comply with the GCP (Good Clinical Practice) guidelines.&#xD;
&#xD;
      STUDY PROCEDURES Quantitative Pilomotor Axon-Reflex Test (QPART): Iontophoresis of&#xD;
      phenylephrine is used to induce axon-reflex mediated piloerection. A drug delivery capsule&#xD;
      electrode (LI-611; Perimed®, Järfälla, Sweden) is affixed on the testing area on the dorsal&#xD;
      forearm. The inner chamber of this capsule, open to the skin surface, is filled with 0.4ml of&#xD;
      1 % phenylephrine solution. The drug delivery electrode is then connected to the&#xD;
      iontophoresis stimulation box (Phoresor II-Auto-PM850; IOMED Inc., Salt Lake City, USA).&#xD;
      Iontophoresis is performed over a 1cm diameter skin region with 0.5mA over 5 minutes.&#xD;
      Silicone impressions of piloerection are obtained to create a local topographic map of&#xD;
      piloerection. A silicone based two-phase material with high liquidity (Honigum Light, DMG,&#xD;
      Hamburg, Germany) is placed over the skin for 10 seconds. The silicone cures for 5 minutes,&#xD;
      has toner applied to mark the pilomotor impressions, excess toner is wiped free and the&#xD;
      silicone is scanned to capture the image digitally. Silicone impressions of erect hair&#xD;
      follicles are quantified by number and area and spatial spread. A high resolution scanner&#xD;
      (Fuel 3D® Technologies Limited, Chinnor, United Kingdom) connected to a personal computer&#xD;
      equipped with image analyzing software (Fuel3D® Studio Starter; Fuel 3D® Technologies&#xD;
      Limited, Chinnor, United Kingdom) is used to quantify additionally the goosebump reaction.&#xD;
&#xD;
      Sympathetic Skin Response (SSR): The skin conductance level (SCL) is measured in µSievert&#xD;
      (µS) from two medial phalanges (index and third finger) with a Powerlab® polygraph (AD&#xD;
      Instruments, Bella Vista, Australia). The maximum increase in amplitude following sudden deep&#xD;
      respiration (Sympathetic Skin Response; SSR) is calculated to quantify the functional&#xD;
      reactivity of sweat glands as previously described. (4)&#xD;
&#xD;
      Quantitative Direct and Indirect Test of Sudomotor Function (QDIRT): Axon-reflex mediated&#xD;
      sweating is measured after iontophoresis of 10% acetylcholine by drying the stimulated region&#xD;
      on the volar aspect of the forearm and dusting with indicator dye (povidone-iodine and&#xD;
      cornstarch) followed by repeated digital photographs taken every 15 seconds for 7 minutes&#xD;
      with a 18 Megapixel camera (EOS 60D; Canon Inc., Tokyo, Japan) with 100-mm macro lens. Images&#xD;
      are digitally analyzed for droplet number, size, and axon-reflex spread as previously&#xD;
      described. (5)&#xD;
&#xD;
      Evaluation of perceived motor and autonomic symptoms: Progression of motor and autonomic&#xD;
      symptoms are assessed through validated symptom scores MDS-UPDRS motor part and SCOPA AUT.&#xD;
&#xD;
      Skin biopsies: a-synuclein/PGP Ratio; Immunhistochemical staining for a-synuclein and&#xD;
      intraepidermal nerve fibers will be performed in 3 skin punch biopsies obtained from the&#xD;
      QPART testing sites and two control sites (lower legs). Three-millimeter biopsies will be&#xD;
      obtained following local anesthesia with 2% lidocaine. Biopsy specimens will be fixed in&#xD;
      Zamboni solution for 18 hours and cryoprotected overnight (20% glycerol and 20% 0.4 M&#xD;
      Sorensen buffer). Skin blocks are cut using freezing microtome and 20 tissue sections are&#xD;
      analyzed. 20 tissue sections will analyzed. Alpha synuclein/intraepidermal nerve fiber&#xD;
      density ratios will be calculated.&#xD;
&#xD;
      TIMELINE Subjects will be assessed for eligibility by a listed study physician. At baseline&#xD;
      all subjects will undergo medical history, physical examination, QPART, SSR, QDIRT, MDS-UPDRS&#xD;
      and SCOPA AUT assessment as described above. These testing procedures will be repeated, after&#xD;
      1-2 weeks, 1 year, 2 years, and 3 years post-baseline. All testing will be performed in a&#xD;
      temperature and humidity controlled environment. Only at Dresden-Site subjects will&#xD;
      additionally undergo the skin punch biopsy procedure as described above at baseline, after 1&#xD;
      year and after 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2016</start_date>
  <completion_date type="Actual">January 28, 2018</completion_date>
  <primary_completion_date type="Actual">January 28, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>QPART Pilomotor Function Parameter - Number of goose bump impressions</measure>
    <time_frame>36 months</time_frame>
    <description>Mean difference in number of goose bump impressions compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>QPART Pilomotor Function Parameter - Mean area of goose bump impressions</measure>
    <time_frame>36 months</time_frame>
    <description>Mean area of goose bump impressions compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>QPART Pilomotor Function Parameter - Spatial spread of axon-reflex pilomotor response</measure>
    <time_frame>36 months</time_frame>
    <description>Spatial spread of axon-reflex pilomotor response compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Alpha-synuclein Ratio</measure>
    <time_frame>36 months</time_frame>
    <description>Intraneural alpha-synuclein deposition normalized to intraepidermal small fiber density. Skin biopsies gained with punch biopsy technique.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perceived Autonomic Symptoms</measure>
    <time_frame>36 months</time_frame>
    <description>Autonomic symptom severity tested via the SCOPA AUT (Assessment of autonomic dysfunction in Parkinson's disease) questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Motor Symptom Progression</measure>
    <time_frame>36 months</time_frame>
    <description>Motor symptom severity tested via the MDS-UPDRS (revised Parkinson's disease rating scale (UPDRS) test).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>QDIRT Sudomotor Function Parameter - Number of Sweat droplets</measure>
    <time_frame>36 months</time_frame>
    <description>Number of sweat droplets in the axon-reflex region compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).</description>
  </other_outcome>
  <other_outcome>
    <measure>QDIRT Sudomotor Function Parameter - Size of sweat droplets</measure>
    <time_frame>36 months</time_frame>
    <description>Size of sweat droplets in the axon-reflex region compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).</description>
  </other_outcome>
  <other_outcome>
    <measure>QDIRT Sudomotor Function Parameter - Axon-reflex spread of sweat droplets</measure>
    <time_frame>36 months</time_frame>
    <description>Axon-reflex spread of sweat droplets in the axon-reflex region compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).</description>
  </other_outcome>
  <other_outcome>
    <measure>Sympathetic Skin Response</measure>
    <time_frame>36 months</time_frame>
    <description>Skin conductance level in µSievert (µS) obtained in two medial phalanges (index and third finger).</description>
  </other_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">50</enrollment>
  <condition>Parkinson's Disease</condition>
  <arm_group>
    <arm_group_label>PD patients</arm_group_label>
    <description>Male and female PD patients (idiopathic parkinsonism, Hoehn and Yahr [H&amp;Y] scores 1-2) aged 35 to 80 years</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control subjects</arm_group_label>
    <description>Age-and gender matched healthy control subjects</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      3mm skin biopsies (punch biopsies)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Male and female patients with early Parkinson's disease, gender matched healthy control&#xD;
        subjects&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        INCLUSION CRITERIA&#xD;
&#xD;
        - Male and female PD patients (idiopathic parkinsonism, Hoehn and Yahr [H&amp;Y] scores 1-2)&#xD;
        aged 35 to 80 years and age-and gender matched healthy control subjects&#xD;
&#xD;
        EXCLUSION CRITERIA&#xD;
&#xD;
          -  any dermatological disorders affecting the cutaneous testing regions&#xD;
&#xD;
          -  treatment with tricyclic antidepressants, noradrenergic antidepressants,&#xD;
             beta-blockers, alpha-adrenergic agonists or antagonists, cholinergic or&#xD;
             anti-cholinergic agents&#xD;
&#xD;
          -  known allergy to phenylephrine or acetylcholine&#xD;
&#xD;
          -  elevated alcohol consumption (more than 4 alcoholic beverages/week)&#xD;
&#xD;
          -  nicotine consumption within the past 5 years&#xD;
&#xD;
          -  known disorders affecting autonomic functions (including diabetes, pure autonomic&#xD;
             failure, inflammatory demyelinating polyradiculoneuropathies, multiple system atrophy,&#xD;
             atypical Parkinson syndromes, body mass index over 25 kg/m2, acute or chronic renal&#xD;
             disease, gout, rheumatoid arthritis, Lupus, Sjogren 's syndrome, Triple- A syndrome,&#xD;
             autonomic neuropathies not related to PD)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Timo Siepmann, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ben MW Illigens, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Autonomic and Peripheral Nerve Disorders, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Autonomic and Peripheral Nerve Disorders, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden</name>
      <address>
        <city>Dresden</city>
        <state>Saxony</state>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Departement of Neurology, Charite University Medicine Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>13353</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Neurology, Semmelweis University</name>
      <address>
        <city>Budapest</city>
        <zip>1083</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Hungary</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=1476</url>
    <description>Michael J. Fox Foundation Grant Site of CAPTURE PD</description>
  </link>
  <reference>
    <citation>Wang N, Gibbons CH, Lafo J, Freeman R. alpha-Synuclein in cutaneous autonomic nerves. Neurology. 2013 Oct 29;81(18):1604-10. doi: 10.1212/WNL.0b013e3182a9f449. Epub 2013 Oct 2.</citation>
    <PMID>24089386</PMID>
  </reference>
  <reference>
    <citation>Siepmann T, Gibbons CH, Illigens BM, Lafo JA, Brown CM, Freeman R. Quantitative pilomotor axon reflex test: a novel test of pilomotor function. Arch Neurol. 2012 Nov;69(11):1488-92. doi: 10.1001/archneurol.2012.1092.</citation>
    <PMID>22868966</PMID>
  </reference>
  <reference>
    <citation>Freeman R. Autonomic peripheral neuropathy. Lancet. 2005 Apr 2-8;365(9466):1259-70. doi: 10.1016/S0140-6736(05)74815-7.</citation>
    <PMID>15811460</PMID>
  </reference>
  <reference>
    <citation>Hu F, Jin J, Qu Q, Dang J. Sympathetic Skin Response in Amyotrophic Lateral Sclerosis. J Clin Neurophysiol. 2016 Feb;33(1):60-5. doi: 10.1097/WNP.0000000000000226.</citation>
    <PMID>26844971</PMID>
  </reference>
  <reference>
    <citation>Gibbons CH, Illigens BM, Centi J, Freeman R. QDIRT: quantitative direct and indirect test of sudomotor function. Neurology. 2008 Jun 10;70(24):2299-304. doi: 10.1212/01.wnl.0000314646.49565.c0.</citation>
    <PMID>18541883</PMID>
  </reference>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>February 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 6, 2017</study_first_posted>
  <last_update_submitted>July 19, 2022</last_update_submitted>
  <last_update_submitted_qc>July 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Parkinson's disease</keyword>
  <keyword>Autonomic</keyword>
  <keyword>Diagnosis</keyword>
  <keyword>Pilomotor</keyword>
  <keyword>Alpha-synuclein</keyword>
  <keyword>Axon-reflex</keyword>
  <keyword>Peripheral nerve fibers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03043768
org study id: CAPTURE PD,Vs.02.0,06/29/2015
nct id: NCT03043768
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
In Parkinson's disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor
      and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in
      the early stages of the disease. The investigators recently introduced a non-invasive
      technique to assess autonomic adrenergic fiber function using the quantitative pilomotor
      axon-reflex test (QPART). In the present study the investigators aim to assess the
      association between alpha-synuclein mediated structural autonomic nerve fiber damage and
      nerve function in PD, elucidate the role of neuropathy progression during the early disease
      stages, and test reproducibility and external validity of pilomotor function assessment using
      quantitative pilomotor axon-reflex test (QPART) and sudomotor function via quantitative
      direct and indirect test of sudomotor function (QDIRT).

      A prospective controlled study will be conducted in four sites (Dresden, Germany; Berlin,
      Germany; Budapest, Hungary; Boston, USA). A total of 52 male and female patients with
      idiopathic PD (Hoehn&Yahr 1-2) and 52 age- and sex-matched healthy controls will be
      recruited. Pilomotor function will be evaluated after iontophoresis of phenylephrine on the
      dorsal forearm to elicit a cutaneous axon-reflex mediated response (goosebumps). Silicone
      impressions of the stimulated area will be obtained, scanned and quantified for pilomotor
      muscle impressions by number, impression size and area of axon-reflex pilomotor erection
      spread. Sudomotor function will be evaluated after axon-reflex stimulation via iontophoresis
      of acetylcholine on the dorsal forearm. Stained sweat droplets will be captured using
      repeated digital photography and will be quantified over time for droplet number and
      axon-reflex spread. Sympathetic skin responses following deep inspiration will be analyzed
      using skin conductance quantification. Testing and evaluation of autonomic and motor symptoms
      will be performed at baseline, after 2 weeks, 1 year, 2 years and 3 years. Skin biopsies will
      be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and
      alpha-synuclein accumulation.

      The investigators expect that this study will unveil whether progression of autonomic nerve
      dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression
      of autonomic symptom severity and alpha-synuclein deposition in PD. Additionally, potential
      applications of the used techniques include interventional studies evaluating
      disease-modifying approaches and clinical assessment of autonomic dysfunction in patients
      with PD.
PURPOSE OF THE PROTOCOL With the goal of developing novel endpoints for early stage trials of
      disease modifying therapies in Parkinson's disease (PD) the objective of this study is to a)
      assess reproducibility b) external validity and reliability c) to perform a longitudinal
      assessment of sudomotor (QDIRT) and pilomotor (QPART) responses in early PD patients.

      Moreover, this study aims to assess the hypothesis that functional impairment in pilomotor
      and sudomotor nerve fibers in early PD correlates with a-synuclein deposition mediated
      structural fiber damage and may therefore constitute a potential non- invasive biomarker for
      autonomic involvement in PD.

      BACKGROUND In skin biopsy studies of PD, alpha-synuclein accumulation in cutaneous autonomic
      nerve fibers has been linked to autonomic nervous system disturbances even in the early
      stages of the disease. (1) The investigators recently introduced a non-invasive technique to
      assess autonomic adrenergic fiber function using the quantitative pilomotor axon-reflex test
      (QPART). (2)

      OBJECTIVES Demonstrating generalizability and reliability of the QPART technique, the
      anticipated positive results of this protocol might lend support to the utility of QPART as a
      diagnostic tool. This might be of particular interest in clinical practice as the QPART
      technique has been shown to assess small fiber function with low variability and
      comparatively low technical effort whereas vasomotor assessment is limited by high
      variability and sudomotor assessment requires technical demanding settings. (3) Moreover, the
      anticipated positive correlation between functional and structural pilomotor nerve fiber
      impairment might support the capacity of the QPART technique to assess specific fiber damage
      and thus provide a non-invasive tool to 1.) study pilomotor nerve damage in research studies
      and 2.) allow for longitudinal clinical assessment in PD patients to monitor disease
      progression.

      ETHICAL STANDARD The study protocol has been approved by the institutional review board of
      Technische Universität Dresden (IRB study reference: EK349082015) as well as by the
      institutional review board of each participating site (Berlin accepted the protocol based on
      Technische Universität Dresden IRB approval; Budapest IRB number: 004513-004/2016/OTIG;
      Boston IRB number: 2016P000141)

      This study will be conducted according to the principles expressed in the Declaration of
      Helsinki. Written informed consent will be obtained from each study participant. The consent
      will be reviewed with the subject by one of the study physicians. The subject will sign the
      informed consent before any procedures pertaining to the study are initiated. A copy of the
      signed informed consent will be given to the participant and another copy kept on file.
      Conduction of this study will comply with the GCP (Good Clinical Practice) guidelines.

      STUDY PROCEDURES Quantitative Pilomotor Axon-Reflex Test (QPART): Iontophoresis of
      phenylephrine is used to induce axon-reflex mediated piloerection. A drug delivery capsule
      electrode (LI-611; Perimed®, Järfälla, Sweden) is affixed on the testing area on the dorsal
      forearm. The inner chamber of this capsule, open to the skin surface, is filled with 0.4ml of
      1 % phenylephrine solution. The drug delivery electrode is then connected to the
      iontophoresis stimulation box (Phoresor II-Auto-PM850; IOMED Inc., Salt Lake City, USA).
      Iontophoresis is performed over a 1cm diameter skin region with 0.5mA over 5 minutes.
      Silicone impressions of piloerection are obtained to create a local topographic map of
      piloerection. A silicone based two-phase material with high liquidity (Honigum Light, DMG,
      Hamburg, Germany) is placed over the skin for 10 seconds. The silicone cures for 5 minutes,
      has toner applied to mark the pilomotor impressions, excess toner is wiped free and the
      silicone is scanned to capture the image digitally. Silicone impressions of erect hair
      follicles are quantified by number and area and spatial spread. A high resolution scanner
      (Fuel 3D® Technologies Limited, Chinnor, United Kingdom) connected to a personal computer
      equipped with image analyzing software (Fuel3D® Studio Starter; Fuel 3D® Technologies
      Limited, Chinnor, United Kingdom) is used to quantify additionally the goosebump reaction.

      Sympathetic Skin Response (SSR): The skin conductance level (SCL) is measured in µSievert
      (µS) from two medial phalanges (index and third finger) with a Powerlab® polygraph (AD
      Instruments, Bella Vista, Australia). The maximum increase in amplitude following sudden deep
      respiration (Sympathetic Skin Response; SSR) is calculated to quantify the functional
      reactivity of sweat glands as previously described. (4)

      Quantitative Direct and Indirect Test of Sudomotor Function (QDIRT): Axon-reflex mediated
      sweating is measured after iontophoresis of 10% acetylcholine by drying the stimulated region
      on the volar aspect of the forearm and dusting with indicator dye (povidone-iodine and
      cornstarch) followed by repeated digital photographs taken every 15 seconds for 7 minutes
      with a 18 Megapixel camera (EOS 60D; Canon Inc., Tokyo, Japan) with 100-mm macro lens. Images
      are digitally analyzed for droplet number, size, and axon-reflex spread as previously
      described. (5)

      Evaluation of perceived motor and autonomic symptoms: Progression of motor and autonomic
      symptoms are assessed through validated symptom scores MDS-UPDRS motor part and SCOPA AUT.

      Skin biopsies: a-synuclein/PGP Ratio; Immunhistochemical staining for a-synuclein and
      intraepidermal nerve fibers will be performed in 3 skin punch biopsies obtained from the
      QPART testing sites and two control sites (lower legs). Three-millimeter biopsies will be
      obtained following local anesthesia with 2% lidocaine. Biopsy specimens will be fixed in
      Zamboni solution for 18 hours and cryoprotected overnight (20% glycerol and 20% 0.4 M
      Sorensen buffer). Skin blocks are cut using freezing microtome and 20 tissue sections are
      analyzed. 20 tissue sections will analyzed. Alpha synuclein/intraepidermal nerve fiber
      density ratios will be calculated.

      TIMELINE Subjects will be assessed for eligibility by a listed study physician. At baseline
      all subjects will undergo medical history, physical examination, QPART, SSR, QDIRT, MDS-UPDRS
      and SCOPA AUT assessment as described above. These testing procedures will be repeated, after
      1-2 weeks, 1 year, 2 years, and 3 years post-baseline. All testing will be performed in a
      temperature and humidity controlled environment. Only at Dresden-Site subjects will
      additionally undergo the skin punch biopsy procedure as described above at baseline, after 1
      year and after 3 years.
observational model: Cohort
time perspective: Prospective
measure: QPART Pilomotor Function Parameter - Number of goose bump impressions
time frame: 36 months
description: Mean difference in number of goose bump impressions compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).
measure: QPART Pilomotor Function Parameter - Mean area of goose bump impressions
time frame: 36 months
description: Mean area of goose bump impressions compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).
measure: QPART Pilomotor Function Parameter - Spatial spread of axon-reflex pilomotor response
time frame: 36 months
description: Spatial spread of axon-reflex pilomotor response compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).
measure: Alpha-synuclein Ratio
time frame: 36 months
description: Intraneural alpha-synuclein deposition normalized to intraepidermal small fiber density. Skin biopsies gained with punch biopsy technique.
measure: Perceived Autonomic Symptoms
time frame: 36 months
description: Autonomic symptom severity tested via the SCOPA AUT (Assessment of autonomic dysfunction in Parkinson's disease) questionnaire.
measure: Motor Symptom Progression
time frame: 36 months
description: Motor symptom severity tested via the MDS-UPDRS (revised Parkinson's disease rating scale (UPDRS) test).
measure: QDIRT Sudomotor Function Parameter - Number of Sweat droplets
time frame: 36 months
description: Number of sweat droplets in the axon-reflex region compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).
measure: QDIRT Sudomotor Function Parameter - Size of sweat droplets
time frame: 36 months
description: Size of sweat droplets in the axon-reflex region compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).
measure: QDIRT Sudomotor Function Parameter - Axon-reflex spread of sweat droplets
time frame: 36 months
description: Axon-reflex spread of sweat droplets in the axon-reflex region compared between Cohort 1 (PD Patients) and Cohort 2 (healthy volunteers).
measure: Sympathetic Skin Response
time frame: 36 months
description: Skin conductance level in µSievert (µS) obtained in two medial phalanges (index and third finger).
arm group label: PD patients
description: Male and female PD patients (idiopathic parkinsonism, Hoehn and Yahr [H&Y] scores 1-2) aged 35 to 80 years
arm group label: Control subjects
description: Age-and gender matched healthy control subjects
3mm skin biopsies (punch biopsies)
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 35 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Timo Siepmann, MD
role: Principal Investigator
affiliation: Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden
last name: Ben MW Illigens, MD
role: Principal Investigator
affiliation: Center for Autonomic and Peripheral Nerve Disorders, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School
facility: 
facility: 
facility: 
facility: 
country: Germany
country: Hungary
country: United States
url: https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=1476
description: Michael J. Fox Foundation Grant Site of CAPTURE PD
citation: Wang N, Gibbons CH, Lafo J, Freeman R. alpha-Synuclein in cutaneous autonomic nerves. Neurology. 2013 Oct 29;81(18):1604-10. doi: 10.1212/WNL.0b013e3182a9f449. Epub 2013 Oct 2.
PMID: 24089386
citation: Siepmann T, Gibbons CH, Illigens BM, Lafo JA, Brown CM, Freeman R. Quantitative pilomotor axon reflex test: a novel test of pilomotor function. Arch Neurol. 2012 Nov;69(11):1488-92. doi: 10.1001/archneurol.2012.1092.
PMID: 22868966
citation: Freeman R. Autonomic peripheral neuropathy. Lancet. 2005 Apr 2-8;365(9466):1259-70. doi: 10.1016/S0140-6736(05)74815-7.
PMID: 15811460
citation: Hu F, Jin J, Qu Q, Dang J. Sympathetic Skin Response in Amyotrophic Lateral Sclerosis. J Clin Neurophysiol. 2016 Feb;33(1):60-5. doi: 10.1097/WNP.0000000000000226.
PMID: 26844971
citation: Gibbons CH, Illigens BM, Centi J, Freeman R. QDIRT: quantitative direct and indirect test of sudomotor function. Neurology. 2008 Jun 10;70(24):2299-304. doi: 10.1212/01.wnl.0000314646.49565.c0.
PMID: 18541883
responsible party type: Sponsor
mesh term: Parkinson Disease