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Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of A-T

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ClinicalTrials.gov Identifier: NCT02285348
Recruitment Status : Unknown
Verified November 2014 by Stefan Zielen, Johann Wolfgang Goethe University Hospital.
Recruitment status was:  Recruiting
First Posted : November 7, 2014
Last Update Posted : November 7, 2014
Sponsor:
Information provided by (Responsible Party):
Stefan Zielen, Johann Wolfgang Goethe University Hospital

Brief Summary:
Ataxia telangiectasia (A-T) is a rare devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. The underlying mechanism and process of neurodegeneration leading to loss of cerebellar neurons and neurological function is largely unknown. Laboratory diagnostic approaches to neurodegeneration in A-T are hampered by sampling issues. It is dangerous, impractical, and not ethically to directly sample brain tissue by surgical biopsy. In contrast cerebrospinal fluid (CSF), a fluid that is in direct contact with brain tissue, is relatively easy to sample in a safe procedure (lumbar puncture). The aim of the proposal is to investigate oxidative stress, low grade inflammation and tissue break down in the brain of A-T patients by analyzing CSF. In addition the alterations in protein expression related to A-T will be quantified by liquid chromatography/mass spectrometry (LC/MS)-based proteomic analysis of CSF from healthy individuals and A-T patients to determine candidate proteins (new biomarkers) which relative expression levels could be used as surrogate marker of disease progression.

Condition or disease Intervention/treatment Phase
Ataxia Telangiectasia Procedure: Lumbar puncture Not Applicable

Detailed Description:

Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterized by progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and cancer susceptibility. For clinicians and scientists the underlying mechanism and process of neurodegeneration leading to loss of cerebellar neurons and neurological function is largely unknown. In addition no surrogate marker of neurological degeneration and disease progression exist.

Three major factors may be responsible for progression of neurodegeneration:

  1. A-T patients exhibit elevated levels of reactive oxygen species (ROS) and reduced anti-oxidative capacity. It has been proposed that ROS is responsible for destruction of the purkinje cells in the cerebellum.
  2. Ongoing low grade inflammation due to immunodeficiency. Elevated serum interleukin-8 (IL-8) levels in patients with A-T are postulated that systemic inflammation may contribute to the disease phenotype. How inflammation and neurodegeneration interact is, however, a matter of ongoing debate.
  3. Low levels of growth hormones (GH). Extracerebellar MRI - lesions in A-T go along with deficiency of the GH axis, high Ataxia scores and advanced age.

The aim of the proposal is to investigate oxidative stress, low grade inflammation, tissue breakdown and biomarkers in cerebrospinal fluid (CSF), a fluid that is in direct contact with central nervous system (CNS), of A-T patients.

  • To analyse functional gene expression of oxidative stress and low grade inflammation by means of reverse transcriptase-polymerase chain reaction (RT-PCR) and cytometric bead array.
  • To characterize the alterations in protein expression related to A-T, a LC/MS-based quantitative proteomic analysis of CSF from control and A-T patients
  • To compare alterations in protein expression levels in CSF with MRI findings in different age groups of classical A-T.
  • To determine candidate proteins whose relative expression levels could be used as surrogate marker of disease progression?
  • To established an analysis system on a basis of multiplex ELISA-technique to evaluate potential candidates/surrogate markers for disease progression in a larger cohort of patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of Patients With Ataxia Telangiectasia
Study Start Date : April 2013
Estimated Primary Completion Date : May 2015


Arm Intervention/treatment
Ataxia Telangiectasia
20 patients with clinically and/or genetically diagnosed Ataxia telangiectasia will get a lumbar puncture
Procedure: Lumbar puncture
Lumbar puncture is done according to general practice

Healthy Control
20 patients without inflammation, infection or any other pathology of the CNS, in that a lumbar puncture is indicated for either diagnostic or therapeutic reason (i.e. for the exclusion of a meningitis, subarachnoid hemorrhage or in therapeutic liquor drain in idiopathic intracranial hypertension)
Procedure: Lumbar puncture
Lumbar puncture is done according to general practice




Primary Outcome Measures :
  1. Concentration of IL-8 and oxidative stress in cerebrospinal fluid [ Time Frame: 24 months ]
    • To analyse functional gene expression of oxidative stress and low grade inflammation by means of RT-PCR and cytometric bead array.


Secondary Outcome Measures :
  1. Alterations in protein expression related to A-T [ Time Frame: 24 months ]
    • Alterations in protein expression related to A-T, a LC/MS-based quantitative proteomic analysis of CSF from controls and A-T patients

  2. Number of Participants with Adverse Events [ Time Frame: 24 months ]
    Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  3. Alterations in protein expression levels in CSF compared with MRI findings in different age groups of classical A-T. [ Time Frame: 24 months ]
  4. Alterations in protein expression levels in CSF with MRI findings in different age groups of classical A-T. Candidate proteins whose relative expression levels could be used as surrogate marker of disease progression. [ Time Frame: 24 months ]


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Ages Eligible for Study:   2 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Aim group: clinically and/or genetically diagnosed Ataxia telangiectasia; Control group: neurologic non-inflammatory disease with an indication for diagnostic or therapeutic lumbar puncture
  • age between 2 and 40 years
  • written informed consent

Exclusion Criteria:

  • fever or clinical signs of an infection
  • leucocyte count >12´000/µl and C reactive protein (CrP) >2mg/dl
  • chronic diseases with need of immunomodulatory therapies (bronchial asthma, rheumatoid arthritis)
  • medication with statins
  • other diseases with influence in the immunosystem (i.e. diabetes mellitus, malignoma, renal failure requiring dialysis)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02285348


Contacts
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Contact: Stefan Zielen, Prof. Dr. 0049-69-6301-83063 Stefan.Zielen@kgu.de
Contact: Ralf Schubert, Prof. Dr. 0049-69-6301-83063 ralf.schubert@kgu.de

Locations
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Germany
Johann Wolfgang Goethe University Hospitals Recruiting
Frankfurt, Hessen, Germany, 60590
Contact: Stefan Zielen, Prof.    004969630183063    stefan.zielen@kgu.de   
Contact: Sandra Voss, MD    004969630183063    sandra.voss@kgu.de   
Sub-Investigator: Ralf Schubert, Prof.         
Sub-Investigator: Matthias Kieslich, Prof.         
Sponsors and Collaborators
Johann Wolfgang Goethe University Hospital

Additional Information:
Publications:
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Responsible Party: Stefan Zielen, Stefan Zielen, Prof. Dr., Johann Wolfgang Goethe University Hospital
ClinicalTrials.gov Identifier: NCT02285348     History of Changes
Other Study ID Numbers: FRA-AT.CSF.2012
First Posted: November 7, 2014    Key Record Dates
Last Update Posted: November 7, 2014
Last Verified: November 2014
Keywords provided by Stefan Zielen, Johann Wolfgang Goethe University Hospital:
Ataxia Telangiectasia
cerebrospinal fluid
inflammation
proteomic analysis
Additional relevant MeSH terms:
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Ataxia
Cerebellar Ataxia
Ataxia Telangiectasia
Telangiectasis
Inflammation
Pathologic Processes
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Cerebellar Diseases
Brain Diseases
Central Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Spinocerebellar Ataxias
Neurocutaneous Syndromes
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Immunologic Deficiency Syndromes
Immune System Diseases