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

August 30, 2021 updated by: Stefan Zielen, Johann Wolfgang Goethe University Hospital

Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of Patients With Ataxia Telangiectasia

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
    • Hessen
      • Frankfurt, Hessen, Germany, 60590
        • Johann Wolfgang Goethe University Hospitals

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 40 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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
Other: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
24 months
Number of Participants with Adverse Events
Time Frame: 24 months
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
24 months
Alterations in protein expression levels in CSF compared with MRI findings in different age groups of classical A-T.
Time Frame: 24 months
24 months
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
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johann Wolfgang Goethe University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 1, 2013

Primary Completion (Actual)

May 30, 2015

Study Completion (Actual)

July 31, 2017

Study Registration Dates

First Submitted

October 28, 2014

First Submitted That Met QC Criteria

November 6, 2014

First Posted (Estimate)

November 7, 2014

Study Record Updates

Last Update Posted (Actual)

August 31, 2021

Last Update Submitted That Met QC Criteria

August 30, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • FRA-AT.CSF.2012

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Ataxia Telangiectasia

Clinical Trials on Lumbar puncture

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Malaysia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe