Oxidative Stress, Low Grade Inflammation, Tissue Breakdown and Biomarkers in Cerebrospinal Fluid of A-T
Condition: Ataxia Telangiectasia
MeSH terms: Ataxia; Cerebellar Ataxia; Ataxia Telangiectasia; Telangiectasis; Inflammation
Study type: Interventional

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.
    

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.
    

Intervention name(s): Lumbar puncture
Intervention type(s): Procedure
Intervention description(s): Lumbar puncture is done according to general practice
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Ataxia Telangiectasia; cerebrospinal fluid; inflammation; proteomic analysis