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Project Topic
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Amyotrophic lateral sclerosis (ALS) is the most frequent motoneuron disease with a devastating prognosis. Even
today, it takes on average 12 months from the onset of motor symptoms to establish the diagnosis of ALS and
approximately half of the patients are initially misdiagnosed. Although several molecules have been proposed as
biomarker candidates, such as neurofilaments in serum and cerebrospinal fluid (CSF), or soluble p75ECD in urine, a
clinically established signature for an early or even premotor diagnosis of ALS is not available. Due to the already
advanced disease stage at the time of diagnosis as well as rapid disease progression, an early diagnosis is mandatory
for efficacious disease-modifying therapies. About 10% of all ALS patients have a genetic cause and genetic testing
can identify premotor gene mutation carriers (PGMC) among family members of these familial ALS patients. PGMC
are at risk to develop the disease due to the causative gene mutation, but have not yet developed motor symptoms.
In this project, we will develop a clinico-molecular fingerprint of PGMC that will shed light on the molecular
pathogenesis of ALS and allow for a timelier diagnosis. We will recruit PGMC (n=80) and control subjects (n=40),
through expert centers and their networks in Germany, France, Switzerland, Israel. Longitudinal data and CSF
samples from 20 gene carriers who have already developed motor symptoms of ALS will also be included through
cooperation with M. Benatar/USA. All subjects will be asked to (1) complete a questionnaire about current and past
clinical symptoms and environmental factors spanning the last 10 years of their life, to (2) donate biological samples
(blood, urine, tear fluid, and CSF), and perform a smell test. Tear fluid, blood plasma and CSF samples will be used
to analyze the proteomic profile of the PGMC cohort using a combination of discovery mass spectrometry and
targeted immunoassays. In addition, we will test for established biomarker candidates, such as Nf-L (blood), sp75ECD
(urine), tau/p-tau and GFAP (CSF). Clinical data obtained in the questionnaire and molecular data will be integrated
to create a clinico-molecular fingerprint of PGMC. Two evaluations will be performed at an interval of one year to
characterize the evolution of the fingerprint in ALS and control subjects.
Previously obtained data from multiple studies in ALS patients and control subjects will guide our analysis to identify
features in the PGMC fingerprint that have the best discriminatory power for ALS: The questionnaire will leverage the
ongoing EARLY-ALS trial which assesses early symptoms and environmental influences based on a patient survey
in several hundreds of ALS patients in Germany. Data from the EARLY-ALS trial will be used to adapt the questions
for the present project selecting those that most accurately differentiate between ALS and control subjects.
Furthermore, we have characterized the multi-omic landscape of CSF in ALS patients (within the scope of the
currently funded E-Rare MAXOMOD consortium) and we recently extended this analysis by the differential proteome
derived from tear fluid of ALS patients.
Finally, the PGMC fingerprint will be subjected to biological validation on a cohort with pure motor symptoms, which
comprises patients at very early stages of ALS, or one of its clinical mimics (n=100). This cohort will be collected in
parallel at all clinical sites. We expect that the clinico-molecular fingerprint will not only improve diagnostic accuracy,
but also yield information about molecular and pathophysiological causes driving ALS, ultimately empowering
efficacious treatment strategies
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