An investigator-initiated prospective, longitudinal, single center, observational study to investigate biomarkers of TDP-43 and oxidized lipid metabolism in Amyotrophic Lateral Sclerosis (ALS).

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder
characterized by the degeneration of motor neurons in the brain and spinal cord
leading to muscle weakness, paralysis, and ultimately death. The exact cause of
ALS is not fully understood. Developing biomarkers in ALS is crucial.
Biomarkers can aid diagnosis, track disease progression, and monitor treatment
response. Biomarkers can also offer insights into ALS's molecular and cellular
pathways, aiding in new therapeutic developments.
Protein aggregation and inclusion body formation are hallmarks of
neurodegenerative diseases, including ALS. The common proteinopathy in sporadic
ALS (sALS) is the aggregation of wild-type TDP-43. Aggregation is mediated by
both the loss of function and the gain of toxic function of the TDP-43 protein.
Additionally, recent studies have shown that ALS spinal motor neurons have
altered lipid metabolism, with an upregulation of pathways related to
glycerophospholipid metabolism and a specific increase of phosphatidylcholines
(PC). Oxidative stress potentiates the oxidation of PCs at the cellular
membrane, generating phosphatidylcholines (OxPC), which have been linked to
many pathologies.
Identifying biomarkers associated with TDP-43 and OxPC levels in CSF and blood
samples of ALS patients could aid to the development of new therapeutic
approaches targeting TDP-43 and OxPC toxicity in the early stages of the
disease. Neurofilament light (NfL) is identified as a significant biomarker of
neuronal damage and has been found to correlate with disease progression and
severity in ALS patients, its potential as a pharmacodynamic biomarker is
noted.

Primary Objective: To characterise longitudinal changes in biomarkers of TDP-43
pathology and oxidized lipid metabolism in ALS patients.
Secondary Objective: To characterize the relationship of longitudinal changes
in these biomarkers to changes in the phenotypical characteristics of the
disease.

Observational, single center, longitudinal, cohort study. biospecimens: blood
will be collected at 4-monthly intervals during a 12-month observation period
and cerebrospinal fluid (CSF) will be collected at baseline and at 12 months.

This is an observational study. Four study visits take please, at month 0, 4, 8
and 12, including blood sampling (month 0, 4, 8, 12) and lumbar puncture (month
0 and 12). The frequency of lumber punctures is determined by the natural
history of ALS and the changes anticipated over a 12-month interval. 6 ml of
CSF and a maximum of 20 ml blood will be collected on each occasion. Subjects
will be closely monitored up to discharge and are free to withdraw from the
study at any stage and for any reason. Participants may opt to participate at
only the baseline visit or at any of the subsequent follow-up visits. Lumbar
puncture is generally considered a safe procedure when performed by a skilled
clinician, and any discomfort or side effects are usually temporary.
Post-lumbar puncture headache is the most common side effect of lumbar puncture
occurring in 25% of the patients.
Analysis of the CSF can provide insight into the disease processes in ALS that
cannot be obtained by other procedures. The hypothesis of this study is that
identifying biomarkers associated with TDP-43 and OxPC levels in CSF and blood
samples of ALS patients could aid to the development of new therapeutic
approaches targeting TDP-43 and OxPC toxicity in the early stages of the
disease.
Given these considerations, the potential scientific benefits of performing a
lumbar puncture in an observational study are likely to outweigh the risks,
provided the procedure is carried out correctly and ethically, and informed
consent is obtained.
All procedures are not part of regular care and are additional assessments.