Urinary biomarkers for amyotrophic lateral sclerosis: candidates, opportunities and considerations

Abstract

Amyotrophic lateral sclerosis is a relentless neurodegenerative disease that is mostly fatal within 3-5 years and is diagnosed on evidence of progressive upper and lower motor neuron degeneration. Around 15% of those with amyotrophic lateral sclerosis also have frontotemporal degeneration, and gene mutations account for ∼10%. Amyotrophic lateral sclerosis is a variable heterogeneous disease, and it is becoming increasingly clear that numerous different disease processes culminate in the final degeneration of motor neurons. There is a profound need to clearly articulate and measure pathological process that occurs. Such information is needed to tailor treatments to individuals with amyotrophic lateral sclerosis according to an individual's pathological fingerprint. For new candidate therapies, there is also a need for methods to select patients according to expected treatment outcomes and measure the success, or not, of treatments. Biomarkers are essential tools to fulfil these needs, and urine is a rich source for candidate biofluid biomarkers. This review will describe promising candidate urinary biomarkers of amyotrophic lateral sclerosis and other possible urinary candidates in future areas of investigation as well as the limitations of urinary biomarkers.

Keywords: ALS; biomarker; metabolites; proteins; urine.

Graphical Abstract

Figure 1

Urinary biomarkers for ALS derived from normal kidney function. Urine is a rich source of candidate ALS biomarkers, whose solute content is determined by the size and charge of components passing through the nephrons. The functional unit of the kidney is the nephron that consists of the glomerulus, which filters blood, and the renal tubule, which reabsorbs necessary components back into the blood. These components include salts like sodium chloride (NaCl), potassium (K⁺) and chloride (Cl⁻) ions. Hydrogen (H⁺), ammonia (NH₃⁺) and bicarbonate (HCO₃⁻) are among other ions that are reabsorbed, alongside glucose, amino acids, vitamins and urea. All the blood metabolites and proteins less than 20 kDa in size pass through the nephron and into the urine. Most proteins of 20–50 kDa size are excreted, while only some 50–70 kDa proteins, especially cationic proteins, are excreted. Most proteins larger than 60–70 kDa are actively transported back into blood at the proximal convoluted tubule. Levels of other urinary components such as salts and urea are determined by their active and passive transport along the tubule, while most vesicles found in urine are derived from the urogenital system.

Figure 2

Urinary biomarker development and implementation for ALS. The urinary biomarker development includes discovery, validation and utilization. Urine samples are collected from people with ALS and controls for discovery-type experiments. Biomarkers are isolated, measured and compared with clinical characteristics and pathology to determine if a possible candidate biomarker. The biomarkers are then validated across larger cohorts of ALS and controls, including mimic diseases. Validated prognostic, pharmacodynamic and predictive biomarkers can then be utilized to reduce heterogeneity and determine efficacy in clinical trials and determine outcomes (drug was a success or not).