Table 1.
Classification of potential biomarkers of metabolism in amyotrophic lateral sclerosis (ALS).
| Marker | Observation | Utility as a biomarker in ALS | Biomarker Score | References | |||||
|---|---|---|---|---|---|---|---|---|---|
| Specific to ALS | Reproducible | Pre-diagnostic | Diurnal stability | Independence | Change with progression | ||||
| ANTHROPOMETRIC MARKERS | |||||||||
| Body mass index (BMI) | Lower BMI is an indicator of poor prognosis. U-shaped association; lower BMI is associated with increased risk and faster progression whereas BMI in the range of morbid obesity is associated with shorter survival. Degree of premorbid loss of BMI predicts risk of ALS | N | N | Y | Y | N | Variable | 2.5 | (8, 11–22) |
| Body weight | Weight loss correlates with faster disease progression; weight loss suggested as a risk factor for ALS | N | N | N | Y | N | Variable | 1.5 | (14, 21, 23–27) |
| Fat mass | Fat mass at diagnosis is not a determinant of survival. Increased fat mass is correlated with longer survival | N | N | Insufficient data | Y | N | Y | 2 | (14, 28) |
| Fat free mass | Fat free mass at diagnosis is not a determinant of survival. Loss of fat free mass is associated with shorter survival | N | Y | Insufficient data | Y | N | Y | 3 | (14, 23) |
| Fat distribution | Redistribution and increased deposition of fat in muscle | N | Insufficient data | Insufficient data | Y | N | Insufficient data | 1 | (29) |
| IMAGING MARKERS | |||||||||
| Brain glucose use | Hypometabolism specific to select brain regions; varies between studies | N | Insufficient data | Insufficient data | Likely | Likely | Y | 2 | (30–33) |
| Spinal cord glucose use | Hypermetabolism; changes in glucose metabolism correlates with disease progression | N | Insufficient data | Insufficient data | Likely | Likely | Variable | 1.5 | (34, 35) |
| MUSCLE MARKERS | |||||||||
| Creatine kinase | Increased in blood; variability in correlation with disease progression/survival. Greater increase observed in male subjects and limb-onset ALS | N | Y | Y | Likely | Likely | Variable | 3.5 | (36–43) |
| Mitochondrial function | Decreased activity of complex I and IV. Activity also declines over course of disease | N | Insufficient data | Insufficient data | Y | Y | Variable | 2.5 | (44, 45) |
| PDK4 levels | Increase in pyruvate dehydrogenase kinase 4 (PDK4) correlated with increased denervation and fuel switch | N | Insufficient data | Insufficient data | Y | Y | Likely | 2.5 | (46) |
| Glucose | Increased | N | N | Insufficient data | N | N | N | 0 | (47) |
| Sphingolipids | Increased | N | Insufficient data | Insufficient data | N | N | Y | 1 | (48) |
| Phosphatidylcholine | Increased | N | Insufficient data | Insufficient data | N | N | N | 0 | (48) |
| Cholesterol + Carriers | Increased | N | Insufficient data | Insufficient data | N | N | N | 0 | (49) |
| Lactate | Increased | N | Insufficient data | Insufficient data | N | N | Insufficient data | 0 | (47, 50) |
| CEREBROSPINAL FLUID (CSF) MARKERS | |||||||||
| Pyruvate | Increased | N | Insufficient data | Insufficient data | N | N | Insufficient data | 0 | (51) |
| Insulin | Decreased | N | Insufficient data | Insufficient data | N | N | N | 0 | (52) |
| Growth hormone | Decreased | N | Insufficient data | Insufficient data | N | N | N | 0 | (52) |
| CIRCULATING MARKERS (BLOOD, PLASMA AND SERUM) | |||||||||
| Glucose | Increased (33% of patients achieve World Health Organization (WHO) criteria for impaired glucose tolerance) | N | N | Insufficient data | N | N | N | 0 | (53) |
| Mannose | Increased | N | N | Insufficient data | N | N | Insufficient data | 0 | (54) |
| Free fatty acids | Increased | N | N | Insufficient data | N | N | N | 0 | (53) |
| Sphingolipids | Increased | N | N | Insufficient data | N | N | N | 0 | (54) |
| Cholesterol + Carriers | Major variations and contradictory reports mask any specific trend | N | N | Insufficient data | N | N | Variable | 0.5 | (53, 55–62) |
| β-hydroxy-butyrate | Increased | N | N | Insufficient data | N | N | Insufficient data | 0 | (63) |
| 2-hydroxy-butyrate | Increased | N | N | Insufficient data | N | N | Insufficient data | 0 | (54) |
| α-ketoglutarate | Increased | N | N | Insufficient data | N | N | Insufficient data | 0 | (54) |
| Acetate | Increased | N | N | Insufficient data | N | N | Insufficient data | 0 | (63) |
| Adiponectin | Increased | N | N | Insufficient data | N | N | N | 0 | (64) |
| Cortisol | Increased | N | N | Insufficient data | N | N | N | 0 | (65) |
| Cortisol (morning peak) | Decreased | N | N | Insufficient data | N | N | N | 0 | (65) |
| Insulin | Decreased | N | N | Insufficient data | N | N | N | 0 | (52, 64) |
| Gastric inhibitory peptide | Decreased | N | N | Insufficient data | N | N | N | 0 | (64) |
| Ghrelin | Decreased | N | N | Insufficient data | N | N | N | 0 | (64, 66) |
| SALIVA MARKERS | |||||||||
| Cortisol (night-time) | Increased | N | Insufficient data | Insufficient data | N | Likely | Insufficient data | 0.5 | (67) |
| Cortisol (Stress-induced) | Decreased | N | Insufficient data | Insufficient data | N | Likely | Insufficient data | 0.5 | (67) |
| Cortisol (circadian rhythm) | Decreased | N | Insufficient data | Insufficient data | N | Likely | Insufficient data | 0.5 | (67) |
| URINE MARKERS | |||||||||
| p75 neurotrophin receptor extracellular domain | Increased | N | Likely | Insufficient data | Y | Y | Y | 3.5 | (68) |
The strength of proposed biomarkers are scored relative to their potential to serve as markers that are specific to ALS, and that conform to the requirements as detailed in text.
Specific to ALS refers to uniqueness of the marker to ALS over other diseases, reproducible refers to whether the indicated change is reproducible across patient cohorts, pre-diagnostic indicates where changes are apparent prior to symptom onset, diurnal stability refers to the consistency of the marker throughout the day, independence indicates the ability of the marker to remain stable regardless of changes in food intake or behavior, change with progression identifies whether the marker changes as disease progresses. For each potential biomarker, a score out of 6 was determined (biomarker score, indicated in bold), where Y (Yes) = 1 point, N (No) = 0 points, Variable = 0.5 points, Likely (supported by animal or statistical modeling studies) = 0.5 points, and Insufficient data = 0 points.