Table 1.
Hypothesis driven investigation of biomarkers in ALS-FTD spectrum diseases.
| Biomarker | ALS | FTD | AD | Sample | Ref. | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical Subtypes | Pathology Subtypes | Genetic Subtypes | |||||||||||||
| all | C9ORF72 | all | bvFTD | PPA | FTD-ALS | -TDP | -Tau | C9ORF72 | GRN | MAPT | |||||
| SD | PNFA | ||||||||||||||
| Neurofilaments + | ↑ (vs. controls, FTD-ALS, FTD, AD) |
↑ (vs. asymptomatic C9-carriers, C9-FTD) |
↑ (vs. controls, AD) |
↑ (vs. controls) |
↑ (vs. controls) |
↑ (vs. controls) |
↑ (vs. controls, bvFTD, PPA) – (vs. FTD) |
Not sufficiently studied (n = 2) |
Not sufficiently studied (n = 2) |
↑ (vs. asympomatic C9-carriers, sporadic FTD) |
↑ (vs. asympomatic GRN-carriers, sporadic FTD, C9-FTD, MAPT-FTD) |
↑ (vs. asympomatic MAPT-carriers) |
↑ (vs. controls) |
CSF Serum |
[144,145,146,147,148,149,150] |
| CHIT1 | ↑ (vs. controls, FTD, AD) |
↑ (vs. controls, asymptomatic carriers, genetic FTD) * |
↑ (vs. controls, not vs. ALS, AD) |
– (vs. PPA, FTD-ALS) |
– (vs. bvFTD, FTD-ALS) |
– (vs. bvFTD, PPA) |
Not sufficiently studied | Not sufficiently studied | ↑ (vs. controls, asymptomatic carriers) * |
Not studied | Not studied | ↑ (vs. controls, not vs. FTD) |
CSF | [109,112,113] | |
| YKL-40 | ↑ (vs. controls, not vs. ALS) |
↑ (vs. controls, asymptomatic carriers, not vs. genetic FTD) * |
↑ (vs. controls, slighty vs. ALS, not vs. AD) |
– (vs. PPA, FTD-ALS) |
– (vs. bvFTD, FTD-ALS) |
↑ (vs. bvFTD, not PPA) |
Not sufficiently studied | Not sufficiently studied | ↑ (vs. controls, asymptomatic carriers, not vs. genetic ALS) * |
Not studied | Not studied | ↑ (vs. controls, not vs. FTD) |
CSF | [112,113] | |
| GFAP | – (vs. controls) |
– (vs. controls, asymptomatic carriers) * |
↑ (vs. controls, ALS, not vs. AD) |
– (vs. PPA, FTD-ALS) |
– (vs. bvFTD, FTD-ALS) |
– (vs. bvFTD, not PPA) |
Not sufficiently studied | Not sufficiently studied | ↑ (vs. controls, asymptomatic carriers, genetic ALS) * |
Not studied | Not studied | ↑ (vs. controls, not vs. FTD) |
CSF | [112,113] | |
| TREM2 | ↑ (vs. controls) |
Not studied | – (vs. controls) |
– (vs. controls, PPA) |
– (vs. controls, bvFTD) |
– (vs. controls, bvFTD) |
Not studied | Not studied | Not studied | – (vs. controls, C9-FTD, MAPT-FTD) |
↑ (vs. controls, C9-FTD, MAPT-FTD) |
– (vs. controls, C9-FTD, MAPT-FTD) |
↑ (vs. controls) |
CSF | [96,151,152] |
| Progranulin | – (vs. controls, GRN-negative FTD, AD) |
Not studied | ↓ (vs. controls) |
↓ (bvFTD and SD vs. controls, PNFA) |
↓ (SD and bvFTD vs. controls, PNFA) |
– (vs. controls) |
Not studied | Not studied | Not studied | – (vs. controls) |
↓ (vs. controls) – (vs. asymptomatic carriers) |
Not studied | ↓ (vs. controls) |
Plasma CSF |
[153,154,155,156] |
| Neurogranin | ↓ (vs. AD) |
Not studied | ↓ (vs. AD, controls) |
↓ (vs. AD) – (vs. SD, PNFA) |
↓ (vs. AD) – (vs. bvFTD, PNFA) |
↓ (vs. AD) – (vs. bvFTD, SD) |
Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | ↑ (vs. controls, ALS, FTD) |
CSF | [157,158] |
| SNAP-25 | Not studied | Not studied | – (vs. controls) |
Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | ↑ (vs. controls) |
CSF | [159,160] |
| Transthyretin | ↑/↓ (vs. controls) |
Not studied | ↑ (vs. controls) |
Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | ↑/↓ (vs. controls) |
CSF | [161,162,163] |
| Clusterin | ↓ (vs. controls) |
Not studied | ↑ (vs. controls) |
Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | Not studied | ↑ (vs. controls) |
Serum plasma |
[164,165,166] |
| p/t ratio | Not studied | Not studied | ↓ (vs. controls) |
↓ (vs. controls) |
↓ (vs. controls) |
↓ (vs. controls) |
↓ (vs. controls, FTD without ALS, AD) |
Not sufficiently studied | Not sufficiently studied | Not studied | Not studied | Not studied | ↓ (vs. controls, FTD) |
CSF | [150,167,168] |
| TDP-43 | ↑ (vs. controls, FTD) |
↑ (vs. controls, FTD, C9-FTD) |
↓ (vs. ALS, C9-ALS) ↑ (vs. controls) |
↓ (vs. controls) |
– (vs. controls, FTD) |
– (vs. controls, FTD) |
↓ (vs. FTD, controls) |
↓ (vs. FTD-Tau) |
Not sufficiently studied | ↓ (vs. GRN-FTD) |
↑ (vs. C9-FTD) |
↑ (vs. FTD-TDP) |
↓ (vs. FTD-TDP, FTD, AD-TDP) ↑ (vs. controls) |
CSF serum |
[169,170,171,172,173,174,175] |
↑/↓ arrows indicate increased or decreased biomarker levels. Arrows do not always reflect statistical significance. + includes neurofilament light and phosphorylated heavy chain levels, * genetic ALS/FTD with the majority being C9ORF72-carriers. AD—Alzheimer’s disease, ALS—Amyotrophic lateral sclerosis, FTD—Frontotemporal dementia, bvFTD—Behavioral variant frontotemporal dementia, GRN—Granulin, PNFA—Progressive non-fluent aphasia, PPA—Primary progressive aphasia, SD—Semantic dementia.