Table 3.
Studies showing the use of EVs as biomarkers in patients with ALS. Abbreviations: AD—Alzheimer’s Disease, DC—disease control, FTD—Frontotemporal dementia, HC—Healthy control, SBMA—spinal bulbar muscular atrophy, MD—muscular dystrophy, PD—Parkinson’s Disease, LMVs—Leukocyte derived microvesicles, ALSFRS—ALS functional rating scale, IL-6—Interleukin-6, IP—immunoprecipitation, UC—ultracentrifugation, NBI—nickel based isolation, PEG—polyethylene glycol, NOC2l—Nucleolar complex protein 2 homolog, PDCD6IP—Programmed cell death 6-interacting protein, VCAN—Versican core protein, BLMH—bleomycin hydrolase, HSP90—Heat shock protein 90, PPIA—peptidyl-prolyl cis-trans isomerase A.
| Study | Source | Isolation Method | Patients | Metabolites Analysed | Results |
|---|---|---|---|---|---|
| Protein | |||||
| Feneberg et al. 2014 [138] | CSF-Exosomes | UC | 9 ALS, 4 FTD, 8 HC | TDP 43 | TDP 43 detectable in EVs but not different between groups |
| Sproviero et al. 2018 [139] | Plasma- exosomes and MVs | Filtration and UC | 30 ALS, 30 HC | SOD1, TDP 43 and FUS | Increased SOD1, TDP 43, phosphorylated TDP 43 and FUS in ALS MVs |
| Chen et al. 2019 [112] | Plasma- astrocyte derived exosomes | Polymer based precipitation followed by IP with anti-ACSA-1 | 40 ALS, 39 HC | IL-6 | IL-6 increased in ALS and correlated with rate of ALSFRS change |
| Sproviero et al. 2019 [140] | Plasma-Leukocyte, endothelial, platelet and erythrocyte derived MVs | UC followed by IP with anti-CD45 | 40 ALS, 36 HC, 28 AD | SOD1, TDP 43 | Misfolded SOD1 detectable in plasma LMVs SOD1 levels in LMVs correlated with rate of ALSFRS change in slow progressors |
| Chen et al. 2020 [141] | Plasma-exosome | IP with anti CD63 | 18 ALS | FUS | FUS present and increased at 3 and 6 months |
| Hayashi et al. 2020 [142] | CSF-exosomes | Size exclusion chromatography | 3 ALS, 3 NPH | 334 proteins | NOC2l, PDCD6IP, VCAN increased in ALS 11 proteins decreased |
| Thompson et al. 2020 [143] | CSF- EVs | Ultrafiltration liquid chromatography | 12 ALS, 5 HC | 1020 proteins | Downregulation of BLMH |
| Pasetto et al. 2021 [144] | Plasma- EVs | UC and NBI | 106 ALS, 36 HC, 32 SBMA, 28 MD | TDP 43, HSP90 and PPIA | HSP90 reduced in ALS compared to HC and SBMA ALS EVs smaller than SBMA |
| Micro RNA | |||||
| Xu et al. 2018 [145] | Serum-exosomes | membrane affinity spin columns | 10 ALS, 20 HC | miR-27a-3p | miR-27a-3p downregulated in ALS |
| Katsu et al. 2019 [113] | Plasma- neural derived EVs | PEG precipitation followed by IP with anti CD171 | 5 ALS, 5 HC | 332 miRNAs | 13 upregulated miRNAs, greatest increase in 4736, 4700-5p, 1207-5p, 4739, 4505 17 downregulated miRNAs |
| Saucier et al. 2019 [115] | Serum-EVs | Vn96 peptide affinity capture | 14 ALS, 12 HC | Total miRNA profile | Upregulated 532-3p, 144-3p, 15a-5p, 363-3p and 183-5p 22 downregulated miRs, greatest reduction in 4454, 9-1-5p and, 9-3-5p, 338-3p and 9-2-5p |
| Banack et al. 2020 [116] | Plasma-neural derived | PEG precipitation followed by IP with anti CD171 | 20 ALS, 20 HC | 34 miRNAs | Upregulated 146a-5p, 199a-3p, 151-a-3p, 151a-5p, 199a-5p Downregulated 4454, 10b-5p, 29b-3p |
| Yelick et al. 2020 [146] | CSF-EVs | Polymer based precipitation | 14 ALS, 9 DC, 9 HC | miR-124-3p | miR-124-3p correlated with ALSFRS in males with ALS |
| Pregnolato et al. 2021 [147] | Plasma- exosome miRNA | Polymer based precipitation | 7 ALS, 3 HC | 179 miRNAs | No difference in miRNA expression |
| Sproviero et al. 2021 [114] | Plasma—large and small EVs | Filtration and UC | 6 ALS, 9 FTD, 6 AD, 9 PD, 6 HC | total miRNA | 45 upregulated and 22 downregulated miRNA in both small and large EVs in ALS vs. HC |
| Banack et al. 2022 [117] | Plasma-neural derived | PEG precipitation followed by IP with anti CD171 | 50 ALS, 50 HC |
8 miRNAs | Upregulated 4a-5p, 146a-5p Downregulated 4454, 10b-5p and 29b-3p |
| Messenger RNA | |||||
| Otake et al. 2019 [127] | CSF- EVs | membrane affinity spin columns | 4 ALS, 4 HC | 5006 mRNAs | 133 upregulated 410 downregulated |
| Sproviero et al. 2022 [128] | Plasma—large and small EVs | Filtration and UC | 6 ALS, 9 FTD, 6 AD, 9 PD, 6 HC | Total mRNA | 542 upregulated 88 downregulated |
| Lipids | |||||
| Morasso et al. 2020 [137] | Plasma EVs | UC | 20 ALS, 20 HC | Raman spectra | Total lipid content increased in ALS Phenylalanine decreased |