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Figure 1. Plasma extracellular vesicle tau and TDP-43 proteins aid in the diagnosis of FTD and ALS spectrum disorders. In neurons of patients with FTD and ALS spectrum disorders, alternative splicing of the tau gene produces 3R tau and 4R tau isoforms. Under normal conditions, 3-repeat and 4-repeat tau are present in approximately equal amounts in the adult brain. However, in patients with FTD and ALS, the ratio of 3R to 4R tau may become abnormal. Some tau protein is directly secreted into the extracellular space and is cleaved by extracellular proteases, resulting in fragmented tau in the extracellular fluid and very low levels of full-length tau protein. Another portion of tau protein is released into the extracellular environment in the form of EVs. Additionally, in FTD and ALS patients, TDP-43 protein abnormally accumulates in the cytoplasm, forming inclusions (abnormal nuclear localization), with some being carried extracellularly via EVs. By collecting EVs from patient blood and cerebrospinal fluid, TDP-43 levels and 3R/4R tau ratios can be measured. Based on the detection thresholds, different pathologies and diagnostic groups can be distinguished. The blue arrow represents downregulation, and the red arrow represents upregulation. FTD: Frontotemporal dementia; ALS: amyotrophic lateral sclerosis; Evs: extracellular vesicles; CSF: cerebrospinal fluid; PSP: progressive supranuclear palsy.