A study published in Nature Medicine finds that a type of particle associated with specific cell subtypes could potentially be utilized as a biomarker for FTD and ALS disorders. The particle, known as an “extracellular vesicle,” contains tau and TDP-43 proteins, which are both altered with FTD-ALS.
Extracellular Vesicles Facilitate Spread of FTD Proteins
Extracellular vesicles (EVs) are naturally released from most types of cells and play a key role in cell-to-cell communication by transporting proteins, lipids, and RNA between cells.
FTD and ALS are proteinopathies, a condition or disease caused by the dysfunction of proteins like tau and TDP-43. While tau levels in the bloodstream can identify people with Alzheimer’s disease early in progression, its use as a biomarker in other tauopathies is hampered by tau fragmentation in fluids outside of cells. Researchers have looked at levels of other pathological forms of tau and TDP-43 in plasma and cerebrospinal fluid (CSF) as biomarkers, with studies underway to make improved assays better capable of detecting the protein in blood and CSF.
However, EVs are known to transport healthy proteins and pathological forms of tau and TDP-43 between cells, protecting them and facilitating the formation of protein clumps that play a crucial role in FTD and ALS. Anja Schneider, MD, and researchers at the German Center for Neurodegenerative Diseases (DZNE) launched a pilot study to evaluate whether tau and TDP-43 levels in EVs could be biomarkers for FTD and ALS disorders.
The pilot study included 704 participants from the DZNE Clinical Register Study of Neurodegenerative Diseases (also known as “DESCRIBE”), including 37 people with genetically confirmed cases. Participants had a diagnosis of either behavioral variant FTD (bvFTD), progressive supranuclear palsy (PSP), Alzheimer’s disease, semantic variant primary progressive aphasia (svPPA), or ALS.
Tau and TDP-43 Levels in Extracellular Vesicles Can Distinguish FTD Disorders
A main area of focus for the study was the proportion of two different forms of tau to one another, known as “three repeat” and “four repeat” tau (3R and 4R) subtypes or isoforms. While 3R and 4R tau levels are typically balanced in healthy individuals, diseases like FTD and ALS can disrupt this and cause one form to become more prominent. Researchers found that the ratio of 3R to 4R tau in bvFTD, svPPA, and Alzheimer’s disease was skewed towards 3R. In PSP, which is associated with 4R tau, the skewed ratio was reversed.
The researchers noted that the ratio reflected disease severity but differed by disorder. For bvFTD, for example, a higher ratio of 3R/4R tau indicated that people experienced more severe symptoms, while a lower 3R/4R ratio was observed in people with PSP.
While there was no secondary protein against which to compare TDP-43, researchers noted that higher levels of pathological TDP-43 in EVs correlated with increased disease severity. TDP-43 levels could also be used to discriminate between disorders similarly to tau; EVs in people with ALS had 45 picograms per milliliter (pg/ml) of TDP-43, while people with PSP and control participants without FTD had approximately 9 pg/ml of TDP-43 on average.
Together, the biomarkers could be used to diagnose bvFTD, which is notoriously difficult to diagnose clinically due to its symptomology, which overlaps with other neurodegenerative diseases and psychiatric disorders. The study authors found that in people with FTD-causing genetic mutations, EVs reflected the proteinopathy associated with the mutation. In people with a C9orf72 mutation, which is associated with TDP-43, the 3R/4R tau ratio was 1.0, while TDP-43 levels were heightened – the opposite was true for people with a tau-associated MAPT mutation, with the tau ratio three to four times higher and TDP-43 reduced.
To validate their findings, the authors turned to a second cohort of participants outside of DESCRIBE, obtaining data from a group of people with FTD who participated in research at the Hospital de la Santa Creu i Sant Pau in Spain. The group included 65 people with ALS, 58 with ALS-FTD, 50 with bvFTD, 41 with PSP, and 23 with an FTD risk gene, as well as 50 without FTD to serve as controls. The researchers discovered that the data from the Spanish cohort, by and large, matched the data from the initial cohort.
While some researchers believe that the tested EVs originate in the brain, there is ongoing discussion about the possibility that they did not. While the origin of the EVs does not matter much for clinical testing, Dr. Schneider noted that finding the origin may be necessary for clinical trials.
“If you want to measure target engagement, then it would be nice to Dr. Schneider told Alzforum. “We need better ways to detect brain-derived extracellular vesicles.”
Are you interested in learning more about the search for FTD biomarkers? In May, the Foundation for the National Institutes of Health Biomarkers Consortium announced that the US FDA accepted its letter of intent to qualify a protein as a biomarker for the onset of genetic FTD symptoms.
Stay updated on opportunities to participate in research by joining the FTD Disorders Registry. The Registry is a powerful tool that connects people with lived experience to studies and allows them to share their insights with researchers, in order to drive FTD research forward.
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