Frontotemporal Dementia (FTD) is the second most common form of early-onset dementia, but no effective treatments are currently available. Although FTD symptoms are highly variable, the presence of harmful deposits of proteins in the brains of patients results in distinct disease subgroups. The toxic protein deposits consist of either TDP-43 or tau, which cause FTD through different mechanisms and will likely need different treatments. This poses a major problem for researchers, as at present we are only able to confirm whether a patient has the TDP-43 FTD or the tau FTD when the brain is examined after death. FTD research is slow partly because in life we cannot tell if someone has TDP-43 FTD or tau FTD. This means we are unable to decide whether a patient should go into trials of drugs to treat TDP-43 FTD or tau FTD. Before we can test treatments in patients with FTD we must be able to determine which type of FTD they have.
About 50% of FTD patients have TDP-43 pathology, but so far efforts to detect TDP-43 itself in living patients have been unsuccessful. A team of researchers have attempted to overcome this issue, by looking for changes or ‘biomarkers’ in the bodies of people with FTD, that mark them out as having TDP-43 FTD. In this paper they explore the relationship of stathmin-2 with TDP-43 and its suitability as a biomarker. Stathmin-2 is a protein found in nerve cells that has functions linked with repair and maintenance of the nerve cell structure.
First, the researchers used nerve cells grown in a lab, showing that a shortened version of the protein known as truncated stathmin-2 accumulates only in the presence of the harmful TDP-43 deposits. Next, they used post-mortem brain tissue donated from FTD patients, and extracted RNA – the set of instructions cells use to make proteins. The shortened stathmin-2 RNA was found to be higher in the TDP-43 FTD patient group, but importantly not in individuals without any neurological disease, or those with PSP, a different neurological disease associated with tau but not TDP-43. This indicates shortened stathmin-2 may be specifically associated with TDP-43 pathology, and therefore may be viable as a biomarker. Researchers believe this is because TDP-43 directly regulates stathmin-2. They argue that in FTD, TDP-43 becomes dysfunctional, and only then does this lead to the production of the shortened form of stathmin-2. Therefore, if researchers can detect the stathmin-2 in this shortened form it shows the patient must belong to the TDP-43 group.
This study is not exhaustive, and the authors raise several significant challenges ahead before stathmin-2 could be used in a clinical setting. More work is needed to establish that shortened stathmin-2 is a true proxy for TDP-43 pathology and will be sensitive enough to reliably detect TDP-43 patients without misidentifying patients with other pathologies. The study authors highlight the need to determine the point in FTD in which shortened stathmin-2 begins to accumulate, as the best biomarkers should detect the earliest stages of disease where the likelihood of successful treatment intervention is highest. However, the major question unanswered by this study are the practical issues around shortened stathmin-2 detectability. Its usefulness as a biomarker hinges largely on the ease of detection in patient blood or spinal fluid. While these important questions require much more work to answer, this remains an interesting study that reflects the research community’s increased focus on biomarkers as essential for FTD research progress.