Two recent studies on proteins and FTD are helping to lay the foundation for the potential development of diagnostic and prognostic FTD biomarkers, a Feb. 9 Alzforum post reported.
Studies Identify Relationships Between Certain Proteins and FTD Disorders
Getting an FTD diagnosis is an extensive process that can involve multiple rounds of cognitive or behavioral testing, MRI and PET scans, and referral to one or more specialists. With usable biomarkers, clinicians would not only be able to identify FTD disorders more quickly but also discriminate between pathologies, which is currently only possible post-mortem. Because many experimental drugs and interventions for FTD are often specific to a pathology, it is important for clinicians to be able to tell them apart.
Two studies have identified novel pathways for biomarker development by focusing on proteomics, the study of proteins and their interactions. The studies analyzed protein levels in cerebrospinal fluid (CSF) to determine which were affected by the onset of FTD and not by other disorders, which would provide a benchmark for further biomarker research.
The first study analyzed levels of 1,981 different proteins in a cohort of 162 participants with FTD risk-creating genetic variants who are enrolled in the Genetic Frontotemporal Dementia Initiative (GENFI), finding proteins that were altered compared to controls. In some cases, the authors noted protein levels changing before symptoms developed. The researchers found proteins unique to each of the mutations: C9orf72, GRN, and MAPT; for example, elevated levels of the calcium-binding protein calbindin 2 strongly correlated with disease severity in the persons with C9orf72 genetic mutation, with concentrations of it and other less-prominent proteins rising as FTD worsens.
The study also found that general biomarkers for neurodegeneration that rise in many forms of dementia also rise with FTD. However, these biomarkers are not specific to FTD; raised levels of the protein neurofilament light, for example, are a general biomarker indicating damage to the communicative components of neurons. Of the 1,192 proteins surveyed, only 221 were specific to FTD. So while these types of proteins may not be able to differentiate between different neurodegenerative diseases, this information could indicate that something is causing neuronal damage.
The second study involved a smaller cohort of 116 people participating in the ALLFTD study, with researchers analyzing the levels of 4,138 proteins, the most extensive assortment by an FTD study so far. The authors noticed that proteins associated with synapses (the structures neurons use to communicate with each other) and lysosomes (a cell component acting as a “recycling center” for waste and invading pathogens) were lower compared to controls without FTD, while spliceosomes (a “ribonucleoprotein complex” that combines RNA and proteins to perform essential tasks in a cell) were elevated. When the researchers sorted proteins according to gene mutation, changes in spliceosome and lysosome protein levels were more common with C9orf72 and GRN, which suggests that they are associated with a pathology centered around the protein TDP-43.
Proteomics and FTD: What Comes Next?
While the two studies achieved a milestone by identifying proteins related to FTD, the authors of both emphasized that further research is needed to develop accurate biomarkers specific to FTD disorders. One contributing factor to the heterogeneous nature of FTD disorders is the variability of proteins that can drive the pathological underpinnings of the disease, with TDP-43 and tau making up the majority of cases. Distinguishing between these pathologies will be crucial for making the diagnostic process more accurate and for ensuring that people with FTD receive the right treatment.
Moving forward from the current studies, researchers will conduct more extensive and in-depth proteomic studies to further narrow the potential biomarkers field and validate existing research.
As highlighted by Julio Rojas, MD, PhD, co-author of the ALLFTD-focused study, both studies are limited by the number of proteins analyzed. Dr. Rojas notes that the GENFI-focused study captured roughly 10% of the total proteins in CSF.
“Also, although findings in CSF are great progress, the field needs blood-based biomarkers, which are more easily implemented on clinical grounds, especially in clinical trials,” Dr. Rojas told Alzforum. “There is also a need to run proteomics studies in diverse populations of non-European descent. The field of clinical FTD research is living a golden era, and more progress on biomarkers and therapeutics will likely be seen in the upcoming years for this devastating group of diseases.”
Proteomics has uncovered relationships between proteins and different FTD pathologies. Last year, Dr. Benjamin Ryskeldi-Falcon and his team discovered how the protein TAF15 may play a role in the development of an FTD subtype once thought to be associated with the FUS protein. Longitudinal studies like ALLFTD and GENFI provide families facing FTD an opportunity to contribute to FTD research. If you have questions about how to join a study, contact AFTD’s HelpLine at 1-866-507-7222 or [email protected].
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