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  • Writer's picturePenn FTD Center

Pathology: Bringing the Microscope to Clinic

In his presentation at our 2021 Caregiver Conference, Penn FTD Center co-director and cognitive neurologist Dr. David Irwin highlighted that a clinical diagnosis of FTD can tell us what changes and symptoms to expect, but it does not identify the pathology in the brain, the true cause of the disease. Predicting pathology is key to future treatments for FTD, and for that we need “biomarkers”.  



To understand why a clinical diagnosis does not predict pathology, we must first know how diagnoses are made. When you see a clinical neurologist, they will take you through a neurological and cognitive exam, which evaluates affected brain regions and symptoms like poor multitasking, disinhibition, changes in language or appetite, and motor weakness. By looking at these different signs and symptoms, neurologists can arrive at a clinical diagnosis, such as frontotemporal dementia (or FTD). The issue is that clinical diagnoses can tell us what is wrong in the brain, but they do not identify the cause.  


By comparison, a neuropathologist evaluates brain tissue at autopsy. They identify the different proteins under the microscope that caused the syndrome diagnosed in life. Instead of a clinical diagnosis of “FTD”, neuropathologists provide a pathological diagnosis of frontotemporal lobar degeneration or “FTLD”. In fact, there are multiple types of FTLD based on which proteins accumulate in the brain: the two major types of FTLD proteins are tau and TDP-43.


We all have both proteins (tau and TDP-43) in our brains, and they normally serve important functions. For reasons we don’t understand, in some individuals they start to stick together in brain cells, leading to cell death and impaired brain functioning. The clinical syndrome of FTD can be caused by either tau or TDP-43, and a precise neuropathological diagnosis of FTLD is still only available through a postmortem exam of brain. But to try and stop the disease, we must be able to identify which protein is abnormal. 


Ideally, we would be able to diagnose an individual both by their symptoms and by underlying pathology. Biomarkers may provide that link to providing a pathological diagnosis in the clinic. Biomarkers are neuroimaging or biofluid tests that indicate pathology type and location.  Biomarkers for FTLD-tau or FTLD-TDP-43 pathology are currently in the research realm, but the ultimate goal is to bring them to the clinic.   


Research in the field of biomarkers is ongoing. Knowledge that we gain from autopsy and brain bank donations today is important so that one day biomarkers may be able to identify FTLD pathology in a living patient. Currently, we use advanced imaging techniques to analyze a slide that has been stained for either tau or TDP-43. This can tell us about which proteins have accumulated and where they have spread through the brain. Dr. Irwin’s work indicates that tau is higher in the white matter connections between cells in the brain, and that TDP-43 is higher in the grey matter cell bodies, and that different brain regions are more affected by one protein over the other. In individuals clinically diagnosed with FTD, we can combine pathology data with MRI images taken during life to gain a deeper understanding of the disease process.  


Ongoing studies in Dr. Irwin’s lab are working to bring this from the microscope into the clinic. If you would like to view the recordings of our previous caregiver conferences, you can visit our webpage here.

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