Clinical-pathological correlations are an essential research method to improve our understanding about the causes and mechanisms of Frontotemporal degeneration (FTD). This approach relates the changes in behavior, language and cognition that we see clinically to the part of the brain that is compromised by an abnormal protein. While there are several ways to try to study the abnormal proteins that cause FTD, clinical-pathological correlations are most informative when derived from an autopsy. This allows scientists to examine these proteins directly and study their severity, distribution and overall impact on the brain.
FTD is caused by the accumulation of misfolded proteins in the brain and, as these proteins accumulate, they interfere with normal brain functioning and result in clinical changes. While neuroimaging studies like MRI and cognitive studies can tell us about the region of the brain that is affected in an FTD patient, they do not indicate the specific protein that is causing the disease. Others studies involving biofluid biomarkers from cerebrospinal fluid can sometimes identify the abnormal protein but can not localize this protein to a specific region.
Clinical-pathological correlations are essential because they allow us to understand the underlying biology of the disease. The abnormal proteins that accumulate in the brain are derived from proteins that naturally occur in our brain cells. However, these proteins can accumulate phosphorus, acetyl residues, or other modifications and become misfolded interfering with the normal role of these proteins in the brain: this is a loss of a normal function. For example, the protein tau ordinarily helps microtubules distribute metabolic substrate throughout the neuron so that it can function normally, and also acts like a skeleton to help a neuron maintain its shape. These functions are lost when tau becomes misfolded. There can also be a toxic gain of an abnormal function as misfolded tau accumulates in bundles inside a neuron, for example, and can interfere with other neuronal functions.
Another protein implicated in FTD is TDP-43. This protein ordinarily functions in the nucleus of a neuron where it facilitates normal production of RNA from DNA in a process called transcription, helps protect against inflammation, and participates in other processes that help repair a brain cell. In some FTD and ALS patients the protein becomes misplaced along with some of the DNA and RNA it normally helps transcribe, and therefore cannot perform its normal functions. This is a loss of normal functioning of TDP-43. It is also believed that there is a gain of toxic function as TDP-43 accumulates in the wrong part of the brain cell and interferes with the functions in the processes performed in these other areas of the neuron.
Clinical-pathological correlation studies help us to learn about the function of proteins involved in Frontotemporal degeneration . We can use this information to develop potential treatments that target these proposed loss of function and gained toxicities in the brain. Some potential treatments aim to block the accumulation of phosphorus and acetyl residues; other potential treatments try to act as surrogates for a misfolded protein; yet other potential treatments aim to perform a lost function; finally, there are treatment strategies that try to remove the abnormal protein from the brain. A detailed examination of these processes with clinical-pathological studies can ultimately lead to important therapeutic advances.