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Discovery of PPA’s Pathological Signature Can Help with Treatment Finding

By Chloe Hilles

A new finding by the Mesulam Center confirms primary progressive aphasia’s (PPA) unique pathologic signature, which is a critical step to eventually discovering a treatment for PPA.

“When you are able to understand the underlying pathology, only then can you find a treatment. You first have to disentangle the complex relationship between the symptoms experienced by the patient, and the actual disease that destroys cells in the brain,” Tamar Gefen, PhD and lead researcher of a new publication in the Journal of Neuropathology & Experimental Neurology, said.

Primary progressive aphasia is a type of dementia that affects an individual's ability to communicate. Symptoms can include difficulty in one’s ability to express their thoughts or in finding particular words.

PPA can arise as a result of many different types of pathologies — the actual disease — in the brain: the three most common are Alzheimer’s disease pathology with characteristic amyloid plaques and tau-tangles, FTLD pathology with tauopathy, or FTLD pathology with TDP-43 protein inclusions. Gefen and her team discovered that regardless of the type of pathology, the general regions of the brain that are affected remain the same. In all cases of PPA, the pathology has a unique signature that affects the left-sided language network of the brain.

“The manifestation of disease doesn’t depend on the type of pathology, it depends on the actual location of the pathology in the brain,” Gefen said. “It’s the where, not the what.”

This means that the left side hemisphere of the brain, the part that controls language functions including speech, communication, and understanding, is selectively vulnerable to PPA’s pathologies. 

In order to come to this conclusion, Gefen and her team had to follow the progression of individuals’ disease course to gather observational, clinical data during life. Then, postmortem, Gefen dissects the brain bilaterally, on both the left and right sides of the brain, from frontal, temporal, parietal, and limbic (memory-related) region. Lastly, an analysis of the regional distribution of pathology across the multiple brain regions occurs; the analysis showed that regardless of the type of pathology in the PPA cases, there was always left-sided atrophy (shrinkage), which together, gives rise to the clinical symptoms of language disturbance that an individual with PPA may experience.

This research establishes the relationship between the presenting symptoms (the clinical syndrome) and the underlying disease (the pathology) that causes the symptom; this is known as establishing "clinicopathologic concordance." With this key information, the search for a mechanistic cause, and subsequent, treatment can begin.

For research participants and patients with PPA, this research helps provide a more holistic understanding of the syndrome. There are many underlying postmortem pathologies that can lead to one single antemortem diagnosis. Additionally, it’s not the type of postmortem pathology that causes the PPA syndrome, it's what region of the brain the pathology affects that causes the symptoms during life.

“I think this finding is really important for education, for treatment planning, and from a research perspective because we are coming to a place where we can understand in depth this rare disease and are at the cusp of making major advances,” Gefen said. “If I were to be diagnosed with PPA, I would feel reassured knowing that this research is taking place, because we are answering questions that must be addressed in order to advance the science, with the ultimate goal of guiding treatment.”

Gefen noted a discovery like this is only possible because of commitment of the Center’s research participants, especially those individuals who donate their brain.

“Kudos to our research participants; they are doing everything in their power to understand the disease, and to help others. They are selflessly committing themselves to years and years of evaluations so that this research can be possible.”

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