You’ve probably heard about the disease called frontotemporal dementia (FTD).  It produces many of the same cognitive and behavioral symptoms as PSP, but more intensely, with much less of PSP’s other symptoms.  Familial forms of FTD are much more common than in PSP, amounting to about 20% of all cases.  Of those, about a quarter have a mutation in their MAPT gene – that’s the one that encodes the tau protein.  (Most of the rest have mutations in two obscure genes called “C9orf72” and “progranulin.”)  As for nearly all neurodegenerative diseases, a protein aggregates in the affected brain cells in FTD and that protein corresponds to the specific mutated gene in that individual.  So, MAPT-associated genetic FTD is a tauopathy very much like PSP, but in a slightly different set of brain cells.

Neurologists at UCSF and the Mayo Clinic are leading a large, multi-institutional observational study of FTD called “ALL-FTD.”  They’re gathering histories, neurological exams, imaging, skin biopsies, blood, and most relevant here, spinal fluid.  They re-gather much of this every year and track the patients’ progression.  The idea is to find diagnostic markers not only to diagnose the disease, but to predict its onset in healthy mutation carriers and to predict the progression of the disease in those who already have symptoms.  All of this can be useful in designing clinical treatment trials and in patient and family counseling.

Using spinal fluid from 116 people with FTD mutations and 39 controls, the ALL-FTD neurologists analyzed the levels of over 4,000 proteins.  They found some of the proteins increased or decreased as functional modules.  That means that subgroups of the affected proteins tended to share a common function in the brain. Then they tested spinal fluid from people with ordinary, non-familial PSP-Richardson syndrome for the same protein disturbances, and found some.  In fact, all 31 of the functional modules disrupted in genetic FTD were disrupted in PSP as well. (This research article is posted on a site for manuscripts not yet peer-reviewed called “Research Square.”)

Mind you, this doesn’t mean that non-familial PSP is actually caused by genetic mutations in the three FTD-related genes.  We still don’t know the initial cause of PSP.  But the study does show that familial FTD and non-familial PSP share some very fundamental similarities. 

The most important modules disrupted in the two conditions relate to the brain cells’ “extracellular matrix.”  That’s the soup of chemicals outside and between the brain cells that serves many protective and nutritive functions.  I suspect that it descended from the coat of slime secreted by our ocean-dwelling, single-celled ancestors.  In ourselves it functions in cell growth, fetal development and injury repair as well as providing physical protection against trauma and a trap for nutrients floating by. It’s easy to see how a genetic or non-genetic defect in the contents our brain’s extracellular matrix could be a problem.

So, let’s add the extracellular matrix to our list of potential drug targets in PSP.