A bit of help with prognosis

A paper of mine just hit the streets today.  Actually, the idea and most of the work came from an old friend and colleague at the University of Chicago, Dr. Tao Xie.  (His last name is somewhere between “she” and “chee” and his first name is perfect for a PSP researcher.)  Here’s the story of that project, from the beginning.

From 1994 to my retirement from practice in 2020, I kept a careful record of the PSP Rating Scale (PSPRS) results in all 526 patients I saw with PSP.  The database includes each patient’s sex, birth year, month/year of PSP symptom onset, and death month/year (if deceased).  For each visit, I recorded the month/year and each of the 28 PSP Rating Scale item scores.  Back in 2020, some other colleagues and I published a paper on how to use the raw PSPRS scores to help predict prognosis in individual patients.

Tao asked if he could use my database, with my formal collaboration, to find a better way of predicting long-term survival.   He said he didn’t just want to look at raw scores – he wanted to look at their magnitude and rate of progression at one critical point: the time when the person first developed difficulty looking down.  That’s easily approximated by finding the date of the visit when the score on the PSPRS item for downgaze first exceeded zero.  He would then correlate those “input variables” with, as “output variable,” the patient’s overall survival.  The progression rate would be calculated as the raw item score divided by the number of years since PSP onset.  I said, “great idea.”  

Why choose the onset of downgaze palsy as the benchmark?  That’s when the insidious pathological process of PSP has first broken out of its three places of origin in the brain: the substantia nigra, the subthalamic nucleus and the globus pallidus.  Why it starts in those three places is a mystery, but from there the abnormally folded tau protein molecules travel along the axons to other places, and pretty much their first stop is the area where downgaze is controlled, in the dorsal midbrain.  (Perhaps relevantly, downgaze palsy is by far the most “specific” feature of PSP, meaning that of all of the disease’s features, that’s the one shared with fewest other diseases.)

So, Tao figured that once the process gets to the downgaze area, it has emerged from its birthplaces and is on its unfortunate way to other parts of the brain, probably at whatever speed is specified by the individual’s particular chemical and genetic makeup.  Because that rate of transmission varies among individuals with PSP, it makes sense to measure the progression rate of PSP as of that stage of the disease rather than at a one-point-fits-all stage such as a set number of years after symptom onset.

Here’s what we found:  The shorter survival is associated with older onset age and, as of the time of initial downgaze palsy, the PSPRS item scores for 1) difficulty swallowing liquids and 2) difficulty arising from a chair.

So, what does this mean?  For care of an individual patient, the neurologist’s recommendations might be shaded to an extent by the knowledge that the patient’s future course will be more – or less – favorable than the published averages for PSP.  In a large clinical trial, the statistician analyzing the data might want to achieve a more valid comparison of the active drug and placebo groups by weighting the progression data according to these factors. 

Yes, research proceeds in small steps, but proceed it does.

4 thoughts on “A bit of help with prognosis

  1. “as of the time of initial downgaze palsy, the PSPRS item scores for difficulty swallowing liquids for difficulty arising from a chair.”

    I’m not sure I understand what this means. Does it mean that at the time downward gaze palsy is initially scored, these two additional items show up in scoring, too? Thanks

    • Sorry to be unclear. It means that as of the time downgaze palsy is first noticed by the neurologist, the severity and rate of progression of the additional items at that visit can serve as guides to long-term survival.

  2. How do we know that “the abnormally folded tau protein molecules travel along the axons to other places”, i.e. tau proteins in the dorsal midbrain were not originated there? It is not possible that tau proteins in the dorsal midbrain were originated there? Has any study been able to tag a tau protein and follow its movements? I am Álvaro, a first-year student of Neuroscience. Thank you for your time and your wonderful blog.

    • Dear Álvaro:
      Good question. The answer is circumstantial, meaning that, to my knowledge, no one has actually labeled tau to track its progression in PSP. But there is one excellent study of PSP autopsies at various clinical stages. The dorsal midbrain is involved in fewer cases than the substantia nigra, globus palludus or substantia nigra, which strongly suggests that it receives the pathology later. Here’s that paper: https://pubmed.ncbi.nlm.nih.gov/32383020/
      Actually, labeling tau to track its movement wouldn’t answer you question, as the spread of tau isn’t just a matter of transporting molecules — it’s also templating normal copies of tau to midfold, and for each of them to cause other normal copies to misfold, in a kind of chain reaction. So the labeling would not be transmitted far enough to answer your question. That said, there is evidence of cell-to-cell spread of misfolded tau.
      I hope this is helpful.
      Best of luck in your studies and your career!
      Dr. Golbe

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s