Knowing one’s limitations

As promised, here’s the next installment in my series on impactful posters on PSP from the annual conference of the International Parkinson’s and Movement Disorders Society that is winding up today on line.  This poster, like the one in my last post, is from Japan.

Most of you know that corticobasal degeneration (CBD) is very similar to PSP in many ways, though only about a tenth as common.  The most common typical clinical syndrome of PSP, called PSP-Richardson syndrome, correlates extremely closely with the typical pathological autopsy appearance that we call PSP.  But for CBD, the most common clinical syndrome, called corticobasal syndrome (CBS) has a much looser correspondence with the typical autopsy picture called CBD.  Only about half of all people with CBS have CBD at autopsy.  Of the rest, the most common autopsy picture is PSP, then Alzheimer’s disease, with a half-dozen or so others comprising the rest.  Unfortunately none are more treatable at present than CBD.  Here’s an up-to-date, authoritative, technical description of that for you to chew on if you want the details.

Here’s some more background:  One of the ways that PSP can present itself clinically is with the corticobasal syndrome.  In other words, about 3 percent of people with PSP in the brain look outwardly like they have the typical appearance of CBD.  How to tell if those folks have PSP-CBS or CBD-CBS itself?

The leading clinical PSP expert in Japan, in my biased opinion, is my friend Ikuko Aiba, MD.  She and her colleagues in Nagoya compared the medical records of 12 autopsy-proven patients with CBD with those from eight with autopsy-proven PSP-CBS.  The only clinical feature that was more common in the CBD-CBS patients was urinary incontinence and the only one more common in PSP-CBS was limitation of vertical gaze and slowed eye movements (“saccades”) in general.  The CBD-CBS patients tended to progress a little more quickly with regard to overall loss of mobility.

The take-home is that in the absence of specific treatment for either condition (i.e., treatment directed at the cause rather than the symptoms) this information could be useful in refining recruitment in clinical trials, in prevalence studies and diagnostic biomarker development, each of which would like to be able to create a patient series consisting purely of the disease under study.

The other take-home is that it’s actually next to impossible to distinguish PSP-CBS from CBD-CBS in the living patient.  Neurologists who claim to be able to do so, even with this bit of new information, are just kidding themselves — and their patients.  They should just diagnose “corticobasal syndrome” and leave it at that. Thanks to Ikuko Aiba and colleagues for pointing that out.

A clue from proteomics

The annual conference of the International Parkinson and Movement Disorders Society (“MDS”) is in progress this week on line.  The location of this meeting normally migrates from city to city world-wide and this year was supposed to be Philadelphia.  Nice city to visit – great history, great art, great restaurants (both fancy and ethnic).  Oh, well.  One of our many sacrifices to the pandemic and all things considered, not a serious one.

Of the 1,000 posters reporting new research, 17 were on PSP.  One that sounds very interesting is from Hiroshi Takigawa and colleagues at Tottori University in Yonago, Japan.  They did a proteomic survey of cerebrospinal fluid (CSF) from people with PSP, Parkinson’s, corticobasal syndrome and some healthy, age-matched volunteers.  Proteomics is a generic term for big-data studies of all the proteins in a biological samples, just as genomics is the study of all the genes.  In this case, they compared the collection of thousands of CSF proteins among the four groups listed and found that the only one that’s higher, on average, in PSP relative to the other three to a statistically significant degree is something called chromogranin B.  They also found that a small fragment of the 657-amino acid chromogranin B protein was the only protein (or fragment thereof) that was less abundant in CSF in PSP, on average, than in the other conditions. The fragment, which is only 31 amino acids long, is called bCHGB-6255.

For neither of these findings was the magnitude or consistency of the difference enough for use as a diagnostic test at the individual level.  (Statistical digression: For the biostatisticians among you, the area under the ROC for bCHGB-6255 was only 0.67.  For the rest of you, the receiver operating characteristic is a graph comparing the likelihood of true positives with that of false positives for the full range of possible definitions of an abnormal level.  The area under the ROC, if the each axis of the graph goes up to 1.00, has a theoretical maximum of 1.00, in which case there’s no risk of false positives in exchange for full identification of the true positives.  A result of 0.80 is barely acceptable for a test to be useful at the individual level and 0.90 is preferred.)

The value of the finding is the demonstration that chromogranin B might have something to do with the degenerative process underlying PSP but none of the related diseases.  Furthermore, the inverse relationship of the full chromogranin B molecule and its bCHGB-6255 fragment suggests that there’s something about the fragmentation process that may be uniquely important to PSP.  Maybe an enzyme that cleaves chromogranin B is deficient, damaged or suppressed in PSP.  Only further research will work that out.

What does chromogranin B normally do?  We don’t know.  It’s present in a wide variety of brain cells that use norepinephrine as their neurotransmitter and also in many cells in other organs.  It’s somehow associated with the secretion of norepinephrine and is known to be in elevated level in the blood in certain tumors.  Tests for it are available from commercial medical labs.  But as I emphasized above, the test would be diagnostically useless at the individual level.

Most of the presentations at important meetings like the MDS are research that has not yet passed peer review, or at least not yet published.  So you have to take it with a grain of salt.  Of course, the same thing can be said for any research that has not been confirmed by other labs using other methods.  And even then . . . I’ll tell you about other interesting MDS posters in the next few days.

A family matter

Want to know what’s hot in lab research on PSP?  Or, more accurately, want to know what will be hot in a year or two?  This week, CurePSP will announce its four newest research grant awardees.  Most of the 20 competing applications, a very large crop for CurePSP, were of excellent quality and in a less competitive cycle many of them would have been funded.   A fifth and possibly a sixth application may be funded next month after CurePSP’s leaders have had a chance to discuss the use of a new, unexpected, seven-figure donation.

Since I’m driving this bus, I’ll start with the funded grant I consider the most intriguing, though it’s the smallest of the four.  For two decades, researchers at the University of Southern California have been following a Mexican-American family with PSP in 14 members over three generations.  Two of the 14 have had autopsies confirming the diagnosis.  The inheritance pattern is most likely autosomal dominance (look it up).  There are six living, affected members and another 19 who are at 50% risk because they have an affected parent or sibling.  One of the affected members has had sequencing of the gene that encodes tau (called the MAPT gene).  That revealed no mutations.  Now, John M. Ringman, PhD and his USC colleagues plan to sequence the entire genome of four affected and one unaffected family members.

It’s entirely possible that the result will be a mutation in one of the half dozen or so genes besides MAPT that have already been identified by other methods as conferring a slight risk of developing PSP.  That wouldn’t be so exciting, though it would show that one mutation in that gene suffices to cause the disease while other mutation(s) in the same gene only raise PSP risk slightly.  That would shed light on just how that gene works with respect to PSP.

A more exciting result would be if the culprit gene in this family turns out to be one that has not been previously associated with PSP.  Even though this particular mutation would clearly not be the cause of “regular” PSP, perhaps the protein that this gene encodes will prove to be part of a molecular pathway critical to the pathogenesis of PSP but not yet investigated carefully.  That could point to scads of new treatment targets for drug developers and maybe even a diagnostic test.  Very cool.

I led a project like this on Parkinson’s disease back in the 1980s and 1990s, though we didn’t have whole-genome sequencing then.  I won’t get into the details, but you can read about the big family I found and worked with here, my subsequent clinical analysis of the family here, the report of the culprit gene here, the discovery of its significance to PD in general here, the development of a diagnostic test based on the gene’s product here, the efforts to prevent PD in lab models by reducing the gene’s product here and an initial safety report on a Phase 1 human trial here.  Maybe that’s why I find Dr. Ringman’s little project so intriguing.

More on the other new grantees in the next post.