As a PSP-ologist, it takes a lot to discourage me, but the excellent review of CSF markers in the diagnosis of PSP did it. Nadia Magdalinou, Andrew Lees and Henrik Zetterberg of University College London, writing in the JNNP, point out that no CSF measure has been consistently or reproducibly found to differentiate PSP from all of the relevant competing diagnostic considerations.
An excellent study cited in the review found low levels of CSF α-synuclein in Parkinson’s, DLB and MSA relative to PSP and other brain disorders. A value less than 1.6 pg/μl had good (91%) positive predictive value for any synucleinopathy but higher concentrations had poor (20%) negative predictive value. So that measure is of some small value.
Neurofilament light chain in CSF is elevated in PSP, MSA and CBD, according to another study, with an area under the ROC curve of 0.93. This has been confirmed by others since. This is useful in distinguishing PSP from PD, but when your patient has a poor levodopa response and downgaze problems, PD isn’t really the issue; PSP, MSA and CBD are.
One study of neurofilament heavy chain found that it can differentiate PSP from CBD but not from MSA. That study was published in 2006 and we’re still awaiting confirmation.
You’d think that tau would be the object of intense scrutiny in the differential diagnosis of PSP by CSF, but there’s been relatively little on that. One good study found that the ratio of phospho-tau to total tau is lower in PSP and MSA than in PD. The other studies of phospho-tau in PSP have been negative.
So the winner so far for PSP, limping across the finish line, seems to be neurofilament light chain. It’s not available commercially as far as I can tell; nor should it be, without further study.
Adding to this discouraging picture is the fact that most or all of the studies of CSF markers in PSP have sampled patients in a stage of PSP that allowed clinical diagnosis. By that time, the CSF picture may be more diagnostic than in the earlier stages, when a state marker would be most useful. In other words, the studies were retrospective rather than prospective.
For now, I’m putting my money on imaging.
Monthly Archives: April 2014
A road map to a cure, or maybe a grant
For as long as I’ve directed the research grants program at CurePSP, I’ve been a champion of the investigator-initiated approach. Let the experts decide what’s scientifically ripe and feasible for them, I say. I’ve seen too many RFAs produce opportunistic applications that are a stretch for an investigator both intellectually and practically.
But I thought it was best to compromise that principle by creating this “Road Map to a Cure.” It presents a general approach to developing neuroprotective treatment for PSP that builds on recent advances and hot ideas, interacts with the private sector, and is feasible with present technology. Perhaps best of all, its definitions are flexible enough to accommodate a wide variety of investigator-initiated ideas.
In developing the Road Map, I collaborated with Yvette Bordelon, a movement disorders specialist at UCLA and Chair of the Research Committee of CurePSP’s Board of Directors; and Jeff Friedman, a pediatrician/biochemist at Friedman Bioventures and Scripps and a member of CurePSP’s Board.
As you can see, the Road Map chooses three general hypotheses: a genetic etiologic component, a prion-like (the preferred term is “templating”) mechanism, and a problem with protein folding and management. It also identifies two broad categories of experimental tools that need improvement: animal (or cellular) models and human biomarkers. The Road Map then seeks to develop treatments based on one or more of the three hypotheses and using one or both of the two tools. Then comes the familiar the cascade of treatment development, from target identification to in-vitro or cellular screens to more complex model organisms to early-phase humans trials to late-phase trials.
Of course, some treatments may be ready for testing in animals or humans right now without the preliminary steps, and that would be great. Will CurePSP triage out any applications lying outside of this development model? Not at all. The Road Map is formulated more as a general guide and we recognize that there are other paths.
We also recognize that the Road Map ignores important things like symptomatic or surgical treatments, studies of exogenous risk factors, descriptive and nosologic studies and, perhaps most important, completely new and risky ideas.
The Road Map, as you’ve guessed, is designed partly as a fundraising tool that allows potential donors to understand how scientists would spend their money. The donors deserve to know that and are quite capable of understanding it if we scientists just take the trouble to explain it to them.
Now for something you can use today: the PSPRS
I’m in awe of the scientific creativity and astuteness of the researchers whose work I feature in this blog. My own original work is more modest — but has its uses. In fact, hardly a week goes by without a publication of a research project using the PSP Rating Scale. This post is a shameless attempt to evangelize for it. Click here to download the PSPRS form.
Since my statistician colleague Pam Ohman-Strickland and I published it in 2007, the PSPRS has gradually become the standard way to quantify overall symptomatology and disability in clinical research in PSP. It is equally useful in routine clinical care and requires only 10 minutes to perform. It’s not copyrighted.
Yes, the Unified Parkinsonism Disability Rating Scale, the standard scale for PD, has been validated in PSP, but has nothing about frontal behavioral signs, eye movements, sleep and some other things that are important in PSP. The PSPRS has a nice, round 100 possible points divided into six sections and 28 items. Rather than attempting to rate every possible feature of PSP with equal emphasis, the items’ relative importance in the PSPRS mirrors that in the most common form of PSP itself. This design feature results in the PSPRS progressing about 11 points per year regardless of the magnitude of the score or disease duration. The score is useful as a prognostic indicator and I’m presently working on refining that.
The PSPRS requires some skill in the neurological exam, so cannot be applied by patients or caregivers. But they can bring it to the attention of their neurologists. Click here for the original paper in Brain that explains the details of how to administer the PSPRS.
Like everyone, I’m hoping for a more objective, reproducible test to quantify the state of neural degeneration in PSP – maybe something with spinal fluid or MRI. But until then, the PSPRS is the best we’ve got and it’s dirt cheap.
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