Adopt an orphan

If PSP is an orphan disease, corticobasal degeneration (CBD) can’t even get into the orphanage.  Like PSP, it’s a “pure 4R tauopathy”; it can resemble PSP in many cases; it leads to disability and death after a similar span of time; and it’s no more treatable.  But its prevalence is about 10-20% that of PSP and it’s very difficult to diagnose in a living person.  People fulfilling the accepted, published diagnostic criteria for the most common type of PSP (PSP-Richardson syndrome) actually have that disease at autopsy in over 90% of cases, but for CBD, the figure is less than 50%.  That makes it hard to recruit a group of subjects for a drug trial — or any research — without other diseases influencing the result.  That has put quite a damper on CBD research.

To add injury to injury, googling “CBD” reveals a lot more about cannabidiol than about corticobasal degeneration.

So, an objective diagnostic test for CBD would be great.  Now, researchers mostly at Washington University in St. Louis (WUStL) and University of California, San Francisco (UCSF) have shown that two tiny fragments of the tau protein are less abundant in the spinal fluid of people CBD than in healthy people or those with PSP or three other rare tau disorders called argyrophilic grain disease, Pick’s disease and frontotemporal lobar degeneration associated with aggregation of TDP-43.  They found no difference between CBD and Alzheimer’s disease or frontotemporal lobar degeneration with mutations in the tau (MAPT) gene, but in practice, those two disorders can be readily distinguished from CBD by other means.

The paper appears in the prestigious journal Nature Medicine and it’s open access, so I can provide you this file to download.  The first author is Kanta Horie, PhD and the senior authors are Chihiro Sato, PhD and Randall Bateman, PhD, all of WUStL. 

Panel “a” shows the tau protein. The four microtubule-binding domains are R1 to R4. The one whose inclusion or exclusion makes the difference between the 4R and 3R tauopathies is R2, which is encoded by the gene’s exon 10. The amino acids are numbered starting at the N terminus on the left. Two short stretches of amino acids, numbers 275 to 280 and 282 to 290, were the object of this paper’s analysis. N1 and N2 are two other sections, encoded by exons 2 and 3, respectively, that can be included or excluded in the finished tau protein.

Panel “b” shows the analysis of the 275-280 fragment of tau in the spinal fluid (CSF). The vertical axis is the ratio of the concentration of the 275-280 fragment divided by the concentration of total tau. The horizontal axis lists the tauopathies analyzed in this project. Each circle is one patient. The “box-and-whisker” plot shows, from top to bottom, the maximum value, the 75th percentile, the median, the 25th percentile, and the minimum value. The asterisks indicate the statistical significance of the comparison between the two groups at the ends of each horizontal line segment. One asterisk is a weak difference and four is the strongest. Pairs of groups without a horizontal line connecting them did not differ (i.e. the p value was greater than 0.05, meaning that any difference between them could have occurred by chance with a likelihood of more than 1 in 20).

Panel “c” shows the same thing, but for the 282-290 fragment of tau. The results are essentially the same as for the 275-280 fragment.

The odd thing is that the same analysis using autopsy brain tissue rather than spinal fluid gave a very different result: The values (i.e., the ratio of the fragment to total tau) was actually higher for CBD than for the other groups. The authors present various theories to explain this, but in any case, it does not detract from the diagnostic value of the spinal fluid results. Take a look and the brain tissue results:

So, what does this mean for people diagnosed with CBD, present and future?  It means that if someone like a drug company has an experimental treatment that might help CBD, they could recruit a group of patients with a high level of confidence that they have excluded other diseases that could confound their results.  That level of confidence is expressed as the “area under the receiver operating curve” or AUC.  A previous post on this blog explains that statistic, which varies from 0.5 for a diagnostic test no better than a throw of the dice to 1.0 for a test that’s perfectly accurate every time.  The AUC for this test to distinguish CBD from those other disorders (other than AD and FTLD-MAPT) is 0.800 to 0.889.  That’s close to the figure for PSP using the neurological history and exam.

If this diagnostic test is confirmed (a big “if”) and enters use by researchers and drug companies, and if a drug company sees a route to profitability in so rare a disease, the only problem is finding enough patients with CBD for a trial.  If CBD is 20% as common as PSP, and the new test for CBD is just as good as the present clinical diagnosis of PSP, then it will require five times the number of participating clinical test sites to fill a trial.  But with international collaboration, it’s do-able. 

Now, let’s hope that this test is adopted and that CBD is adopted. 

A how-to guide for doctors

Educating health care providers about PSP and CBD has long been a goal of mine and of CurePSP.  Most of my patients relate unfortunate stories of bothersome or even disabling symptoms for years before any physician suspected the correct diagnosis.  During those years, they may have endured futile, expensive, and potentially harmful diagnostic tests and treatments.  Even after PSP or CBD is correctly diagnosed, attempts to manage the symptoms are often unsupported by evidence, prescribed at an inappropriate dosage, or continued after any benefit has disappeared — while their side effects continue.

All too often, the neurologist tersely informs the patient that no treatment is available for PSP or CBD and that they should just go home, do the best they can and maybe get some physical therapy.  While it’s true that there’s no “specific” treatment or way to slow the underlying disease process, there are treatments that ease most of the symptoms as symptoms.  This is called “palliative” or “symptomatic” management and it’s up to the neurologist and other clinicians to understand and offer it.

These management measures are not unique to PSP or CBD – they are standard drugs and therapies used for symptoms regardless of their underlying cause.  Having said that, it’s also true that patients with PSP may differ from others in their reactions to common medications. 

You may recall that in 2018 a brief single-author book appeared that described management of PSP for clinicians.  For better or worse, the author (that would be me) relied heavily on his own experience, his own reading of the literature and his own philosophical point of view to recommend diagnostic and therapeutic approaches.  That was great as far as it went, but it didn’t reach much of an audience.  The book’s cover price — $75 for the paperback or digital editions – deterred many, and the publisher didn’t advertise it at all.

But now we have a new resource – the CurePSP Centers of Care.  In 2017, when CurePSP organized this network of highly-qualified academic centers in the US and Canada, the mission was to have a list of geographically well-distributed centers providing first-rate care for PSP and CBD.  The network has now grown to 30 sites with plans for 10 more in the next few years.  But besides providing care, the CoC’s are also uniquely positioned to work collaboratively to improve care.  

So in 2019, I and the other three members of the CoC Steering Committee (Drs. Irene Litvan, Brent Bluett and Alexander Pantelyat) organized the other 21 (at the time) CoC site directors to write a “best practices” document on the symptomatic management of PSP and CBD.  We divided the topic into 12 section and for each, created a writing committee from the list of site directors and any institutional colleagues whom they chose to recruit as collaborators.  Each committee submitted a 2- or 3-page draft that the Steering Committee edited and stitched together into a coherent article.  We returned that to the whole group so that every co-author could have some input into the whole document and then submitted the result for publication.

We chose Frontiers in Neurology, an “open-access,” on-line journal, meaning that viewing and downloading articles does not require a subscription or a per-article fee.  Such journals cover their expenses by having advertising and by charging a fee to the authors; in our case CurePSP paid the $2,950 bill.

Here’s the link to the article and here’s the URL:

Please consider sending the link (or a hard copy) to any clinician you know who takes care of people with PSP or CBD.  That’s not only neurologists, but also primary care physicians and nurse practitioners, ophthalmologists, optometrists, rehabilitation medicine specialists, neuropsychologists, physical therapists, speech/swallowing therapists, and occupational therapists.  Maybe keep a copy in your “go-bag” to provide to your doctors and nurses in a hospital or emergency room.  CurePSP will soon start a North America-wide campaign to distribute the link along with a series of videos of experts discussing and enlarging on points raised in the publication.

I think the authors of the paper did a great job, if I do say so myself.  But now begins the real work of broadcasting our advice so that clinicians can be competent and comfortable taking care of people with PSP and CBD.

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.