Monthly Archives: November 2022

Adopt an orphan

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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 step forward or backward? Let’s vote.

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I’m interested in your opinions on this.

An important paper just appeared in the prestigious British journal Brain from researchers in Bordeaux, France and Lausanne, Switzerland led by Dr. Morgane Darricau, a junior scientist working with eight other scientists under senior researchers Dr. Erwan Bezard and Dr. Vincent Planche. 

The work was performed using rhesus monkeys, also called “macaques,” which have been productively and frequently used in research for over a century. The researchers injected abnormal tau protein from patients with PSP into the midbrain of two macaques. As controls, they injected normal tau from the brains of two people whose autopsies showed no neurological disease into the midbrain of two other macaques.  The result was that starting six months later, the first group started to show abnormal control of walking and loss of performance on a cognitive task requiring opening a box containing a treat. 

The deficits progressed, and after another 12 months, the animals were euthanized.  Brain tissue of the two recipients of the abnormal tau showed the same sort of tau aggregation seen in human PSP. Also, crucially, the tau abnormality had spread to several areas known to be connected to the original injection. Those areas — the putamen, caudate, globus pallidus and thalamus — are among the main sites of involvement in human PSP.  They must have received the abnormality from the injection site through axons and across synapses, not by mere proximity. The two control macaques had neither symptoms nor brain abnormalities at autopsy.

Similar experiments have been done with mice over the past decade with similar results, but:

  • The mice did not display the full range of PSP-related brain changes that occurred in the monkeys.
  • The mouse brain’s simpler circuitry and much smaller size do not closely mimic the “environment” in which the abnormal tau spreads in human PSP. 
  • The types of normal tau in the brain, a mix of 3R and 4R, is like that of humans, while normal mice produce only the 3R type.  (“R” is a stretch of amino acids in the tau protein that allows it to attach to the brain cells’ microtubules.  The number is how many such stretches exist in the tau molecule.)  This suggests that macaques and humans share a similar genetic control of tau production.
  • The complexity of monkeys’ normal movements and cognitive processes more closely resemble those of humans, allowing more valid extension of the experimental observations to humans and their diseases.  This complexity also allows a finer-grained evaluation of the effects of the experimental intervention.

The authors point out that while only four macaques were necessary to demonstrate this result, larger numbers would be needed to confirm the findings and to turn this model into a practical research tool.  Once that happens, many research labs the world over could use this technique in studying PSP and testing drugs designed to slow, stop or reverse its progression.

Now here’s the issue at hand:  The last line of the paper is:

“ . . . our results support the use of PSP-tau inoculated macaques as relevant animal models to accelerate drug development targeting this rare and fatal neurodegenerative disease.”

At one level, they are probably right: using macaques in research would bring a cure for PSP faster than using mice.  But some people oppose the use of animals of this level of intelligence in scientific research, no matter the benefit to humans.  I’m interested in your opinion: should macaques be used in PSP research? 

No, I don’t know how many macaques might ultimately be needed.  Nor do I know how much sooner a cure would be found compared to the present practice of using only rodents.  So, try to provide an opinion that transcends those important specifications. 

Please use the “reply” or “leave a comment” feature (whichever your browser shows) below.  Thanks.

Research on quality, accessibility and equity of care

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In 2017, CurePSP created a network of 30 academic medical centers with special expertise in PSP, CBD and MSA.  They’re called the “CurePSP Centers of Care” and are the equivalent of what many other medical non-profits call their “centers of excellence.”  Of the 30 sites, 28 are in the US and 2 in Canada.  Each site is directed by a neurologist specializing either in movement disorders or cognitive/behavioral neurology with a record of excellence and achievement in at least one of the three disorders, and with a certain minimum patient flow, community involvement and availability of other relevant professionals such as physical therapists, speech/swallowing therapists and neuropsychologists.

In 2018 and 2019, its members collaborated on a consensus paper summarizing the latest in the management of PSP and CBD.  It was published in 2020 in an open-access journal, and you can download it here.  It’s written for physicians and other professionals, but the language is accessible to the educated layperson.  You might consider sending copies to your own clinicians.

But that’s old news.  What’s new is that the CoC program has just awarded its first set of grants, totaling $81,000.  The rules are that only CoC sites are eligible to apply and that each project must be a collaboration of at least two sites.  The subject matter has to be the quality, accessibility and equity of care.  It’s not for lab research or drug trials, but each project does have to include some sort of measurable, publishable outcome.

Here are the first year’s grant awardees:

  • The University of Chicago, Northwestern University and Rush University will produce ten live, on-line, hour-long educational sessions for patients and their families and caregivers covering many aspects of PSP, CBD and MSA.  The presentations will be recorded and made available subsequently.  Participants will be tested on the material before and after the sessions.
  • The centers at Johns Hopkins University and at the Harvard-affiliated Massachusetts General Hospital will compare three different methods of improving access to care at their facilities.  They will enroll a total of 30 patients with PSP, CBD or MSA.  Each will receive either an internet-enabled tablet for tele-neurology visits, free transportation to their neurologist’s appointments, or free parking there.  At the start and after six months, the patients and caregivers will complete surveys assessing overall disability, emotional state, stress level, general well-being and level of relevant medical knowledge.
  • The University of Pennsylvania and University of California San Diego centers will assess end-of-life care preferences among White and non-White individuals with PSP, CBD and MSA.  Fifty patients and their caregivers will be invited to participate and ten to 15 are expected to accept.  They will receive a survey called “Attitudes of Older People to End-of-Life Issues” and will participate in hour-long focus groups of two or three patients each.  The analysis will compare White with non-White participants in order to gain insight into racial differences affecting this highly culture-driven set of attitudes.

Not your average set of neurology research projects, right?  I’ll report the results to you in a year.  The Centers of Care plans for another set of projects in late 2023.

Disclosure: I helped organize CurePSP’s Centers of Care program in 2017 and I continue as a member of the CoC’s Steering Committee and as a member of the ad hoc committee evaluating grant applications.    

A conspiracy theory

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In August 2022, over 2 months ago, the august journal Science published an important paper on the genetics of PSP.  I had difficulty wrapping my head around the complicated, cutting-edge technical aspects of the work, so I procrastinated in relaying it to you. 

But last week, at CurePSP’s annual International Scientific Symposium in New York City, the paper’s senior author, Daniel Geschwind of UCLA, presented the work clearly enough for a non-lab person like myself and I now feel comfortable telling you that this paper is a real game-changer for PSP.  The first author is a very junior member of Dr. Geschwind’s lab, Yonatan Cooper, a recent PhD who’s studying for his MD.  The name of the paper is “Functional regulatory variants implicate distinct transcriptional networks in dementia.”

Until now, pretty much all we’ve known about the molecular genetics of PSP is that there are two places in MAPT (the gene encoding the tau protein), where one version of the gene is a little more common in people with PSP than in healthy people, and that there’s similar incrimination of a handful of other genes on other chromosomes.  These variants are all in “markers,” rather than in the genes themselves.  That is, a spot near the gene is the thing whose variant is statistically over-represented in those with the disease relative to healthy people.  That doesn’t tell us for sure which of the dozens of genes in the vicinity of the marker is the actual disease-associated gene and it definitely doesn’t tell us the nature of the gene’s defect, or how it contributes to brain cell loss.

But now, the researchers at UCLA have analyzed the actual function of the genes in the chromosomal neighborhood of each of 9 markers associated with PSP.  This is a huge undertaking, so they use a new technique called a massively parallel reporter assay (MRPA), which reveals gene expression.  That is, it shows the types and amounts of proteins encoded by each of the 9 PSP-related genes and the other nearby genes incriminated by that marker.

The result was that the PSP-associated genes didn’t encode proteins themselves, but rather, served a regulatory function.  The two genes most heavily associated with PSP were PLEKHM1 and KANSL1.  Both are on chromosome 17, very near the MAPT gene.  The disordered DNA sequences for PSP were transcription factor binding sites, the places in the gene where regulatory proteins can attach in order to do their job of adjusting the amount and composition of the protein encoded by that particular stretch of DNA. 

So, what does this mean?  To quote the paper, “These analyses support a mechanism underlying noncoding genetic risk, whereby common genetic variants drive disease risk in aggregate through polygenic cell type-specific regulatory effects on specific gene networks.”  The English-language version is that they showed that the genetic contribution to PSP consists of variants in members of groups of genes that work together to regulate a specific cellular function.  An individual with PSP simply has the bad luck to harbor enough such genes to get the disease process going. 

The research paper shows that the gene variants themselves don’t directly encode a toxic version of a normal protein, as occurs in Huntington’s disease or other highly heritable brain degenerations.  The toxic levels of tau in PSP must therefore be the indirect result of the disordered gene regulation, and as Dr. Geschwind emphasized, this and many other possible indirect effects of genetic variation contributing to the cause(s) of PSP remain to be discovered. 

The fact that multiple genes must conspire together to produce the disease could explain why PSP is almost never familial: it’s very rare that more than one member of a family would have enough of the gene variants to accomplish any nefarious purpose.  Someone with PSP would have had to inherit some variants from Mom and some from Dad, neither of whom had enough variants to cause the disease in themselves.  Then, of course, one or more environmental exposures or experiences are probably also necessary but insufficient co-conspirators.  But that wasn’t part of this project.

Enough for now.  In a future post I’ll speculate with abandon on the implications for anti-PSP drug development.