Now that CurePSP’s December 1 deadline for its next semi-annual crop of grant applications has passed, I’ll try to finish reporting on the crop of funded projects from July’s deadline. 

This one’s pretty cool.  It tests an FDA-approved drug for AIDS called efavirenz (brand name, Sustiva) for  its ability to prevent tau from aggregating and causing brain cell loss in a mouse model.  The principal investigator is Rik Van der Kant, PhD of the Vrije University in Amsterdam.  Like most of CurePSP’s grant recipients, he’s relatively junior, having completed his PhD in 2013 and his postdoctoral training only in 2019.

Dr. Van der Kant and his colleagues have shown that efavirenz improves degradation of tau in brain cells that were created from human stem cells.  In fact, the drug is already in a very small, early-phase clinical trial for Alzheimer’s disease at Case Western and at Mass General. That trial was expected to finish in December 2020 (this month), but I assume that the Covid lockdown has delayed that.

The new project will give efavirenz to P301S mice.  Those critters carry not only their own normal mouse tau gene, but also a human gene for tau with a mutation that causes a PSP-like illness in people.  (It’s actually a familial form of frontotemporal dementia that closely resembles PSP.)  Tau P301S mice are probably the best PSP model we have at present, all things considered, though stem-cell-based models are gaining fast.

The tauopathy-prone mice will receive either efavirenz or a control solution in their drinking water from age 3 months to 6 months.  After another 3 months, they will be tested for their motor and cognitive abilities and their brain tissue will then be analyzed for tau, phosphorylated tau, number of neurons and synapses, and for the efficiency of one of their brain cells’ garbage disposal mechanisms, the proteasomal system.  Dr. Van der Kant’s hypothesis is that efavirenz revs up the proteasomal system by reducing cholesteryl esters.  Evidence from his stem cell work supports that idea, but he would now like to investigate this in a whole animal.

The next step, not covered by the current grant, would be a trial in people with PSP.  Efavirenz reached the US market in 1998 and has been available as a generic since 2016.  It crosses the blood-brain barrier and is acceptably safe and well-tolerated in patients with AIDS.  There’s no reason to suspect that those with PSP wouldn’t tolerate it as well, but we can’t just assume that.  Of course, as a generic, it may be difficult for efavirenz to find funding for clinical trials for a new indication.  CurePSP might be willing to chip in what it can, but their maximum grant is $100,000, while the median phase II trial costs $8.6 million and the figure for phase III trials is $21.4 million.  Sometimes this problem is solved when a deep-pocketed drug company invents a new version of the drug that works the same but is chemically different enough to win a new patent. 

But first let’s all hope the drug works in the P301L mice.  Pessimism alert: Maybe in a future post, I’ll opine on why davunetide, tideglusib and two monoclonal antibodies worked in similar mice but not in human PSP.  That’s one of the biggest questions in PSP research right now.

Drilling into a gene

So here’s the second of five installments in this fall’s series on CurePSP’s newly funded grants. 

Do you recall that the 2011 publication by CurePSP’s Genetics Corsortium discovered four new places in the genome where a slight variant is associated with slightly greater chance of developing PSP?  The genes containing those variants are cryptically called MAPT, STX6, EIF2AK3 and MOBP.  The first one stands for “microtubule-associated protein tau” and the protein it codes for is, of course, our old frenemy, the tau protein.  Well, when you break the effect down statistically, it turns out that in the MAPT gene, two different variants are each independently associated with increasing PSP risk.  One has been known since 1998 and remained the only known PSP genetic risk factor until 2011.  Its name is the “H1 haplotype.”  (Click on the link for explanatory details. )  The other one, previously unknown, is called only “rs232557.” That variation specifically is the substitution of one “letter” in the genetic code for another, called a single-nucleotide polymorphism, or SNP, pronounced “snip.”  The substitution is probably not itself be the cause of the PSP risk; it’s only a “marker,” a variation that was already present in the MAPT gene in the individual in which the PSP-causing mutation originally occurred. That person then passed both the innocuous old marker variant and the new disease-causing variant together to subsequent generations.  The two stayed together on the chromosome (in this case, chromosome 17) through all those generations because their very close physical proximity means that a break between them during the reproductive process (where sperm cells or ova are made, called “meiosis”) is statistically unlikely. 

Still with me here?  Back to the new grant, where Rueben G. Das, PhD of the University of Pennsylvania proposes to figure out just how the variant revealed by the rs242557 marker increases PSP risk.  We already know that rs242557 is located in an intron of the MAPT (tau) gene.  Introns are long stretches of DNA between the shorter stretches, the exons, which actually encode the structure of proteins.  Introns can do a variety of things, though many of them seem to be just “junk DNA” deactivated by the evolutionary process somewhere between single-celled creatures and ourselves.  But some introns regulate the “expression” of the exons, i.e., the number of RNA molecules the exons produce, which in turn determines the number of molecules of the corresponding protein that the cell makes. 

Introns may also regulate which specific exons in the gene actually get encoded into RNA and which don’t.  That’s relevant for PSP, where nearly all the tau molecules in the neurofibrillary tangles include the product of MAPT’s exon 10, producing “4-repeat” tau.  This contrasts with normal tau in adult human brain, which includes exon 10’s stretch of amino acids on only half of the copies.  The other half are called “3-repeat” tau.

One of Dr. Das’ experiments will simply excise (“knock out”) the variable nucleotide at the rs242557 site.  Others will knock out or change one of the nucleotides nearby.  These experiments will be tried in both mouse and human brain cells.  One of the outcomes the researchers will look for will be the ratio of messenger RNA for the two forms of tau, 3-repeat tau and 4-repear.  A ratio favoring 4-repeat tau would suggest a PSP-causing effect.  Of course, they will also look at the finished tau proteins corresponding to these MAPT gene variants.

Additional readouts will be the messenger RNAs for other genes located in the same general area of chromosome 17 (and their associated proteins) that have bene associated with PSP or Alzheimer’s disease.  Those genes are called NSF, KANSL1, LRR37A and CRHR1.

Dr. Das completed a postdoctoral fellowship (the final stage of training for a lab scientist) at Penn in 2017 under the mentorship of Gerard Schellenberg, PhD, a world authority in the genetics of neurodegenerative disorders.  They continue to work together now that Dr. Das has graduated to Senior Research Investigator at Penn.  Jerry serves on CurePSP Scientific Advisory Board and of course recused himself from the evaluation of this grant application.

Back to science: To create these tiny, targeted changes in the DNA at the rs242557 site, Dr. Das and colleagues will use the new gene-editing technique called CRISPR-Cas9.  Just a month ago, the two scientists most prominent in the development of that technique, Jennifer Doudna and Emmanuelle Charpentier, received the Nobel Prize for that work, which appeared in 2012 and has been called one of the most important advances in biological science in history.   Like many useful techniques in biology and medicine, this one harnesses something from nature, in this case an anti-viral defensive mechanism present in about half of all species of bacteria, an enzyme called CRISPR (clustered regularly-interspaced short palindromic repeats).  The CRISPR protein is coupled with another bacterial protein, Cas9, which can cut DNA.  (“Cas” means CRISPR-associated, and yes, there are at least eight other Cas enzymes.)  The researcher then adds to the complex of CRISPR and Cas9 a stretch of synthetic RNA custom-designed to complement the stretch of DNA targeted for alteration.  That “guide RNA” allows the complex to recognize the DNA site of interest, where the Cas9 proceeds to make a cut. 

If this project is successful and reveals which nearby genes are up- or down-regulated by variants in rs242557, the next steps would be to try to normalize the function of the resulting protein by other means such as conventional drugs. Another approach might reduce the expression of the offending DNA variant by giving an anti-sense oligonucleotide.

This grant is only a one-year project and I’ll report its results once published or otherwise publicly presented.  Stay tuned now for posts on the other new CurePSP grants.

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 its blood levels are known to be elevated by 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.

All the world wants stages

[This expands on the idea of PSP stages from my last post, so you’ll want to read that one first.]

“Does PSP have stages?” is a question frequently posed by patients justifiably concerned about how far along they are in the degenerative course of the illness and what new symptoms might lie ahead. 

Many people have become familiar, however reluctantly, with the widely used TNM staging system for cancer, where T refers to the size and extent of the primary tumor, N the extent of spread to lymph nodes and M the presence or absence of metastasis to other organs.  Each is assigned a value and summed to generate a stage from I to IV.  For some types of cancer, a letter is appended to denote additional detail.  Complicated but useful. 

Parkinson’s disease takes a simpler approach.  The Hoehn-Yahr Scale, published in 1967, has five stages: 1)  symptoms only on one side of the body, 2) symptoms on both sides or in the face, voice or trunk but no balance problem, 3) balance problem that does not require assistance, 4) balance and/or gait problem requiring assistance, 5) confinement to bed or wheelchair most of the time.  Notice that only the laterality and gait/balance are considered here.  Still, the H-Y Scale is very useful and popular.  The paper by Hoehn and Yahr presenting their scale remains far the most widely-cited publication on Parkinson’s disease.  (A little Internet snark, if you’ll excuse me: My former chairman and mentor, Roger Duvoisin, actually did most of the work on the scale before reporting for duty as a medical officer in the Navy, headed for Vietnam, at which point his two senior colleagues wrote up the paper without him.)

PSP is a complicated disease, with dozens of symptoms that can be very roughly lumped into four main areas: parkinsonism (meaning stiffness, slowness and problems with speech and swallowing), loss of mental function (including both cognitive and behavioral issues), impaired eye movement, and balance problems.  In creating a staging system for PSP, one could follow the cancer model, assigning a rating to each disease feature, summing those, and then defining each stage as a specific range of that total.  Or, one could use the Parkinson’s model, relying on just one feature of the disease that’s easy to evaluate and important to the patient’s daily function.

Now let’s consider the purpose of a staging system.  Its main virtue is convenience.  Ideally, it shouldn’t require any imaging or lab tests and should be usable by any clinician.  If patients and caregivers can apply it, that would be a plus. 

A staging system, like any diagnostic test, should have both validity and reliability, and yes, there’s a difference.  There are multiple subtypes of validity that we need not discuss here.  But in general, validity is the degree to which an accurate answer to the question actually measures what it purports to measure.  For example, if I want to know how severe your PSP is and I only ask about your bladder function, the validity for assessing PSP overall would be low.  But if you know your bladder symptoms well and communicate that information to me accurately, the question would have high reliability.   The opposite sort of example is if I try to assess the severity of PSP by measuring the number of neurofibrillary tangles in the brain.  That would be a highly valid way to assess PSP, but the ability of the available imaging techniques or spinal fluid tests to actually do that is not good enough just yet, meaning that their reliability as a measure of PSP is inadequate.

The staging system that my colleagues and I provisionally devised for PSP and used in our prognostic study described in the August 9 post uses an approach similar to cancer’s TNM system.  It uses only information obtainable from the PSP Rating Scale scores.  It considers only swallowing and gait/balance, as those two issues are the most closely related to long-term complications from malnutrition, aspiration, falls and immobility. 

We assessed the validity of the staging system by showing that stage parallels the same patients’ total PSPRS scores almost exactly.  That’s called criterion validity.  But the proposed staging system still needs to be tested for multiple other kinds of validity as well as for reliability.

Just FYI, here’s how to calculate the stage using our proposed system:  First, rate the following four items from the PSP Rating Scale:

3.  Dysphagia for solids by history

0  Normal; no difficulty with full range of food textures

1  Tough foods must be cut up into small pieces

2  Requires soft solid diet

3  Requires pureed or liquid diet

4  Tube feeding required for some or all feeding

13.  Dysphagia for half a glass of water

0 None

1 Single sips, or fluid pools in mouth or pharynx, but no choking/coughing

2 Occasionally coughs to clear fluid; no frank aspiration

3 Frequently coughs to clear fluid; may aspirate slightly; may expectorate frequently rather than swallow secretions

4 Requires artificial measures (oral suctioning, tracheostomy or feeding gastrostomy) to avoid aspiration

26.  Gait without assistance if possible

0  Normal

1  Slightly wide-based or irregular or slight pulsion on turns

2  Must walk slowly or occasionally use walls or helper to avoid falling, especially on turns

3  Must use assistance all or almost all the time

4  Unable to walk, even with walker; may be able to transfer

28.  Sitting down without using hands

0  Normal

1  Slightly stiff or awkward

2  Easily positions self before chair, but descent into chair is uncontrolled

3  Has difficulty finding chair behind him/her and descent is uncontrolled

4  Unable to test because of severe postural instability

Then total the four scores.  Stage 1 is 1-4 points, Stage 2 is 5-8 points, Stage 3 is 9-12 points, Stage 4 is 13-15 and Stage 5 is the full 16.

Reasonably simple, but it takes training and experience to administer the items accurately and there’s a whole list of little rules and tips that I’ve published in my book but didn’t include here.  I’ll continue to test the validity of the system using a larger dataset and I may fool around with other schemes.  I’ll keep you posted.

Some prognostic help

Sooner or later, most patients with PSP or someone they rely on will ask the doctor, “What’s going to happen next, and when?”  Until now, that question has only been answerable by saying, “Well, the symptoms you have now will slowly get worse and you may develop some additional ones.” or “I don’t know; everyone’s different.”  If the question is, “How long will I survive?” the only available answer has been to quote the published averages for PSP, which have a wide variance. All too often, the answer is, “Don’t worry about that — just take it one day at a time.”

A long-gestating project of mine has finally seen the light of day.  It uses scores on my patients’ PSP Rating Scale (PSPRS) scores gathered from 1995 to 2016 to allow clinicians to predict how much longer it will take for a given patient to reach certain disability milestones and death.  It also proposes a new five-point clinical staging system that we used as some of the disease milestones.  It appears in the August 2020 issue of Movement Disorders Clinical Practice and is available here.

Assisting in the effort was my trusty statistician, Pam Ohman-Strickland, of the Rutgers School of Public Health.  She was also my co-author in the original validation of the PSPRS in 2007.  BTW, if you want to read that paper, here’s your chance. Since then I’ve refined the rules and instructions for administering the PSPRS and that’s available here.

Two undergrads helped out in the new project: Emily Beisser did most of the analysis for the new staging system and Francesca Elghoul helped with data wrangling.

The outcome milestones number 13 in total.  The first seven are severe difficulty with swallowing solids, swallowing liquids, speech, eye movement, general movement, balance and thinking. For each, “severe” is defined as exceeding a specific score on the relevant PSP Rating Scale item(s).  The next five are the stages on the proposed “PSP Staging System” and the last milestone is death.  

We created the five PSP stages by totaling four of the 28 items on the PSPRS: swallowing solids, swallowing liquids, gait, and the ability to return to one’s seat safely from a few steps away without using the hands.  They’re items 3, 13, 26 and 28 on the PSPRS.  The point total for those four items, each rated 0 to 4, are divided into five groups: 0 points, 1-4, 5-8, 9-12, 13-15 and the full 16.  Although this staging rubric uses only two of the many possible deficit areas in PSP, we found that the total of these those four items correlates very closely with the total PSP Rating score.  We chose swallowing and gait/balance as candidates because so many of the serious complications and disabilities of PSP lie in those areas. I’ll devote a future post to the issue of “stages” in PSP.

Tables 3 and 4 in the new paper show the meat of the matter.  You’ll see that the input data are gender, the total PSP Rating Scale score at the time of the visit, and the rate of progression to date.  The last one has to be calculated by dividing the current PSPRS score by the number of months since the onset of the first PSP symptom.

Just a quick caveat: Please don’t try this at home. Many of the exam items on the PSPRS require training and experience to administer correctly; the scale and its instructions are in technical language; and the dating of the onset of PSP symptoms may not be interpreted by the patient or family as an experienced neurologist would.

I hope that these new results, to quote myself from the paper’s introduction, “may influence decisions to retire from work, hire caregivers, alter the home environment, move to a seniors-oriented or institutional living arrangement, decide on a feeding gastrostomy and not least, prepare psychologically for advanced disability and death.”  Until we have a way to prevent or halt the progression of PSP, this will be an important part of how clinicians can help their patients.

PSP clinical trials in the time of Covid

Yesterday’s blog post was my first since the onset of the Covid-19 pandemic.  As you’d imagine, the lockdown has delayed PSP clinical trials.  It’s just too risky to patients, caregivers and staff for an older population to make visits to hospital centers for purposes of research on a chronic condition, even one as serious as PSP. 

The drug companies sponsoring these expensive trials want to wait for a major decline in Covid-19 risk in all of the geographically disparate study site locations. They also want to minimize the risk of another wave a few months later interrupting a study and making them start over.  

The clinical trial closest to launch was from the big Belgian company UCB.  It would test intravenous infusions of a monoclonal antibody directed against the tau protein.  You probably know that two such trials, from Biogen and AbbVie, gave negative results last year, with no efficacy but also no serious or frequent toxicity.  Those antibodies were directed at the “N terminal” of tau, meaning the end of the molecule encoded first during the cell’s manufacturing process.  UCB’s antibody, on the other hand, is directed at the “microtubule binding domain,” which is about two-thirds of the way toward the other end.  So it’s worth testing.  That trial will be delayed to April 2021, per UCB’s present plan.

At least a few months behind UCB’s trial is one from a small Swiss company called Asceneuron (pronounced “uh-SEH-nu-ron”).  I’ve discussed it in a previous post. This oral drug inhibits the detachment of a certain type of sugar molecule from tau, reducing its likelihood of misfolding and aggregating.  I haven’t heard when that trial might be starting and I’m sure that the company is playing it by ear. 

A third trial will test an “anti-sense oligonucleotide,” a strand of RNA injected directly into the spinal fluid in the lumbar spine. It circulates around the brain to reduce the production of tau.  A number of companies have ASO programs for tauopathies. There is also early work on ASO molecules small enough to be dosable by mouth, but those are much further from clinical trials.

A company called Retrotope received FDA permission in April 2020 to start testing an oral drug, RT001, to reduce the level of a toxic process in the brain cells called lipid peroxidation. They are testing this approach not only in PSP, but also in multiple other brain disorders where that defect seems to play a role. No word on a start date.

Another approach is an oral drug from the company called Alzprotect that increases production of a protein called progranulin, a neurotrophic factor (i.e., a normally occurring chemical that encourages the growth or repair of brain cells). The drug is AZP2006 and is in a small trial solely to assess safety in 36 patients in France.

Further from a large-scale trial is a non-steroidal anti-inflammatory drug called tolfenamic acid, which is available by prescription in the UK for migraine. Unlike other NSAIDs, it reduces the production of tau and its abnormal phosphorylation. The drug is in an early-phase clinical trial for PSP at the Cleveland Clinic in Las Vegas.

I’ll keep you updated as required.

Hope matters.

Of spice and dog breeds

Got some catching-up to do.  Since my last blog post about six months ago, I’ve retired from my professorial job at Rutgers, which means I’ve stopped seeing patients.  But I’ll still do clinical PSP trials as a volunteer, so I’ll still see that kind of patient.  Retiring from Rutgers also means that I retire from teaching.  But I’ll continue my work with PSP, so I’ll continue that kind of teaching.  Still working a little on my own research, which is mostly about that cluster of PSP in France.  Then there are all of my non-neurological retirement activities (see spouse for details).  I’ve been neglecting my PSP blog, but that has just changed.

Today a journal article caught my eye.  It found that a slight modification of a naturally-occurring component of turmeric may slow or halt the progression of the tau-based neurodegenerative disorders like PSP and Alzheimer’s disease. At least in cells growing in a dish.

First a little background: You probably know that the brain cells being damaged in PSP contain abnormal clumps of a normal protein called tau.   You also know that the clumps are called neurofibrillary tangles.  In the course of forming the tangles, tau molecules first form smaller accumulations called oligomers (Greek for “a few parts”).  The oligomers are toxic but they’re still soluble in water, like ordinary, monomeric tau (you got it: “one part”).  But the oligomers have an Achilles heel: They tend to form larger clumps, the neurofibrillary tangles, which are no longer soluble in the brain cells’ fluid.  The tangles’ inability to float around and interact with things renders them harmless and means that they serve the useful purpose of taking the toxic, soluble oligomers out of the brain cells’ internal soup.

More background: You’ve heard of turmeric, a popular spice related to ginger.  It’s a traditional remedy for what ails you and some responsible researchers feel that it may actually help certain inflammatory conditions and the metabolic syndrome (high blood pressure, diabetes, abnormal lipids and obesity).  But despite some success in animal models, it has never been proven by modern standards to help any medical condition in actual humans.  Furthermore, we don’t know which of the dozens of chemical components of turmeric explains its apparent benefits.  One minor component of turmeric is curcumin, which by itself is used as a coloring agent in food and cosmetics.  Its chemical structure renders it very difficult to absorb from the digestive tract into the blood or from the blood into the brain.  Here’s the good news: We’ve known for a few years that curcumin, when directly applied to brain cells in a dish, can actually can induce the water-soluble, toxic tau oligomers to form insoluble, harmless neurofibrillary tangles. 

The new journal paper is from neuroscientists at the University of Texas Medical Branch in Galveston and the University of Palermo, Italy.  The group’s leader is Rakez Kayed, PhD of UTMB, a respected and well-published researcher in tauopathies and other forms of neurodegeneration.  The first-named author is Filipa Lo Cascio, PhD, a young post-doctoral trainee in his lab.  They cultured two off-the-shelf types of neural cells and added abnormal tau extracted from autopsied brain tissue from people with PSP, Alzheimer’s disease and dementia with Lewy bodies.  Ordinarily, the abnormal tau would misfold, cause the normal host’s tau to misfold in the same disease-specific way, form oligomers, cause damage, spread to other cells and eventually be taken out of action by forming neurofibrillary tangles.  The curcumin caused the toxic oligomers to more rapidly form tangles, thereby reducing their cell-to-cell spread.  By making the tau less soluble, the curcumin also limited its ability to damage components of the cells with the result of improving the cells’ survival. 

The researchers didn’t actually use curcumin itself, as that compound has no future as a neurological treatment because, as mentioned, it can’t get into the brain. So they tweaked its structure by replacing some hydroxy (-OH) and methoxy (-O-CH3) groups (don’t worry about it) with fluorine atoms.  The resulting compound, which they dubbed CL3, had the same beneficial effect regardless of whether the abnormal tau introduced into the cells was from people with PSP, Alzheimer’s or dementia with Lewy bodies. 

The next step is for another lab to replicate the results using different methods.  At the same time, researchers could try the experiment in mice that have received an abnormal tau gene that forms aggregates and kills their brain cells.  That’s currently the best lab model for PSP and the other tauopathies.  But the multiple examples of drugs that prevented this sort of mouse tauopathy and then failed to prevent PSP in clinical trials show that the mouse models, albeit based on human tau, are inadequate as surrogates for people with real PSP or other tauopathies.

The experiments of Lo Cascio, Kayed and colleagues also confirmed that the aggregates forming from tau taken from people with different tau disorders differ from one another in some other important ways.  That’s the new, hot idea of tau strains – they’re like dog breeds.  They’re all tau, but they differ in some important details and when they reproduce (i.e., by templating their abnormal folding pattern onto normal copies of tau in a host cell), their specific variation continues in the next generation.  More about tau strains soon.

Now let’s see if I can keep this up.

The elusive limelight

No rare disease advocate wishes illness on anyone, but we do all hope that one of PSP’s inevitable sufferers will happen to be a celebrity. 

When Michael J. Fox announced his diagnosis, awareness of Parkinson’s disease and fundraising for its research took off.  Amyotrophic lateral sclerosis, its prevalence no more common than that of PSP, would still languish in obscurity without Lou Gehrig.  Awareness that Alzheimer’s disease was not “accelerated aging” nor a circulatory problem was boosted early on by the plights of Rita Hayworth and more recently of Ronald Reagan, Glenn Campbell and Pat Summitt.  Robin Williams brought Lewy body dementia to popular consciousness for the first time.

PSP has never had a celebrity advocate who was an affected person.  The only real candidate emerged in 1999, when British comic actor Dudley Moore announced his diagnosis.  Shortly thereafter, a profile of Mr. Moore on the TV newsmagazine “20/20” brought the disorder some degree of attention.  In fact, at least a couple of new patients came to me after recognizing their own neurological deficits in the 20/20 piece.  A few months later, Mr. Moore himself became my patient.  He told me that he appreciated that PSP needed a celebrity spokesperson and offered to help in fundraising, but declined to become its “poster boy” (his words, not mine).  He did participate in one fundraiser before his death in 2002 and I never tried to wheedle any video clips, interviews or other forms of publicity out of him.

CurePSP did attract as its spokesperson for a number of years a celebrity whose father had PSP.  Starting in about 2005, Patricia Richardson, an accomplished actor who in the 1990s had played opposite Tim Allen in the TV sitcom “Home Improvement,” joined CurePSP’s Board of Directors.  When we appeared at events together, she was admirably persistent in prodding me to translate my scientific presentation into language appropriate to the audience.  She was generous with her time for CurePSP’s outreach and support services.  But in 2015, she and CurePSP parted ways. 

About a year ago, Linda Ronstadt announced that she had been diagnosed with PSP.  The CurePSP leadership immediately attempted to propose a spokesperson relationship, but were unable to establish contact at all.  In a September 2019 “New Yorker” magazine profile ahead of the release of the new documentary, “The Sound of My Voice”, she said, “I’ve just accepted it. There’s absolutely nothing I can do. I have a form of Parkinsonism that doesn’t respond to standard Parkinson’s meds, so there’s no treatment for what I have. It’s called P.S.P.—Progressive Supranuclear Palsy.”  But the documentary itself mentions only “Parkinson’s disease.”  (A digression: Perhaps, like many patients and caregivers, Ms. Ronstadt is under the misimpression that PSP is only a more severe form of PD, in which case she may think that someone with PSP could be said have both, one being a subset of the other.  I won’t share my own diagnostic impression on PD vs PSP based on her current speech, facial movement and eye movement as they appear in the documentary.  I’ve been around long enough to know that diagnoses relying of such fragmentary data are risky.) 

So PSP still struggles to enter public consciousness. A glimmer of hope appeared on major network TV on January 7, with the premiere of the NBC series, “Zoey’s Extraordinary Playlist.”  The star hallucinates that others communicate their feelings in the form of impromptu song-and-dance numbers.  Her father, with advanced PSP, is played with admirable accuracy by Peter Gallagher.  Sure enough, in one of the pilot episode’s musical scenes, the father, aware of his daughter’s multiple professional and personal anxieties, breaks out of his immobile, mute state into a tender song of encouragement.  The script does not include the term “PSP” or “progressive supranuclear palsy” but press blurbs and cast interviews do so.  Of course, this does not provide a real-life celebrity spokesperson, but at least it’s publicity.

Of course, I hope that no celebrity – or anyone else – ever comes down with PSP.  But once the inevitable happens, perhaps he, she or a loved one will be willing to sacrifice some time, energy and privacy to the cause.