Lecanemab: now for the (not that) bad news

A bombshell hit the news yesterday (11/20/22) about a breakthrough treatment for Alzheimer’s disease.  But the drug company announced the same news two months ago in the form of a press release.  Today’s story was merely about a formal presentation of the results at an Alzheimer’s conference that added some important safety data.  Here’s my blog post from September.

The drug is called lecanemab, and as its last three letters indicate, it’s a monoclonal antibody – in this case directed against the beta-amyloid protein.  That’s present in an abnormal, aggregated form in brain cells in Alzheimer’s but not in PSP.  In the trial, the antibody solution was infused intravenously every two weeks for 18 months and compared with a group of participants receiving placebo infusions.  The news was that lecanemab slowed the rate of worsening of Alzheimer’s by 27%.  This is great news from the PSP standpoint because it’s the first time that a monoclonal antibody was shown to slow progression of any neurodegenerative condition, even if it’s a different one.  We call that a “proof of principle.”

Today’s new information on the drug’s safety was most notable for a potentially serious issue called hemorrhagic encephalitis.  That’s where areas of the brain tissue undergo swelling and/or bleeding.  That combination is evidence of inflammation, the equivalent of a very sore arm after a Covid shot.  Among the 898 participants with AD who received active lecanemab over the 18 months of the trial, 13% had swelling, but for the 897 receiving placebo, the figure was 2% – a major difference.   For bleeding, the proportions were 17% for lecanemab and 9% for placebo – a minor difference.  Fortunately, none of those participants suffered important or permanent symptoms from the swelling or bleeding, which in most cases would not even have been suspected without the trial’s routine brain MRIs, and in all cases resolved in a few weeks.  However, one wonders how serious the problem could hypothetically be in a tiny percentage of people — too small a fraction to be detected in the 897 on lecanemab in this study.

The group on active lecanemab was a bit more likely than the placebo group to report a variety of serious side effects unrelated to brain swelling or bleeding: 14% vs 11%; and the lecanemab patients were more likely to drop out of the study because of other, assorted side effects: 7% vs 3%.

Now the FDA and Medicare/Medicaid have to decide if they’ll approve this treatment or if the cost (whatever that might turn out to be) and side effects outweigh the benefit. Or, they may require another large trial first.

So, the takeaway for those with PSP is that it’s possible to modestly slow the rate progression of a neurodegenerative disease with a monoclonal antibody treatment with probably only mild risk. The numbers about the hemorrhagic encephalitis are not to be ignored.  But I think that if a hypothetical treatment for PSP gave similar risk and benefit, and the out-of-pocket cost is affordable, I think the majority of people with PSP would ask where to sign up.

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 step forward or backward? Let’s vote.

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

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

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.

Current clinical trials

As always, at your service.

Here’s an updated list of current and possible future clinical trials that I know of for PSP. For more information, visit www.clinicaltrials.gov and in the search box, enter the ID number in the first column. If you’re interested in joining an observational study (i.e., one not involving treatment), those are listed on the website as well.

clinicaltrials. gov IDDrugSponsorPhaseMechanismLocation(s)DosingComments
noneSodium selenateGov’t of Australia2Enhances dephosphoryl-ation of tau by protein phosphatase 26 sites in AustraliaOralRecruiting
NCT 04734379FasudilWoolsey2aRho kinase inhibitorUCSFOralCompleted recruiting; Study to end in 11/2023.
NCT 04993768TPN-101Transposon2aReduces tau productionBoca Raton, FL, Farmington Hills, MI, Las Vegas, NV, Gainesville, FL, Englewood, COOral30 patients on drug, 10 on placebo; completed recruiting; completion 7/2023
NCT 04937530RT001 (di-deuterated linoleic acid ester)BioJiva (product from Retrotope)2aReduces lipid peroxidation, enhancing mitochondrial activityUniversity of Munich (Germany)OralNon-controlled study showed very slow PSP progression over 2 years.  Small RCT results due in 11/2022.
NCT 04539041NIO-752Novartis1Anti-sense oligonucleotide; reduces tau productionRochester MN, Nashville TN, La Jolla CA, Boca Raton FL; 2 in Montreal; 5 in Germany; 1 in UKInfusion into spinal fluid at lumbar spaceStill recruiting; 4 injections into spinal space over 3 months. Completion in 5/2024.
NCT 04008355AZP2006AlzProtect1Reduces phosphor-tau by enhancing progranulin3 sites in FranceOral solution~24 patients on drug, `12 on placebo
noneAtomoxetine (brand: Strattera)Cambridge University2aFor mood disorders of PSPCambridge, UKOralNoradrenaline for Progressive Supranuclear Palsy Syndromes (NORAPS).  Contact james.rowe@mrc-cbu.cam.ac.uk
NCT 04468932TMS in PSPOregon Health & Science U, Portland; NIHNATranscranial magnetic stimulationPortland, ORNon-invasive magnetic fieldRecruiting; Expected completion: June 2026
NCT 04014387Suvorexant and zolpidemUniv of California, San Francisco4Two approved sleep aids never before evaluated in PSPAll evaluations are remoteOralCompletion expected May 2024. No need for patient to travel to research center. The expected benefit is in sleep, not movement.
NCT 03924414Zoledronic acidCalifornia Pacific Medical Center Research Institute4Anti-osteoporosis drug to prevent fractures in neurological diseases with falling55 locations, all in the USOne intravenous infusionCompletion expected Nov 2023.
May start recruiting in the next year: 
?ASN120290Asceneuron1Reduces tau misfolding and aggregation by inhibiting O-GlcNAcase? Press release info only
?MP201Mitochon1Mitochondrial decoupler? Early in planning per press release
?Tolfenamic acidNeuroTau2NSAID that reduces tau productionCleveland Clinic, Las Vegas + others?  
        

We can dream, can’t we?: An unscientific survey

Here’s a hypothetical question for you all:  How effective does a neuroprotective drug have to be for you to want to use it?

What prompted this question is the recent FDA approval of a new drug to slow the progression of ALS (Lou Gehrig disease).  It gives the patient, on average, 25% more survival time.  Now, suppose a drug to slow the progression of PSP provided the same benefit?

The average person with PSP received the correct diagnosis about 3½ years after the first symptoms appear and, with currently available treatment, die an average of 4 years later.  So if a new drug slowed the progression by 25% and is started immediately after the diagnosis of PSP is made, then that 4 years becomes 5 years – not much of an improvement, but better than nothing.

The cost of Relyvrio for ALS is $158,000 per year.  The cost of Aduhelm, which was approved last year for slowing the progression of Alzheimer’s disease, is $28,000.  Let’s say our hypothetical PSP drug splits this difference, at $93,000.  We don’t know how much of that would be covered by the various drug insurance plans, and of course, not everyone has drug insurance. 

Let’s assume that the hypothetical PSP drug has no important side effects and that it requires a monthly intravenous infusion lasting 2 or 3 hours.  (Some of the experimental PSP drugs are just oral pills and one is an injection every 3 months into the spinal fluid, as for a spinal tap.)

So, my question boils down to this:  Would you opt to receive this PSP drug with a 25% slowing benefit – or not?  The benefit to the average patient would be one more year of survival – more for some, less for others. 

A point in favor: The drug wouldn’t just prolong the final year, when the person is most disabled.  Rather, it would prolong each year of those 4, so that the first year’s mild level of disability would persist for 15 months rather than 12, and so on.

Two points against: 1) You’d have to take the drug for the rest of your life, or until something better came along. 2) Future participation in a clinical trial of a potentially better drug might not be allowed for people already on another PSP-protective drug.

Any thoughts for my highly unscientific survey would be appreciated.  Click “Leave a comment” just below this line.  Feel free to explain your thinking.

Genetic testing advice

I’ll plagiarize myself again. CurePSP asked me to write up a piece in response to someone asking if a person with PSP or CBD (or suspected PSP or CBD) should have genetic testing. The short answer is mostly “no,” but here are the details:

People with an established diagnosis of PSP or CBD and a close relative with one of those conditions (or a strong suspicion thereof) should consider having their MAPT gene sequenced.  That’s the gene encoding the tau protein.  But the vast majority of those with PSP or CBD have no similarly affected relatives, and for them, genetic testing is neither necessary nor useful.

The test should sequence the entire MAPT gene and not merely check for the ten mutations, all of them very rare, that have been associated with PSP (seven with CBD) in the past.  If the person with the disorder (called the “proband”) proves to have a mutation in MAPT, then other family members with similar symptoms can be tested as well. 

Variants in eight genes other than MAPT have been associated with PSP and five with CBD, but each of these raises the disease risk only slightly and testing for them is not useful in an individual or even in a family.  That’s because these are only “marker associations,” not specific mutations altering a protein known to be involved in the PSP process. The markers are called “single-nucleotide polymorphisms” or “snips” and unlike the MAPT mutations, they incriminate a span of about 100 or so genes, not a specific gene, much less a specific mutation that can be tested for.

We must keep in mind that many mutations, even in genes like MAPT, are harmless and do not cause disease.  Sixty MAPT mutations have been reported in humans so far, and only ten of them are known to cause PSP. So having a mutation in MAPT and having PSP doesn’t necessarily mean that one caused the other.  If a relative with the same symptoms has the same mutation, it may still not be cause-and-effect, but if that relative is distant, or the proband and two or more relatives share symptoms and a mutation, then the likelihood of cause-and-effect is greater. 

Even if there’s a good statistical likelihood that the proband’s mutation is the cause of their disease, and a healthy relative proves to have the same mutation, one still would not be able to predict how soon the relative might start to develop symptoms.  That information could be available soon from some other type of “pre-symptomatic” or “predictive” testing, but no such test has yet proven to be sufficiently accurate in such a situation.

People with suspected PSP or CBD with no relatives with similar symptoms have no need for genetic testing.  Even if one of the known PSP/CBD-causing mutations were found, it would not contribute much to the likelihood of PSP or CBD as the diagnosis explaining the symptoms.  The same is true for the healthy relatives of someone with established PSP/CBD.

So, as you can tell, estimating disease risk from genetic testing can be complicated.  That’s why a professional genetics counselor or a physician with expertise in adult neurogenetics should advise anyone considering having family genetic testing for PSP or CBD. Don’t just rely on the simple report supplied by 23andMe.

I’ll update this as necessary.

Let’s talk about paw-paw.

Rousting me out of my recent blog-post drought was some click-bait I saw about the growing popularity of a fruit called paw-paw.

The paw-paw fruit with its seeds

So-named because of its outward resemblance to papaya, paw-paw grows on trees both wild and cultivated, in the eastern US and Canada.  The flesh is sweet and creamy, like a banana, and can be consumed in many forms.  Maybe the only reason it’s not more popular is that the fruit is easily bruised during shipping.  It’s one of the faves of the locavore, farm-to-table movement in eastern North America.  So, what’s not to like?

Here’s what: Paw paw contains a mitochondrial toxin called “annonacin.”  It’s not only on the seeds, leaves and roots, where toxins exist in many plants with harmless fruit, but also in the fruit itself.  The toxin inhibits the action of “complex I,” a critical part of the process in the mitochondria that makes energy from sugars and oxygen.  It seems likely that the toxin serves the plant as a defense against insects, whose mitochondria, like ours, are susceptible to it.

Annonacin first reached the attention of scientists studying neurodegeneration after the 2002 publication of a description of a tauopathy endemic on the Caribbean island of Guadeloupe.  A third of the people with that disease met diagnostic criteria for PSP. The others had falling, frontal cognitive loss and disinhibited emotional responses, but not the eye movement palsy of PSP.  Compared with people on Guadeloupe with typical Parkinson’s disease or healthy controls, those with “Guadeloupean tauopathy,” as it came to be called, were far more likely to have consumed a tropical fruit called soursop. You guessed it: soursop turns out to have harbor annonacin, like paw-paw.

Prompted by that information, scientists in Germany injected annonacin intravenously into rats.    The result was a tauopathy that resembled PSP in the rats’ motor behavior and in the appearance of their brain cells under the microscope. The same group subsequently found that annonacin can cause tauopathy by a very different mechanism as well.

Shortly thereafter, I did a dietary risk factor survey among my patients with PSP, comparing them to controls with non-degenerative neurological diseases from our clinic.  So few had ever eaten paw-paw (or soursop) that the study didn’t have the statistical power to answer the question and I never published it.  (The more common foods included in the questionnaire gave no statistically significant results, either, in case you were wondering.)

Bottom line: There’s probably not enough annonacin in paw-paw to cause PSP or other tauopathies after only occasional consumption.  But over decades?  And what about people with a genetic predisposition to develop tauopathy?  Or people who just love paw-paw and eat them like candy? (There are some!) I think more research and some careful thinking by the FDA is needed before paw-paw becomes more widely marketed and consumed alongside apples, bananas and oranges.

Lecanemab for Alzheimer’s: “Proof of Principle” for PSP

I’m not above plagiarizing myself. What follows is a piece I just wrote for the CurePSP website. It’s pitched at a simpler level than most of my blog posts, but it’s close enough. As I learn more about this drug, I’ll fill in some technical details for you.

Great news for people with Alzheimer’s disease:  A monoclonal antibody for intravenous infusion called “lecanemab” has been found to slow the rate of worsening of early-stage AD by 27%.  The Japanese drug company Eisai, which developed the drug, and the US company Biogen, which is assisting in the testing, jointly announced the news on September 26.  If approved by the FDA, lecanemab would be the first drug available to slow the underlying disease progression in AD rather than merely treating the symptoms, as Aricept and other existing drugs for AD do.

In almost all neurodegenerative diseases, one or more proteins forms clumps called “aggregates” in brain cells.  Lecanemab is an antibody directed against beta-amyloid, which is one of the two proteins that aggregate in AD.  The other such protein is tau, which of course is the one protein that aggregates in PSP and CBD.  In MSA, the protein is alpha-synuclein.  Beta-amyloid protein is not involved in PSP, CBD or MSA.  Two different monoclonal antibodies directed against the tau protein have failed to slow progression in PSP.  Nevertheless, the lecanemab news is welcome for people with PSP, CBD and MSA.  Here’s why:

  • This is the first demonstration that reducing levels of the aggregating protein in a neurodegenerative disease can actually slow the ongoing progression of the condition in humans.  (This has been accomplished in many ways in lab animals, but their artificial versions of human brain diseases are very incomplete models.)  This means that some other way of reducing tau protein in humans with PSP/CBD might work.
  • The two monoclonal antibodies that have failed in PSP were directed against the same end of the tau protein (called the “C-terminal” or “microtubule-binding domain,” if you want to get technical).  Other monoclonal antibodies directed against the other end of tau (the “N-terminal”) might work better, especially as fragments of tau that include the N-terminal now seem to be the bad actors.  Such monoclonal antibodies are in early-phase testing.
  • Until now, it has not been fully clear that in human neurodegenerative diseases, the aggregating protein is what’s causing the loss of brain cells.  Competing theories suggest that something else is damaging the brain cells and the protein aggregation is merely a result of that process rather than its cause.  The lecanemab news suggests that the aggregates themselves are to blame.  This makes future drug development a lot easier and more focused.
  • Although no monoclonal antibody trials are currently in progress for PSP, CBD or MSA, there is a current trial of another way to reduce tau protein.  Rather than destroying protein as antibodies do, this approach prevents the offending protein from being manufactured in the first place.  It’s called “anti-sense oligonucleotide” treatment, and an early-phase safety trial for PSP is under way at several sites in the US and elsewhere.  Trials of other ASOs for other neurodegenerative diseases are planned.

So, we congratulate the AD world on this successful trial, which we hope and expect will be the first of many, and we take heart that this “proof of principle,” as scientists call it, can soon be applied to PSP, CBD and MSA.