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I’ve spent my summer in futility

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If you’ve been disappointed with the long intervals between my posts over the past few months (and I hope you are), there’s a reason.  I’ve been using much of my discretionary sitting-at-the-computer time writing a long review article on clinical trial design in PSP.

The editor of the journal Alzheimer’s and Dementia: Translational Research and Clinical Interventions invited me to write something on PSP for a special issue on a trial outcome measure called “minimum clinically important difference.”  The MCID is the smallest change in an existing, validated, accepted clinical rating scale that can be perceived by the patient as making a difference to their everyday level of disability or quality of life.  An alternative definition I’ve seen is the smallest difference that would prompt the clinician to recommend a change in treatment. The MCID has never to my knowledge been used in PSP trials, though for over a decade it has served at least as a secondary measure in trials in other conditions, including Parkinson’s disease. 

The most widely accepted outcome measure for PSP clinical trials is still the original, 28-item version of the PSP Rating Scale, which uses a point scale of 0 (best) to 100 (worst). But the original PSPRS been criticized, most prominently by the FDA, as too dependent on the neurological examination, with insufficient attention to the patient’s daily life. The European Union’s equivalent of the FDA, the European Medicines Agency (EMA), still prefers the original PSPRS. (Disclosure: I developed the PSPRS and receive a share of its licensing fees from Rutgers University, the scale’s official owner.)

I collaborated in this writing project with Ronald G. Thomas, PhD, a biostatistician at UC San Diego.  We calculated an MCID for PSP using data from the placebo groups of five published, 12-month double-blind clinical trials.  I won’t get into more details lest I plagiarize myself or invite scoops, as the manuscript was submitted only a couple of weeks ago and has not yet cleared peer review.  But I can tell you that the MCID is only a small part of our paper, which discusses many aspects of PSP trial design with an eye toward allowing trials to enroll participants faster and to become smaller, cheaper, shorter, and easier for the patient and caregiver.

Aside from obvious the patient/caregiver consideration, why is all this so important?  Because we need to lower the bar for small pharma or biotech companies to try their new drugs in PSP. One obstacle is the cost – fewer patients and shorter trial durations are simply cheaper.  Another is that during a trial, the clock is ticking on the drug’s patent protection.

A very interesting outcome of the calculations Dr. Thomas performed for our paper (again, provisional pending peer review) relates to the number of participants required for a PSP “futility trial.”  That kind of trial typically uses controls from previously published sources, thereby reducing recruitment time and costs.  It is designed to determine relatively cheaply if a drug should be abandoned or it’s worth testing in a formal, expensive, traditional trial meeting government requirements for potential approval.  A small company whose futility trial “rules out futility” (to use the formal, statistical term for success in this context) could find it easy to license or sell that drug to a larger company or to attract venture capital for a large trial of its own.

Dr. Thomas found that a futility trial needs only 100 participants on the active drug, assuming it uses placebo data from 200 people from previous trials, and has 80% power to detect a 35% slowing of progression with a statistical significance of .05. That’s not really huge news, as futility trials have been performed in PSP before, albeit using different statistical parameters than these. 

The take-home is that the unsuccessful double-blind PSP trials of the past have provided a valuable resource in the form of their placebo groups’ data, which can allow futility trials and permit many other improvement to our current clinical trial designs in PSP. That could make the clinical trial pipeline easier, faster, cheaper and less of an obstacle to small, start-up pharma companies.

Let’s pick up and dust off

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Some not-so-good news, I’m afraid: ORION trial has been discontinued for lack of benefit.

A combination of two oral drugs collectively called AMX0035 has been in a double-blind trial since late 2023. One component, sodium phenylbutyrate (brand name Buphenyl), helps brain cells get rid of misfolded, worn out or defective proteins, including tau. The other, taurursodeoxycholic acid (brain name TUDCA), stabilizes dysfunctional mitochondria. Both drugs are known to be safe in non-PSP populations, as they have long been approved and marketed for other conditions.

A few days ago, with about half of the ORION subjects having completed their 12-month double-blind observation, the sponsoring company performed an interim analysis. Their statisticians, under strict secrecy rules, “peeked” at the active drug vs. placebo assignments, comparing the groups on their degree of worsening on the PSP Rating Scale since the first visit. They found no difference, which means that allowing the remaining patients to complete their double-blind observation could never show a statistically significant improvement for the trial as a whole. Nor was there any slowing of progression on any of the secondary efficacy measures such as brain atrophy on MRI. Fortunately for the study participants, the frequency and severity of adverse effects were very low in both the active drug and placebo groups.

Where does PSP go from here, trial-wise?  Lots of places:

  • The trial of FNP-223, an oral drug that reduces abnormal phosphorylation and misfolding of tau, is nearly complete.
  • A trial of NIO-752, an anti-sense oligonucleotide injected into the spinal fluid that reduces the manufacture of tau, will start in a few months.
  • The PSP Platform Trial, which has teed up two two drugs and expects a third soon, should start later this year if changes in its NIH funding don’t stand in the way. Those are an active anti-tau vaccine called AADvac1 and AZP-2006, an oral drug that reduces inflammation and helps brain cells dispose of garbage. They will be tested separately, but using a common control group.
  • The trial of GV-1001, a subcutaneous injection that works at the RNA level to reduce brain inflammation, will probably start in 2026 or late 2025 if all goes well.  

Two drugs a bit further behind in the pipeline, based on my reading of the tea leaves, are:

  • bepranemab, an anti-tau monoclonal antibody for intravenous infusion and
  • an oral reverse transcriptase inhibitor called censavudine, where the results of the Phase I trial are sparsely reported to date.

That makes five new drugs to start trials within the next year or so — plus another one or two slightly later.

I liked the ORION trial’s idea to give two drugs simultaneously to address two different parts of PSP’s pathogenesis. Many PSP experts feel that at least that many drugs will be needed to do much to slow the progression of this complex disease. That’s what has proven necessary for things like AIDS, severe hypertension and many kinds of cancer. Those are only a few examples of multi-pronged attacks turning life-threatening, progressive diseases into chronic, manageable, non-disabling conditions.

I’m bullish on the same kind of thing happening to PSP.

Why didn’t I learn this in med school?

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“Palliative care” is too often considered to be confined to the final stages of illness: pain medications or sedatives as needed, anti-bedsore measures, adequate nutrition – and little else.  Wrong.  It’s now a medical specialty in its own right, with post-residency training programs, fat textbooks and dedicated medical center departments.  True, it’s for people with irreversible conditions, but its offerings include far more than those basics. 

Most palliative care exists in the world of oncology, of course, but it’s now gaining attention for PSP.  My PubMed search on the terms “progressive supranuclear palsy” and “palliative care” revealed 50 articles, all since 2000, of which 45 appeared since 2011.

CurePSP’s Centers of Care network has a sub-group of neurologists and site coordinators dedicated to palliative care in PSP, CBS and MSA.  Its task is to research and better understand the role of palliative care, to educate clinicians, patients, caregivers and government regulators, and to recommend changes to improve the quality and availability of such care.

That “working group,” as it’s called, took a major step this week with the publication of a paper entitled, “Serious Illness Conversation in the Care of Atypical Parkinsonian Disorders: A Practical Guide for Neurology Clinicians.” Its lead author is Dr. Michiko Bruno of The Queen’s Medical Center at the University of Hawaii.  Also playing a major role was Jessica Shurer, CurePSP’s Director of Clinical Affairs and Advocacy. (Full disclosure: I know both well, have worked with each on other projects, and vouch for their skills and dedication.)

The paper formulates four “practical guides” not confined to the traditional end-of-life role of palliative care.  They are: 1) informing the patient and family of the diagnosis and likely prognosis, 2) discussing the patient’s goals for the management of their illness given the lack of curative or very effective symptomatic treatments, 3) addressing safety, especially given the impulsivity that is a common part of PSP, and 4) guiding, ascertaining and respecting the preferences of patient and family regarding end-of-life issues.  For each, there’s a list of “dos and don’ts” that, I assure you, would be news to many neurological professionals.

How to transmit this paper to your own physicians without risking insulting them?  Maybe mention some point from the paper at an opportune moment at your next visit and cite its source. (All you need to say about the source is, “a PSP blog I read” or “doctors at CurePSP.”)  A clinician with any inclination to learn more may then ask you for a link.  Maybe the next paper from the Centers of Care should be on how patients and caregivers can diplomatically get neurologists to educate themselves on PSP.  But meanwhile, this one on palliative care will meet another important need.

“Rain upon the blinding dust of earth”

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A new candidate has emerged in the ever-frustrating quest for a valid diagnostic test for PSP.  It turns out that microRNA in tear fluid has something to contribute.

As you no doubt recall from high school biology, DNA is transcribed in the cell’s nucleus into long strands of messenger RNA, which are then translated by the ribosomes into proteins. The messenger RNA strands can be hundreds of nucleotides long. (Nucleotides are the four “letters” comprising the genetic code.) 

But some genes, or parts of genes, are transcribed into RNA that’s never translated into protein.  These short stretches, called microRNA (miRNA), have only 21 to 23 nucleotides.  They act on regular messenger RNA in some way to reduce its likelihood of being translated into its protein.  Essentially, this system is a way for some genes to regulate others.  About 60% of our 20,000 genes are regulated by miRNAs and errors in this molecular mechanism are associated with (but not necessarily causing) things like Parkinson’s, Alzheimer’s, Huntington’s, cancers of various kinds, atherosclerosis, kidney diseases, obesity, clotting disorders and alcoholism.

It turns out that sometimes miRNA leaks from the interior of nerve, brain or spinal cord cells into accessible body fluids like blood, spinal fluid and urine, where it can be sampled and tested using PCR, that now-familiar test for diagnosing Covid and catching crooks.

It’s pretty hard to sample spinal fluid, but blood is a lot easier, and urine is easier than that.  Easier still is tear fluid.  All it takes is a quarter-inch-wide strip of filter paper, like that in coffee filters, bent into a hook that hangs from the lower lid for 5 minutes, absorbing tear fluid.

A new publication in the journal Molecular Neurobiology from Dr. Antonia Demleitner and colleagues in Munich, Germany have taken the first step to using tests of miRNA in tear fluid to differentiate among PSP, MSA and PD.  The study was small, with only 10 participants with PSP, 29 with PD and 7 with MSA, plus 10 healthy people as controls.  In each of the 56 people in the 4 groups, they measured levels of 1,113 kinds of miRNA.

After correcting the data for things like age, disease duration and medications that might reduce tear production, they found 286 miRNAs in all four groups and 244 in none.  35 kinds of miRNA occurred in at least some members of the PSP group and in no one in the other three.  27 miRNAs occurred in all groups except PSP.

They then uploaded their data into an app that finds commonalities among groups of miRNAs.  It found that the miRNAs present exclusively in PSP had to do with immune function and inflammation, the apoptotic pathway (a normal program by which cells cause their own death when necessary), and the microtubules (the brain cells’ internal skeleton/monorail system that the tau protein helps maintain).

In the image above, each column is a subject group, as labeled at the bottom. Each of the 1,113 thin layers (not demarcated from one another) indicates whether a specific type of miRNA was present (red; “amplified”), absent (gray; “not amplified”) or uncertain (pink). About half of the miRNA types were either present or absent across all 4 groups, but some were present or absent specifically in one of the groups. (From Demleitner AF, et al. Mol. Neurobiol. 2025)

The miRNAs absent in PSP but present in the other 3 groups tended to be associated with the function of a certain trophic factor (a protein devoted to helping brain cells sprout new connections and maintain the old ones).

If a tear-based test for PSP becomes available in a few years, it could make it much easier to know at an early stage of the illness if some new PSP medication would be worth trying.  It would also make it easier to recruit patients into clinical trials hoping to find such medications.  Non-interventional research such as surveys of environmental risk factors would also be easier to do and more valid with a diagnostic test that works in early stages of the disease and is cheap, harmless and painless. Even if miRNAs provide a useful diagnostic test, it doesn’t mean that the genes they regulate are the causes of PSP.  Equally, or more likely is that those miRNAs are produced as a normal response to the damage being caused by the PSP process. 

As Dickens indicates in the above quote from Great Expectations, tears can actually solve problems.

Testing our metal

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My post from two days ago was about a 2024 paper that had just won an award from the Alzheimer’s Association.  It found and confirmed some subtle genetic risk factors for PSP.  One of them has to do with the part of the immune system called the complement cascade because it complements the role of antibodies. 

The finding on the complement-related gene prompted me to update my theory of the cause and pathogenesis (the subsequent sequence of events in the brain) of PSP.  That includes exposure to metals, at least in some cases. 

In response to that, a commenter asked which specific metals I had in mind. I responded directly in the comments section, but I thought it would make a good post for today:

—

We don’t know which specific metals might be involved in the cause of PSP, or how important they would be relative to other causes we don’t yet understand

  • The formal case-control surveys implicating metals asked about metals in general. Besides, that association was weak and lost statistical significance after other exposures were accounted for as confounders.
  • US Army veterans who developed PSP years later were more likely to have frequently fired weapons during their service than other Army veterans without PSP. So that incriminates lead, but gunfire undoubtedly aerosolizes other metals as well. My quick search reveals that gunfire can aerosolize aluminum, antimony, barium, cadmium, chromium, copper, iron, lead, manganese, nickel, tin, tungsten and zinc.
  • The PSP cluster in a couple of adjacent industrial towns in France suggests chromium, but that’s only the most important of the many metals contaminating that environment. Others with circumstantial associations are arsenic, copper and nickel, but others must exist as well.
  • The metals that caused PSP-susceptible cultured neurons to develop tauopathy in a 2020 lab study were chromium and nickel, but other metals weren’t tested because of insufficient lab capability at that time.

So that’s it, and it’s not much. It would be great if the existing genetic risk data could be analyzed for genes involved in metals detoxification. They might have fallen below the threshold of statistical significance for a genome-wide study, but a much more focused gene marker study might be able to show an association with the disease.

It could also be fruitful to analyze available autopsied brain tissue from the French cluster for metals content, comparing it to controls without PSP from the same contaminated area and elsewhere.

Also, let’s not forget that it might take certain combinations of metals, or of metals with other toxins, to increase one’s PSP risk. That could explain why there’s only one known geographical cluster of PSP — that area in France was multiply contaminated.

Nick Charles at the dinner party

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What’s really fun about blogging is that I can express scientific or medical opinions without having to get past experts like peer reviewers, journal editors or conference organizers.  (Hence most of the evil trash on the Internet.) 

But a frequent, insightful commenter called “mauraelizabeth3” asked this question after reading my last post about a new genetic finding in PSP incriminating to the myelin-producing cells, the oligodendrocytes, as a major possible starting point for PSP.

Is it known how these findings relate to (or perhaps result in) the hyperphosphorylated tau protein that aggregates in the brains of PSP patients?

I’ll respond to that excellent question with my own current theory of the etiology and pathogenesis of PSP.  It’s based on legit science, but of course, I don’t really know how much emphasis to place on each of the disparate current facts, or how many additional facts await discovery.

Dear me3: 

That’s really the question, isn’t it!  My own formulation at this point is that the loss of myelin from those multiple gene variants is a sideshow that impairs neurological function but isn’t actually part of the cause of PSP.  Instead . . .

  1. I’d propose that the first abnormal event is some inherited or de novo mutations or epigenetic alterations in the MAPT gene (which we know do exist in PSP) changes the structure or the post-translational modifications of tau in a way that stimulates its hyperphosphorylation as a reaction designed to facilitate its degradation.  Hyperphosphorylation tau might also be the result of some sort of toxin exposure, with metals currently the leading contender.
  2. Then, hyperphosphorylated tau falls off the microtubules and is free to do mischief all over the cell.  Maybe the first (or only) thing it does is to make the genomic DNA in the nucleus lose some of its protection against inappropriate transcription into RNA.  It’s been shown that such inappropriate transcription allows retrotransposons to be transcribed.  (Those are pieces of DNA implanted there by viruses millions of years ago.  They have reproduced themselves to other parts of the genome and now account for about 40% of our DNA.)  
  3. The RNA so produced is recognized by the immune system as viral.  An immune response ensues, which attacks and degrades a lot of RNA and innocent bystanders.  The resulting molecular garbage is a major challenge for the cell’s regular garbage disposal, the ubiquitin-proteasome system and the autophagy/lysosomal system. 
  4. Meanwhile, all that hyperphosphorylated tau is misfolding and then aggregating with itself.  This does take place under normal, healthy conditions to some extent, and the disposal systems can handle that.  But now, with the garbage from the inflammation and the unusual amount of aggregated tau to degrade, the garbage disposal is overwhelmed.  This allows all sorts of normal toxic garbage to accumulate, and that’s eventually fatal to the cell. 
  5. This whole process starts in the astrocytes or oligodendrocytes and spreads to the neurons courtesy of the microglia (the brain’s immune cells), synaptic connections and direct contact. 

Keep in mind that I’m a clinician with little laboratory experience beyond delivering fluid samples from my patients to my smarter colleagues with the pocket protectors.  But I try to keep up with the latest in all aspects of PSP, and there’s lab support for all of the assertions in my hypothesis.  It’s just that putting those facts together is tricky, like cracking a complicated criminal plot.  I hope that my hypothesis at least illustrates that we’re starting to get more of a handle on the pathogenesis of PSP.

Thanks for the complement

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The Alzheimer’s Association’s division devoted to frontotemporal dementia and related disorders has just announced its award for best publication of the year for 2004.  It’s entitled, “Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes.” The lead author is Dr. Kurt Farrell of the Icahn School of Medicine at Mt. Sinai in New York, and the senior author is Dr. Adam Naj of the David Geffen School of Medicine at UCLA.  Full disclosure: I played a very minor role in an early phase of the work and am 34th of the 48 co-authors.

The study sought to identify new genes conferring risk for PSP by comparing genetic markers between a group of 2,779 people with PSP (a large majority autopsy-confirmed) and 5,584 people with no neurodegenerative conditions.  This is the largest such study in PSP to date, the first having been published in 2011. The study’s large size gives it greater power to distinguish a genuine PSP-related genetic variant from a statistical fluke. 

This technique can identify not a specific gene, but a small region of a chromosome, typically with 50 to 200 genes.  But the researchers then nominated a couple of the most likely genes in that region and tested brain tissue for excessive amounts or abnormal forms of the protein encoded by the candidate genes.

Besides confirming PSP’s previously-identified genetic risk factors, Farrell and colleagues identified a new risk gene called C4A, located on chromosome 6. The protein it encodes is part of the cell’s “innate immune system.” The C stands for “complement,” a complicated group of proteins that assist the antibodies.  Once an antibody latches onto an unwanted invader like a bacterium or virus, proteins from the complement system attach to the other end of the antibody, initiating a series of interactions that eventually produces an “attack complex” that pokes a major hole in the invader.

The other important finding from the same study was a strong tendency for all the genes known to increase PSP risk to affect the oligodendrocytes.  Those are the brain cells that form the myelin sheath insulating the axons of most of the brain’s neurons, greatly facilitating electrical conduction.  We’ve known for decades that loss of myelin is an early feature in PSP, and that some PSP risk genes encode proteins related to oligodendrocytes.  But the new paper provides important confirmation in a larger patient group, using techniques not previously available.

So, bottom line: Although the genetic basis of PSP is not usually enough to make the disease occur in more than one member of a family, it could still be one important factor, along with things like a poorly-understood toxin exposure.  Furthermore, the new evidence that the oligodendrocytes might be the first cells to get sick in PSP points researchers in that direction in their search for new, easily addressable drug targets.  Plus, the discovery that an important part of the immune system could be what’s ailing the oligodendrocytes means that the array of potential drug targets is now much better focused. Shotgun approaches to taming components of the complement system have been under way for about a decade now, and the new finding of Farrell et al could focus those efforts nicely.

I like “Parkinson-like.”

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Does anyone like being called “atypical”?  That adjective often conveys a foreign-ness or other-ness, and not in a good way.  If you agree, you will be glad to know that a colleague, Dr. Junaid Siddiqui of the Cleveland Clinic, and I are about to publish an opinion piece entitled, “Time to Retire the Term “Atypical Parkinsonism.”

Over my career as a movement disorders subspecialist, I’ve heard both from professional colleagues and my patients that the term “atypical Parkinsonism” for PSP, CBD, MSA and a few other conditions is unwelcome.  First, it implies that those conditions are simply unusual variants of Parkinson’s disease.  However, they are actually independent diseases at the microscopical, molecular, and clinical levels with some features in common with PD.  A similar problem applies to the term “Parkinson-plus.”  PSP, CBD, and MSA aren’t simply PD with some additional features. 

Yes, those three disease do include some degree of “Parkinsonism,” but that only means that they share a collection of outward slowness, muscle rigidity, impaired balance, and in some cases, tremor. Of course, the Parkinsonism of PSP, CBD, and MSA differ from that of PD.  But that’s not because the first three are atypical versions of the fourth – it’s because they’re fundamentally different diseases.  

That’s the scientific argument, but there’s also an emotional one.  As I mentioned at the outset, no one wants their uncommon disorder to be considered an appendage of some other, more frequent one with superficial similarities.  That would suggest that the uncommon condition is unworthy of its own approaches to support, treatment, and scientific study.  

So, Dr. Siddiqi and I propose replacing the terms “atypical Parkinsonism,” “atypical Parkinsonian disorder,” and “Parkinson-plus disorder” with “Parkinson-like disorder.”  This avoids the implication of inferiority and other-ness without losing the “Parkinson” term familiar to every physician.

The “-like” term has precedent in “Huntington-like disorder,” “polio-like syndrome,” and “stroke-like syndrome,” and that’s only in neurology.  Yes, changing medical language can be a heavy lift, but it’s been done before.  Examples just in movement disorders are Steele-Richardson-Olszewski syndrome to PSP, paralysis agitans to Parkinson’s disease, striatonigral degeneration to MSA-Parkinson, sporadic olivopontocerebellar ataxia to MSA-cerebellar, and corticodentatonigral degeneration to corticobasal degeneration.

Glossary of proposed terminology:

ExistingProposedDefinition/comments
Parkinson’s diseaseParkinson’s diseaseNo change proposed
parkinsonismParkinsonismA group of phenotypic features, not specific disease(s).  The first letter should be upper-case.
ParkinsonismsParkinsonian disorderMultiple members of a group of specific disorders featuring Parkinsonism
Primary parkinsonismPrimary Parkinsonian disorderAny neurodegenerative disorder featuring Parkinsonism as a major component, at least in a majority of cases
Secondary parkinsonismSecondary Parkinsonian disorderAny non-degenerative disorder featuring Parkinsonism in at least some cases or at some point in the illness
Atypical Parkinsonism or typical Parkinsonian disorderParkinson-like disorderReserve “Parkinsonism” for a group of phenotypic features.  Reserve “Parkinson-like” for specific diseases. Replace “Parkinson-plus” with “Parkinson-like disorder” as well.

Our paper will appear in the journal Parkinsonism and Related Disorders in a few days or weeks, at which time I’ll post you a link.  Of course, if the journal itself follows our recommendation to confine the term “Parkinsonism” to a collection of signs and symptoms rather than allowing it to refer to specific diseases, then it will have to change its own name!  But — one step at a time, I always tell my students and patients.

14 shots on goal coming up

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Time for my occasional update on current and upcoming neuroprotection trials for PSP. The tables here are slides from a lecture I gave a few days ago on that topic at the University of Chicago.

This first table shows trials that have completed patient recruitment but for which there are no available results. This is usually because the analysis is incomplete or some of the patients are still having their study visits, but in a few cases it’s for the company’s own business reasons.

The second table shows PSP trials currently recruiting or likely to start doing so in the next year or two. Note that the trial of selenium supplementation, in the first row, is happening only in Australia. The only one recruiting anywhere else right now is FNP-223. If you’re interested in enrolling in that one, call the sponsor company in Spain at +34 609 850 565 or email them at medinfo@ferrer.com. They can tell you which of their study sites is closest to your home and then you’d contact that site’s coordinator directly.

Note that the GV1001 trial is presently only in South Korea, but the company says it will come to the US in late 2025.

Also note that the AZP-2006 and AADvac1 trials are the first two of what will soon be three drugs in the PSP Trial Platform. The third will be announced soon and the trial is scheduled to get under way in late 2025.

If you’re thinking of volunteering for a trial, do it sooner rather than later. Several reasons:
• The drug is more likely to work in earlier-stage PSP.
• The trials all require participants to have no more than a certain level of symptom severity and duration.
• If you insist on waiting for the perfect drug trial, you will be waiting a long time!

It slices! It dices!

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Yesterday’s post was about the clinical heterogeneity of PSP and how it prompts a theory about the cause(s) of the disease. A couple of hours after I hit “send” I saw a new paper that indirectly supports my idea.

As you probably know, PSP comes in ten known subtypes. The original type, first described in detail in 1963, is called PSP-Richardson syndrome and accounts for about half of all PSP. The other nine have been described since 2005. The new paper reports five subtypes among PSP-Richardson syndrome itself.


The study is from Dr. Mahesh Kumar, a post-doc at the Mayo Clinic, with Dr. Keith Josephs as senior author. They performed statistical tests called “network analysis” and “cluster analysis” on their 118 patients with PSP-Richardson. The five PSP-Richardson “sub-sub-types” emphasize, respectively, tremor; light sensitivity; reduced eye movement (i.e., supranuclear gaze palsy); cognitive loss and slowness/stiffness.


These are not just points on a continuous spectrum. Rather, in each of the five PSP-Richardson sub-sub-types, a group of features and their severities occurs together in individuals in a combination that would not be expected by random combination based their respective frequencies in the total PSP-RS population. For example, people with worse slowness/stiffness tended to have milder eye movement problems and worse cognition than chance would dictate.


Here’s a graphical representation of the results. The features represented by the circles in each group interact with one another in a mutually reinforcing (the black bars) or interfering (the red bars) way. The thickness of the bars represents the strength of the interaction. An explanation in the researchers’ own words follows:

From Kumar et al. Mov Dis Clin Prac 2025
Network Analysis showing 16 signs/symptoms and their associations. Each node in figure represents symptom/sign, Black edges represent positive connection, and red edges represent negative connection; thicker edges represent stronger association.
V1, Sensitivity to bright light; V2, MoCA (Cognition Score); V3, Neck Rigidity; V4, Urinary Incontinence; V5, Emotional Incontinence; V6, Upward ocular movement dysfunction; V7, Downward ocular movement dysfunction; V8, Horizontal ocular movement dysfunction; V9, Eye lid dysfunction; V10, Limb apraxia; V11, FAB (Executive Score); V12, Gait dysfunction; V13, Bradykinesia; V14, Postural tremor; V15, Kinetic tremor; V16, Rest tremor.

All this begs the question as to the basis of the specific groups of signs and symptoms. The answer will probably apply as well to the ten PSP subtypes as to the five PSP-Richardson sub-sub-types. It probably has to do with the specific combination of PSP’s menu of causative factors at work in the individual. As I pointed out in my last post, there are 14 known gene variants contributing to PSP risk and that number is growing. Exposure to toxic metals may also be a factor and those exposures could come at different times of life and in various durations, intensities and combinations. The number of genetic/toxic combinations of these factors sufficient to cause PSP would be astronomical, and the likeliest combinations might account for the likeliest PSP subtypes and sub-sub-types.


Then throw in the stochastic factors, meaning random throws of the dice. I’ll get to that in a future post.