A smorgasbord of PSP information

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Every so often I’ll make the rounds of what’s out there on the Web by way of PSP information.  So I thought a nice use of a cold day would be to share my latest observations with you all.

Every proper scientific literature review starts with a description of methods.  Mine was to type “progressive supranuclear palsy” into Google and to go with the first seven sites listed.  They’re allegedly the most-visited unless the sponsor has paid to be listed on top, which is the case for one of these.  I added CurePSP’s main page on PSP information, which didn’t make the top seven probably because people new to PSP have heard of the other organizations but not CurePSP.  I also added what ChatGPT had to say, which was a high-level summary that offered users some search terms for further details.

Clearly, CurePSP and Wikipedia were the winners, but many users could be stressed or confused by their level of detail. If that’s you, my next recommendation would be ChatGPT, but if you don’t like their very terse, outline style, I’d go with Penn Medicine.  But I advise checking out more than one.

Again, like every proper scientific paper, this one has a disclaimer statement, which is that I helped write the material in the CurePSP website and am the guy lecturing in its videos mentioned here.

The sources are listed alphabetically.

Source (alpha-betical)Word countNumber of links to more infoAccuracy (absence of incorrect state-ments)Compre-hensiveness (relative to others here)Technical level (relative to others listed here)Quality/quantity of illustrations, charts, graphs, videosMonths since last updateCom-ments
ChatGPT302096ModerateNone0Offers examples of search terms for more detail
CurePSP4,116Dozens1010Moderate2 videos of lectures,
1 of an affected family		ContinualOne page in a very large website on PSP, CBS & MSA
Davis-Phinney Founda-tion1,4612465Moderatenone29Paid for Google search place-ment
Mayo Clinic1,477397Easynone useful24  No statistics; 8th-grade reading level
NIH1,8031095Moderatenone10No statistics or lab science
National Health Service (UK)708895Easynone6Very super-ficial
Penn Medicine7989104Easynone?Basic but well-pre-sented
UC San Diego955098DifficultIncludes excellent video interview with expert?Outdated; few topics in text but more in video
Wikipedia4,593Dozens1010DifficultA useful tableContinualMissing non-tau genetics & current diagnostic criteria

URLs:

Spread the word

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A reader just commented on the need to improve public awareness of PSP and asked how that could be accomplished.

CurePSP devotes a large chunk of its budget and staff to raising awareness of PSP.  For example, a few months ago, some of CurePSP’s leaders, including myself, met on Capitol Hill with 12 members of the House and Senate from both parties to make them aware of PSP, CBD and MSA and to discuss ways the Federal Government might help.

The Michael J. Fox Foundation is certainly aware of PSP and this year is co-funding multiple research projects in PSP alongside CurePSP. Its website mentions PSP as a condition related to PD that needs to be considered as a diagnostic possibility alongside PD.

Celebrities, certainly not exempt from PSP, have stepped forward:

  • In 2020 and 2021, “Zoey’s Extraordinary Playlist” was a series on NBC. One of its producers had a relative with PSP and arranged for the main character’s father, played by Peter Gallagher, to be similarly affected.  The actor did a reasonable job mimicking its disabilities and the effects on his family were portrayed in an accurate, thorough and sympathetic way. 
  • Linda Ronstadt announced that she has PSP in 2019, six years after receiving an initial diagnosis of PD.  The long survival and initial misdiagnosis as PD suggest that she has the “PSP-Parkinsonism” subtype, but I have no inside information.
  • Back in 1999, the British-American comic actor and musician Dudley Moore was diagnosed with PSP.  A few months before he passed away in 2002, he and his family organized a high-profile fundraiser for CurePSP at Carnegie Hall in New York City.
  • In 2023, Congresswoman Jennifer Wexton of Virginia announced that she had PSP.  She retired in 2024, but not before using an AI-powered speech enhancement device to deliver a speech on the House floor.  She was instrumental in adding PSP, CBD and MSA to a bipartisan bill establishing a way to efficiently coordinate all Federally-supported research in that area. The bill easily passed and is now the Dr. Emmanuel Bilirakis and Honorable Jennifer Wexton National Plan to End Parkinson’s Act.
  • Rev. Jesse Jackson, the 84-year-old civil rights leader and activist, announced his diagnosis of PSP in 2025.

I have no doubt that once a drug shows promise against PSP and looks like it will be approved, the sponsoring pharma company will cover the Earth with PSP awareness.  Let’s all hope that happens soon, but until then, anyone can help. Just mention something about PSP on social media platforms and other Websites. Include links to CurePSP (psp.org) and to other reputable sources of information and support (hint – hint).

A neurodegenerative panacea? Maybe so!

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In a reply to a commenter back in July 2022, I expressed pessimism about the neuroprotective potential of buntanetap, formerly known as posiphen.  That drug is claimed to reduce genetic transcription of multiple neurodegeneration (NDD)-related proteins, including tau, at the messenger RNA (mRNA) level.  I thought it unlikely that one drug could do that without impairing production of other proteins necessary to health and life. 

Later in the same year, 2022, a double-blind trial of buntanetap in Parkinson’s disease and Alzheimer’s disease was published. The N was small, with 54 participants with PD and 14 with AD.   The treatment period was very short, only 25 days, which means that any result would reflect only symptomatic, not neuroprotective (disease-slowing), effects. That’s because the progression of PD and AD are too slow to be measured over only a 25-day period.  However, the main purpose of the trial was to study safety and tolerability, not efficacy.  The trial also checked spinal fluid levels of multiple proteins associated with the diseases – i.e., biomarkers.

The result were small but statistically significant improvement in some of the cognitive and motor measures in PD and some of cognitive measures in AD.  Most of the biomarkers showed improvement, but none were statistically significant.

Some cell/molecular biology here, folks: The authors argue that previous attempts to treat NDDs by targeting only one protein at a time have failed because all the diseases actually include defects in multiple proteins.  They point out that the mRNAs of multiple NDD-related proteins and iron-metabolizing proteins share a section called an iron-responsive element (IRE).  But the mRNA for the iron-metabolizing proteins is very slightly different from that for the NDDs. IREs are not translated into any part of its parent protein, but they do regulate that protein’s production by the ribosomes: When the level of iron in the cell is too high, the IRE prevents the ribosomes from making the protein. The butanetap molecule binds to a specific part of the IRE, mimicking a high-iron effect.  Luckily, the drug does not bind to mRNA of actual iron-metabolizing proteins – only to that of NDD-related proteins.   

So, if you skipped that nerd interlude, the executive summary is that there’s a good scientific rationale for why buntanetap could work.

But there are some potential issues with the 2022 clinical trial:

  • Many of the patients experienced minor side effects such as headache, rash or muscle spasms.  This could have impaired the blinding scheme and produced a placebo effect.  That issue could have been addressed by asking the patients at study’s end, before the randomization assignments were revealed, whether they thought they had been on placebo or active drug. 
  • Some of the spinal fluid markers that improved related to neuro-inflammation.That, and the improvement in the NDD-related markers, would not have been directly caused by a placebo effect. However, the increased mobility resulting from a placebo effect might have reduced neuro-inflammation, reducing in turn the markers of brain tissue damage.  (Only the patients with PD, not AD, received testing for physical mobility and there was no record of the patients’ exercise habits.) 
  • Like many drug trials at this early stage, this one was not only sponsored by the drug company, but the first and last authors were company employees.  I found no evidence of dishonesty in reading the paper, but a potential financial and professional conflict-of-interest does exist.
  • As stated, this trial was only 25 days long, and we really need to know the longer-term side effects of depriving the brain of a whole raft of normal proteins, even if some of those molecules later cause mischief.

Enough for now.  My next post will discuss the results of a larger, more recent trial of buntanetap that has not yet been published in a peer-reviewed journal.  Cliffhanger.

I haven’t forgotten about you

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My post on June 24, 2025 was entitled, “I like Parkinson-like.”  It was about a paper that was about to hit the stands (a Boomerism) authored by myself and Dr. Junaid Siddiqui of Cleveland Clinic.  It proposed replacing the terms “atypical Parkinsonism,” “atypical Parkinsonian disorder” and “Parkinson-plus disorder” with a new term, “Parkinson-like disorder” (or “Parkinson’s disease-like disorder” because let’s not get TOO prescriptive).  

The June blog post promised to make a copy of the paper available to you all once it was published. Better late (by seven months) than never. My mind was jogged by one of my current projects, preparing a lecture on the atypical Parkinsonian disorders in general that I will deliver at the University of Vermont in April. Also jogging my mind was that it’s been nearly two weeks since my last post.

The pdf is at the bottom. If you have difficulty downloading or viewing it, here’s a link to the abstract and highlights and here’s a chart showing the gist of our proposed new terminology:

Siddiqui Golbe Parkinson-like published versionDownload

It’s awards season (part 2 of 2)

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Yesterday’s post was about how the 10 most-frequently-visited news items in Parkinson’s News Today (PNT) of 2025 might relate to PSP.  The list appeared here.

Top 10 Parkinson’s news stories of 2025

I covered items #10 to #6 in my last post.

It’s awards season

And now: #5 to #1 . 

#5: FDA clears early trial of stem cell therapy for Parkinson’s

The treatment, called XS-411, is made from stem cells derived from multiple healthy donors and converted into dopamine-producing cells.  Each patient would receive one injection of such cells into each side of the putamen, the brain area where the dopamine synapses are located.  The FDA approved a Phase I trial in April 2025, but now, nine months later, clinicaltrials.gov lists two small studies in China but none in the US.  Most current stem cell trials in neurology derive the cells from the patient’s own bone marrow or skin biopsy, so I really don’t know why the company, XellSmart Bop-Pharmaceutical Company of Suzhow, China, is using cells from people other than the patients themselves.  Maybe they have a new way to suppress the immunologic rejection or maybe production using multiple donors is more easily scalable to serve large numbers of patients.  Could XS-411 work in PSP?  Perhaps it could help the same fraction who respond to levodopa, which is only a minority, and their benefit is usually modest and transient.  The problem is that in PSP, unlike in PD, the cells in the putamen receiving the dopamine-encoded signals are degenerating along with the dopamine-producing cells.  So, we need more research into injecting stem cells producing neuroprotective molecules or non-dopamine neurotransmitters.

#4: Program offers psychedelics as treatment for Parkinson’s

Ibogaine is a psychedelic drug legal only in a few states, and even then only for FDA-approved research use.  Ambio is a company offering the drug to people with a wide variety of conditions on a “research” basis at clinics in Mexico and Malta.  There’s no such listing in clinicaltrials.gov, so I can’t be sure of the protocol except that patients are charged $6,050 for a four-day treatment initiation at one of their clinics and “micro-doses” for the next six months.  Based on the little information available, this fits the profile of many “research trials” of alternative treatments: a hefty fee, minimal pre-treatment evaluation or followup, no control group and no peer-reviewed publication.  In this case, I must also wonder about the risk of habituation to the treatment itself, and where do you suppose you could buy something to satisfy that?  Enough – you now know what I think about this drug for PSP, even if the initial $6,050 and the travel expenses are not an issue for you.  To be sure, some alternative treatments do have legitimate potential, but when there’s a major risk of financial or medical harm (both of which apply here), their use should be confined to formal FDA-approved research protocols.

#3:  Bacteria in digestive tract tied to cognitive decline

Parkinson’s disease is a natural candidate for causation by intestinal bacteria because the first stage of the disease, aggregates of the alpha-synuclein protein in neurons, starts not in the brain, but in the intestines and lungs.  But PSP does appear to start in the brain.  There’s been little research on gut bacteria and PSP, but something important was reported in 2023 from researchers in China and summarized in my 4/2/23 post. That short-term study found that replacing the colonic bacteria produced about a 10 percent benefit in the PSP Rating Scale score.  The trial was too short and small to conclude anything about long-term slowing of progression.  Bottom line: Although PSP does not start in the GI tract as PD does, gut bacteria may play a role and should be studied further for any therapeutic implications. 

#2: Study identifies potential way to treat Parkinson’s constipation

Ghrelin is a string of 28 amino acids with many basic gastrointestinal functions including stimulating appetite at the level of the brain and defecation at the level of the spinal cord.  The article reported by PNT teased out an important detail that could hold implications for treatment of constipation in those with PD.  We don’t know if applies as well to the constipation of PSP, but I can say that some of PSP’s constipation is caused by degeneration of a cluster of cells in the lower spinal cord that are not involved in PD.  One research study, from 2013, did find a role of ghrelin in multiple system atrophy but not in PSP or corticobasal syndrome.  So, those few strands of evidence suggest that people with PSP will have to rely on traditional methods of keeping things moving – exercise, fluids, fiber, a stool softener, and avoidance of drugs that block acetylcholine synapses (“anticholinergics”).  Many drugs in the last category are used for other PSP symptoms such as imbalance, vertigo, urinary incontinence and depression, so getting off those is a good topic for discussion at the neurologist’s office.

#1: Research shows disrupted mitochondrial DNA tied to inflammation

For decades, we’ve known that in both PD and PSP, the cells’ mitochondria malfunction and there’s excessive inflammation in the brain.  But we don’t know which is cause and which is effect, or if they’re both effects of a common cause.  The new study used a novel genetic technique to find evidence that it’s the inflammation causing the mitochondrial loss.  In theory, the same study could be performed in PSP.  A similar result would suggest that to slow PSP progression, targeting excessive inflammation might do better than those targeting mitochondria directly.  Early in my career, I had narrowed my subspecialty choices down to movement disorders and neuroimmunology/multiple sclerosis.  I chose the former because I was flummoxed by the complexity of the immune system.  Little did I know . . .

It’s awards season (part 1 of 2)

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A couple of weeks ago I posted my curated list of the top 10 PSP-related research developments of 2025.  They appeared in two installments on 12/31/25 (#1-5)

PSP’s Top 10 of 2025: part 1 of 2

and 1/1/26 (#6-10).

PSP’s top 10 of 2025: part 2 of 2

Clearly inspired by my effort, the publication “Parkinson’s News Today” (PNT) has done something similar for Parkinson’s disease, summarizing their 10 most-often-visited (not necessarily the most important) news stories of 2025.  Their article is very well supplemented with links to both basic explanations and to the PNT articles themselves.  Those PNT items link, in turn, to original journal articles and to press releases from drug companies or research institutions.

Top 10 Parkinson’s news stories of 2025

PNT is owned by a for-profit medical communications company and its on-line publication is monetized by advertising, mostly from drug companies.  So be aware that their choice of what’s important may be biased in favor of drug companies’ products and scientific narratives.  No such concrete instances have hit me over the head, but the potential for a conflict of interest is there.  

Armed with that caveat emptor, you can learn a lot from this list, which is numbered from least to most important. Here are my annotations for each item, pointing out the relevance, or lack thereof, for PSP:

#10: Virus long thought harmless may trigger Parkinson’s

The brain tissue in PSP looks very similar to that of “post-encephalitic Parkinsonism” (PEP), which was quite common from the 1920s to 1950s.  Both feature tau-based neurofibrillary tangles and attack the basal ganglia, but PEP is static over decades.  It appears to be a immunologically-based , residual effect of a brain infection called “von Economo’s encephalitis” or “encephalitis lethargica.”  The virus itself has never been isolated or identified.  The disease overlapped, but is different from, the great flu pandemic following World War I.  Otherwise, despite ample search, there’s little to no evidence that any virus can cause PSP.

#9: Scientists develop weekly injectable implant for Parkinson’s treatment

The implant (actually a viscous, intra-muscular, self-injected liquid) provides levodopa/carbidopa (LD/CD) for a week.  Unfortunately, most people with PSP respond little or not at all to levodopa/carbidopa.  However, in those with the PSP-Parkinsonism subtype and few with other subtypes, there can be a useful response for a few months of daily dosing.  While those with PSP who do respond don’t need a long-acting form, avoiding having to take pills could be a major advantage for those with swallowing difficulty.

#8: DBS plus exercising may rewire Parkinson’s brain

The brain, even in older persons, can route its circuits around areas of damage, especially if those circuits are used often.  That’s called “exercise” or “physical/occupational therapy” or just “practice,” (note my sarcasm) and it does work.  This is true in PSP as well as in PD.  But deep brain stimulation (DBS), at least the kind used in PD, does not work in PSP.  That’s because the brain areas that are overactive in PD simmer down in response to DBS.  But in PSP, those areas are part of the degenerative process itself, and are underactive.  But to repeat: Informal physical activity and formal physical/occupational therapy do work in PSP. They should be an important part of the daily routine, assuming that one’s physician decides that any balance problems, osteoporosis, or cardio-pulmonary disorders are not contraindications.

#7: FDA approves bilateral Exablate Neuro treatment for Parkinson’s

Exablate is the brand name for a device that focuses destructive ultrasound beams on those over-active brain areas of PD.  (It usually appears in the literature as “focused ultrasound” or FUS.) So, the idea is same as DBS, but FUS produces a permanent lesion that can’t be adjusted by the doctor based on the patient’s response. But its advantage of FUS over DBS is no hardware in the head, wires under the skin, pacemaker device in the chest, periodic battery changes, or explanations at metal detectors.  Unfortunately, the FUS lesion locations used in PD would not work in PSP, but novel lesion locations could, in principle, be discovered for PSP for problems like balance, speech or cognition.

#6: Dosing starts in trial of anti-inflammatory therapy for Parkinson’s

PNT’s news item reporting the start of this single-center, Phase I trial appeared in March, as their blurb states, but I’ve got an update for you. The drug’s safety and tolerability were satisfactory but trial, with only 30 patient and one month’s observation, was not powered to demonstrate efficacy. The sponsor company, Ventus Therapeutics, has now started a Phase II trial for PD at 23 US sites.  The drug, called VENT-02, targets NLRP3, a receptor protein activated by stress signals in the microglia, the brain’s equivalent of white blood cells.  That could be relevant to PSP, where microglia help spread the abnormal tau protein through the brain and otherwise mediate the brain inflammation of PSP.

I’ll cover items #5 through #1 tomorrow or whenever my week’s chores permit. 

Speech! Speech!

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Just today a review article on voice and speech in PSP and the other atypical Parkinsonian disorders (APDs) appeared in the journal Movement Disorders – Clinical Practice.  The article is written for neurologists, but it should be comprehensible by educated laypersons, which is why I’m recommending it to you all.  

Two terms used in the article that are probably not familiar to you in this context are “spasticity” and “apraxia.” 

  • Spastic speech has a “rubber-band” quality, with abrupt variations in speed and loudness. It’s very common in PSP. It corresponds to spastic limb movements (rare in PSP), where joints can suddenly flex or extend in response to gentle movement or sensory input.
  • Apraxic speech features reduced ability to make certain sounds or words without a corresponding inability to form their components. It’s common in some of the APDs, but not in PSP. It corresponds to limb apraxia (common in PSP), where power and simple tasks are preserved, while more complex, learned tasks are impaired.

The paper includes videos of people with some of the APDs performing a standardized series of speech tasks, including describing the picture below:

The famous “cookie theft scene” test is designed to assess perception, judgement and language, but it serves as a test of voice and speech as well.  

That brings us to the differences among “voice,” “speech” and “language.” 

  • Voice difficulties include things like hoarseness and low/high volume. 
  • Speech difficulties include things like slurring, slowing/speeding and disordered rhythm of sentences. 
  • Language problems include things like wordfinding problems, word substitutions and reduced grammatical ability.  It’s not discussed in the current paper but may be the topic of a subsequent review by the same group of neurologists. 

A quick-and-easy way to organize this scheme is to consider voice problems as arising from the lungs and larynx; speech problems from the mouth, tongue and lips; and language problems from the brain. 

The paper’s authors are all at institutions within CurePSP’s Centers of Care network.  The leader of the project was Dr. Federico Rodriguez-Porcel of the Medical University of South Carolina.  The other 25 authors, including yours truly, are listed in alphabetical order. So, as a clearly biased contributor, I recommend this paper on voice and speech in the APDs to those interested in understanding the range of such problems and their potential for rehabilitation.

PSP’s top 10 of 2025: part 2 of 2

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Happy New Year, all!

Yesterday’s post was the first five of my top ten PSP news items of 2025. Here are the rest, again in approximate and subjective descending order of importance.

  1. New ways of interpreting standard MRI images have gained ground as diagnostic markers for PSP. One is a test of iron content in brain cells called “quantitative susceptibility mapping” (QSM). Nine papers on that topic appeared in 2025, four in 2024 and none previously. It’s looking like combining QSM data from ordinary measurements of atrophy of PSP-related brain regions could be the ticket, as both measures come from the same test procedure, unpleasant though it may be, and they measure different things.
  2. Positron emission tomography (PET) imaging of PSP’s type of tau (“4-repeat tau”) has made advances in 2025. This test requires intravenous injection of a “tracer” with a radioactive component that enters the brain tissue,sticks to the target molecule and is then imaged. It can distinguish PSP from non-PSP, distinguish among various PSP subtypes, and quantify the disease progression. The leading such tracer in terms of readiness for submission to the FDA is [18F]PI2620 and a distant second is [18F]APN-1607 ([18F]-PM-PBB3; Florzolotau). A tau PET tracer called Flortaucipir is on the market as a test for Alzheimer’s disease, but it performs poorly for PSP.
  3. There’s brain inflammation in PSP, but it’s not clear whether it’s a cause or a result of the loss of brain cells, or both. Regardless, measuring the quantity and type of inflammation using blood or PET could shed light on the cause of the disease, identify new drug targets, and serve as a diagnostic marker. A good example of 2025 research on blood markers of inflammation in PSP is here and on PET imaging of inflammation is here .
  4. We know of variants in 21 different genes, and counting, each of which subtly influences the risk of developing PSP or its age of onset. The area of the genome most important to PSP is the one that includes the gene encoding tau (called “MAPT”) on chromosome 17. The most important PSP genetic advance in 2025 was probably the discovery that some PSP risk is conferred by extra copies of a stretch of DNA, not the sequence itself. This news could inspire investigation of other places in the genome for other copy-number variants, which are much trickier to find than sequence variants. Here’s a great review of the latest in PSP genetics.
  5. And lastly, a disappointment: a negative result of a double-blind trial of the combination of two drugs already approved for other conditions: sodium phenylbutyrate (“Buphenyl”) and taurursodeoxycholic acid (“TUDCA”). Blog post here. Sponsor’s press release here. Buphenyl protects the endoplasmic reticulum, which helps manufacture proteins, and TUDCA helps prevent brain cells from undergoing self-destruction (“apoptosis”) in response to various kinds of stressors. The pair were theorized to act synergistically. The trial’s upside is that its placebo group data can be used to provide better statistical support for future innovations in clinical trial design.

PSP’s Top 10 of 2025: part 1 of 2

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We saw some real progress against PSP in 2025. This post and the next list my top 10 developments from the past year in approximate and very subjective descending order of importance:

  1. AZP-2006, a drug that enhances the breakdown of abnormal tau protein by the cells’ lysosomes, was found to slow the progression of PSP by 64%.  The catch is that even that impressive-sounding result did not reach statistical significance because the trial was too small, having been designed mainly to assess safety.  Furthermore, its design did not exclude the possibility of random bias in the selection of the participants. But the sponsor company plans to start a much larger and better trial in the second quarter of 2026 as part of the PSP Trial Platform.  My blog post on that is here.
  2. A new subtype of PSP has been identified and named PSP-PF. It was formed from chunks of two of the previously known ten subtypes, PSP-frontal and PSP-postural instability.  If confirmed by other researchers, it will probably be the third-most common subtype, and the second-most rapidly progressive.  The discovery could allow the expansion of drug treatment trials, which prefer to enroll rapidly-progressing participants, to include a more people with PSP than just the ~half with PSP-Richardson syndrome. My blog post is here.
  3. The PSP Trial Platform announced that it will start testing a PSP vaccine called AADvac1 in the second quarter of 2026.  Unlike the passively administered anti-tau antibodies that failed a few years ago, this is an active vaccine, meaning that it stimulates the immune system to make its own antibodies. As my May 2025 blog post point out, AADvac1 has given encouraging early results against one large sub-group of people with Alzheimer’s disease.   
  4. CurePSP announced its new Biomarker Accelerator Program, offering grants of up to $500,000 for major projects to identify and characterize diagnostic tests for PSP.  The program will consider applications involving not only markers to distinguish PSP from other disorders, but also those predicting an individual’s course and to assess change in the disease to use as outcome measures in treatment trials and other research.  
  5. Neurofilament light chain, a protein released into the spinal fluid and blood by many kinds of damage to brain cells, accumulated more evidence of its potential as a diagnostic marker of PSP.  Although NfL is the most promising fluid marker for PSP, it’s not quite ready for routine use because of as yet insufficient sensitivity, specificity and consistency across different labs.  Another major outstanding issue is to what extent blood can replace spinal fluid as a test medium.  However, with the publication of each small advance, more research groups and funders become interested.

My next post will cover developments 6-10.

Strains and veins

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I’ve been thinking about PSP subtypes a lot lately, mostly because of last week’s report of an eleventh subtype, PSP-PF, comprising elements of the PSP-PI and PSP-F types.  See my recent post for more explanation.  I’ve read what I can about what causes the various subtypes to prefer slightly different parts of the brain.  The general thought on that right now is “tau strains.” 

Think of tau as a species, like the dog, and its strains as breeds.  Let’s not get into the molecular nature of the inter-strain differences or what produces them.  Instead, let’s recognize that those strains could theoretically underlie the differences among the 11 PSP subtypes by introducing differences in predilections for different groups of brain cells sharing a location or function.  But this week, another possibility emerged as an explanation of the subtypes’ brain-area preferences: abnormal venous circulation.

The study in Parkinsonism and Related Disorders performed brain MRIs and routine clinical office exams on 95 people with PSP.  Of those, 64 had one of the three “cortical” subtypes (PSP-speech/language, PSP-corticobasal syndrome, and PSP-frontal).  The other 31 had one of the “subcortical” subtypes (PSP-Parkinsonism, PSP-progressive gait freezing, PSP-postural instability).  There were also 50 healthy participants as controls. 

The three groups of participants were compared with regard to the size, number and location of any “white matter hyperintensities” (WMHs), examples of which appear in the MRIs below as the irregular white dots and splotches.  In mild form, they’re common in healthy, older people and more so in those with high blood pressure, diabetes and other vascular risk factors.  You can see how some of them sit smack up against the black slits in the middle of the brain, the spinal-fluid-filled lateral ventricles, and some are much closer to the outer, convoluted surfaces of the brain, the cerebral cortex.  (Image from Inzitari D, Pracucci G, Poggesi, et al. BMJ. 2009 Jul 6;339:b2477. doi: 10.1136/bmj.b2477

The graph below shows the current paper’s main results: (from Fu M-H, Satoh R, Ali F, et al. Parkinsonism and Related Disorders. 2025 Dec 22:143:108170. doi: 10.1016/j.parkreldis.2025.108170).

This graph’s vertical axis is a measure of the WMHs’ total volume, expressed as a percentage of total intracranial volume. The horizontal axis is the WMHs’ location expressed as average distance from the lateral ventricle.  The participants with the subcortical subtypes of PSP had the greatest volume of WMHs and their average distance from the lateral ventricles was greatest.  The people with the cortical subtypes ranked lower in both measures, and the control participants ranked lowest.  However, after correcting for various potential confounders, the differences remained statistically significant only for the areas between 12 and 30 mm from the lateral ventricles.

How to interpret this?  Let’s start with some background:

  • The tiny veins draining blood from the brain are divided into deep and superficial systems.  Each flows into its own set of larger veins en route to the heart. 
  • WMHs are areas of scarring. They’re largely of unknown cause, but they correlate with risk factors for stroke, which is mostly related to narrowing of arteries, not veins.
  • Multiple sclerosis, which produces areas of white matter inflammation and scarring more severe than those of PSP, has been linked to insufficiency of venous drainage of the brain.
  • Normal-pressure hydrocephalus, which is similar in many ways to PSP and even can have PSP-like changes in the brain cells, has been shown (by the same research group as the present paper) to include insufficiency in one of the deep veins.

The areas of brain yielding the graph’s statistically significant results drain into the deep venous system.  They’re unrelated to brain territories supplied by any specific arteries.  The authors tentatively conclude that the WMHs may be caused by insufficiency in the brain’s deep venous system.  They are appropriately cautious about assigning cause-and-effect, but the obvious question raised by their results is whether narrowing of the deep veins, and not any differences in tau or its post-translational modifications, could explain some, or maybe all, of the variety of PSP subtypes.

—

The authors of this paper overlap with those of last week’s about the new PSP-PF subtype summarized in my last post.  All from the Mayo Clinic in Rochester or Jacksonville, they include first author Dr. Mu-Hui Fu working under senior author Dr. Jennifer Whitwell, a veteran leader in PSP-related imaging research.