A treatable PSP mimic

Yesterday’s post updated my diagram showing relationships between PSP/CBD and the other major neurodegenerative diseases.  The only substantive change was the addition of a tauopathy called “anti-IgLON5 syndrome,” which we’ll call “AIS.”  It’s not “major” in the sense of “common,” but in the sense of “important to know about because it’s treatable, especially if diagnosed early.” 

AIS sits on the border between the autoimmune and the neurodegenerative diseases.  (In fact, multiple sclerosis does that, too, but unlike most neurodegenerative diseases, it has no known protein aggregates in the affected brain cells.)  In AIS, the blood and/or spinal fluid have antibodies directed against one type of the “cell adhesion molecules” on the surface of brain cells.  Those molecules assist in the function of the microtubules, which are the cell’s internal skeleton and transport system, and also where tau normally works.  The problem is that we don’t yet know for sure whether the antibody attack causes the cell damage or if the antibodies are merely the immune system’s reaction to damage caused by something else.

The classic symptoms of AIS are major difficulties in the control of sleep and involuntary movements called “chorea.”   But more recently, four different types of AIT have been described, and one of them mimics PSP, with severe loss of balance and milder cognitive loss and predominantly vertical eye movement problems.  As in ordinary PSP, sleep problems are present as well, but with more dream enactment and obstructed breathing than occur in PSP. 

About a quarter of those with AIT have the PSP type.  The other three types emphasize problems with sleep (the most common); speech and swallowing; and cognitive problems, respectively.  All four types also display autonomic disturbances in a majority of patients, including episodes of sweating, incontinence, and slow or fast heartrate.  Oddly, only a few have low blood pressure. Otherwise, the autonomic features are similar to those of MSA, and of course the motor features of MSA, like those of PSP, can be similar to those of AIS, but without the chorea.

An important difference between AIT and PSP, CBD or MSA is that AIT has no muscle rigidity, movement slowness or tremor. Those three things are collectively called “parkinsonism.”

AIS’s average onset age of 64 plants it firmly in the range of most neurodegenerative diseases, rather than in the younger range typical of autoimmune diseases.  Furthermore, the female predominance of most autoimmune diseases does not exist for AIS.  Also, only one case in the literature has been reported to spontaneously improve, and the course is slowly progressive rather than fluctuating.  These points favor a neurodegenerative origin.

On the other hand, all patients with AIS have a specific genetic variant in one member of a set of genes on chromosome 6 associated with autoimmune disease.  It’s called the human leukocyte antigen, or HLA system.  And here’s the most important point favoring an autoimmune origin: treatment with standard immune modulating drugs such as steroids, intravenous immunoglobulin and azathioprine, helps about two-thirds of the patients.  

It’s interesting that the classic form of AIT, where sleep disturbances predominate, is much less responsive to immune modulatory drugs than the more recently-described variants.  So maybe the different types sit slightly on one side or the other of the autoimmune/neurodegenerative fence.

Here’s a colorful (but blurred – sorry) diagram showing features in 22 patients with AIS.  It’s from the research team in Barcelona that and first described AIS in in 2014 and is probably the world’s leader in neuro-autoimmune disorders.

The four subtypes appear in the second column (where “bulbar” means speech and swallowing), the intensity of each of seven features is represented by the shade of color in the boxes, and the immunological and genetic findings are on the right. From: Gaig C, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017 May 2; 88(18): 1736–1743. PMID: 28381508

This diagram doesn’t mention that some patients with AIS exhibit hyperexcitability in the form of muscle cramps, muscle jerks and easy startle. 

I must emphasize that while AIS is a tauopathy, it’s not PSP or CBD.  It affects different parts of the brain, has both 3R and 4R tau (PSP and CBD have only 4R), it has a longer survival untreated, and it has anti-IgLON5 antibodies.

So here’s the take-home: 

  1. People in the early stages of an illness suspected of being PSP, CBD or MSA should make sure their doctor knows about AIS so that testing for the antibody can be considered.  If it’s positive, immunomodulating treatment may make a big difference, especially if two or more such drugs are used together, and if treatment is started in the first two years of the illness.  Often, rheumatologists know more about the treatment of autoimmune disorders than neurologists, especially movement disorder specialists.
  2. Even if there’s no response to immunomodulatory treatment, finding anti-IgLON5 antibodies should prompt a search for small but growing cancer. While none of the publications on AIS has examined this issue thoroughly, other autoimmune disorders in the nervous system are very often associated with cancer.  Most of the published case series either didn’t work up the patients for cancer or lost follow-up before a small cancer would have revealed itself.  Detection and removal of a small, early cancer could help the AIS, and even more important, save a life.

Infographics march on

Here’s an update of my diagram showing the relationships of PSP and CBD to other major neurodegenerative diseases. I’ve added anti-IgLON5 tauopathy-PSP type and created an “Autoimmune” category just for it. This required a little rearranging of other things, and I’ve cleaned up some redundant blue lines, too.

Attention, t-shirt designers: Licensing deals are available.

I’ll have more to say about anti-IgLON5 tauopathy soon.

A new drug out of the gates

My post on December 19 mentioned that an early-phase trial of a drug called TPN-101 in PSP was about to start recruiting participants at two sites – one in Florida and one in Michigan.  I just learned that recruitment has begun and there are now five sites.  They’re in Boca Raton, Florida; Gainesville, Florida; Farmington Hills, Michigan; Las Vegas, Nevada; and Englewood, Colorado.  Contact information is available here.

The drug, whose new generic name is “censavudine,” is an inhibitor of the enzyme reverse transcriptase.  As you’d guess, it was originally developed for the treatment of AIDS.  The mechanism of action against PSP is via reducing levels of hyperphosphorylated tau.  It’s administered as an oral tablet.  This trial is designed to test safety.  With only 40 participants and less than six months of placebo-controlled treatment (followed by the same period of open-label observation), it isn’t large/long enough to assess benefit unless the magnitude of that benefit is improbably huge.

Figure that it will take six months to fully recruit, which means that the last patient will finish in mid-2023.  So I’d expect results in late 2023.  Let’s hope that this is safe and well-tolerated and that a Phase 2b or Phase 3 trial of hundreds of patients at dozens of sites will start soon thereafter.

A sneak preview

The Tau2022 Global Conference is coming up soon — on February 22 and 23!  It was all set for a hybrid format, with most of the speakers having committed to attend in person.  I’m on the meeting’s leadership committee representing CurePSP, one of the organizers along with the Alzheimer’s Association and The Rainwater Charitable Foundation.  Last week we decided to go entirely virtual.  It wasn’t a slam dunk, as we all ache to return to in-person, informal interactions with colleagues from around the world.  

Here’s a rundown of a few of the original presentations.  I’m keeping these blurbs very brief and vague so as not to steal anyone’s thunder:

  • A new organoid model grown from skin cells of a patient with PSP mimics PSP brain tissue closely.
  • New incrimination of disordered iron metabolism in the pathogenesis of PSP.
  • New evidence that hyperphosphorylated tau induces the misfolding and aggregation of normal tau.
  • A PET ligand for tauopathies has new evidence for utility in PSP and CBD.
  • A new technique, single-nucleus RNA sequencing, has identified two new glial cell types involved in PSP, offering possible new drug targets.
  • An FDA-approved AIDS drug reduces tau pathology in a PSP mouse model in a newly-discovered way and will soon enter clinical trials.

I’ll report back after the conference.

Some light reading

A textbook-style description of PSP for physicians just appeared in a publication called StatPearls.  The authors are Drs. Shashank Agarwal and Rebecca Gilbert, both of New York University School of Medicine. (Full disclosure: I did med school and residency there.)  It’s well-written and scientifically sophisticated without challenging the scientific background of most neurologists.  It’s definitely not for most laypersons, and many non-neurologists will have difficulty with some of the terminology.  Maybe best of all, it’s free, and here’s a link.  You may want to forward it to your doctor(s). 

My only quibbles with the piece are: 1) In listing the various PSP subtypes, they omit the 4 least-common ones: PSP-cerebellar (which is much more common in Japan), PSP-primary lateral sclerosis, PSP-ocular motor and PSP-postural instability; 2) They give the “median survival after diagnosis” as 6 to 9 years.  That’s actually the median survival after symptom onset, which typically occurs about 3 years before diagnosis.  3) The 4 drug trials that they describe as “current” as of April 2021 (TPI-287, C2N-8E12/ABBV-8E12, BMS-986168/BIIB092, and salsalate) are all now complete — and unsuccessful.  It’s unfortunate that the publication date of January 2022 is so long after the completion of the manuscript.

As an educational piece for physicians, this article is of about the same high quality as that in UpToDate, a popular on-line medical textbook that, as you’d guess, is continually updated.  My only major complaint about it is that many of the references are outdated.  Plus, UpToDate charges physicians $579 a year. 

As for Wikipedia’s article on PSP – don’t bother. 

In 2017, I wrote my book, entitled, “A Clinician’s Guide to Progressive Supranuclear Palsy.” It was published in late 2018 and labelled as 2019. (Ain’t capitalism great?)  So while it has plenty of still-useful stuff, it’s now slightly dated, and it will cost you $76. Plus, at 173 pages, it’s a bit of a project for a busy physician who’s not a movement disorders specialist. Also, it has almost nothing on the scientific underpinnings or pathology of PSP — it’s purely practical.

More short stuff

Three more brief items:


Another case of paraneoplastic PSP has been reported, making 7 in the world’s literature.  This was a 62-year old woman with ductal breast cancer whose PSP-like features evolved over only 4 months to an advanced state of disability.  The brain MRI and spinal fluid were normal.  None of the known paraneoplastic antibodies were present in her blood.  A PET scan using fluorodopa was negative, a result expected with non-degenerative forms of parkinsonism.  Treatment with steroids and other immunomodulatory agents helped dramatically, restoring an independent gait and a “good quality of life” until the breast cancer became metastatic.  This case was reported in the Annals of Indian Academy of Neurology by Dr. Ajith Cherian and colleagues. The take-home: When any neurodegenerative disease, including a PSP-like syndrome, evolves rapidly to disability over a period of months rather than years, a strong possibility is a paraneoplastic syndrome.  That’s where the immune system’s fight against a tumor produces antibodies that also attack normal components of other organs such as the brain.  Not only may the neurological symptoms improve with immunoregulatory treatment, but if those symptoms appear before the tumor has been suspected, the workup could include a thorough search for a small tumor, removal of which could be lifesaving.  (Note: The information from the PET scan could have been obtained nearly as well from a dopamine transporter scan, which is far more widely available and is covered by insurance.)


Depression occurs in about 60% of people with PSP, according to a published review.    Now, an article in Journal of Neurology reports MRI scans in 40 patients with PSP, comparing the 21 with depression to the 19 without.  The research group works at the University of Bari, in Tricase, at the tip of the heel of Italy’s boot, and was led by Dr. Daniele Urso, a well-published expert in neuroimaging of neurodegenerative disease. In patients with PSP and depression, they found more thinning of the cerebral cortex in the temporal, parietal and occipital lobes, moderately worse on the right than the left.  (In the linked image, the colored areas are those where atrophy was greater in patients with depression than in patients without. The left cerebral hemisphere is shown on the left and the right on the right. The upper two images are the medial (inner) surface and the lower two the lateral surface.) This confirms once again that depression is part of the disease process in PSP and not (or not only) a normal psychological reaction to the overall disability.  The right/left asymmetry shows that it wasn’t just that the overall PSP was more severe in the patients with depression, as the cortical atrophy of PSP is generally symmetric. 


A few years ago, CurePSP created a network of 25 academic centers in the US and Canada with special expertise in care of patients with PSP and CBD, calling it the “CurePSP Centers of Care.”  I’ve been one of its organizers and leaders.  Last year, we published a “best-practices” article on medical management of the disorders.  This year, we have expanded to 28 centers, including 2 in Canada.  To keep things moving and accountable, we have doubled the size of our Steering Committee to include 4 Center directors and 4 representatives of the CurePSP Board of Directors and staff.  For the first time, we’ve drafted a list of projects designed to improve clinical care and to provide clinicians of many kinds with education and awareness of PSP and CBD (and for some centers, MSA as well).  Also for the first time, CurePSP is providing the Centers some modest financial support for expenses related to delivering first-rate clinical care. I’ll let you know how it’s going. 

. . . borne back ceaselessly into the past

A perennial question for researchers studying neurodegenerative disease is how long before the onset of symptoms the cause of the disease (whatever THAT may be) starts to act on the individual.  This is important for several reasons: 

  • Epidemiological efforts to identify an external cause of a disease such as (in the case of PSP) toxins, infections or trauma could sure use some clue as to how far in advance of the individual’s symptom onset to focus the search.
  • Trials of drugs to slow the progression of PSP would like to initiate treatment as early in the disease course as possible, so identifying patients before they display symptoms would be great.
  • If we ever find a vaccine or some other way to prevent the underlying disease process from starting in the first place, we’d need to know the age by which it should be administered.

Now the very productive Cambridge Centre for Frontotemporal Dementia and Related Disorders at University of Cambridge, led by behavioral neurologist James Rowe, has shed some light on that question.  The PSP study’s first author was Duncan Street, a clinical research fellow working under Prof. Rowe. They have mined the database of the UK Biobank, a non-profit organization operating what’s called a prospective, cohort risk factor study. A famous U.S. study of this type, but just for cardiovascular disease, is the Framingham Heart Study, which started in 1948 and is the source of most our present knowledge of risk factors for hypertension, heart attack and stroke.

The UK Biobank project enrolled 502,504 randomly selected, healthy people between 2006 and 2010, when their average age was 57.  At baseline, they received a raft of neurological and many other tests and were then monitored for the development of diseases of any type.

By the end of 2020, 176 people in the cohort had developed PSP diagnosable by standard clinical criteria.  The researchers found several subtle ways in which the average baseline scores among those 176 differed from the average baseline scores of the group who did not develop PSP or Parkinson’s.  (All of these differences were statistically significant, which means each has less than a 5% chance of being a random fluke.)   

  • Those developing PSP were heavier, on average, by 7.9 pounds though the PSP group had a slightly lower proportion of men (60% vs 62%).
  • Their reaction time was slower by 7.6% and their right-hand grip strength was weaker by 5.2%.
  • They did 15.4% less well in a test of fluid intelligence and 13.7% less well in a test of digit recall. 

The fluid intelligence test posed 13 questions requiring logical reasoning over a 2-minute span and the digit recall score was the longest string of digits that could be repeated immediately, in the same order. 

The researchers also compared the 176 people developing PSP to a group of 2,526 developing Parkinson’s.  Here, as you’d expect, there were fewer differences, the only one being a 10.5% lower performance in the PSP group’s fluid intelligence score.   

The database did not include the year of onset of PSP symptoms, but it did have the year of initial PSP diagnosis. That allowed the average time from the baseline evaluations to that point to be calculated at 7.8 years.  Other research has found a delay from symptom onset to diagnosis to average around 3 years. So, the take-home from this research article is that abnormalities hinting at PSP can be detected, if one looks for them, at an average of about 5 years (7.8 minus 3, rounded off) before symptoms appear. That, in turn, means that the underlying disease process must start some time before that, though we don’t yet know how long before.  The average symptom onset age of PSP is about 63, so any screening test for PSP should be given no later than the mid-50s.  But would giving the test in the early 50s or late 40s — the better to institute treatment early — be too soon to detect many cases of PSP?  We don’t know.  Once we settle on a test or a battery of tests that works in early-stage symptomatic PSP – an “early trait biomarker” – we can try it out in a pre-symptomatic cohort of people in their 40s and 50s who score below a certain cutoff on a screening battery.

One final thought:  Back in 1996, I published a paper showing for the first time that people with PSP had completed slightly fewer years of formal education than matched control individuals without PSP.  That has been confirmed by multiple subsequent studies, but the reason for it is unknown.  Here are three possibilities:

  • Does the disease start subtly in the first couple of decades of life and reduce one’s ability to do schoolwork? 
  • Or is it that people less inclined to stay in school for whatever social or economic reasons develop fewer synapses in their brains, which makes any subsequent neurodegenerative process more likely to produce symptoms and to come to medical attention? 
  • Or is it that people with less education are more likely subsequently to live or work in areas with toxins that contribute to the cause of PSP?

If the first explanation (early-life onset) is correct, then administering a screening test battery at any point in adult life might be able to detect early stages of PSP, providing opportunity for disease prevention to be instituted even earlier.

A welcome word from Australia

Here’s some nice news.  The Phase 2, double-blind trial of sodium selenate that I mentioned in my December 19 post as pending has just started recruiting patients.  That orally-administered drug may slow the progression of PSP and other tauopathies.  Unfortunately, at this point, it’s taking place only at six sites in Australia.

The trial is described in an article from late 2021 in the open-access journal BMJ Open. The first author is Lucy Vivash, a research fellow at Monash University in Melbourne.  Terence J. O’Brien, MD, the neurology chief at that prestigious institution, is the senior (i.e., last-named) author.  Australia does not require its trials to be listed in www.clinicaltrials.gov, and it isn’t.  But it is listed in an equivalent database for Australia and New Zealand trials.

The mechanism of action of sodium selenate against PSP is to activate an enzyme called protein phosphatase 2.  Like any phosphatase, it removes phosphate groups from the proteins to which they have become attached.  Our bodies normally use phosphates as a way to regulate the activity of enzymes, but under some disease conditions, phosphates are attached to excess or in the wrong spots.  In PSP, there is excellent evidence that inappropriate phosphorylation of tau encourages it to fold into a toxic form.  In the words of the researchers:

“Protein phosphatase 2 (PP2A) is the major tau phosphatase in the brain accounting for more than 70% of brain phosphatase activity, and thus stimulation of its activity presents a compelling strategy for reducing hyperphosphorylated tau. PP2A is colocalised [in the same locations within the same brain cells] with tau, and in many neurodegenerative diseases, reduced PP2A activity is observed alongside reductions in tau dephosphorylation.”

The year-long trial will include 70 patients with PSP-Richardson syndrome, half of whom will receive placebo.  This trial is unusual in that the primary outcome measure will not be a clinical evaluation of patients’ neurological performance and subject reports of symptoms such as the PSP Rating Scale (PSPRS).  Rather, the primary outcome will be a slowing of the rate of brain atrophy as measured by before-and-after MRI scans.  This has been shown to correlate better with the passage of time than the PSPRS or any other clinical measure of PSP progression.  However, it’s not clear if it actually correlates as well with daily functioning.  True, traditional measures are included as secondary outcome measures, but no drug developer wants to rest their case for drug approval on a secondary measure when the designated primary measure failed to show benefit.  

I suspect, but don’t know, that the MRI measure was chosen as the primary outcome measure because its greater sensitivity to change over time permitted enrolling only 70 patients (to be able to detect a 50% reduction in progression rate), as opposed to the 102 patients required by the next-most-sensitive measure, the PSPRS. Each additional patient increases the cost of the trial, and this one is financed by a grant from the Australian government rather than by any drug company. So financial constraints may have been more of an issue than usual in the study design.

So, let’s wish Dr. Vivash and her colleagues and patients every success in this trial and let’s hope that the pandemic allows it to proceed smoothly.

A welcome word from Scotland

I just learned that since 2014 there’s been a medical publication called Journal of Patient Experience.  It’s on-line and open-access.  They’ve just published an article entitled “Progressive Supranuclear Palsy: The Other Side of the Fence” by Beatrice Sofaer-Bennett PhD, an accomplished academic nurse with a faculty position at the University of Edinburgh.  Most of her work has concerned the care of people with chronic pain. 

Now, as you’ve surmised, Professor Sofaer-Bennett has been diagnosed with PSP and has described her own thoughts and feelings in a way that’s moving without being maudlin and informative without being technical.  Her experience of receiving multiple other diagnoses before PSP will be familiar to most patients and their families.  She makes a welcome and eloquent plea for better education of physicians about the disease.  Perhaps her most helpful points describe how she handles the issue of her prognosis.

The article includes a couple of minor mis-statements of neurological fact, so don’t use this as a reference source.  Also, I must tell you that her sudden sweating episodes and constant shortness of breath are very unusual in PSP.  They are more common in people with MSA, which can be difficult to distinguish from PSP diagnostically.  I mention these points only to avoid having anyone with PSP think that they can expect these things to happen to them, or if they do occur, to neglect having those symptoms specifically evaluated, thinking they’re just “normal” for PSP.  Both can be symptoms of non-neurological, highly treatable conditions. But I haven’t evaluated her myself, so I’ll not criticize her neurologist’s diagnosis from afar. 

So, Professor Sofaer-Bennett, thank you for sharing your thoughts and suggestions.  Those of us working to improve the quality and accessibility of care for people with PSP appreciate your help and wish you the best in your journey.

Proteomics hits paydirt

If you know anything about PSP at its molecular level, you know that the tau protein in the neurofibrillary tangles is almost entirely of the “4-repeat” or 4R variety.  The other kind is “3-repeat” or 3R.  Normal adult human brain has equal amounts of 3R and 4R.  So do the tangles of Alzheimer’s disease.  But the tangles of Pick’s disease are 3R. 

The thing that’s repeating is the section of the protein that binds it to microtubules, the brain cells’ internal skeleton and monorail system for transporting chemicals along axons.  The gene encoding tau, called the “microtubule-associated protein tau” (MAPT) gene, has four sections, called exons, each encoding one microtubule-binding repeat.  MAPT has 16 exons and the four in question are exons 9, 10, 11 and 12.  4R tau includes the repeat encoded by exon 10 and 3R tau doesn’t.

There’s pretty good evidence that in PSP, the extreme imbalance of 3R and 4R tau is a major factor in making the tau toxic to brain cells.  But why can’t the brain cells in someone with PSP make enough 3R tau?  In other words, what prevents the brain cells in PSP from excluding the repeat from exon 10 half of the time, as normal brain cells do?

In the latest issue of the journal RNA Biology, a group mostly from McMaster University in Hamilton, Ontario, Canada report at least part of the answer.  They have found that the protein called “heterogeneous nuclear ribonuclear protein C” (hnRNPC) prevents the normal process from happening by binding to messenger RNA.  hsRNPC has been known for years in relation to certain types of cancer, but its role in the brain or in neurodegenerative disease was not previously well studied.  To accomplish this work, the team developed a new technique called “RNA antisense purification by mass spectroscopy” (RAP-MS).  They also found, critically, that in PSP brain, the level of hnRNPC is abnormally elevated, an important confirmatory observation.  (Why is it elevated?  I can’t wait for the next installment in this story!)

The authors point out that hnRNPC can now be considered a target for drugs to slow or halt the progression of PSP.  Pharmaceutical companies, take note.

The senior author of the study and lab head at McMaster was Yu Lu, PhD, a specialist in proteomics.  His grad student Sansi Xing was first author.  The team included others from McMaster, the University of Iowa in Iowa City and Mount Sinai in New York.