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A week in the life

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I’ve never used social media.  I did learn to write computer code in high school, but I guess I’m just too much of a Boomer to feel comfortable using the computer as a medium of social interaction.  What especially puzzles me is why anyone thinks that even close friends, much less peripheral acquaintances, are interested in a dutiful chronicle of their daily activities.

That said, here’s what I’m doing over the next seven days that’s PSP-related:

  • Today, I listened in on the latest CurePSP “Ask the Expert” webinars.  This one was Dr. Kristy Borawski, a urologist at the University of North Carolina School of Medicine, with a superb, lay-language presentation on what goes wrong with the bladder in PSP, CBD and MSA, and what can be done about it.  Later today, I decided to write a blog post, which you’re reading.  (Bored yet?)
  • CurePSP’s Centers of Care network has a special working group to create a convenient algorithm for general neurologists to use in diagnosing the atypical Parkinsonian disorders.  Dr. Michiko Bruno of Queen’s University Medical Group in Honolulu and I are leading that effort.  We had another exchange of emails today and a Zoom call tomorrow.  We’re making good progress on a first draft.
  • Tomorrow morning I have a Zoom call with representatives of CurePSP, the Alzheimer’s Association and the Rainwater Charitable Foundation to continue planning a conference in April 2024 called “Tau 2024.”  Like Tau 2020 and Tau 2022 before it, it will be held in Washington, DC and should attract top lab scientists from all over the world.  Registration will be open to the public, but the presentations will be at a very high technical level.
  • The next day, I have a Zoom call with a drug company that’s consulting me to help them plan a trial of a new drug for PSP.  Can’t reveal more than that, except that this drug would be the first in its class to be tried for PSP.
  • The day after that, I have a Zoom meeting with another company that’s working on a new kind of PET scan technique to diagnose PSP.  Again, can’t say more.  That night I fly down to Charlotte, NC for the quarterly CurePSP Board of Directors meeting.
  • After that one-day shindig, I fly directly to Boston for the semiannual meeting of the Tau Consortium.  That’s a group of about 50 world-class researchers working on the tau-based disorders with funding from the Rainwater Charitable Foundation.  Attendance at the conference is only for RCF-funded scientists (which I was for a couple of years, long ago), but now I’m invited as a representative of CurePSP, with which the Tau Consortium has multiple collaborations.
  • On the second day of the three-day TC meeting, I’ll try to break away to join a Zoom meeting of the Parkinson Study Group’s Atypical Parkinsonism Working Group.  The PSG is a US/Canada clinical research consortium of academic centers.  Over the past couple of years, this particular sub-group has validated and published a telehealth-compatible version of the PSP Rating Scale and analyzed some old clinical trial data to show that concomitant benzodiazepine use may speed the progression of PSP.  At this meeting, Dr. Tao Xie of the University of Chicago will briefly present some data that he and I have gathered on irregularities of symptom progression in PSP.  The paper is under review at a journal right now.

I allegedly retired in 2020, but I think the only things I’ve really retired from are direct patient care, getting a paycheck, and being able to share personal chit-chat with colleagues in my old department at Rutgers.  But for that last one, I have you!  Want to know what kind of fruit I put in my oatmeal this morning?

Sorry – you’re just not my sub-type

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One day in 7th grade, my science teacher started a lesson by walking around the room with a big bag of old, cancelled postage stamps and dumped a large handful on each desk.  The assignment was to sort them into groups using any method we liked.  There were many features to choose from, especially if combined to produce finer groupings.  (That’s what obnoxious, smarty-pants Larry did.)  The point was to demonstrate that living things can be classified in many ways, too.  Now hold that thought.

We once thought all PSP was pretty much alike, with no more variation than any other neurological disease (“disease” being defined as a common autopsy or biochemical picture, typically with a common causality, if one is known).  But in 2005, a group at University College London led by David Williams and Andrew Lees reviewed the clinical records of all 103 patients in their files with autopsy-proven PSP.  For each, they tabulated a long list of clinical features and, as I did with my pile of stamps, created groups using combinations of features. 

They found that 54% conformed more or less to the original combination of features (called a “syndrome”) described by Steele, Richardson and Olszewski in 1963 and 1964, where the first and worst symptom was poor balance with falls, also with symmetric motor signs, prominent cognitive loss, poor response to levodopa, little or no tremor and rapid progression.  They called this combination PSP-Richardson’s syndrome. 

Another 32% had a different picture for the first few years, with general slowness and stiffness as the initial deficits, asymmetric feature, little cognitive loss, a useful response to levodopa, moderate tremor, and slower progression.  They recognized this type as similar in many ways to Parkinson’s disease and dubbed it PSP-Parkinsonism.  The other 14% of the patients of Williams et al didn’t conform well to either PSP-RS or PSP-P.  

The basic picture at autopsy for PSP-RS and PSP-P was identical, though subsequently, as one would expect, the tau aggregation of PSP-RS would be found to emphasize the brainstem, while that of PSP-P emphasizes the basal ganglia.  Williams et al found that the MAPT H1/H2 ratio (the most important genetic risk factor for PSP) and the tau 4R/3R ratio (a feature of the structure of the tau protein in the neurofibrillary tangles) were each higher in PSP-RS than in PSP-P, but I haven’t seen confirmation of this since the original 2005 paper.

This PSP-RS vs PSP-P differentiation by Williams et al rested on the results of a statistical procedure called “principal component analysis,” which tabulated which of a list of common PSP features tend to occur in the same patients.  It’s what I was doing in my head with the stamps in 7th grade, but in a much less sophisticated way.

Over the next decade, a variety of other PSP types were found to account for the last 14% of Williams et al.  Like PSP-RS and PSP-P, they all had the same set of autopsy abnormalities with minor differences in the areas of the brain involved corresponding to their specific, predominant symptoms.  However, their definitions relied only on a single feature occurring first and worst rather than on a more complex analysis of a long list of features as a principal component analysis would.  So, we can’t be sure that they represent biologically relevant differences that might, for example, be susceptible to different kinds of diagnostic markers or neuroprotective treatments.

A first step toward resolving that issue has now come from a group of researchers mostly in London, Cambridge and San Francisco led by William J. Scotton of University College London, with senior author Peter A. Wijeratne.  They analyzed existing MRI images in a group of 426 living patients with a variety of PSP subtypes and 290 control individuals without PSP.  They divided the PSP types into 3 categories:

  1. PSP-Richardson’s syndrome (PSP-RS) (84% of the total)
  2. A “cortical” group comprising PSP-behavioral variant frontotemporal dementia (PSP-F), PSP-corticobasal syndrome (PSP-CBS) and PSP-speech/language (PSP-SL) (12%)
  3. A “subcortical” group comprising PSP-Parkinsonism (PSP-P) and PSP-primary gait freezing (PSP-PGF) (4%)

(A statistical detail, for those interested: Note that in this study the percentage of all PSP accounted for by PSP-P is much lower than in most surveys, where it’s about 30%.  This is explained by a new way of assigning a sub-type using a statistical approach called “multiple allocation extinction rules,” which helps avoid the frequent problem of individual patients satisfying criteria for multiple subtypes.) 

(Now a clinical detail, for those interested: In most referral centers, the fractions of PSP accounted for by these sub-types are roughly: PSP-RS 50%, PSP-P 30%, PSP-PGF 5%, PSP-CBS 4%, PSP-F 4%, PSP-SL 3%.  That makes 96%.  Four others not included in the Scotton et al series, each at about 1%, are PSP-cerebellar (PSP-C), PSP-primary lateral sclerosis (PSP-PLS), PSP-ocular motor (PSP-OM) and PSP-postural instability (PSP-PI).  In Japan, PSP-C is far more common for some reason: about 10-15% of all PSP.)

The result was that MRI in the cortical subtype showed atrophy starting in the:

  1. frontal lobes and
  2. insula (the surface of cortex on the side of the brain hidden by the temporal lobe), and in the brainstem, which of course is a subcortical area. 

The subcortical subtype’s atrophy was most prominent in the:

  1. brainstem,
  2. ventral diencephalon (the area of cerebrum just above the brainstem),
  3. superior cerebellar peduncles (fiber tracts carrying most of the output of the cerebellum to the brainstem and cerebrum), and the
  4. dentate nucleus (the part of the cerebellum where the fibers of the superior cerebellar peduncle originate, so called because its zig-zag shape resembles a row of teeth).

Here are some of their additional observations:

  1. For both the subcortical and cortical patients, 82% conformed to the MRI pattern described above. 
  2. The subcortical subtype had worse PSP Rating Scale scores after potential confounders were accounted for.   
  3. The subtypes held up over a period of years in the patients in whom multiple successive exams were available, but the pattern of atrophy at the end stage was similar for the cortical and subcortical subtypes.
  4. The PSPRS subtype behaved in these respects almost exactly like the subcortical subtype except that it progressed faster, on average.

What does this mean?  As I sometimes do in this blog (probably not often enough), I’ll let the authors speak for themselves:

“The results suggest that the PSP-RS and PSP–subcortical syndromes share a similar trajectory of atrophy, though the latter tends to be at an early stage at diagnosis and progresses at a slower rate. Being able to accurately subtype and stage PSP patients at baseline has important implications for screening patients on entry into clinical trials, as well as for tracking disease progression.”

A major issue right now for clinical trial design for PSP is how to include the non-PSP-RS subtypes.  The PSP Rating Scale, still the world’s standard primary outcome measure for trials, was designed for what would a decade later be named the PSP-RS subtype.  For that reason, and because the diagnostic criteria for non-RS sub-types aren’t as accurate, PSP treatment trials have excluded non-RS subtypes.  But by tracking how the PSP Rating Scale progresses in the other sub-types, the statistical analysis of the trials’ data could be adapted to include those patients.   Another conclusion might be that we should design trials to include the two subcortical sub-types along with PSP-RS, as all three have a similar pattern of progression, albeit at different rates.  Of course, that would throw the cortical subtypes under the bus, awaiting development of their own trial outcome measure.

So, just as postage stamps can be classified in different ways, so can PSP.  Understanding all the resulting sub-types, if they’re based on validating factors like patterns of atrophy on MRI, allows potential PSP preventatives to be tested more democratically across the PSP population.  It also eases patient recruitment into clinical trials, speeding their completion and reducing their cost. 

Down and sideways

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Eye movement was the topic of the fourth of the five papers on PSP to be published on a single day last week and is the topic of the fifth as well.  It’s altogether fitting and proper that on this dies mirabilis for PSP, disproportionate attention should go to the most specific single feature of PSP and the source of its name. 

One of the most important early symptoms of PSP is difficulty reading that many patients describe as difficulty shifting from the end of one line to the start of the next.  The problem isn’t the long leftward horizontal movement to pick up the next line, but the short downward component, and patients may report that they can’t avoid re-reading the same line.  This can happen long before the neurologist’s exam can detect any loss of downward eye movement on a simple pursuit (“follow my finger”) or voluntary saccade (“look left”) test.

A group of scientists in Yonago, Japan have studied this phenomenon in a new way.  Yasuhiro Watanabe, Suzuha Takeuchi, Kazutake Uehara, Haruka Takeda and Ritsuko Hanajima tracked patients’ eye movements as they read a paragraph aloud.  In Japan, people are almost equally skilled at reading horizontally and vertically.  Computer screen text and most books use horizontal text, while newspapers and official, formal and traditional publications are vertical.  This makes Japanese people excellent subjects in an experiment comparing horizontal with vertical reading skills. 

The participants included groups with PSP, Parkinson’s disease, multiple system atrophy (MSA) and spinocerebellar atrophy (SCA) as well as a group of healthy controls.  For the analysis. the MSA and SCA participants were combined into one group called “spinocerebellar degeneration” (SCD). 

Shown below are the tracings of their eye movement during reading.  The first and third rows show superimposed tracings of all 19 to 29 participants in each group.  It’s obvious that the group with PSP did reasonably well with horizontal movements but had difficulty finding the start of the next line.  When attempting to read vertically, those with PSP had extreme difficulty, as expected.

The second and fourth rows show eye movements over time (horizontal axis) while reading, with horizontal movements in blue and vertical movement in orange.  The vertical axis shows the size of the movement.  Again, for horizontal text, the horizontal movements are nearly normal in PSP, while the vertical movement is impaired.  For vertical text, horizontal movement to pick up each subsequent line is moderately impaired, but the main, vertical movement down each line of characters is severely so.

The analysis used a “machine learning” procedure, a form of artificial intelligence, to create a statistical profile of the measurements for each disease group.  It showed that the main difficulty distinguishing each group were downward movements in PSP, general slowness and a “stickiness” of ocular fixation in PD and poorly aimed horizontal movement with rhythmic horizontal overlying movement (“nystagmus”) in SCD.  The accuracy in distinguishing controls from the patients as a combined group was 87.5%. (Accuracy combines sensitivity and specificity.)  In this analysis combining the three disease groups, horizontal reading was more useful than vertical reading.  Using vertical reading, PSP was readily distinguished from SCD (accuracy 91.4%) but not as well from controls.  Nor did it do well in distinguishing PSP from PD despite appearances in the tracings shown above.

The authors feel that this technique could be improved in various ways.  They did correct the results for overall cognitive performance using the Montreal Cognitive Assessment (MoCA), but perhaps a correction for overall neurological disability, or at least dysarthria (in this reading aloud task) could be added.  I’d further suggest that to remove most of the cognitive and speech components of reading, the task could be reduced to reading a series of single digits rather than text sentences.  This could also allow the test to be used in populations not as skilled as the Japanese in reading text vertically.

A major virtue of this test is that after the one-time, initial software development, it’s very inexpensive, convenient and non-invasive.  It could be implemented on a desktop computer screen or perhaps on a tablet (a phone screen might be too small).  If we’re trying to detect people with PSP in a very early stage to test a new drug — and eventually to receive a prescription for it — a widely applicable, remotely administered screening test like this could be just the ticket. 

We don’t yet know the sensitivity of this test to PSP progression over time, but if it proves useful in that regard, perhaps it can be used as an outcome measure in treatment trials or as a way for neurologists to monitor their patients’ illness and offer prognostic advice.

Squares and jerks

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The fourth of the five PSP-related research papers to land in PubMed on a single day this week is from Ulm, Germany.   It compared PSP with ALS with regard “small involuntary fixation saccades” or SIFSs.  Here’s what that means and why it’s important: (Red alert: serious, nerdy neuroscience is coming.)

When we stare at a small visual target, we all have small, fast, irregular, eye movements away from the target.  Each is rapidly corrected by an equal and opposite movement and their size ranges from 0.01 degrees to 2 degrees.  (The normal full range of voluntary eye movement in each of the four directions is about 50 degrees.)  In PSP, these SIFSs become larger and more frequent in the horizontal plane (i.e., left and right), ranging up to 3 degrees and occurring up to twice per second.  The largest of these are called “square wave jerks.” They are so common in PSP, even in the earliest stages, that a neurologist finding signs of PSP but no square wave jerks must strongly consider some other diagnosis.  As you’d imagine, SWJs degrade vision by making it difficult to aim the most sensitive, central part of the retina at a target.

Square wave jerks and milder forms of SIFSs also occur in amyotrophic lateral sclerosis (ALS or Lou Gehrig disease).  ALS and PSP both include frontal cognitive loss and affect overall body movement, especially speech and swallowing, have frontal cognitive loss and have a similarly rapid course, but are otherwise not at all similar.  In ALS, the average age of onset is 10 years younger; the cognitive loss is a late occurrence; it affects the spinal cord worst; and the protein aggregating in the cells is TDP-43 rather than tau.  As eye movement are controlled, in part by the frontal lobes, it seems reasonable that the frontal damage is the source of SWJs in both diseases. 

Now, Drs. Wolfgang Becker, Anna Behler, Olga Vintonyak and Jan Kassubek have compared people with PSP and ALS with regard to the details of their SIFSs, including their square wave jerks.  In addition to making some new observations about SIFSs in general, they found that in ALS, the size and frequency of SIFSs are correlated, while such a relationship is absent in PSP. 

The researchers explain this result by suggesting that the basal ganglia, where the substantia nigra, globus pallidus and subthalamic nucleus are the first three nuclei affected in PSP, are the most likely source of SWJs in that disease, while in ALS, the SWJs probably arise from damage to the frontal cortex.  They suggest that in PSP, the amplitude and frequency of the SWJs are regulated by different sites in the basal ganglia, explaining their observed lack of correlation.  More work will be needed to confirm that suspicion, but some support comes from the observation in this paper that the severity of vertical eye movement loss, the cardinal feature of PSP, correlates closely with the amplitude of the (horizontal!) square wave jerks.

Why should anyone care?  First of all, a general point: One never knows when a “basic science” observation may lead to broader insights that could allow treatments to be developed.  More specifically, finding that a feature of PSP arises from multiple parts of the basal ganglia reduces the appeal of targeting just one allegedly critical or rate-limiting area of basal ganglia damage with a preventative or restorative treatment.  Such approaches have been proposed using injection of viral vectors to deliver gene therapy or growth factors.  Non-invasive targeting of the basal ganglia has been proposed using focused ultrasound.  This new paper suggests that a more general approach reaching the whole brain, or at least all the basal ganglia, might work better.

It’s that pedunculopontine nucleus again. (5CP, part 2)

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My last post described the first two of five new (as of yesterday) publications on PSP to suddenly appear on my routine PubMed search.  The third one is sufficiently interesting and complicated to deserve its own post.

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Falls are perhaps the earliest-appearing and most disabling feature of PSP, but we don’t yet fully understand which of the many brain areas involved in PSP deserves most of the blame.

A PSP-like illness endemic to the islands of Guadeloupe and Martinique is called Guadeloupean tauopathy or Caribbean Parkinsonism (CAP).  It may be the result of consuming two fruits, sweetsop and soursop, which have high levels of a mitochondrial toxin called annonacin.  Injected into rats in a lab, annonacin produces a PSP-like illness complete with abnormal tau accumulation.  However, the human CAP illness includes multiple aggregating proteins in addition to tau.  

The new article from neurologists in Paris and on Guadeloupe and Martinique reports on careful measurements of atrophy of specific brain regions on MRI in 16 patients with CAP, 15 with PSP-Richardson syndrome and 17 healthy, age-matched control participants.  They correlated the results with 11 standard scales assessing gait, general movement and cognitive function and also with electronic measures of gait and eye movement.  The group’s senior leader was Dr. Annie Lannuzel of INSERM, France’s equivalent of the NIH.  She has a long record of research in CAP.  The first author was Dr. Marie-Laure Welter, also of INSERM.

The results were that PSP and CAP differed in their anatomical patterns of brain atrophy.  Although their overall average disease severity was similar, CAP had more cognitive loss with correspondingly more atrophy of cerebral cortex.  On the other hand, the PSP group had more gait instability with correspondingly greater involvement of the midbrain and cerebellum.

The overall statistical comparisons showed that the main source of the gait and balance problem in PSP is damage to the supplementary motor area – pedunculopontine nucleus (SMA-PPN) network.  In CAP the gait/balance problem includes the SMA-PPN but with a major contribution from areas serving general attention and self-awareness.

The SMA is an area of frontal cortex just in front of the primary motor cortex.

The PPN is a complex nucleus at the pons-midbrain junction (PMJ, below):

Here’s why this paper’s results could be important: 

The SMA, as you can see from its superficial location, is an easy target for non-invasive magnetic or electrical trans-cranial stimulation.  TCS is still in its infancy but is starting to show some modest benefits for some movement and cognitive disorders.

The PPN has long been known to be important to the balance issue in PSP and Parkinson’s.  This new research result focuses attention on that nucleus as a potential target for deep-brain stimulation or as a target for surgically implantable stem cells or viral vehicles of genes for depleted enzymes.  Dr. Stuart Clark and colleagues at The State University of New York, Buffalo have already created an experimental model of PSP in rats by altering the function of the PPN.  The results from Welter et al tend to validate the relevance of that model to PSP.  

Five complicated pieces – part 1

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Every day I search PubMed on the term “progressive supranuclear palsy.”  In fact, the PubMed bookmark on my browser is set to that search term as the default.  I’m used to seeing about three new articles appear per week, but over the past 10 days or so, nothing. 

But today, just as I was I wondering if some human being critical to this process at the National Library of Medicine had been downsized, five new articles appeared, and they’re all pretty interesting.  To celebrate the event, I thought I’d share elevator explanations of each, starting here with the first two:

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G. Meduri et al. / FKBP52 Decrease is an Early Feature of Different Tauopathies

A group at France’s equivalent of the NIH (called “INSERM”) discovered in 2010 that a protein called FKBP52 plays a role in the normal degradation of the tau protein.  Now, (links: abstract; full pdf) some of those same researchers have found that levels of FKBP52 are reduced in the brain cells with highest levels of abnormal tau.  They used mouse models and also frontal cortex brain tissue from autopsies showing Alzheimer’s, familial frontotemporal lobar degeneration, Pick’s disease, corticobasal degeneration and PSP.

Furthermore, they found those reduced levels even before any damage had taken place.  This suggests that the direction of causation proceeded from reduced FKBP52 to excessive tau to brain cell damage.  This in turn suggests that a hypothetical imaging procedure showing FKBP52 in the brain could serve as a pre-symptomatic or very early-stage diagnostic test.

The most important implication of this insight is that increasing FKBP52 production (or slowing its rate of loss) could prevent, slow or halt the disease process.  Just as important, it found the same thing in all of those tauopathies, suggesting that they could share the same treatment.

All the more reason for researchers and drug companies interested in Alzheimer’s disease to start out by looking at PSP, which for several reasons is easier to do research on.

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Calisi D et al / Case report of FSH dystrophy Obscuring PSP

Facio-scapulo-humeral dystrophy (FSHD) is a common form of slowly-progressive muscular dystrophy that can start anywhere from childhood to late middle age.  It can eventually cause major disability, but does not shorten lifespan or affect cognition or behavior.

Neurologists in Chieti, Italy report a man in his early 60s with FSHD since childhood confirmed by genetic testing and muscle biopsy.  (Here’s the abstract.) About 5 years before, he had begun to develop more general difficulty with movement that progressed rapidly.  It was diagnosed as atypically rapid progression of FSHD until a neurologist noticed specific signs of PSP that do not occur in FSHD such as vertical gaze palsy, rigidity in the neck, trouble swallowing liquids, impairment of “executive” cognitive abilities and compulsive behavior.  Brain MRI showed atrophy of the midbrain, as is typical for PSP. 

The point is that while PSP is not currently curable, receiving an accurate diagnosis can help in one’s residential, healthcare and financial planning, avoid useless diagnostic tests and treatments, and allow participation in clinical trials.  Once we have a way to slow or halt the progression, an accurate diagnosis could be lifesaving. 

Thanks to this modest case report, physicians taking care of people with FSHD and other chronic, relatively benign disorders affecting movement now know to consider a second diagnosis of PSP in someone with an unusual rapid progression and new neurological features related to the brainstem and frontal lobes.

What’s good for the goose . . . ?

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Biogen is currently testing an anti-sense oligonucleotide drug called BIIB-080 in patients with mild cognitive impairment and very mild Alzheimer’s disease. The goal would be to slow or prevent their conversion to full-blown Alzheimer’s disease. Today someone posted a comment asking if I thought this could work for PSP. I thought this could make a good, brief post:


Biogen has an early-phase trial of BIIB080 in Alzheimer’s, and there’s no reason to think it wouldn’t work as well in PSP.

Actually, the Alzheimer’s trial is mostly for people with “mild cognitive impairment” and the measure of success would be preventing progression (“conversion,” as it’s called) to full-blown Alzheimer’s. They are also enrolling some patients with mild AD, hoping to prevent progression to moderate stages. If the people at Biogen feel that BIIB080 should first be tested in such an early disease phase, that could be why they chose Alzheimer’s over PSP: there is no known equivalent of mild cognitive impairment for PSP.

Another reason Biogen might be starting with AD is the ready availability of a test for beta-amyloid in the brain in the pattern specific for that disease. It’s called an Amyvid scan, and participants in the BIIB080 trial have to show an AD pattern on the scan to qualify. There is no equivalent, road-tested, sensitive and specific diagnostic test for PSP, which means that a much larger trial would be necessary to overcome the “statistical noise” caused by people with a false-positive diagnosis of PSP.


The diagnostic criteria for PSP do define a state called “suggestive of PSP,” but there are still no data on what fraction of those individuals eventually progresses to probable or definite PSP, or how long it takes. On the other hand, there are excellent such data on the conversion of MCI to Alzheimer’s.


A couple of examples of symptoms that would result in a diagnosis of “suggestive of PSP” are repeated falls and slow downward eye movements. As you can tell, such symptoms in isolation are not very specific for PSP, so a trial enrolling such patients would have to have many hundreds of particicpants for a statistically useful fraction of them to convert to possible, probable of definite PSP, especially over only a 12-month period. Furthermore, the size of the trial would have to be large enough for the conversion rate among the recipients of the active drug to be validly compared to the rate among those on placebo.


So, my guess is that if BIIB080 works in mild cognitive impairment and very mild AD, Biogen will test it in PSP. But if a good pre-clinical marker for PSP becomes available, then it would much more practical to try such treatments in pre-clinical PSP.

But there are other drug companies with other anti-tau ASOs. One, from Novartis, is already enrolling patients. Others are approaching clinical trials.

A downside to the back-door approach

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Someone wrote asking if they should seek a fecal microbiota transplant (FMT) for their spouse with PSP. (See yesterday’s post, which reports on a favorable double-blind trial.) Of course, I replied that I can’t give individualized medical advice, but it occurred to me to write this post to mention two downsides that I didn’t mention yesterday.

One problem is that drinking the huge volume of fluid for the 3 bowel preps could be very difficult for someone with PSP. It typically requires drinking a 8 full 8-ounce glasses of a salty-tasting stuff over 2 hours (i.e., one glass every 10-15 minutes) the night before the procedure and then repeating the same thing on the morning of the procedure. That’s 64 ounces twice, which totals one gallon. That has to be repeated at 4 weeks and again at 8 weeks for the other 2 coloscopies/transplants. All those fluids could invite aspiration. I don’t know if using a thickener would be permitted, but that’s not a full guarantee against aspiration, and the mere exertion of the swallowing muscles might not be possible for someone with more than mild PSP.

The other issue is finances. Colonoscopies are expensive — my survey on line suggests an average professional fee of $2,000, another fee for the facility and another for the bacteria to be transplanted. Then, multiply by 3 for the 3 steps in the FMT. I doubt that any public or private insurer would pay for this for someone with PSP, where it’s not FDA-approved. The insurers know that quacks offer FMT for many medical conditions with no proper double-blind trials as evidence of benefit and safety. The insurers may simply lump PSP in with those conditions despite the one small positive trial from China, and it’s hard to argue with them on that.

So, I’ll leave this to the judgment of my commenter’s spouse’s own doctor and to that of the gastroenterologist who would be doing the procedures.

A back-door approach

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For the past few years, fecal microbiota transplantation (FMT) has been part of mainstream medicine’s treatment for a nasty, antibiotic-resistant intestinal infection by the bacterium Clostridium difficile.  Essentially, the idea is to replace the person’s colonic bacteria with a new set obtained from the stool of healthy people.  The new bacteria are introduced to the junction between small and large intestines via coloscopy after a standard bowel prep.  

On the theory that immune-related diseases could be a result of some poorly-characterized problem in the colonic bacteria, clinics have sprung up to use FMT for things like inflammatory bowel disease and multiple sclerosis.  PSP is a disease for which evidence of abnormal immune function has been accumulating.  Furthermore, constipation occurs in PSP to a far greater degree than abnormalities in other autonomic nervous system abnormalities such as urinary incontinence or low blood pressure.  This vaguely suggests that an abnormality of intestinal bacteria could underlie PSP in some way.

A trial of FMT in PSP appears in the current issue of the prestigious British journal The Lancet from a research group at Zhengzhou University in Zhengzhow, China led by Dr. Haiyan Tian with senior author Dr. Xuejing Wang. They randomly assigned 68 people with newly-diagnosed PSP (averaging 2.6 years since onset) to receive identical bowel preps followed by either FMT or placebo transplant, which was a colored saline solution.  Neither the patients nor the researchers performing the transplantations or evaluations knew the treatment assignments.  That is, it was a proper randomized, double-blind trial. 

Each patient received 3 such transplantation procedures – at 0, 4 and 8 weeks.  The patients were examined periodically over 36 weeks using the PSP Rating Scale (PSPRS) at 16 weeks as the “primary outcome measure.” They also received a long list of other standard tests and chemical measures in the stool as secondary outcome measures. 

The result was that at Week 2 (i.e., 2 weeks after the first procedure), the PSPRS, which averaged 40.1 in each group at the start, improved by 1.5 points in the FMT group and worsened by 0.2 points in the placebo group (as expected), for a total “treatment effect” of 1.7 points.  At Week 7, the treatment effect was 2.8 points; at Week 12, 4.8 points; at Week 16 (the “primary” outcome), 4.3 points; and at Week 36, 3.8 points. 

The researchers confirmed that the FMT group’s post-treatment stool had lower levels of inflammation-related compounds than that of the placebo group.  Side effects, all of them minor and transient gastrointestinal symptoms, occurred in 3 patients in the FMT group and 2 in the placebo group.

Taken at face value, this is good news – the primary outcome measure reduced the PSPRS by 4.3 points relative to placebo, which is (4.3 / 40.1 =) a 10.7% improvement. 

Let’s keep several things in mind:

  • As a comparison, the average person with PSP worsens about 11 PSPRS points per year, so a 4.3-point improvement is the equivalent of erasing about 5 months’ progression.  In these 68 patients, the progression before the trial was much faster, averaging 15.4 points per year, possibly because they all had PSP-Richardson syndrome, the most rapidly-progressing form of PSP.  So for them, a 4.3-point improvement is the equivalent of only 3.4 months of progression.
  • This is not a trial of neuroprotection, where the treatment is attempting to slow the long-term progression of the underlying disease process.  Although FMT, in theory, could do that, this particular trial measured only short-term improvement in outward signs and symptoms. We call that “symptomatic treatment,” and that’s what all existing treatments for PSP do for specific symptoms with various degree of success.
  • As you can see from the PSPRS scores above, the benefit started to wane at about Week 12, which was about 2 months after the third transplant.  We only have subsequent measurements at Weeks 16 and 36, so we don’t know how soon another round of 3 transplants would have to be repeated in order to maintain an acceptable degree of improvement.  Hopefully, these researchers are continuing to observe and examine these 68 patients and will report longer-term results.

Bottom line:  I interpret this as a “proof-of-concept” study.  That means that even though the trial’s procedure might not be practical as routine treatment, the results (assuming they’re confirmed by studies elsewhere) show that revising the colonic bacteria can do good things for PSP, at least in the short term. 

Next steps are to:

  • Measure the duration of benefit from the three FMTs;
  • Devise an orally-administered capsule of bacteria that is safe and can accomplish the same thing;
  • Mount a neuroprotection trial, which requires about 200 patients on FMT and another 200 on placebo to detect a 25% slowing of progression.
  • And most importantly, figure out what biochemical action the old bacteria were doing wrong that the new bacteria are doing right, and accomplish the same effect in a simpler way.

Then there’s this minor question: How and why do some people acquire a set of colonic bacteria that increase PSP risk and how can that be prevented?