Monthly Archives: June 2023

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.