Reports from the front

Last week the International Parkinson and Movement Disorder Society held its annual meeting – by Zoom, natch.  (A pity – in normal times, that meeting is held each year in a different, interesting international city, letting us append a culturally-oriented vacation to a consistently great conference.  But COVID has done far worse to others, so I shouldn’t complain, and the Zoom format allowed clinicians working in remote or poor countries to participate, a major plus.)

There were 1,320 original research presentations, all in the form of posters.  Of those, 37 came up in my search on “progressive supranuclear palsy.” Presented now for your delectation, in random order, are summaries of the top five presentations of original research in PSP along with my own take on their importance and implications: 

  • Imaging/Gait Correlates: 

A group from the Mayo Clinic led by Dr. Irene Sintini performed detailed gait analysis in 19 people with PSP and imaged their brains in three ways: non-contrast MRI (looking for atrophy in specific areas), diffusion tensor imaging (an advanced MRI technique showing fibers connecting the various parts of the brain and the speed of fluid slowly flowing through in them), and flortaucipir PET (showing tau aggregation, a research technique not quite ready for routine clinical diagnostic use in PSP, but working quite well for Alzheimer’s).  Then they looked for associations among the gait and imaging measures.    

They identified two general patterns of association:  One was that better gait velocity, stride length, and gait stability were associated with larger frontal lobe volumes and less flortaucipir uptake in the precentral gyrus, which is a part of the frontal lobe that controls movement.  The other was that worse postural imbalance was related to greater flortaucipir uptake in the left paracentral lobule, which helps control movement and sensation on the right side as well as bowel and bladder function.

Admittedly, this was kind of a “fishing expedition,” an unkind term we use for a research project that’s just looking for patterns of abnormalities without a specific hypothesis in mind.  But that’s how the process leading to eventual breakthroughs can begin.  In this case, associating specific gait-related abnormalities of PSP with specific brain regions could point the way to deep-brain stimulation techniques, cell replacement therapies, or transcranial (i.e., non-invasive, painless) magnetic or electrical stimulation treatment.  Besides, who knows what gene therapy might come along in a few years to take advantage of this groundwork in some still-undreamt-of, anatomically-directed way?

  • Diagnostic MicroRNA:

Dr. Ravi Yadav and colleagues at India’s National Institute of Mental Health and Neurosciences in Bangalore compared microRNA in plasma (blood without its cells) from 18 patients with PSP and 17 healthy controls matched for age and sex.  They used a type of polymerase chain reaction (PCR) test that, unlike PCR for forensic purposes or COVID testing, provides quantitative measurements.  MiRNA regulates many things in cells, acting much like enzymes.

They found five kinds of miRNA where the difference between PSP and controls was large enough to serve as a diagnostic test.  A commonly used measure of the ability of a diagnostic test to work well at the individual level rather than merely to distinguish groups by their averages is called the “area under the receiver operating characteristic curve” (AUC).  A good AUC is at least 0.8, with a perfect test being 1.0.  These five miRNAs’ AUC’s ranged from 0.78 to 0.86. 

This is promising, and if refined and perhaps combined with another moderately accurate test, could provide an excellent test for PSP.  But first, we need replication in a larger study and a different lab; PSP has to be compared by this test to other neurodegenerative disorders, not just to healthy controls; and cases with early, diagnostically-equivocal signs of PSP should receive this test and then be followed until a diagnosis declares itself.

  • Astrocyte Proteomics:

Astrocytes are the main type of glial cells in the brain.  They are largely non-electrical but perform many supportive functions for the neurons and may actually process information.  They are where the abnormalities of PSP start.  These cells don’t normally make tau but they can accumulate it in the tauopathies, and their resulting appearance, called “tufted astrocytes,” is the pivotal diagnostic feature of PSP through the microscope. 

Dr. Felipe Ravagnani and co-workers from the University of São Paolo, Brazil were interested in what genes are expressed into protein more intensively in such cells from patients with PSP relative to the same cells from healthy controls.  You can’t take astrocytes from a living person’s brain, so they created them in a dish by taking fibroblast cells from the lowest layer of a skin biopsy from each subject and treated them with various things to first remove their skin specializations and to become stem cells.  Then they treated with other things to turn them into astrocytes and compiled and compared the proteins in PSP-patient-derived astrocytes to those from controls.

Such a technique ordinarily produces a long list of differences that’s hard to draw any conclusions from.  So it pays to classify the proteins that differ between the two groups into the kinds of cellular and biochemical pathways in which they participate.  This incriminated two pathways.  One was for cell cycle activation, which is how the cell decides when to divide and to stop dividing.  The other was for one of the chaperone pathways, in this case CTT/TriC, which is important to axonal transport and to degradation of abnormal or excessive proteins.  Both pathways involve tau.

It’s still too early to know what to make of this, and proteomics research is notoriously subject to methodologic variables.  But the chaperone pathways, which are important in regulating protein folding, have been suspected for many years as part of the cause of PSP.  Cell cycle abnormalities are critical to cancer, but the opposite problem – insufficient cell division – could contribute to glial pathology and start the more general neurodegenerative process.  If the new results are confirmed, they would present new targets for drug development.

  • CBD Diagnostic Accuracy:

Just as PSP has multiple variants, so does corticobasal degeneration (CBD).  The most common and the classic form is called CBD-corticobasal syndrome (CBD-CBS).  Other common ones are CBD-PSP syndrome, CBD-frontal behavioral/spatial syndrome (CBD-FBS) and CBD-nonfluent/agrammatic variant aphasia (CBD-NAV).  A set of clinical diagnostic criteria for CBD was published in 2013. 

Now, Drs. Danielle Lux and colleagues at University College London have evaluated the accuracy of the CBD criteria in predicting actual CBD pathology at autopsy in 133 cases.  They found the positive predictive value (PPV) of the “probable CBD” criteria was only 33% and the PPV for the “possible CBD” criteria was only 51%.  (PPV is equal to the number who actually have the disease on autopsy divided by the number who have tested positive during life by satisfying the clinical criteria.)  They also found that CBD-NAV had a better PPV than the other variants.  As an aside, CBD-PSP had the most rapid course of all of the variants assessed.

These results confirm and extend previous reports in the literature using smaller sample sizes.  They better elucidate CBD’s wide variety of clinical presentations. This variety is the main reason why almost all of the clinical trials so far testing tau-directed treatment enroll people with PSP-Richardson syndrome, not CBD — the PSP-RS diagnostic criteria have a much greater PPV for actual PSP pathology at autopsy.  We hope that tau PET imaging and fluid biomarkers in CSF or blood will soon correct this situation for folks with CBD.

  • A Survival Model:

Until the fine day comes when we can prevent or slow the progression of PSP, predicting survival is important.  Patients and families need to plan psychologically and financially.  Designers of long-term treatment trials need to know the likely dropout rate due to death. 

Dr. Tao Xie and colleagues at the University of Chicago have added usefully to the considerable existing literature on this topic.  In 23 patients who had died with PSP, they recorded the time from onset of the first PSP symptom to onset of downgaze palsy; the severity of downgaze palsy at that point using a scale ranging from 10 to 100; sex; age at PSP onset; motor function; and use of medication for parkinsonism or for pulmonary or cardiovascular diseases.  They used those data to create a formula by which to calculate survival from onset to death.

They found that total survival duration in years can be predicted by the equation: 5.76 + (1.11 x disease duration at the assessment) – (0.03 x downgaze palsy severity at the time of the assessment) – (0.03 x the age of onset).  The result predicted total survival duration reasonably accurately, with an average error of 0.82 (standard deviation 0.67) years.

The method of measuring the downgaze palsy was not described in the brief presentation and may be somewhat subjective, so an even more accurate prediction may be feasible using other measures.  Also, it’s not clear from the material presented that other features of PSP might perform as well as downgaze palsy as a predictor of survival.  For example, last year my colleagues and I published a very different method of estimating PSP survival that works about as well as this new one but requires administration of the whole 28-item PSP Rating Scale. 

At the scientific level, it’s interesting that in the mathematical model of Xie et al, downgaze palsy is an important factor in predicting death despite involving only a small portion of the total brain pathology.  I say that because in PSP, death is not particularly related to visual problems, but is usually the result of overall immobility, poor nutrition, aspiration and bladder infections.  But even if the measure of downgaze palsy only provides the model with an easily-measured proxy for those other disabilities, the model would still be a convenient and useful service for patients and families. 


Keep in mind that despite clearing the bar for acceptance at this conference, these research reports have not been subjected to a detailed peer-review process.  In fact, most original presentations at most conferences are never published in anything like the same form.  But I chose to relay these five to you because I think that in the end, they’re likely to stand up to scrutiny and to influence scientific thinking or bedside practice. 

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s