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. 

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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. 

Of spice and dog breeds

Got some catching-up to do.  Since my last blog post about six months ago, I’ve retired from my professorial job at Rutgers, which means I’ve stopped seeing patients.  But I’ll still do clinical PSP trials as a volunteer, so I’ll still see that kind of patient.  Retiring from Rutgers also means that I retire from teaching.  But I’ll continue my work with PSP, so I’ll continue that kind of teaching.  Still working a little on my own research, which is mostly about that cluster of PSP in France.  Then there are all of my non-neurological retirement activities (see spouse for details).  I’ve been neglecting my PSP blog, but that has just changed.

Today a journal article caught my eye.  It found that a slight modification of a naturally-occurring component of turmeric may slow or halt the progression of the tau-based neurodegenerative disorders like PSP and Alzheimer’s disease. At least in cells growing in a dish.

First a little background: You probably know that the brain cells being damaged in PSP contain abnormal clumps of a normal protein called tau.   You also know that the clumps are called neurofibrillary tangles.  In the course of forming the tangles, tau molecules first form smaller accumulations called oligomers (Greek for “a few parts”).  The oligomers are toxic but they’re still soluble in water, like ordinary, monomeric tau (you got it: “one part”).  But the oligomers have an Achilles heel: They tend to form larger clumps, the neurofibrillary tangles, which are no longer soluble in the brain cells’ fluid.  The tangles’ inability to float around and interact with things renders them harmless and means that they serve the useful purpose of taking the toxic, soluble oligomers out of the brain cells’ internal soup.

More background: You’ve heard of turmeric, a popular spice related to ginger.  It’s a traditional remedy for what ails you and some responsible researchers feel that it may actually help certain inflammatory conditions and the metabolic syndrome (high blood pressure, diabetes, abnormal lipids and obesity).  But despite some success in animal models, it has never been proven by modern standards to help any medical condition in actual humans.  Furthermore, we don’t know which of the dozens of chemical components of turmeric explains its apparent benefits.  One minor component of turmeric is curcumin, which by itself is used as a coloring agent in food and cosmetics.  Its chemical structure renders it very difficult to absorb from the digestive tract into the blood or from the blood into the brain.  Here’s the good news: We’ve known for a few years that curcumin, when directly applied to brain cells in a dish, can actually can induce the water-soluble, toxic tau oligomers to form insoluble, harmless neurofibrillary tangles. 

The new journal paper is from neuroscientists at the University of Texas Medical Branch in Galveston and the University of Palermo, Italy.  The group’s leader is Rakez Kayed, PhD of UTMB, a respected and well-published researcher in tauopathies and other forms of neurodegeneration.  The first-named author is Filipa Lo Cascio, PhD, a young post-doctoral trainee in his lab.  They cultured two off-the-shelf types of neural cells and added abnormal tau extracted from autopsied brain tissue from people with PSP, Alzheimer’s disease and dementia with Lewy bodies.  Ordinarily, the abnormal tau would misfold, cause the normal host’s tau to misfold in the same disease-specific way, form oligomers, cause damage, spread to other cells and eventually be taken out of action by forming neurofibrillary tangles.  The curcumin caused the toxic oligomers to more rapidly form tangles, thereby reducing their cell-to-cell spread.  By making the tau less soluble, the curcumin also limited its ability to damage components of the cells with the result of improving the cells’ survival. 

The researchers didn’t actually use curcumin itself, as that compound has no future as a neurological treatment because, as mentioned, it can’t get into the brain. So they tweaked its structure by replacing some hydroxy (-OH) and methoxy (-O-CH3) groups (don’t worry about it) with fluorine atoms.  The resulting compound, which they dubbed CL3, had the same beneficial effect regardless of whether the abnormal tau introduced into the cells was from people with PSP, Alzheimer’s or dementia with Lewy bodies. 

The next step is for another lab to replicate the results using different methods.  At the same time, researchers could try the experiment in mice that have received an abnormal tau gene that forms aggregates and kills their brain cells.  That’s currently the best lab model for PSP and the other tauopathies.  But the multiple examples of drugs that prevented this sort of mouse tauopathy and then failed to prevent PSP in clinical trials show that the mouse models, albeit based on human tau, are inadequate as surrogates for people with real PSP or other tauopathies.

The experiments of Lo Cascio, Kayed and colleagues also confirmed that the aggregates forming from tau taken from people with different tau disorders differ from one another in some other important ways.  That’s the new, hot idea of tau strains – they’re like dog breeds.  They’re all tau, but they differ in some important details and when they reproduce (i.e., by templating their abnormal folding pattern onto normal copies of tau in a host cell), their specific variation continues in the next generation.  More about tau strains soon.

Now let’s see if I can keep this up.