Monthly Archives: August 2020

All the world wants stages

Posted on by

[This expands on the idea of PSP stages from my last post, so you’ll want to read that one first.]

“Does PSP have stages?” is a question frequently posed by patients justifiably concerned about how far along they are in the degenerative course of the illness and what new symptoms might lie ahead. 

Many people have become familiar, however reluctantly, with the widely used TNM staging system for cancer, where T refers to the size and extent of the primary tumor, N the extent of spread to lymph nodes and M the presence or absence of metastasis to other organs.  Each is assigned a value and summed to generate a stage from I to IV.  For some types of cancer, a letter is appended to denote additional detail.  Complicated but useful. 

Parkinson’s disease takes a simpler approach.  The Hoehn-Yahr Scale, published in 1967, has five stages: 1)  symptoms only on one side of the body, 2) symptoms on both sides or in the face, voice or trunk but no balance problem, 3) balance problem that does not require assistance, 4) balance and/or gait problem requiring assistance, 5) confinement to bed or wheelchair most of the time.  Notice that only the laterality and gait/balance are considered here.  Still, the H-Y Scale is very useful and popular.  The paper by Hoehn and Yahr presenting their scale remains far the most widely-cited publication on Parkinson’s disease.  (A little Internet snark, if you’ll excuse me: My former chairman and mentor, Roger Duvoisin, actually did most of the work on the scale before reporting for duty as a medical officer in the Navy, headed for Vietnam, at which point his two senior colleagues wrote up the paper without him.)

PSP is a complicated disease, with dozens of symptoms that can be very roughly lumped into four main areas: parkinsonism (meaning stiffness, slowness and problems with speech and swallowing), loss of mental function (including both cognitive and behavioral issues), impaired eye movement, and balance problems.  In creating a staging system for PSP, one could follow the cancer model, assigning a rating to each disease feature, summing those, and then defining each stage as a specific range of that total.  Or, one could use the Parkinson’s model, relying on just one feature of the disease that’s easy to evaluate and important to the patient’s daily function.

Now let’s consider the purpose of a staging system.  Its main virtue is convenience.  Ideally, it shouldn’t require any imaging or lab tests and should be usable by any clinician.  If patients and caregivers can apply it, that would be a plus. 

A staging system, like any diagnostic test, should have both validity and reliability, and yes, there’s a difference.  There are multiple subtypes of validity that we need not discuss here.  But in general, validity is the degree to which an accurate answer to the question actually measures what it purports to measure.  For example, if I want to know how severe your PSP is and I only ask about your bladder function, the validity for assessing PSP overall would be low.  But if you know your bladder symptoms well and communicate that information to me accurately, the question would have high reliability.   The opposite sort of example is if I try to assess the severity of PSP by measuring the number of neurofibrillary tangles in the brain.  That would be a highly valid way to assess PSP, but the ability of the available imaging techniques or spinal fluid tests to actually do that is not good enough just yet, meaning that their reliability as a measure of PSP is inadequate.

The staging system that my colleagues and I provisionally devised for PSP and used in our prognostic study described in the August 9 post uses an approach similar to cancer’s TNM system.  It uses only information obtainable from the PSP Rating Scale scores.  It considers only swallowing and gait/balance, as those two issues are the most closely related to long-term complications from malnutrition, aspiration, falls and immobility. 

We assessed the validity of the staging system by showing that stage parallels the same patients’ total PSPRS scores almost exactly.  That’s called criterion validity.  But the proposed staging system still needs to be tested for multiple other kinds of validity as well as for reliability.

Just FYI, here’s how to calculate the stage using our proposed system:  First, rate the following four items from the PSP Rating Scale:

3.  Dysphagia for solids by history

0  Normal; no difficulty with full range of food textures

1  Tough foods must be cut up into small pieces

2  Requires soft solid diet

3  Requires pureed or liquid diet

4  Tube feeding required for some or all feeding

13.  Dysphagia for half a glass of water

0 None

1 Single sips, or fluid pools in mouth or pharynx, but no choking/coughing

2 Occasionally coughs to clear fluid; no frank aspiration

3 Frequently coughs to clear fluid; may aspirate slightly; may expectorate frequently rather than swallow secretions

4 Requires artificial measures (oral suctioning, tracheostomy or feeding gastrostomy) to avoid aspiration

26.  Gait without assistance if possible

0  Normal

1  Slightly wide-based or irregular or slight pulsion on turns

2  Must walk slowly or occasionally use walls or helper to avoid falling, especially on turns

3  Must use assistance all or almost all the time

4  Unable to walk, even with walker; may be able to transfer

28.  Sitting down without using hands

0  Normal

1  Slightly stiff or awkward

2  Easily positions self before chair, but descent into chair is uncontrolled

3  Has difficulty finding chair behind him/her and descent is uncontrolled

4  Unable to test because of severe postural instability

Then total the four scores.  Stage 1 is 1-4 points, Stage 2 is 5-8 points, Stage 3 is 9-12 points, Stage 4 is 13-15 and Stage 5 is the full 16.

Reasonably simple, but it takes training and experience to administer the items accurately and there’s a whole list of little rules and tips that I’ve published in my book but didn’t include here.  I’ll continue to test the validity of the system using a larger dataset and I may fool around with other schemes.  I’ll keep you posted.

Some prognostic help

Posted on by

Sooner or later, most patients with PSP or someone they rely on will ask the doctor, “What’s going to happen next, and when?”  Until now, that question has only been answerable by saying, “Well, the symptoms you have now will slowly get worse and you may develop some additional ones.” or “I don’t know; everyone’s different.”  If the question is, “How long will I survive?” the only available answer has been to quote the published averages for PSP, which have a wide variance. All too often, the answer is, “Don’t worry about that — just take it one day at a time.”

A long-gestating project of mine has finally seen the light of day.  It uses scores on my patients’ PSP Rating Scale (PSPRS) scores gathered from 1995 to 2016 to allow clinicians to predict how much longer it will take for a given patient to reach certain disability milestones and death.  It also proposes a new five-point clinical staging system that we used as some of the disease milestones.  It appears in the August 2020 issue of Movement Disorders Clinical Practice and is available here.

Assisting in the effort was my trusty statistician, Pam Ohman-Strickland, of the Rutgers School of Public Health.  She was also my co-author in the original validation of the PSPRS in 2007.  BTW, if you want to read that paper, here’s your chance. Since then I’ve refined the rules and instructions for administering the PSPRS and that’s available here.

Two undergrads helped out in the new project: Emily Beisser did most of the analysis for the new staging system and Francesca Elghoul helped with data wrangling.

The outcome milestones number 13 in total.  The first seven are severe difficulty with swallowing solids, swallowing liquids, speech, eye movement, general movement, balance and thinking. For each, “severe” is defined as exceeding a specific score on the relevant PSP Rating Scale item(s).  The next five are the stages on the proposed “PSP Staging System” and the last milestone is death.  

We created the five PSP stages by totaling four of the 28 items on the PSPRS: swallowing solids, swallowing liquids, gait, and the ability to return to one’s seat safely from a few steps away without using the hands.  They’re items 3, 13, 26 and 28 on the PSPRS.  The point total for those four items, each rated 0 to 4, are divided into five groups: 0 points, 1-4, 5-8, 9-12, 13-15 and the full 16.  Although this staging rubric uses only two of the many possible deficit areas in PSP, we found that the total of these those four items correlates very closely with the total PSP Rating score.  We chose swallowing and gait/balance as candidates because so many of the serious complications and disabilities of PSP lie in those areas. I’ll devote a future post to the issue of “stages” in PSP.

Tables 3 and 4 in the new paper show the meat of the matter.  You’ll see that the input data are gender, the total PSP Rating Scale score at the time of the visit, and the rate of progression to date.  The last one has to be calculated by dividing the current PSPRS score by the number of months since the onset of the first PSP symptom.

Just a quick caveat: Please don’t try this at home. Many of the exam items on the PSPRS require training and experience to administer correctly; the scale and its instructions are in technical language; and the dating of the onset of PSP symptoms may not be interpreted by the patient or family as an experienced neurologist would.

I hope that these new results, to quote myself from the paper’s introduction, “may influence decisions to retire from work, hire caregivers, alter the home environment, move to a seniors-oriented or institutional living arrangement, decide on a feeding gastrostomy and not least, prepare psychologically for advanced disability and death.”  Until we have a way to prevent or halt the progression of PSP, this will be an important part of how clinicians can help their patients.

PSP clinical trials in the time of Covid

Posted on by

Yesterday’s blog post was my first since the onset of the Covid-19 pandemic.  As you’d imagine, the lockdown has delayed PSP clinical trials.  It’s just too risky to patients, caregivers and staff for an older population to make visits to hospital centers for purposes of research on a chronic condition, even one as serious as PSP. 

The drug companies sponsoring these expensive trials want to wait for a major decline in Covid-19 risk in all of the geographically disparate study site locations. They also want to minimize the risk of another wave a few months later interrupting a study and making them start over.  

The clinical trial closest to launch was from the big Belgian company UCB.  It would test intravenous infusions of a monoclonal antibody directed against the tau protein.  You probably know that two such trials, from Biogen and AbbVie, gave negative results last year, with no efficacy but also no serious or frequent toxicity.  Those antibodies were directed at the “N terminal” of tau, meaning the end of the molecule encoded first during the cell’s manufacturing process.  UCB’s antibody, on the other hand, is directed at the “microtubule binding domain,” which is about two-thirds of the way toward the other end.  So it’s worth testing.  That trial will be delayed to April 2021, per UCB’s present plan.

At least a few months behind UCB’s trial is one from a small Swiss company called Asceneuron (pronounced “uh-SEH-nu-ron”).  I’ve discussed it in a previous post. This oral drug inhibits the detachment of a certain type of sugar molecule from tau, reducing its likelihood of misfolding and aggregating.  I haven’t heard when that trial might be starting and I’m sure that the company is playing it by ear. 

A third trial will test an “anti-sense oligonucleotide,” a strand of RNA injected directly into the spinal fluid in the lumbar spine. It circulates around the brain to reduce the production of tau.  A number of companies have ASO programs for tauopathies. There is also early work on ASO molecules small enough to be dosable by mouth, but those are much further from clinical trials.

A company called Retrotope received FDA permission in April 2020 to start testing an oral drug, RT001, to reduce the level of a toxic process in the brain cells called lipid peroxidation. They are testing this approach not only in PSP, but also in multiple other brain disorders where that defect seems to play a role. No word on a start date.

Another approach is an oral drug from the company called Alzprotect that increases production of a protein called progranulin, a neurotrophic factor (i.e., a normally occurring chemical that encourages the growth or repair of brain cells). The drug is AZP2006 and is in a small trial solely to assess safety in 36 patients in France.

Further from a large-scale trial is a non-steroidal anti-inflammatory drug called tolfenamic acid, which is available by prescription in the UK for migraine. Unlike other NSAIDs, it reduces the production of tau and its abnormal phosphorylation. The drug is in an early-phase clinical trial for PSP at the Cleveland Clinic in Las Vegas.

I’ll keep you updated as required.

Hope matters.

Of spice and dog breeds

Posted on by

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.