A welcome word from Australia

Here’s some nice news.  The Phase 2, double-blind trial of sodium selenate that I mentioned in my December 19 post as pending has just started recruiting patients.  That orally-administered drug may slow the progression of PSP and other tauopathies.  Unfortunately, at this point, it’s taking place only at six sites in Australia.

The trial is described in an article from late 2021 in the open-access journal BMJ Open. The first author is Lucy Vivash, a research fellow at Monash University in Melbourne.  Terence J. O’Brien, MD, the neurology chief at that prestigious institution, is the senior (i.e., last-named) author.  Australia does not require its trials to be listed in www.clinicaltrials.gov, and it isn’t.  But it is listed in an equivalent database for Australia and New Zealand trials.

The mechanism of action of sodium selenate against PSP is to activate an enzyme called protein phosphatase 2.  Like any phosphatase, it removes phosphate groups from the proteins to which they have become attached.  Our bodies normally use phosphates as a way to regulate the activity of enzymes, but under some disease conditions, phosphates are attached to excess or in the wrong spots.  In PSP, there is excellent evidence that inappropriate phosphorylation of tau encourages it to fold into a toxic form.  In the words of the researchers:

“Protein phosphatase 2 (PP2A) is the major tau phosphatase in the brain accounting for more than 70% of brain phosphatase activity, and thus stimulation of its activity presents a compelling strategy for reducing hyperphosphorylated tau. PP2A is colocalised [in the same locations within the same brain cells] with tau, and in many neurodegenerative diseases, reduced PP2A activity is observed alongside reductions in tau dephosphorylation.”

The year-long trial will include 70 patients with PSP-Richardson syndrome, half of whom will receive placebo.  This trial is unusual in that the primary outcome measure will not be a clinical evaluation of patients’ neurological performance and subject reports of symptoms such as the PSP Rating Scale (PSPRS).  Rather, the primary outcome will be a slowing of the rate of brain atrophy as measured by before-and-after MRI scans.  This has been shown to correlate better with the passage of time than the PSPRS or any other clinical measure of PSP progression.  However, it’s not clear if it actually correlates as well with daily functioning.  True, traditional measures are included as secondary outcome measures, but no drug developer wants to rest their case for drug approval on a secondary measure when the designated primary measure failed to show benefit.  

I suspect, but don’t know, that the MRI measure was chosen as the primary outcome measure because its greater sensitivity to change over time permitted enrolling only 70 patients (to be able to detect a 50% reduction in progression rate), as opposed to the 102 patients required by the next-most-sensitive measure, the PSPRS. Each additional patient increases the cost of the trial, and this one is financed by a grant from the Australian government rather than by any drug company. So financial constraints may have been more of an issue than usual in the study design.

So, let’s wish Dr. Vivash and her colleagues and patients every success in this trial and let’s hope that the pandemic allows it to proceed smoothly.

A welcome word from Scotland

I just learned that since 2014 there’s been a medical publication called Journal of Patient Experience.  It’s on-line and open-access.  They’ve just published an article entitled “Progressive Supranuclear Palsy: The Other Side of the Fence” by Beatrice Sofaer-Bennett PhD, an accomplished academic nurse with a faculty position at the University of Edinburgh.  Most of her work has concerned the care of people with chronic pain. 

Now, as you’ve surmised, Professor Sofaer-Bennett has been diagnosed with PSP and has described her own thoughts and feelings in a way that’s moving without being maudlin and informative without being technical.  Her experience of receiving multiple other diagnoses before PSP will be familiar to most patients and their families.  She makes a welcome and eloquent plea for better education of physicians about the disease.  Perhaps her most helpful points describe how she handles the issue of her prognosis.

The article includes a couple of minor mis-statements of neurological fact, so don’t use this as a reference source.  Also, I must tell you that her sudden sweating episodes and constant shortness of breath are very unusual in PSP.  They are more common in people with MSA, which can be difficult to distinguish from PSP diagnostically.  I mention these points only to avoid having anyone with PSP think that they can expect these things to happen to them, or if they do occur, to neglect having those symptoms specifically evaluated, thinking they’re just “normal” for PSP.  Both can be symptoms of non-neurological, highly treatable conditions. But I haven’t evaluated her myself, so I’ll not criticize her neurologist’s diagnosis from afar. 

So, Professor Sofaer-Bennett, thank you for sharing your thoughts and suggestions.  Those of us working to improve the quality and accessibility of care for people with PSP appreciate your help and wish you the best in your journey.

Proteomics hits paydirt

If you know anything about PSP at its molecular level, you know that the tau protein in the neurofibrillary tangles is almost entirely of the “4-repeat” or 4R variety.  The other kind is “3-repeat” or 3R.  Normal adult human brain has equal amounts of 3R and 4R.  So do the tangles of Alzheimer’s disease.  But the tangles of Pick’s disease are 3R. 

The thing that’s repeating is the section of the protein that binds it to microtubules, the brain cells’ internal skeleton and monorail system for transporting chemicals along axons.  The gene encoding tau, called the “microtubule-associated protein tau” (MAPT) gene, has four sections, called exons, each encoding one microtubule-binding repeat.  MAPT has 16 exons and the four in question are exons 9, 10, 11 and 12.  4R tau includes the repeat encoded by exon 10 and 3R tau doesn’t.

There’s pretty good evidence that in PSP, the extreme imbalance of 3R and 4R tau is a major factor in making the tau toxic to brain cells.  But why can’t the brain cells in someone with PSP make enough 3R tau?  In other words, what prevents the brain cells in PSP from excluding the repeat from exon 10 half of the time, as normal brain cells do?

In the latest issue of the journal RNA Biology, a group mostly from McMaster University in Hamilton, Ontario, Canada report at least part of the answer.  They have found that the protein called “heterogeneous nuclear ribonuclear protein C” (hnRNPC) prevents the normal process from happening by binding to messenger RNA.  hsRNPC has been known for years in relation to certain types of cancer, but its role in the brain or in neurodegenerative disease was not previously well studied.  To accomplish this work, the team developed a new technique called “RNA antisense purification by mass spectroscopy” (RAP-MS).  They also found, critically, that in PSP brain, the level of hnRNPC is abnormally elevated, an important confirmatory observation.  (Why is it elevated?  I can’t wait for the next installment in this story!)

The authors point out that hnRNPC can now be considered a target for drugs to slow or halt the progression of PSP.  Pharmaceutical companies, take note.

The senior author of the study and lab head at McMaster was Yu Lu, PhD, a specialist in proteomics.  His grad student Sansi Xing was first author.  The team included others from McMaster, the University of Iowa in Iowa City and Mount Sinai in New York. 

Faulty brakes

After reading my last post, you may be wondering if it’s just a coincidence that lesions in the cerebellum mimic many of the disinhibited behavioral features of PSP.  It’s no coincidence, and here’s why.

The motor role of the cerebellum in effect acts as a “brake” on the actions of the cerebral motor cortex and basal ganglia.  The “ataxic” gait of cerebellar disease is characterized by unchecked lateral movement of the center of gravity.  Once the proprioceptive (joint position sense) and visual functions perceive that one is reeling to one side, a voluntary check and corrective action occur.  But that correction, similarly, goes too far, producing a reeling in the other direction.  This is the familiar gait of the drunk, as alcohol is an acute cerebellar toxin. 

The same goes for other cerebellar motor deficits.  The uncoordinated hand movements consist of overshooting a goal followed by a correction that itself overshoots, and the process repeats, producing a kind of tremor or wavering.  The speech, besides its slurring, is degraded by an unintended, rapid grouping of syllables followed by a long pause. Try it — if you want to mimic drunkenness.  The eyes exhibit a slow, involuntary movement of a few degrees to one side followed by a rapid correction.  This is called “nystagmus” and can produce a constant jittering of the visual scene that may be described by the patient as “double vision.”

The behavioral aspects of cerebellar dysfunction are analogous.  Just as they cause a loss of inhibition of an ongoing motor action, so do they cause a loss of inhibition on behavior, with inappropriate or repetitive comments, compulsive thoughts and incontinent laughter or crying.

So, yes, it makes sense.

In through the back door?

One of my retirement activities is giving an occasional lecture to the neurology residents in my old department at Rutgers Robert Wood Johnson Medical School.  In March, my topic will be the anatomy of the cerebellum.  I’ve never lectured specifically on that before, so I’ve been updating my knowledge and preparing slides.  That led me to something very interesting. 

It turns out that one or more discrete lesions, typically small strokes, of the posterior half of the cerebellum (hence the anatomical connection) can produce behavioral and cognitive abnormalities.  Mind you, the cerebellum has classically been considered only a center of motor control.  But in 1997, Dr. Jeremy Schmahmann, a neurologist at Harvard, and his psychologist colleague Dr. Janet Sherman described what they called the “cerebellar cognitive affective syndrome.” 

This is a mouthful, and “Schmahmann-Sherman syndrome” would have been shorter but more of a tongue-twister.  So the world, as usual, decided to recognize the contribution of the man over that of the woman, and the condition is usually called “Schmahmann’s syndrome.”  In protest, I’ll call it CCAS. 

From: Stoodley CJ, MacMore JP, Makris N, Sherman JC, Schmahmann JD. Location of lesion determines motor vs. cognitive consequences in patients with cerebellar stroke. NeuroImage Clin. 2016;12:765–75.
The Roman numerals are areas of the cerebellum. X, y and z are the three axes of space and the numerical values are the distance of the image plane from a standard reference plane for that axis. Each color is arbitrarily chosen and represents one patient’s stroke(s).

It’s not clear why CCAS arises from disruption of only the back half of the cerebellum, as both halves have pretty much the same kind of circuitry, as far as we know.  The features of CCAS include loss of:

  • executive functions (difficulty with shifting tasks or multitasking, problem solving, planning, organizing, and sequencing)
  • some aspects of affect (disinhibition of speech or behavior, making inappropriate jokes, behaving childishly, inability to suppress laughter or crying, being obsessive or compulsive) 
  • some language functions (loss of fluency of speech, grammatical rule-breaking)
  • some visuospatial skills (inability to copy or understand pictures or to distinguish two objects presented at the same time)

Ring a bell (especially the first two)?  Sound something like PSP? 

We’ve known since its original 1964 description of PSP by Steele, Richardson and Olszewski that the cerebellum, specifically in an important part called the dentate nucleus (because its layers are in a saw-tooth pattern), is a site of tau deposits and cell damage.  But the balance problems and dizziness produced by dentate damage may be swamped by the symptoms from the degeneration in the cerebrum, specifically the basal ganglia.  So, the symptoms of PSP have never been considered to arise importantly from the cerebellum damage.

But now, thanks to Drs. Schmahmann and Sherman, we know that cerebellar problems can cause cognitive and behavioral problems, and that they look like those of PSP.  True, the well-known loss of function in the frontal lobes can explain those symptoms as well.  But here’s the rub:  Cerebellar symptoms in PSP might be amenable to treatment by transcranial magnetic stimulation (TMS).

TMS involves the painless, nearly harmless (as far as we know) application of magnetic fields to the scalp.  It’s an emerging field for a wide variety of neurological problems and has been FDA-approved for depression and migraine.  The European Union has approved it for several other conditions as well, including Alzheimer’s, Parkinson’s, autism, bipolar disorder, epilepsy, chronic pain and PTSD. Adverse effects are very rare, with the most common being fainting.  Some others are seizures, pain, confusion, hearing loss and hyperactivity.  Caution must be exercised in the presence of pacemakers or other implanted or worn devices.  The procedure is typically repeated once or twice a month for six to 12 months.  Unfortunately, Medicare and commercial insurance do not yet cover it, and the cost is several thousand dollars for a course.

In PSP, seven studies of TMS have been published, involving a total of only 47 patients.  Two of the seven were single cases reports.  Three of the seven, involving 32 patients, stimulated over the cerebellum. They all reported modest improvement in motor symptoms, and two studied reported speech improvements.  None found side effects, at least over short-term follow-up.  Unfortunately, none of the three studies evaluated cognition or behavior in detail.

A closely related technique is transcranial direct current stimulation. Its advantage over magnetic stimulation is that it can reach more deeply into the brain, but with more side effects. It has not been studied as well in PSP as TMS. My November 8, 2021 post was about one such study. I’ll return to TDCS in another post.

So we have work to do.  The frequency of the magnetic impulses, their strength, temporal pattern and precise location could make big differences in the outcome, so this will not be simple.  But if careful study shows that the benefit amounts to even a modest improvement in quality of life for those with PSP, and if Medicare eventually decides to pay for it, let’s get busy.

My idea of art

Here’s something I’ve been working on sporadically for months. It’s a diagram providing a quick-and-easy guide to the major neurodegenerative diseases from the standpoint of PSP and CBD. It’s designed to show laypersons that while PSP and CBD are rare, they can provide researchers important insights into the more frequent diseases. It’s kind of like how an advertisement for a retail business shows how centrally located it is through careful centering of the map.

The diagram should be self-explanatory, though most people will have to hit Wikipedia to know what many of these diseases are. At the lower left is a key showing which colors are diseases and which are commonalities and differences (with respect to PSP/CBD).

Don’t interpret the relative positions of the diseases to mean that one disease is a variant or subtype of the other. The lines only indicate similarity, not necessarily classification. The area where classification is justified, but only incidentally, is that “frontotemporal disorders” is an umbrella term for all of the diseases to which that label is connected, including PSP and CBD.

Also, please be aware that the “Genetic” label means “single-gene causation.” Many of these disorders have a more subtle contributions to their causation from multiple variant genes in the same individual, each variant gene providing a slight degree of risk.