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.

PSP treatment trials recruiting now or soon

As promised, I will now start trying to keep you updated on actively recruiting clinical trials in PSP.  Keep in mind a few things before using my list:  

  • In compiling my list, I rely heavily on www.clinicaltrials.gov.  Trials in the US are required to list themselves there, but some take longer than others to comply.  Trials overseas may or not be required to have a listing on clinicaltrials.gov, depending on the country.  My list also includes trials I’ve heard about through the grapevine that are not (yet) listed.
  • In Phase 1 and sometimes in Phase 2, the trials do not typically allow patients completing the protocol to continue receiving the drug, no matter how well they were doing on it.  Later Phase 2 and Phase 3 trials often do allow this, but they do not commit to it in advance.  Typically, if the trial shows the drug to be ineffective (or unsafe) overall, the drug company will discontinue its program for that drug and stop producing it.  That means that even the few patients who might have been doing well on it will not continue to have access to it.
  • In theory, exceptions to that rule could exist for drugs that are being tested in both PSP and another disease such as Alzheimer’s.  If the PSP trial shows lack of efficacy but acceptable safety, the company will continue to manufacture the drug pending the outcome of the other trial and may make it available to those who completed the PSP trial.
  • For trials of neuroprotective treatment, patients may not know if they are benefitting.  (Definitions: “Neuroprotective” drugs are intended to slow the progression of the abnormal brain process in the long term, as opposed to helping the symptoms experienced by the patient in the short term.  For example, for infections, antibiotics are protective, while painkillers are symptomatic.)  To know if an individual in a neuroprotective trial has had slowing of their rate of worsening over the 12 months on the drug, their rate of worsening over at least a few months before the trial would have to have been quantitatively assessed using the same method that the trial used.  We almost never have that data, so trials work by comparing the average result from a group receiving the drug to the average from a group receiving a placebo.
  • Do not expect a neuroprotective drug to improve your symptoms.  At best, it could prevent worsening, and more likely would only slow the rate of worsening.  The trials are typically designed to detect a slowing of the rate of worsening of 30% or 40%. 
  • Bottom line: Participating in a clinical trial, especially one in Phase 1 or 2, requires some level of altruism.
  • For more information on these trials, go to www.clinicaltrials.gov and enter the drug’s name or ID number shown in the first column.

Here’s the current list to the best of my knowledge.  The ones at the bottom labeled as “may start” are awaiting funding in most cases.

Drug /
clinicaltrials.gov ID
SponsorPhaseMechanismLocation(s)Comments
TPN-101

NCT04993768
Transposon2aReduces tau productionBoca Raton, FL Farmington Hills, MI30 patients on drug, 10 on placebo
RT001 (di-deuterated linoleic acid ester)

NCT04937530
Retrotope2aReduces lipid peroxidation, enhancing mitochondrial activityUniversity of Munich (Germany)Non-controlled study showed very slow PSP progression over 2 years.
NIO-752

NCT04539041
Novartis1Anti-sense oligonucleotide; reduces tau productionRochester, MN; Nashville, TN; Montreal; 3 in Germany; 1 in UKRequires 4 injections into spinal space over 3 months.
AZP2006

NCT04008355
AlzProtect1Reduces tau production3 sites in France~24 patients on drug, ~12 on placebo
May start recruiting in the next year:
ASN120290Asceneuron1Reduces tau misfolding and aggregation by inhibiting O-GlcNAcase?Press release info only
MP201Mitochon1Mitochondrial decoupler?Early in planning per press release
Tolfenamic acidNeuroTau2NSAID that reduces tau productionCleveland Clinic, Las Vegas + others? 
Sodium selenateGov’t of Australia2Enhances dephosphoryl-ation of tau by protein phosphatase 2Multiple, in Australia 

It’s about time

I’ve been writing about PSP for patients and families for 30 years, and I realized long ago that what people most want to hear about isn’t my scientific musings about a new diagnostic technique or etiologic theory. They want to know about treatment, especially about clinical trials they might join.


For most of those three decades, there was little to report on that front. But in the past five to eight years, that has changed. Fortunately, clinicaltrials.gov has stepped into the breach starting with the FDA’s 2007 requirement that pharmaceutical companies list their trials on that public bulletin board.


But clinicaltrials.gov has its drawbacks for patients and families seeking a treatment trial. Searching its database on “progressive supranuclear palsy” returns a long list of projects that are mostly either observational, geographically unrealistic, fully recruited, terminated, listed but nowhere near initiation of recruitment, or on hold because of the pandemic. Yes, careful scrutiny can eliminate those, but that takes some insight into clinical research that most people lack.

I haven’t been a complete slacker on this matter. I wrote a 2018 book entitled, A Clinician’s Guide to Progressive Supranuclear Palsy, but that was frozen in time. I led the July 2021 writing, with 36 expert co-authors, of a consensus statement entitled, Best practices in the clinical management of progressive supranuclear palsy and corticobasal syndrome: a consensus statement of the CurePSP Centers of Care. It focused on available, non-specific, symptomatic management, with only vague predictions about what actual disease-specific, neuro-protective or preventive treatments might be on the horizon.


That’s why this blog will henceforth try to keep you all current on clinical trials in PSP and CBD. I’ll do this in concert with CurePSP, which will soon add such a page to its website, which the CurePSP staff and I will update as needed. I’ll get back to you on this soon.

A cluster mystery

Since 2014, I’ve been trying to find the cause of a geographical cluster of PSP in northern France.  It’s the only documented PSP cluster known.  The problem was difficult enough, but now the cluster has mysteriously disappeared.

The clinical aspects of the cluster are detailed in this 2015 paper.  Here’s the executive summary: In 2005, Dominique Caparros-Lefebvre, MD, a geriatric neurologist with experience in PSP research, arrived at her new practice position in Wattrelos, France, an industrial suburb of Lille.  By 2007, she started to notice more PSP than expected and developed an excellent database.  She diagnosed 100 patients over the next decade.  In 2013, she invited me to help her find the cause, as I had had some experience in the epidemiology of PSP.  I calculated the observed-to-expected incidence ratio of PSP to be 12.3 in Wattrelos and its neighbor to the south, Leers.  Most clusters of chronic diseases such as cancer have ratios much lower, in the range of 1.5 or 2.0.  So this was a major cluster.

PSP in the 100 patients has differed only slightly from “sporadic PSP,” with more PSP-Parkinsonism than PSP-Richardson syndrome, and an older mean onset age, 74.3.  The 13 autopsied cases show typical PSP, with the expected 4R tau and the H1/H1 genetic haplotype.  That work was done by a very accomplished research team at the University of Lille led by Luc Bueé, PhD and Vincent Deramecourt, MD, PhD.  No other molecular genetic workup has been performed to date, but none of the affected persons were related to one another and among the patients are 7 Algerian immigrants, a strong point against a genetic origin.  

Wattrelos and Leers have extensive chemical contamination, especially by metals from an ore extraction plant that operated in southern Wattrelos for most of the 20th century.  Huge piles of spent chromate and phosphate ore, now covered, remain on the plant’s property, which has been converted into to a public park after mitigation efforts between 2000 and 2010.   Only 2 of the 100 patients worked in the chromate/phosphate ore plant, but soil from the area adjacent to the slag heaps has been used as fill in construction and road maintenance over a wide area.  Furthermore, multiple chemical-related industries such as tanning and dyeing formed the base of the town’s economy for many decades.

So, the obvious culprit has been metals.  Chromium is a carcinogen but not a good candidate as a direct neurotoxin, as its most common form, hexavalent chromium, does not cross the blood brain barrier.  Nor is phosphorus a good candidate, but phosphate ore often contains important levels of other metals. 

In France, growing one’s own herbs and vegetables is a common practice, even in densely urban areas.  Dr. Caparros suspected thyme, a widely used herb in French cooking that avidly absorbs metals from the soil.  The French government’s soil data and our analysis (by my Rutgers colleague Brian Buckley, PhD) of home-grown thyme samples from Wattrelos suggested that arsenic, cadmium and nickel were the most likely possibilities.

In 2016, I recruited a team of neuroscientists led by Aimee Kao, PhD of UCSF, with skills in stem cell models of PSP and access to stem cells with PSP-related tau gene mutations.  As an initial project, they created brain cells with a rare PSP risk mutation (to create a “background” vulnerability) and exposed them to chromium, cadmium and nickel.  They did the same experiment with cells from the same PSP patient except that the PSP risk mutation was converted to normal using CRISPR.  They found that some of the same damage seen in PSP — aggregation of tau and evidence of apoptotic (i.e., programmed cell death) in the exposed cells with the mutation.  But those abnormalities are not specific for PSP.  We published that in 2020 and unfortunately, I couldn’t keep that team together for follow-on projects.  Equally unfortunately, the local French human research authority would not allow Dr. Caparros to perform further field work that might have pointed to a specific metal and route of exposure.

So why aren’t clusters of PSP seen in the many other places in the world where those metals contaminate the environment?  My own pet theory was that toxicity from multiple metals acting in concert is needed, and no place other than Wattrelos/Leers has a combination of so many metals in one spot together with a physician able to diagnose PSP as well as Dr. Caparros.  So, one of the follow-on projects might be to repeat the lab experiments with combinations of the same and other metals that are known to occur in the environment, either in Wattrelos/Leers or elsewhere, either as a result of industrial pollution or naturally occurring.

As I was starting to make plans for such a project with lab colleagues at Rutgers, it became clear that the number of patients whose onset occurred since 2013 has been declining.  The most recent onset date of the 100 patients is 2016.  This is not how a cluster of toxic (or genetic) cause should act.  It’s possible that the mitigation efforts on the two slag heaps reduced the rate of entry of chromium and phosphate into the local environment, but the metals were pervasive in the area and presumably remain so.

—-

Graph showing the disappearance of cases with onset since 2016. Bars show the number of cases with onset in each year. Dotted lines show the average over the previous 5 years. “Total Cases” refers to all cases in Wattrelos and Leers as well as in nearby towns where patients were likely to use the Wattrelos hospital. The paucity of cases with onset before 2002 is explained by the arrival of Dr. Caparros in Wattrelos in 2005. Before that, no physician likely to have been able to diagnose PSP worked there and few patients with onset before 2002 would have survived to come to Dr. Caparros’ attention. Still, we cannot rule out the possibility that the cluster in fact started in the 1990s and its disappearance by 2017 is consistent with this possibility.

—-

The unexplained abatement of a geographical or temporal disease cluster speaks for an infectious cause.  The salient example of an infection causing a temporal cluster of a neurodegenerative tauopathy is postencephalitic parkinsonism (PEP).  That cluster started 2 years before and ended a decade after the great “Spanish” flu pandemic of 1918-1920 and is independent from it.  PEP was a chronic, levodopa-responsive parkinsonism that affected people of any age who recovered from an encephalitis that was presumably viral, but the specific virus has not been identified.  At autopsy, the brain showed neurofibrillary tangles not very different from those of PSP.  The last patients with PEP died before modern molecular techniques were available, so its cause may never be known.

Could the cause of the Wattrelos/Leers cluster have been a virus?  True, there seemed to have been no antecedent encephalitis, but it may have been mild, self-diagnosed as a cold or the flu, and forgotten by the time Dr. Caparros saw the patient decades later.  But there need not have been any clear acute-phase symptoms at all.  The virus could have set up a slow process of damage involving tau aggregation, starting with inserting its own genetic material into that of the host.  Or the initial infection could have altered the patient’s immune system in a way that encouraged (or allowed) the pathology of PSP to develop.  Let’s not forget that disordered immune modulation is one of the up-and-coming theories of PSP-causative factors.

If a virus contributed importantly to the cluster, could ordinary, “sporadic” PSP outside of the cluster be the result of a similar virus?  Or maybe sporadic PSP is caused by the same virus without the predisposing local factor of the unusual metals exposure.  Or maybe a virus infected the gut microbiome of the Wattrelos population in a way that increased PSP risk.  I could go on.

We know that at least one neurodegenerative condition, sporadic Creutzfeldt-Jakob disease, is caused by an infectious agent (in this case the prion protein) without geographical or temporal clustering.  The idea of a virus or prion as a cause of PSP is not new, and previous attempts to prove that hypothesis starting in the 1970s have been negative.  But the technology for finding viral fingerprints has improved markedly since then.

I’ll try to get some of the research honchos I know interested in this theory and get back to you.

A warning

Here’s something that may seem too good to be true, and in my opinion, it is.  I’m writing about it as a cautionary measure.

Researchers at Guangzhou University, China have published a case report of a man with advanced PSP who received intravenous and intrathecal (into the spinal fluid) infusions of stem cells derived from umbilical cord blood.  His symptoms had started unusually young, at age 53, and 8 years later, his PSP Rating Scale score was 73 – a typical score for that duration of disease.  He received the infusions at that point and has survived another 8 years to date with essentially the same PSPRS score. 

Although the patient is (apparently, but not explicitly) still alive and there has been no autopsy to prove the accuracy of the diagnosis, the clinical history, neuro exam and published MRI images are typical for PSP.  The subtype is probably PSP-Parkinson, as his falls didn’t start until 3 years in and he didn’t need gait aids until 2 years after that.  The authors state that the subtype was PSP-Richardson syndrome because the patient met those criteria at the time they first saw him, 8 years in.  But PSP-P usually evolves into PSP-RS in the advanced stages.  The life expectancy of PSP-P with typical onset age in the 60s is about 10 years, and for those with onset as young as age 53, would be a few years more.  So survival (to this point) of 16 years is not far from expected.

But that’s not the main problem. The main problem is that the PSP Rating Scale has a “ceiling effect.”  That is, patients progress at an average rate of 10 or 11 points per year, and once the score reaches the 70s, it stops progressing although the patients continue to survive and to worsen.  That’s because the worst possible score on many of the scale’s 28 items doesn’t capture the full level of dysfunction that can yet occur.  Another reason for the ceiling effect is that some of the 28 items don’t affect some patients severely or at all, even late in the disease course.  Examples are dystonia, tremor, irritability, emotional incontinence, horizontal eye movement loss, and limb apraxia.  So the patient of Dr. Li et al may simply have reached his PSPRS ceiling and continued to survive by virtue of the unusually good general care that study subjects typically receive.

There are some other issues:

  • There’s no objective evidence that the infused cells survived. 
  • There’s no measure of any sort of growth factor in the blood or CSF that might provide a mechanism of action of stem cells in halting an otherwise rapidly progressive disease in its tracks. 
  • There’s no functional measure of brain metabolism such as fluorodeoxyglucose PET or magnetic resonance spectroscopy to objectively document a halting/slowing of progression.
  • The 2 MRI were performed at the time of the infusions and 2 years later.  Although the authors claim “no deterioration” in the MRI over that time, the 2 sets of images do show progression of atrophy, both to my eye and by the formal measurements superimposed on the images.  The midbrain’s diameter on the before-and-after sagittal images (Fig. 1, images A-1 and B-1) declined from 11.84 mm to 10.64 mm and the pons from 21.07 mm to 19.37 mm.  Both are typical for PSP.  The before-and-after axial images (images A-2, A-3, B-2 and B-3), where the measurements seem to indicate some improvement in the atrophy, are performed different scanning planes.  That can seriously affect the simple measurements performed. In fact, comparing the 2 sagittal images shows that the patient’s head is at 2 very different tilt angles in the scanner.  That problem affects the measurements in the axial plane but not in the sagittal plane.

As Dr. Li and colleagues point out, “randomized controlled trials are needed in the future . . . “ I would advise people with PSP not to undergo this, or any, experimental procedure outside of a formal trial at a reputable academic institution.  If you’re considering it, make sure the study is listed in clinicaltrials.gov, although that by itself no guarantee of anything.  Make sure that the researchers have a track record of peer-reviewed publication in this area.  If the doctors doing the treatment are willing to use it for a wide variety of unrelated disorders, be suspicious.  If the claims omit mention of side effects or toxicity, be doubly suspicious. If there’s no mention of success in any sort of animal model, that could be a problem.  Finally, if a “research study” charges a hefty fee, stay away. (We have no evidence that this was the case for Li et al.)

We should encourage fresh ideas for the treatment of PSP and other neurodegenerative diseases.  We should not be biased against research from countries with still-developing research infrastructure and institutional safeguards.  But we should also know how to evaluate the quality of research reports and to be vigilant for signs of quackery.