Monthly Archives: April 2024

Vindaloo + hockey = PSP?

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Did you know that Toronto is the most ethnically diverse city in the world?  Besides, it’s a pretty big place, with about 6 million people in its metropolitan area.  Besides that, Toronto is home to one of the top PSP research institutions in the world, the Rossy Centre at the University of Toronto, and Canada has universal, free medical insurance, which removes financial impediments to diagnosis and treatment.  That’s why Toronto is a great place to answer the question as to whether the prevalence of PSP is uniform across groups of different ethnic backgrounds.

Dr. Blas Couto and colleagues have done just that, reporting their results in the current issue of Parkinsonism and Related Disorders.  They tabulated ethnicity for 135 patients with PSP living in the officially designated Toronto area and seen at their center as patients from 2019 to 2023.  The group proved unusual in that only 4.4% had the PSP-Parkinsonism variant, compared with figures elsewhere of around 25% to 40%.  The group with PSP-Richardson syndrome comprised 68% rather than the usual 45% to 55% and the other variants gave the expected percentages.

The ethnicities they considered were actually geographical areas, not exactly race, whatever that is. (“Race” has no scientific definition, anyway.)  The categories were — and this is directly copied/pasted from the paper:

  • East and southeast Asia, including China and Pacific Islands such as Philippines
  • Southern Asia, including India, Pakistan and middle east countries
  • Africa
  • South America, Central America and Mexico
  • West Indies, including Guyana, Haiti, Bahamas, Lesser Antilles such as Barbados, Trinidad and Tobago, Dominica, Grenada, Saint Kitts, Antigua and Barbuda, Santa Lucia
  • Europe, Australia and North America, excluding Mexico.

The analysis compared the frequencies of these demographics to those from the census for people aged 65 and older living in the Toronto metro area. 

The result was that the southern Asia group was moderately over-represented among the patients with PSP.  That group accounted for 11.5% of the general population but 25.2% of the PSP population at the researchers’ center.  That was statistically significant at the <.001 level, meaning that the chance of its being a false-positive fluke are less than 1 in 1,000.

They also compared the six groups to one another with regard to the PSP subtypes, finding the same southern Asia group to include more PSP-progressive gait freezing (17.7%) and PSP-corticobasal syndrome (14.7%) than the European-derived patients (6.4% and 9.5%, respectively). 

Couto et al mention the possibility of some sort of genetic effect, but the literature offers no clues as to what that might be, and they cite three previous papers from the UK showing no difference in PSP prevalence between whites and southern Indians there.  Could something in the food or water in Toronto affect Asians disportionately?  The title of this post offers an unserious possibility, but you get the idea.

Chin-stroking on that aside, now is when the rest of us try to poke holes in the findings.  Here are my efforts:

  • Do the ethnic percentages in their PSP practice or in medical institution as a whole accurately reflect those of the Toronto area?  That would be easy to measure.  I ask because in the US in recent years, the medical profession has acquired a disproportionate representation of people of southern Asian background.  Could that group therefore trust academic physicians more and seek their care more readily than do other ethnic groups? 
  • The patient mix of a highly specialized practice like that at the Rossy PSP Centre is subject to the referral habits of outside neurologists.  Neurologists who feel less comfortable with the atypical Parkinsonisms may be more likely to refer patients.  Perhaps that applies to a few neurologists practicing in heavily southern Asian neighborhoods in the Toronto area.
  • Despite the universal availability of free medical care in Canada, racially-based disparities in health and care access do exist there.  Couto et all cite this article. 
  • This is a univariate comparison, meaning that it didn’t correct for a hypothetical effect of other health issues that might be more common in the southern Asian population.  Not that I know what those might be.
  • Although the analysis age-matched the PSP group with the general population by confining itself to the over-65 group, that may not have been enough. Perhaps working-age people immigrating from southern Asia brought elderly parents with them more often than did those immigrating from elsewhere, thereby skewing the over-65 group towards the 80s and 90s and increasing the measured prevalence of an age-related disease like PSP.

An intriguing finding.  Hopefully this paper will stimulate others to dig deeper. That would be a victory for any scientific paper.

Mistaken identity

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I have some homework for you all: Make sure that the diagnosis of PSP has been accurately coded in the doctor’s records. 

Two researchers in Scotland, Diane Swallow and Carl Counsell, published a paper this week reporting that every single patient carrying the code for PSP (G23.1) did in fact have PSP on evaluation of their detailed records.  However, only 52% of the patients whose records showed clear PSP had that code recorded in their records.  In 45% of individuals with PSP, an incorrect code of G12.2 was recorded.  That’s the code for a condition called “progressive bulbar palsy,” which is a form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) that affects the muscles of the face, mouth and throat disproportionately.  (The “bulb” is another term for the medulla, the part of the brain from which most of the nerves to those structures arise. It does look sort of like a light bulb or tulip bulb.) PGP is much more rare than PSP and does not include most of its features, but the reason for the confusion is obvious.

Why is this important? Because accurate statistics on PSP’s prevalence are used by for scientific researchers, medical care planners, government regulatory agencies, insurance companies, pharmaceutical companies, granting agencies, and philanthropists. 

So, next chance you have, ask the neurologist’s office clerk if the diagnosis of PSP rather than progressive bulbar palsy is listed in the medical record’s formal problem list and if the code assigned to it is in fact G23.1.  If it’s not, and if the clerk tells you that they don’t have the access necessary to fix it, make sure that they pass the information along to whoever does have that access, and then it’s your job follow up to make sure it’s been taken care of.

Under the hood

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In response to a reader’s request, here’s a brief description of the mechanism of action of Relyvrio, which is a combination of two drugs, sodium phenylbutyrate and taurursodiol.  The text in bold italics below is copied verbatim from the supplementary material attached to the publication reporting the results of the first ALS trial.  The same explanation applies to PSP and other neurodegenerative diseases. You may feel that any treatment that claims to address all of those complex diseases is claiming too much, and you could be right. But stranger things have happened. If you want more scientific detail, see the five references below. Note that Reference 5 discusses release of cytochrome C from mitochondria. That’s a cell signalling compound that causes cells to start up their “suicide machine,” more formally called the apoptotic pathway. Cells undergo apoptosis when they’re not working well or as a normal “pruning” procedure during growth and development. Taurursodiol prevents that from happening as easily.

Endoplasmic reticulum stress or dysfunction associated with protein misfolding and aggregation has been implicated in the pathogenesis of ALS,[1] as has disruption of mitochondrial function and structure.[2] Sodium phenylbutyrate is a histone deacetylase inhibitor that has been shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress.[3,4] Taurursodiol recovers mitochondrial bioenergetic deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the apoptotic threshold of the cell.[5]

1. Jaronen M, Goldsteins G, Koistinaho J. ER stress and unfolded protein response in amyotrophic lateral sclerosis—a controversial role of protein disulphide isomerase. Front Cell Neurosci 2014;8:402.

2. Mehta AR, Walters R, Waldron FM, et al. Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: A systematic review and meta-analysis. Brain Commun 2019;1:fcz009.

3. Kaur B, Bhat A, Chakraborty R, et al. Proteomic profile of 4-PBA treated human neuronal cells during ER stress. Mol Omics 2018;14:53-63.

4. Suaud L, Miller K, Panichelli AE, Randell RL, Marando CM, Rubenstein RC. 4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells. J Biol Chem 2011;286:45083-92.

5. Rodrigues CM, Solá S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax- induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry 2003;42:3070-80.

The unfolding of the unfolded protein response

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A bit of encouraging news this week.

As explained in my post of March 10 (“No panacea”),  the trial drug Relyvrio was found not to help amyotrophic lateral sclerosis.  This despite positive results last year from a smaller trial that had prompted the FDA to provisionally approve the drug for ALS.  After this new result, the company, Amylyx, withdrew the drug from the market.  However, an ongoing trial of Relyvrio for PSP will continue.

Relyvrio is also being tested not only in PSP, but also in patients with Wolfram syndrome. In case you haven’t heard of this genetic condition that’s about 2% as common as PSP, it causes a combination of insulin-requiring diabetes, excessive urine production (“diabetes insipidus”), blindness from degeneration of the optic nerve, and deafness, along with neurological issues such as seizures, mild cognitive loss and loss of respiratory drive.  Wolfram syndrome starts at an average age of only six, with a range of six weeks to 19 years.  Sufferers die by age 40, usually from complications of diabetes or from respiratory failure.  A sad picture, indeed.

So what’s the encouraging news?  Amylyx issued a press release on April 10 (three days ago) reporting interim results halfway through their 48-week, 12-patient, unblinded trial of Relyvrio in adults with Wolfram syndrome. Eight of the 12 patients had completed the trial by that date.  The levels of a protein involved in the synthesis of insulin, called C-peptide increased and do so more promptly after a meal.  C-peptide is a standard test in medical practice to assess the severity of diabetes.  There was also a small improvement or lack of worsening in hemoglobin A1C; the fraction of the day in the normal blood glucose range; visual acuity as measured by a standard wall chart; and global impressions by the doctor and patient (separately) of how well things are going overall.  Over 24 weeks, these patients would have been expected to worsen, on average, not to improve or stabilize as these eight patients apparently did.

Keep in mind that the comparator wasn’t a placebo group, but “historical controls,” meaning patients from previous research or from the study doctors’ regular practice.  (Unfortunately, the company’s press release didn’t say just how much people with with Wolfram syndrome would be expected worsen in these measures over 24 weeks.) This opens the possibility that the patients in the study might simply have taken better care of themselves, knowing they were being tested in the trial.  Another possibility is that the doctors themselves fell victim to their hopes for the patients, providing more aggressive general management of their symptoms during the trial.  That’s why we do double-blind trials.  If the current trial gives favorable results after all 12 patients have completed the 48 weeks, then presumably Amylyx will move to a larger and double-blind trial.

This is, provisionally, slightly good news for people with Wolfram syndrome, but what about PSP?  Both diseases involve abnormalities in the “unfolded protein response” (UFR) in the brain cells’ endoplasmic reticulum (ER).  After amino acids are strung together in the cell’s nucleus to make proteins, they’re transported to the ER, where they’re folded into the patterns they need to do their jobs.  In both Wolfram syndrome and PSP, there’s an abnormal overactivity of the UFR, and Relyvrio inhibits it.

To date, we know of 11 genes that each confers a slightly increased risk of developing PSP.  The most important is the MAPT gene, which encodes the tau protein.  The next-most important is a gene called EIF2AK3, which encodes a protein called PERK, which is an important part of the unfolded protein response. 

So let’s await the final results in this early-phase trial of Relyvrio in Wolfram syndrome.  More to the point, let’s await results from the 600-participant, double-blind trial of Relyvrio in PSP, which has only just started recruiting and should end in mid-2027.

Disclosure:  I’m a paid consultant for Amylyx.  I assisted in the design of their PSP trial and in teaching the study doctors how to properly use the PSP Rating Scale.  I have no stock in the company or any other financial interest in their commercial success.

The Matrix

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You’ve probably heard about the disease called frontotemporal dementia (FTD).  It produces many of the same cognitive and behavioral symptoms as PSP, but more intensely, with much less of PSP’s other symptoms.  Familial forms of FTD are much more common than in PSP, amounting to about 20% of all cases.  Of those, about a quarter have a mutation in their MAPT gene – that’s the one that encodes the tau protein.  (Most of the rest have mutations in two obscure genes called “C9orf72” and “progranulin.”)  As for nearly all neurodegenerative diseases, a protein aggregates in the affected brain cells in FTD and that protein corresponds to the specific mutated gene in that individual.  So, MAPT-associated genetic FTD is a tauopathy very much like PSP, but in a slightly different set of brain cells.

Neurologists at UCSF and the Mayo Clinic are leading a large, multi-institutional observational study of FTD called “ALL-FTD.”  They’re gathering histories, neurological exams, imaging, skin biopsies, blood, and most relevant here, spinal fluid.  They re-gather much of this every year and track the patients’ progression.  The idea is to find diagnostic markers not only to diagnose the disease, but to predict its onset in healthy mutation carriers and to predict the progression of the disease in those who already have symptoms.  All of this can be useful in designing clinical treatment trials and in patient and family counseling.

Using spinal fluid from 116 people with FTD mutations and 39 controls, the ALL-FTD neurologists analyzed the levels of over 4,000 proteins.  They found some of the proteins increased or decreased as functional modules.  That means that subgroups of the affected proteins tended to share a common function in the brain. Then they tested spinal fluid from people with ordinary, non-familial PSP-Richardson syndrome for the same protein disturbances, and found some.  In fact, all 31 of the functional modules disrupted in genetic FTD were disrupted in PSP as well. (This research article is posted on a site for manuscripts not yet peer-reviewed called “Research Square.”)

Mind you, this doesn’t mean that non-familial PSP is actually caused by genetic mutations in the three FTD-related genes.  We still don’t know the initial cause of PSP.  But the study does show that familial FTD and non-familial PSP share some very fundamental similarities. 

The most important modules disrupted in the two conditions relate to the brain cells’ “extracellular matrix.”  That’s the soup of chemicals outside and between the brain cells that serves many protective and nutritive functions.  I suspect that it descended from the coat of slime secreted by our ocean-dwelling, single-celled ancestors.  In ourselves it functions in cell growth, fetal development and injury repair as well as providing physical protection against trauma and a trap for nutrients floating by. It’s easy to see how a genetic or non-genetic defect in the contents our brain’s extracellular matrix could be a problem.

So, let’s add the extracellular matrix to our list of potential drug targets in PSP.

Currently recruiting trial update

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In response to a reader’s question, here’s the most current list I can create of current or imminent clinical pharmacological neuroprotective treatment trials in PSP.  Maybe soon I’ll list the trials not covered by that list of adjectives, but you can do that yourself at www.clinicaltrials.gov.

For more information, including a phone number or email address, go to www.clinicaltrials.gov and search on the National Clinical Trials number shown or on the disease and drug names.  For the trial in Australia/New Zealand, use the link given.

  • Relyvrio (AMX-0035): A orally-administered combination of two existing medications to help brain cells resist the PSP process.  Will recruit 600 patients in the US, Canada, Europe and Japan. NCT06122662
  • NIO-752: An antisense oligonucleotide given by spinal injection once a month.  Still recruiting only in Germany and the UK.  A small, 3-month trial primarily designed to assess safety and tolerability. NCT04539041
  • GV-1001: a subcutaneously protein fragment administered daily by subcutaneous injection. A small trial primarily designed to assess safety and tolerability.  South Korea only.  NCT05819658

  • Set to start in a few months is the study of FNP-223.  This year-long trial will take place at dozens of sites in the US, Europe and Japan.  It’s an oral pill taken 3 times a day that reduces the abnormal phosphorylation and misfolding of tau.  It’s not yet on www.clinicaltrials.gov. 

You may be interested in joining an observational trial, where there’s no treatment – only testing and examinations, typically with the goal of developing new diagnostic tests and gathering other information of potential future use in developing new treatments.  If so, visit www.clinicaltrials.gov and search on PSP and, in the “focus” column, on “observational studies.”  One that I’d recommend highly is the ALLFTD study.  It’s centered around frontotemporal dementia but also includes PSP.  I know the people running it, and it’s a first-rate study that has already recruited several hundred people with PSP.  NCT04363684

Disclosures: I am, or have been, a paid consultant for the companies that make Relyvrio, NIO-752 and FNP-223. But I have no stock in the companies or other financial interest in the success of these drugs.