Author Archives: Dr. L. Golbe

You gotta know when to fold ’em

Posted on by

The last few posts have been about things at the macro level, from clinical trials to government action.  Now, let’s dive back into some molecular biology — if you’re nerd enough for it.

Yesterday, a paper appeared from researchers at the University of Alberta, in Canada, led by Drs. Kerry T. Sun and Sue-Ann Mok, comparing the folding structure of normal and abnormal versions of the tau protein. 

First, some background.  You all know that proteins are strings of amino acids. The healthy adult human brain has six forms of the tau protein ranging in size from 352 to 441 amino acids.  Tau’s normal job is to maintain brain cells’ internal structure and some other housekeeping tasks.  Tau unattached to something else normally flops around in the cell’s fluid like a piece of overcooked spaghetti in boiling water.  In PSP and the other tau-related disorders, tau becomes abnormally folded onto itself and forms toxic clusters that eventually clump further into neurofibrillary tangles.  Those are visible through a microscope and are critical in the diagnosis of the “tauopathies” although the details of how misfolded or aggregated tau actually causes loss of brain cells remain unknown.

Some more background: Although over 99% of people with PSP have no mutations in the tau gene, there are 50 different mutations in tau that do cause neurodegenerative diseases, many of which closely resemble PSP.  The most widely used experimental animal model for PSP has received a copy of a human tau gene with one of these 50 mutations. 

The new project analyzed the folding structure of normal tau protein and samples of abnormal tau protein, each with one of the 37 most important tauopathy-causing mutations.  It found that, at least as far as this lab technique could determine, no structural difference between normal tau and two of the most popular abnormal versions of tau used in research, the P301S mutation (where the amino acid proline at position 301 is replaced by the amino acid serine) and the R406W (arginine to tryptophan).  Another mutation commonly used in animal models, P301L (proline to leucine) does alter the structure.  That’s the form of tau addressed by the two monoclonal antibodies that AbbVie and Biogen, respectively, recently found did not help PSP. 

Of the other 34 mutations tested, 12 produced no structural change and the location of the mutation had no discernible effect on the folding structure.  Nor did the rate of aggregation influence the resulting structure. 

Interestingly, one of those 12 producing detectable misfolding is the A152T (alanine to threonine) mutation, which is the only single-amino-acid substitution tau mutation we know of that increases the risk of “sporadic” (i.e., non-familial) PSP.   

There are some caveats:

  • This study does not examine the effects of post-translational modifications (PTMs) on the folding structure of tau.  Nor did it study the effects of the various mutations on the ability to accept PTMs.  PTM’s are small molecules such as phosphate, acetate, methyl groups, sugars, and ubiquitin that can be attached to the protein in health to regulate its function, or as an effect of disease processes like PSP. 
  • The study restricted itself to only one of the six adult human tau isoforms, called 0N4R.
  • The 0N4R form of tau has 383 amino acids (the others range from 352 to 441) and locations that can alter the folding pattern occur in only about 45 of those.  So, as you’d guess, an amino acid substitution can change the chemical properties of a protein without changing its folding pattern.  Another major issue is that many of those 45 misfolding spots are hidden inside the folded structure, obscuring them from the researchers’ analysis.

Despite these limitations, we can conclude that the various amino acid substitutions affect the misfolding pattern of tau in different ways.  Any explanation of the cause of ordinary, sporadic PSP at its most profound molecular level can be guided by studying all of those misfolding patterns for hereditary PSP but will also have to take account of whatever bad thing the A152T mutation is doing – and that thing, according to this paper, is NOT to directly cause tau to misfold.

Yes, Congress can accomplish something

Posted on by

Here’s a great step forward: The Energy and Commerce Committee of the US House of Representatives has just approved the “National Plan to End Parkinson’s Act.”  Thanks in part to advocacy by CurePSP and other organizations devoted to the atypical Parkinsonisms, the bill includes not only PD but also PSP, multiple system atrophy, Lewy body dementia, corticobasal degeneration and Parkinson’s dementia. 

For the remaining required approvals, the bill will now proceed to the full House itself, then the Senate, then the President. (I recited that route for my international readers and for my US readers who doodled through civics class.)  Crucially, the bill was passed with full bipartisan support in the committee, which bodes well for its chances the rest of the way.

Here’s video of the committee’s session.

The bill directs the Department of Health and Human Services to create an advisory commission with representation from all relevant Federal agencies and some advocacy and research organizations as well as patients and caregivers.  Each year, the commission would assess the state of research and clinical care and formulate recommendation on how the various relevant Federal agencies could formulate and coordinate further research plans.  It would also interact with similar organizations internationally. A similar bill for Alzheimer’s disease was enacted in 2011 and has been working successfully by all accounts.

The commission would recommend spending levels for the Federal Government to advance these efforts, but the bill provides no funding for the work of the commission itself.  That would have to be absorbed by the existing budget of the Department of HHS.  (This is standard practice when Congress is interested in a specific medical cause.) 

The bill was first taken up by the committee in March, nine months ago.  One of its major advocates has been Congresswoman Jennifer Wexton of Virginia, who was diagnosed with PSP herself last summer and has been working with CurePSP and others to improve awareness of PSP nationally and to raise funding for research.  Here’s a press release from her office.   The lead sponsor of the bill is Congressman Gus Bilirakis of Florida, who has three close relatives with PD, but 167 other House members signed on as co-sponsors.  The Michael J. Fox Foundation has been working tirelessly for the bill.

I know you’ve been waiting for my editorial commentary.  Here it is:  This is great publicity for PSP, and it sure needs it. 

Congresswoman Wexton is the highest-profile celebrity with PSP since Dudley Moore, the British-American comic actor best known for the movies “10” and “Arthur,” announced his diagnosis of PSP in 1998.  His friends organized a star-studded benefit at Carnegie Hall in New York that raised $50,000 for CurePSP but he declined to become an activist in other ways.  (I was his neurologist, and he told me, “I’ll help out, but don’t want to be the poster child for PSP.”) Linda Ronstadt, the popular singer and Rock and Roll Hall of Fame member, announced in 2019 that her longstanding diagnosis of Parkinson’s had been changed to PSP.  She has not yet supported PSP-related activities of which I’m aware.  A few other less-famous celebrities with PSP have advanced awareness and fundraising, and we’re grateful to them and their families.  But when “progressive supranuclear palsy” is mentioned on the floor of the US House of Representatives and included in press releases, that’s rare and valuable publicity.

‘Cause nice and easy does it . . .

Posted on by

A few days ago I received an question from a CurePSP support group leader about whether focused ultrasound has potential for PSP. Here are my words of wisdom:

Over the past few years, high-intensity focused ultrasound has become mainstream as an alternative to deep brain stimulation (DBS) for Parkinson’s, isolated tremor and other things.  It works by killing a small volume of brain tissue that’s over-active because the disease process has deprived it of its normal inhibitory input.  DBS, which has been in wide use for 25 years, accomplishes the same thing, but by over-stimulating the over-active area to the point of paralyzing it.  Before DBS came along, the same thing was accomplished by inserting a metal electrode deep into the brain that emitted microwaves from its tip to permanently destroy the over-active chunk of brain.

The advantage of high-intensity focused ultrasound is that unlike DBS, it requires no holes in the skull or hardware in the brain or under the skin of the chest, and no further stimulator adjustments.  Its disadvantage is that once it’s done, it’s permanent, so if it’s not quite in the right place, you can’t just reposition it or fiddle with the stimulator unit’s settings.  You can only make another lesion in a slightly different spot or a larger lesion in the same spot, with no effect on whatever adverse effects might have resulted from mis-positioning of the first lesion.  But this is all academic for people with PSP, where there is no over-stimulated area of brain for a destructive lesion to address. 

However, it’s possible to non-destructively stimulate the brain using low-intensity focused ultrasound, and PSP definitely produces under-active areas of the brain, particularly in the cerebral cortex.  Early experiments with Parkinson’s and other conditions have shown that measurements of the electrical activity of the cortex do improve with low-intensity focused ultrasound, but there’s no clinical benefit for Parkinson’s so far, according to one published report.  There are no results at all for PSP to date.  So far, the technique seems feasible only for the most superficial areas of the brain such as the cerebral cortex rather than for the primary areas of trouble in PSP much deeper in the brain.

Bottom line:  Low-intensity focused ultrasound of the cortex could prove useful for PSP once it’s refined by painstaking trial and error .  The degree of benefit would probably be limited, but it would be low-risk and better than what we have now.  Of course, that sounds like the age-old formula for snake oil, so we just have to be cautious about medical charlatans pushing this treatment before long-term, controlled trials prove it safe and effective.

Make your opinion heard

Posted on by

I need your opinion on a new way to design clinical trials for PSP.  New except that it was invented back in the 1980s.  It’s called “combined assessment of function and survival” or CAFS.

When a drug is tested for its neuroprotective property, traditional trial designs have measured only the slowing of the rate of worsening of function (i.e., symptoms and disabilities).  Most of the neuroprotective studies of PSP are 12 months long.  The progression rate of PSP being what it is, about 15% of people with PSP will die each year.  Trial participants who die during a trial are  dropped from the analysis and the data they generated are wasted. 

For PSP and most other chronic, progressive diseases, one hopes that the experimental drug wouldn’t just slow decline of function, but that it would prolong survival as well.  So why not somehow integrate measures of both outcomes into one combined outcome measure?  That could reduce the size of the trials needed to answer the question, which means less expense for the drug company.  That’s important to you and me because it lower the bar for a small, start-up company with a promising drug to mount a clinical trial.  Could the CAFS method work for PSP? 


Combining survival and slowing of progression into one statistical measure would work as follows:  Patients are evenly assigned to receive active drug or placebo.  At the end of the observation period, each patient is compared with each of the other patients, generating either -1 or +1 points for each patient for each comparison.  A patient receives a point if they have survived the observation period but the comparator patient has not.  A patient receives a negative point for the reverse.  If both have died, the patient receives a point if they survived longer than the comparator.  If both have survived (probably the plurality), whoever has progressed more slowly on the standard disability measure over the observation period receives a point.  So, in a study with 50 patients on active drug and 50 on placebo, the best possible score for each patient would be 99, and the worst, -99.  Then, the average points for the patients on active drug is compared with the average for those on placebo.

Sounds great so far, but here’s the rub:  For PSP, the statistics on the progression and survival dictate that this study design assign 50% of the patients to placebo, which is more than the 33% or 25% placebo proportion for most traditional PSP trials.  Furthermore, the observation period would have to be 2 years long, as opposed to the one year of most PSP trials . By that time, your PSP is likely to be too far advanced to qualify for another trial.

That raises some difficult questions for a prospective study subject: What if the drug works but I’m on placebo for the 2 years?  Would converting to the active drug at that later stage of PSP help me?  What if instead I have the opportunity to enroll in a traditionally designed trial  with only a 33% chance of receiving placebo and an observation period of only one year, but with some unattractive features such as greater risk or discomfort or distant and frequent study visits?

So, here are my questions for you. 

Question 1: Suppose that you’re offered a spot in a trial of an experimental drug – let’s call it “PSP1.”  It’s the only trial available to you for the next 6 months, but after that, there may be other trials.  The PSP1 trial uses the novel CAFS design I’ve just described, with a 50% chance of being assigned to placebo and a 2-year duration.  Assume that the science behind the drug suggests that it might slow the rate of PSP progression by 40%, which is quite a large benefit.  Assume that the mode of administration of the drug, the frequency and distance of the study visits and the likelihood of adverse effects are all quite acceptable for you. Would you want to participate despite the possibility that you might receive placebo and that by the end of the 2-year trial you’d be unlikely to benefit much from any neuroprotective drug?

Question 2: Now suppose that 2 drug trials are available to you and, of course, you can join only one.  The first is the PSP1 trial described just above.  The other, for drug “PSP2,” has only the standard 33% chance of placebo and only the standard 12-month duration.  That shorter duration means that you’re likely to still qualify for another drug trial afterwards. Assume the same 40% potential disease-slowing benefit as PSP1.  But the PSP2 trial has some problems such as a greater likelihood of adverse effects, a difficult administration method, or a greater distance or frequency for the study visits. How bad are those problems?  Assume that if the placebo likelihood and the duration were the same as for PSP1, the problems would make PSP2 half as attractive for you as PSP1.

Here’s a convenient summary of all that for you:

 Trial
 PSP1PSP2
DesignCombined assessment of function and survival (CAFS)Assessment of function only
Duration2 years1 year
Placebo likelihood50%33%
Chance of substantial benefit40%40%
Practical issues (mode of administration, chance of adverse effects, distance to travel, visit frequency)Very acceptableMore difficult, making PSP2 half as attractive as PSP1 if all other things were equal.
Likelihood that you could participate in another trial after thisLowHigh

OK – time to vote.  Using the Comments feature or ligolbe@gmail.com, please answer these 2 questions:

Question 1:  Would you enroll in the PSP1 trial?  YES or NO

Question 2:  Would you choose the PSP1 trial or the PSP2 trial?

Feel free to include any comments or explanation.

Putting the cat back into the bag

Posted on by

Here’s a nice piece of news.

My periodic updates on active PSP neuroprotection treatment trials have mentioned a drug called TPN-101.  That’s an oral drug that inhibits an enzyme called reverse transcriptase.  If that term sounds familiar, it’s because that’s one of the mechanisms of anti-HIV drugs. 

Transposon Therapeutics issued a press release yesterday announcing that a 24-week, Phase 2 trial of TPN-101 in 30 patients showed a reduction of spinal fluid levels of neurofilament light chain (NfL) by 18.4% compared with the 10 patients on placebo.  NfL is a normal protein in brain cells that leaks out into the spinal fluid during active brain degeneration.  TPN-101 also reduced spinal fluid levels of interleukin-6 (IL-6) by 51.6%.  IL-6 is a component of the immune response in the brain that correlates with inflammation, part of the neurodegenerative process in PSP.  There were no important side effects. 

A study of only 30 patients is far too small to show any outward neuroprotective effect that might exist.  This trial was designed to look for chemical evidence of engagement with the “target” cells and proteins in the brain and also to detect major side effects. 

The findings will be presented as a poster at the 18th International Conference on Alzheimer’s and Parkinson’s Diseases in Lisbon in March 2024.

If you’d like to know how this drug works, put on your nerd hat and hang on:  Our genomes are riddled with short stretches of DNA called “transposable nucleotide elements” inserted there by a viruses infecting ancestors hundreds of millions of years ago.  But we have ways to prevent this viral DNA from being translated into proteins.  One protective mechanism, called “chromatin packing,” uses a variety of proteins to surround our DNA strands like insulation on a copper wire, preventing our protein-making machinery from gaining access.  The chromatin, however, does have to grant access to allow normal protein manufacture, and as we age, the chromatin starts to grant too much access.  The old viral DNA can now be encoded into RNA, which our immune system promptly recognizes as foreign.  The result is an inflammatory immune response that, via a variety of pathways, encourages the tau protein to misfold and aggregate.  Those, of course, are the hallmarks of PSP and a couple of dozen other “tauopathies.”  TPN-101 inhibits an enzyme called “LINE1 reverse transcriptase,” which is necessary for the transcription of the transposable nucleotide elements into RNA but is not involved on normal cell processes. In other words, the drug puts that cat back into its bag.

I hope and assume that the next step will be a larger study attempting to show clinical benefit in slowing progression of PSP.  This typically takes months to organize, months more to recruit all the patients, 12 months for the last-recruited patient to complete the double-blind phase, and another few months to analyze.  That totals about 3 years, but at least things are moving in the right direction.

Another four-poster

Posted on by

Four more poster presentations from the PSP/CBD conference in London in October. Keep in mind that this work has not yet been peer-reviewed by a journal. It has merely been screened by CurePSP and the PSP Association of the UK.

  • “Strategy adherence” is a measure of the degree to which one is consistent in going about a complicated cognitive pen-and-paper task.  Researchers administered the measure every 3 months for a year to people with PSP or PD and also to healthy controls of similar ages.  Each visit also included two more conventional cognitive measures – the Mini Mental Status Exam and the Montreal Cognitive Assessment.  Over the year, they found — in PSP but not in PD nor controls –a very clear and progressive problem with strategy adherence, but not in the conventional tests.  This provides a statistically sensitive test by which to assess disease-slowing ability of experimental drugs for PSP. (Maksymilian Brzezicki, et al, Oxford University, UK)
  • A new gene contributing modestly to the cause of PSP has been found.  It’s called C4A and is involved in the complement cascade, an important part of the immune system.  Ten other genes had been previously found to contribute similarly modest degrees of causation to PSP.  One additional gene influences PSP onset age.  Even if the effects of all 10 causative genes are totaled, most of the cause of PSP remains unexplained.  The current leading theory is that some outside influence is also necessary.  In fact, it may take multiple genes from this list plus multiple outside factors – plus a dose of randomness. (Kurt Farrell, et al, Icahn School of Medicine at Mt. Sinai, New York, NY)
  • Neurofilament light chain (NfL) is a protein in spinal fluid and blood that is elevated in PSP and several other brain degenerations.  Its role as a diagnostic test for PSP remains uncertain, but it does seem to correlate well with rate of symptom progression.  In this report, patients with PSP-Richardson’s syndrome, a rapidly-progressing form of PSP, had higher NfL levels in spinal fluid but only borderline-higher levels in blood, relative to patients with more slowly progressing forms of the disease.  Furthermore, the correlation between spinal fluid and blood levels was only modest.  The conclusion is that levels of NfL in spinal fluid, but so far not in blood, could prove valuable as a prognostic test in PSP. (M. Fernandez, et al University of Barcelona, Spain)
  • The PSP Rating Scale (PSPRS) is nearly universally used as the primary outcome measure in clinical treatment trials.  It progresses in a statistically reliable way over a 1-year timespan,but has been criticized for relying in large part on the neurological exam rather than mostly on patient-reported symptoms.  The PSP Quality of Life Scale (PSP-QoL), on the other hand, relies entirely on patient/caregiver-reported data but has been found in the past not to progress in a sufficiently robust fashion.  Now, researchers have directly compared the two using data from a 124-week, completed, negative drug trial. They found only a modest but still statistically significant correlation between the two, with a correlation coefficient of 0.325 (perfect correlation is 1.0) and conclude that the PSP QoL could provide an adequate outcome measure for PSP trials in the future if this result is confirmed. (Jay Iyer, et al, Harvard Medical School)

Another Fab Four from England

Posted on by

Yet another, and not my last, installment of research reports from Neuro 2023, the PSP and CBD International Research Symposium held a month ago in London. Please note that many of these reports have not yet been peer-reviewed at a journal.

:: A review of speech therapy records compared various devices to improve communication in people with PSP with severe speech deficits.  In 37 patients, the most successful were large print for reading and a stylus or keyguard (photo) for typing.  As the combination of deficits in motor, cognitive and eye movement control progressed, even these methods lost most of their initial utility.  This study demonstrates the need for better devices to assist in communication by those with advanced PSP.  (CML Foy et al, Sussex Community NHS Foundation Trust, North Chailey, East Sussex, UK)

:: As you’re all aware, two similar anti-tau monoclonal antibodies tested a few years ago failed to slow PSP progression.  However, the trials provided valuable data on the course of the disease over a 12-month period for the middle-stage patients with PSP-Richardson’s syndrome whom the trials enrolled.  The most recent such analysis of the trial for AbbVie’s tilavonemab showed that the patients with greatest language deficits were the ones who progressed most quickly over the ensuing year.  The study measured language in a variety of ways, including naming pictures, following written instructions, writing a dictated sentence, and quickly generating words of a specified category. These results could be of use in understanding the mode of disease spread in PSP, in designing future disease-slowing trials and in counseling patients in routine care. (Indira García-Cordero, et al, University of Toronto, Canada)   

:: A study compared the ongoing production (technically called “expression”) of tau molecules in neurons and glial cells in autopsied PSP brain tissue, correlating the results with the presence of tau aggregates, the pathologic hallmark of PSP.  It found continued tau production in cells with existing tau aggregates.  In fact, in oligodendroglia, where the PSP process probably starts, production was greatest in those cells with the most aggregates.  These findings argue against the theory that existing tau aggregates exert their toxic effect by shutting down normal tau production.  Another conclusion is that the abnormal tau in oligodendroglia doesn’t just come from adjacent neurons, but also (or exclusively) from within the oligos themselves. The results have implications for design of new PSP-slowing drugs. (Shelley Forrest et al, Macquarie University, Sydney, Australia; and University of Toronto, Canada)

:: The Pharma company Amylyx has announced details of their upcoming trial of AMX0035, an orally administered combination of sodium phenylbutyrate and taurursodiol.  It has already shown modest success in ALS in slowing symptom progression and in Alzheimer’s disease at the level of spinal fluid chemistry.  The 600-patient trial in PSP is scheduled to start in December 2023 in 200 centers in Europe, Japan and North America.  The benefit will be measured by comparing the placebo and active-drug groups with regard to rate of progression in the PSP Rating Scale over a one-year period.  Amylyx has not yet posted contact information for prospective participants.   (Disclosure, I’m a consultant for Amylyx and one of the 16 authors of this presentation at Neuro 2023.  The lead author is Günter Höglinger, Ludwig Maximilian University, Munich, Germany.)

London calling, again

Posted on by

Three more encouraging reports from the Neuro 2023 conference jointly sponsored by CurePSP and the PSP Association of the UK, held in London on October 19 and 20.

  • In a series of 48 people with corticobasal syndrome (CBS) during life who had brain autopsies, the underlying pathology was actually corticobasal degeneration (CBD) in 16 (33%), PSP in 14 (29%), Alzheimer’s disease in 6 (13%) and other conditions in the rest.  Similar results have been found many times before, but this study analyzed the neurologists’ office notes and found that actual CBD pathology was most likely in patients with gait freezing as one of the first symptoms.  Among those without early freezing, CBD was most common in those with no early speech problems and onset before age 66.  Those with PSP pathology tended to have had early speech difficulty and onset after age 61.  These observations could be useful to neurologists in separating CBD from PSP during life for purposes of prognostication and treatment trial enrollment. (Ikuko Aiba, et al., Higashinagoya National Hospital, Japan)
  • In 2018, the TRIM11 gene on chromosome 1 was identified as the location of a variant influencing the onset age of PSP, but the precise molecular mechanism underlying that effect remained unknown.  Now, researchers have teased out a single nucleotide variant in an intron (a section of the gene regulating the rate of manufacture of the protein it encodes rather than its amino acid sequence) of TRIM11.  They found that the protein encoded by TRIM11 tags abnormal tau for degradation by the 26S proteasome, which is one of the cell’s garbage disposal systems, and that the variant reduces the production of that protein. This means that somehow stimulating TRIM11’s expression (the rate at which it encodes its protein) could slow the spread of abnormal tau and the progression of PSP. (Sumi Bez et al, University College, London, UK)
  • The drug ezeprogind (previously called AZP2006) has shown favorable results in an early-phase test for safety in people with PSP.  The trial was too brief and small to establish efficacy, but the sponsor, Alzprotect of Loos, France, notes “very promising trends” in slowing progression of the disease.  The orally-administered drug works by reducing inflammation and by improving the action of the lysosomes, one of the cell’s garbage disposal mechanisms.  It will now enter a 120-patient efficacy trial using slowing of progression on the PSP Rating Scale after 12 months as its primary outcome measure.  Half of the 24 trial sites will be in the US and half in Europe.  A start date has not been announced. (Noelle Callizot, et al, Alzprotect, Loos, France)

. . . and the hits keep on coming

Posted on by

As promised, another installment of new research tidbits from Neuro 2023, held in London from October 19- 23, 2023 and co-sponsored by CurePSP and the PSP Association of the UK:

  • Now that inflammation has come under suspicion as an important part of the pathogenesis of PSP and other tauopathies, researchers have realized that many of the known or suspected risk factors for PSP include an inflammatory component.  These include bacterial infection, repetitive mild head injury, seizures, and autoimmune disease. (Karen Duff, University College London, UK)
  • The PROSPECT-M-UK study of the atypical Parkinsonisms, based in London but involving 29 centers throughout England and Wales, has been funded since 2015. This long-term observational study’s overall goal is to find diagnostic markers.  It has recruited 1,472 patients so far, of whom 661 have PSP.  Participants undergo neuro exams, receive brain imaging, and provide samples of blood, spinal fluid, and DNA.  (Riona Fumi, UCL, UK)
  • A form of tau protein known for 25 years is “high-molecular-weight tau.”  What makes it heavy is the inclusion of a couple of optional stretches of amino acids.  It turns out that this form of tau is more likely than ordinary tau to spread through the brain (called “seeding capacity”), and that the prevalence of HMW tau in various brain regions correlates well with the vulnerability of those regions to PSP. (Ivan Martinez-Valbuena, Rossy Institute, University of Toronto, Canada)
  • Previous comparisons of genetic variants between PSP and controls has revealed five genes that each contribute a bit to PSP risk.  Now, a sixth such gene, called C4A, has been discovered in the largest such study ever, including 2,779 patients with PSP and 5,584 controls.  C4A is involved in an important part of the immune system called the “complement cascade,” and is most active in the oligodendrocytes, one type of the brain’s glial cells. (Kurt Farrell, Mt. Sinai School of Medicine, New York, US)

More progress, more hope

Posted on by

Sorry for the absence.  I was on vacation in the UK leading up the Neuro 2023 conference in London, co-sponsored by CurePSP and its British counterpart, the PSP Association.  Despite its generic name, the meeting was specifically on PSP and CBD.  But it did cover new developments in everything from DNA to lifestyle.  A few of the more interesting things I heard, and I’ll have another equally pithy batch for you soon:

  • There’s is good evidence that the protein misfolding starts in the intestine and migrates to the brain in Parkinson’s disease, but this seems not to be the case in PSP.  There’s little misfolded tau in the gut in PSP and it’s in a different form than misfolded tau in the brain. (Wendy Noble, University of Exeter, UK)
  • An infrastructure for a “rolling platform” trial is expected to be funded by the NIH as soon as a new federal budget is approved.  That’s where multiple medications are tested in parallel and all use the same placebo group.  This greatly reduces each participant’s chances of receiving a placebo.  It’s “rolling” because as one drug either succeeds or fails, another can replace it without disrupting the overall protocol. (Adam Boxer, UCSF, USA)
  • In PSP, inflammation is found in direct proportion to brain cell damage in the same areas.  This is further evidence that inflammation is an integral part of the pathogenesis of the disease. (Nigel Leigh, Brighton and Sussex Medical School, Brighton, UK)
  • Some drug companies contemplating PSP treatment trials are starting the process by studying the “patient journey” to determine how best to evaluate the effectiveness of their drugs. (Stephanie Oscarson, SJO Research and Consulting, Valley Forge, PA, USA)
  • A new way to measure drug trial outcome is “artificial intelligence-curated music therapy.”  That’s where a trial participant listens to various kinds and volumes of music with EEG electrodes in place on the scalp.  Then an AI algorithm selects the music that optimizes the frequencies and locations of brainwaves known to be associated with a feeling of wellbeing. (Colin Ewen, UCB (Pharma company), Slough, UK
  • Clinical trials expected to start in the next 6-12 months (Günter Höglinger, Ludwig Maximilian University, Munich, Germany)
    • Bepranemab: Anti-tau monoclonal antibody
    • FNP-233 (formerly ASN90): Promotes the attachment of N-acetylglucosamine to tau, reducing its likelihood of misfolding and aggregating.
    • AMX0035 (combination of taurursodiol and sodium phenylbutyrate): stabilizes mitochondrial membranes and improves protein quality-control
    • AZP2006: Improves recycling of progranulin by lysosomes, thereby reducing inflammation
    • GV1001: A fragment of the enzyme telomerase reverse transcriptase, mimicking its anti-inflammatory and other action