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Make your opinion heard

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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

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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

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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

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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

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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

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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

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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

Imaging points to problems — and solutions

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Here are two more research presentations from the Movement Disorders Society conference in Copenhagen back in August. These, both pretty technical (sorry!), report on imaging techniques elucidating how the brain is mis-firing in PSP. Both of them offer ideas for new treatment approaches.

Localizing a brain network of progressive supranuclear palsy

E. Ellis, J. Morrison-Ham, E. Younger, J. Joutsa, D. Corp (Melbourne, Australia)

A brain network is a set of areas in the brain that have direct connections with one another and work together to perform a task.  When a neurodegenerative disease like PSP occurs, an important way for the abnormality to spread through the brain is along such networks.  That produces areas of brain cell loss (“atrophy”) in a specific pattern for a specific disease.  These researchers pointed out that in some people with PSP, the “textbook” list of brain areas showing such loss on conventional MRI imaging is not present.  They hypothesize that the usual brain network may nevertheless be abnormal, but without producing enough actual brain cell loss to show up as the full, textbook pattern.  So, they analyzed a database of MRI, PET, and SPECT scans of 363 people with PSP and tabulated the areas of abnormality.  They compared that list to a database of known brain networks that had been compiled using functional MRI in 1,000 healthy people.  (Functional MRI is a standard research technique where a movement or thinking task is performed or a certain sensory input is provided to a person in an MRI machine.  The image is obtained in such a way as to reveal which brain areas’ baseline activity increase or decrease  together in response.)  They found a consistent brain network to be affected in people with PSP, even if conventional imaging fails to show it.  The claustrum, basal ganglia, and midbrain increase their activity, and the cuneus and precuneus reduce theirs.  The authors conclude that their findings “help to reconcile previous heterogeneous neuroimaging findings by demonstrating that they are part of a common brain network.”  

This information could be useful in designing non-invasive, transcranial electrical or magnetic stimulation treatment for PSP.  If the absence (or mildness) of brain cell loss in some patients with PSP means that those cells are still only malfunctioning rather than dying, it could have important implications for development of treatments aimed at rescuing such cells before the damage becomes irreversible.

Topography of cholinergic vulnerability correlates of PIGD motor deficits in DLB and PSP: A [18F]-FEOBV PET study

P. Kanel, T. Brown, S. Roytman, J. Barr, C C. Spears, N. Bohnen (Ann Arbor, USA)

Neurotransmitters are chemicals used by brain and nerve cells to signal to one another across synapses.  Any given brain cell (or related cluster of brain cells, called a “nucleus”) uses a single neurotransmitter type.  One of the more commonly used neurotransmitters in the brain is acetylcholine, and neurons using it are among the most important to become damaged in PSP.  These researchers imaged the brains of patients with PSP using a positron emission tomography (PET) imaging technique that shows acetylcholinergic synaptic activity.  They compared the abnormal areas in each patient to their degree of balance difficulty and gait problems.  They found correlations in basal forebrain, septal nucleus, medial temporal lobe, insula, metathalamus, caudate, cingulum, frontal lobe, cerebellum, and tectum, especially the superior colliculus.  They found that the first areas on this daunting list, the basal forebrain, where the basal nucleus of Meynert is located, is hit hardest and connects to most of the other areas on the list. They conclude that treatment strategies attempting to replace or regenerate damaged neurons for PSP might want to start there.

It’s been known for decades that the basal nucleus of Meynert is heavily involved in PSP and Alzheimer’s disease, but attempts to compensate for the loss of acetylcholine by inhibiting an enzyme that degrades it (using marketed oral medications such as rivastigmine, donepezil, or galantamine) have produced only minimal results.  Perhaps a targeted, surgical approach to regenerating basal nucleus of Meynert neurons using gene therapy could work better.

Know our enemy

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Here are the last 3 of the 7 research posters on clinical features of PSP from the Movement Disorder Society’s August 2023 meeting in Copenhagen. My editorial comments in italics.

Narcolepsy type 1, supranuclear vertical gaze palsy, and agrypnia excitata in a patient with anti-Ma associated encephalitis.

C. Espinoza-Vinces, A. Horrillo, R. Villino, A. Solis, P. Domínguez, J. Arbizu, MR. Luquin, E. Urrestarazu, I. Avilés-Olmos (Pamplona, Spain)

Ma is a normal protein located in the parts of the brain serving vertical gaze, sleep, memory, personality, and motor control.  The immune system can make antibodies against Ma, usually in the process of fighting off a cancer that contains that protein or sometimes for no apparent reason.  The result is usually one of severe cognitive/behavioral changes or cerebellar ataxia but can occasionally mimic PSP.  This poster is such a case report in of a 53-year-old man with a 3-year diagnosis of narcolepsy who then rapidly developed features of PSP.  His spinal fluid and MRI were diagnostic of encephalitis.  The authors caution physicians that in patients with apparent PSP presenting with important sleep problems, to consider anti-Ma encephalitis.  That condition may respond to steroids or to removal of an underlying tumor. 

Anti-Ma encephalitis is one of the 52 disorders listed in the guide to the differential diagnosis of PSP that a working group of CurePSP Centers of Care is about to submit for publication.  Neurologists have long known it as a potential but rare cause of cerebellar ataxia but should also consider it in someone with apparent PSP that develops rapidly or at a relatively early age.

Atypical progression of motor symptoms in facio-scapulo-humeral dystrophy: clinical worsening or overlap?

D. Calisi, M. de Rosa, M. Russo, A. Thomas, M. Onofrj, S. Sensi (Chieti, Italy)

Facio-scapulo-humeral dystrophy, unlike most other kinds of muscular dystrophy, can start at any age and allow many decades of survival.  This case report describes a man in his 60s with FSHD since childhood confirmed on muscle biopsy and genetic testing.  The typical weakness in his face, neck, shoulders and upper arms progressed very slowly until he started to show slowness, vertical gaze palsy, falls, freezing and dysphagia.  His symptoms were attributed to the FSHD until imaging proved consistent with PSP.  The authors’ caution physicians that the diagnosis of PSP can be missed for years when it develops in the context of an unrelated, progressive motor disorder.

While the previous poster, on anti-Ma encephalitis mimicking PSP, is an example of a false positive, this one is a false negative.  These are excellent teaching cases for neurology residents.  I always taught my students and residents to consider concomitant neurological diagnoses and diagnostic mimics at each follow-up visit with a patient with a chronic disease, no matter how routine the visit was expected to be.

Prognostic impact of frontal-lobe clinical bedside signs in progressive supranuclear palsy

Ruiz Barrio, A. Horta Barba, S. Martinez Horta, J. Kulisevsky, J. Pagonabarraga (Barcelona, Spain)

These researchers tabulated frontal lobe signs in 61 people with PSP and compared those results with overall disability in the form of PSP Rating Scale total score.  (Problems with the frontal lobe explain the common PSP symptoms of loss of inhibition, repetition of words or movement, grasping, and many others.)  They found that grasping, orobuccal apraxia (inability to coordinate movements of the muscles around the mouth), and anosognosia (loss of awareness of illness) each correlated with PSPRS score independent of other neurological or demographic features.  In a sub-analysis of 51 patients evaluated during the first 4.3 years of the disease, groping was found to be an independent risk factor for shorter eventual survival.

Such observations can be highly variable across studies, but if confirmed, data like this could allow more rational analysis of neuroprotection drug trial outcomes and could also assist in patient and family counseling.

Next post on MDS conference posters:  Two science-nerdy ones on what’s working wrong in the brain in PSP.

Khao pad, arancini, and corn dogs

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Here’s installment 3 in my series on research posters at the Movement Disorders Society conference in Copenhagen in August.  The first 2 posts covered treatment and non-imaging diagnostic testing, respectively.  The topic now is clinical features.  Don’t forget – these have not yet been submitted for publication in most cases.   All I have to work with are the abstracts, typically of about 400 words.  I don’t even have the full posters, much manuscripts.  I found 7 that I expect to survive the peer review process at respectable journals.  The first 4 are here.  Give me a couple of days for the last 3.  As before, my own editorial comments appear in italics.

The prevalence and characteristics of REM sleep behavior disorder in progressive supranuclear palsy patients.

A.P.H. Phoumindr, J.S.R. Srignean, R.B.H. Bhidayasiri (Bangkok, Thailand)

The set of symptoms called “rapid eye movement behavioral disorder” (RBD) occurs in 95% of people with Parkinson’s disease (PD) and in virtually everyone with dementia with Lewy bodies (DLB).  In RBD, one acts out dreams in the form of limb twitches; talking or shouting; sleepwalking; or even violent movement that can endanger the bedpartner.  In the morning, the patient recalls none of it.  For both PD and DLB, RBD can start years before the movement problem and is considered a major “pre-motor” predictive factor for those diseases.  It was originally thought to be rare in PSP, but more recent research has shown that it occurs in something like 30-40% of patients.  In this poster, neurologists in Bangkok, Thailand found that 10 (53%) of their 19 patients with PSP had experienced RBD.  The survey was performed after 6 years of PSP, on average.  

It’s hard to draw conclusions from the statistics because of the small size of the group, but the take-home is that a Thai population corroborates the general observation that RBD can occur in PSP.  Neurologists hearing of fragments of RBD in people with PSP should bear in mind the possibility of RBD because precautions against injury can be instituted and effective medication, usually melatonin or clonazepam, at bedtime can be started.  If the clinical symptoms seem diagnostically equivocal, a formal sleep study would tell the tale.

Impulse control disorder related to dopaminergic therapy in progressive supranuclear palsy

T. Thammongkolchai, P. Termsarasab (Bangkok, Thailand)

Two other neurologists from Thailand report one patient with PSP who experienced impulse control disorder, in his case pathological gambling and ice cream consumption, after starting pramipexole, a dopamine agonist medication.  This effect is well-known in Parkinson’s, where that drug class often provides good benefit, but this case shows that it can also happen in PSP, where dopamine agonists give little to no benefit.

This is another reason not to use the dopamine agonists in PSP without some special reason.  Whatever benefit they do provide is exceeded by the benefit of levodopa, which has far fewer side effects in PSP.  For a list of dopamine agonist drugs in clinical use world-wide, click here.

An acoustic-perceptual analysis of speech in clinical PSP phenotypes

G. Di Rauso, F. Cavallieri, A. Gessani, D. Fontanesi, S. Coniglio, V. Fioravanti, S. Contardi, E. Menozzi, S. Meletti, F. Antonelli, V. Rispoli, F. Valzania, C. Budriesi (Modena, Italy)This is a detailed, careful and very technical comparison of speech disturbances between 25 people with PSP-Richardson’s syndrome (PSP-RS) and 16 with PSP-Parkinsonism (PSP-P).  The researchers evaluated both the speech produced and the ability to understand speech.  They found no differences between the two subtypes and conclude that the formal diagnostic criteria for PSP-RS and PSP-P were justified in not attempting to use the type of speech disturbance to distinguish between them.

This finding makes sense because the main features of PSP dysarthria, spasticity (an explosive or rubber-band-like quality) and ataxia (a drunken-type, irregular pattern) are not part of the features distinguishing PSP-RS from PSP-P in other parts of the nervous system.  The finding is helpful in that it dissuades neurologists from trying to differentiate PSP-RS from PSP-P by their motor or perceptual speech abnormalities.  This is a fine example of a “negative” trial that is nevertheless important and useful.

Progression of the clinical features of progressive supranuclear palsy-Richardson syndrome in early and advanced stages

T. Xie, C. Liao, L. Golbe (Chicago, USA)

This project demonstrates that difficulty swallowing solids and liquids progressed faster late in the course of PSP, while all the other items in the PSP Rating Scale progressed at a uniform pace throughout the disease course.  The analysis was original in benchmarking each patient’s course not by calendar years, but by progression milestones of their own time downgaze palsy – a central feature of PSP.  It’s also unique in tabulating patients’ exam results from onset to within a few months of death, on average. 

Full disclosure: Yes, “L. Golbe” is yours truly.  Tao Xie (pronounced “she”) is a prominent neurologist at the University of Chicago with whom I’ve worked before and Chuanhong Liao is a biostatistician there.  Dr. Xie gets all the credit for the creative scientific thinking and the study design.  My most important contribution was a database of 462 patients I saw from 1994 to 2020 and evaluated with the PSP Rating Scale at each visit. The results can be used to counsel patients in symptomatic management.  They may also serve as “historical control” data in the long-term, open-label phase of neuroprotective treatment trials in which the double-blind phase lasts only 12 months and occurred much earlier in the course.  We have submitted a paper for publication.