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. . . 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. 

Diagnostic baby steps

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Back to my reports on the new PSP research presented at the International Parkinsonism and Movement Disorder Society conference in Copenhagen last month.  Last week I started with the treatment-related things.  Today it’s five presentations on diagnostic tests other than imaging.  As before, my editorial comments appear in italics.

Machine learning classifies Parkinson’s disease and progressive supranuclear palsy on saccade, pupil, and blink measures during a naturalistic free-viewing task

D. Brien, H. Riek, R. Yep, J. Huang, B. Coe, B. White, M. Habibi, D. Grimes, M. Jog, A. Lang, C. Marras, M. Masellis, P. Mclaughlin, A. Peltsch, A. Roberts, B. Tan, D. Beaton, W. Lou, E. Finger, A. Frank, D. Tang-Wai, C. Tartaglia, S. Black, R. Swartz, W. Oertel, D. Munoz (Kingston, Canada)

The researchers tracked eye movements using artificial intelligence software in 120 people with Parkinson’s disease, 8 with PSP, and 97 controls viewing a 10-minute movie.  They told the software the diagnosis and allowed it to create a profile of what sorts of eye movements correlated with which disease.  The result was 87% accuracy in distinguishing PD from PSP in a separate group of patients.  (The percentage refers to the area under the receiver operating curve – see my post on that statistical technique if you like). 

This technique is no more accurate than an exam by a skilled movement disorders specialist, but is potentially much easier to obtain and pay for.  Plus, it’s non-invasive.

Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson disease

K. Kang, A. Nunes, M. Sharma, A. Hall, R. Mishra, J. Casado, R. Cole, G. Barchard, A. Vaziri, A. Wills, A. Pantelyat (Baltimore, USA)

This is similar to the previous presentation in that it uses computerized analysis of patients’ fine movements to differentiate PSP from PD.  In this case, researchers analyzed multiple features of speech during passage reading, counting and a sustained “aah” sound.  They found multiple clear differences between PSP and PD in the average measurements of many features of speech but did not report areas under the receiver operating curve, so we don’t know how useful the measurements are at the individual level.  The researchers conclude that automated analysis is a feasible and non-invasive way to differentiate PSP from PD.  

We’ve long known that the speech of PSP differs from that of PD, and an experienced neurologist can easily distinguish the two over the phone. But this may be the first time the differences have been quantified so precisely.  This small study (only 11 patients with PSP, 10 with PD) should be replicated and its value at the individual level measured.  It all goes well, this could become a smartphone app.

Cognitive interference in postural control as a diagnostic and prognostic biomarker in Parkinsonian disorders.

R. Lloyd, C. Fearon, R. Reilly (Dublin, Ireland)

It’s well known that in PSP and PD, the balance problem is worse when the person has to concentrate on a cognitive task at the same time.  These researchers presented their plans for using that phenomenon to distinguish between the two diseases.  They will use an automated platform for balance assessment and the popular Stroop color-word test for cognition, with the patients attached to an electroencephalogram (EEG; brain wave recording) machine.  They expect that the cognitive task will aggravate forward/backward sway in PD and side-to-side sway in PSP, and that corresponding EEG changes will occur.  There’s no description of the results as of the conference’s submission date, nor on my PubMed search today. 

While this elaborate testing set-up would not be practical for real world use, it may be relatively easy to have patients walk down a clinical corridor, with appropriate safety measures, with and without simultaneous performance of a cognitive task.  The neurologist could eyeball the result.  Of course, that simplified version would require its own validation procedure before being recommended.

Remote monitoring of physical activity in progressive supranuclear palsy (PSP) using wearable sensors

A.-M. Wills, R. Mishra, M. Sharma, AJ. Hall, J. Casado, R. Cole, A. Vaziri, A. Pantelyat (Boston, USA)

This project tested a wearable motion sensor that has been proven in PD for its value in PSP.  Eleven patients with PSP wore the “PAMSys” device to measure overall activity, gait, and posture.  The results were compared to a version of the PSP Rating Scale modified for tele-neurology use.  The device was able to document disease progression over the 12-month period of observation.

Although little actual analysis of the data was presented in the abstract available.  But this result does show that objective measurements of the ability of patients with PSP to move around may not have to rely on snapshots in time every 3 months for clinical trials or less often for regular clinical care.  This avoids the technical difficulties in performing evaluations by video and the subjectivity of reports from patients or caregivers.  I’d expect such measurements to start appearing as secondary outcome measures in clinical trials very soon.

Posturography as an objective measure of disease progression and prognostication in progressive supranuclear palsy

G. Nuebling, S. Katzdobler, J. Levin, G. Höglinger, S. Lorenzl (Munich, Germany)

As an add-on to a 12-month drug trial for PSP from a decade ago, these researchers used an automated platform to measure the degree of sway of 44 patients with PSP with eyes open and then with eyes closed.  The delay since the data were gathered isn’t a result of procrastination.  It was to be able to assess the sway data as a predictor of long-term survival.  The result was that the data correlated very well with survival.  But the precision of the test for sole use as an outcome measure in 12-month neuroprotection trials was insufficient.  The result with eyes open was a better predictor than with eyes closed (hazard ratios 1.098 vs 1.001), but the sizes of that effect were small and the difference between them is not statistically significant. 

We know a lot about factors that affect long-term disability and survival in PSP, but not in an easily applied, quantitative way that could be used in clinical care.  This test could provide that if the apparatus can be modified to require less space in a clinic. 

A true public servant

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U.S. Congresswoman Jennifer Wexton of Virginia has just announced that she has been diagnosed with PSP at age 55. 

Here’s the story in this morning’s Washington Post.

Here’s Rep. Wexton’s own press release.

Rep. Wexton announced a diagnosis of Parkinson’s disease five months ago, but after noticing that her medication was not helping her as it did others in her PD support group, she sought additional professional opinions.  This is a very common route to a PSP diagnosis, as this blog’s readership well knows. Even the experts may not be able to distinguish the two disorders in the first year of symptoms.

Rep. Wexton’s staff has contacted CurePSP to coordinate efforts to help raise public awareness of PSP. 

We all wish Rep. Wexton well in her journey and congratulate her on her decision to publicize her diagnosis as a way to help others.

New advances in PSP treatment

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As promised, here’s the first installment of summaries of new, still-unpublished research from at the International Parkinson’s and Movement Disorders Society conference held in Copenhagen in August 2023. I’m starting with the presentations on treatment, the topic of most interest to this audience. As usual, I’ll be generous in sharing my own opinions on these developments, shown in italics.

A retrospective review of amantadine in progressive supranuclear palsy

N. McFarland, R. Farrukh, S. Mahn (Gainesville, Florida)

Amantadine is an old anti-Parkinson drug with modest symptomatic benefit but with some important side effects, including confusion and hallucinations in patients with existing cognitive symptoms, along with dry mouth, constipation, ankle swelling and other issues.  A few small, non-controlled series have shown benefit in some people with PSP.  Dr. McFarland and colleagues reviewed their own records, finding 44 patients with PSP who had been treated with amantadine and whose responses were adequately recorded.  Six claimed improvement and 31 claimed to be worse, but the change in the PSP Rating Scale over the 8 months of treatment was similar in the two groups.  It’s possible that the 14% improved in a way not measured by the PSP Rating Scale, or that much of the benefit was lost by the time of the follow-up exam, or that it was just placebo effect.  These unfavorable numbers do not change my own opinion that despite the possibility of side effects, a short trial of amantadine in non-demented patients who have reached maximal benefit on levodopa is worth trying until something better comes along.

Effects of exergaming-based tai chi and eye movement training on balance and gait in progressive supranuclear palsy: a case report

Y. Levitan-Marcus (Tel Aviv, Israel)

This is a case report of a 66-year old man with mid-stage PSP who underwent a 3-month course of 3 physical therapy sessions per week, 50 minutes each, over 12 weeks.  The therapy comprised “exergaming-based Tai Chi and eye movement training software.”  His frequency of falls and other measures of gait and balance improved noticeably, though quantification is not provided in the abstract.  This confirms previous case reports and small case series showing that eye-movement-based balance therapy can help the symptoms of PSP.  A randomized trial is now fully justifiable.

A tau-directed monoclonal antibody could alter the tau pathology of progressive supranuclear palsy

G. Beck, R. Yamashita, Y. Yonenobu, K. Ikenaka, S. Murayama, H. Mochizuki (Suita City, Japan)

You’ll recall that in 2019, the drug company AbbVie announced that its multi-center, controlled trial of tilavonemab, a monoclonal antibody directed against tau, had failed to slow the progression of PSP.  At about the same time, Biogen announced similar results for its own anti-tau antibody, gosuranemab.  Now, researchers in Japan have compared a brain autopsy from one of the patients randomized to active drug in the tilavonemab study to brains of three people with PSP who did not participate in the study.  They found that the brain’s immune system had been activated in the patient on tilavonemab, at least in the substantia nigra, one of the most important areas of damage in PSP.  The response comprised macrophages and microglia engulfing abnormal tau.  This is the sort of response hoped for, though clearly it was too little to help the patients.  Although this report includes only one patient to receive the treatment, it suggests that monoclonal antibodies against tau have potential against PSP.  Other drug companies are now testing antibodies directed against different parts of the tau molecule in hopes of improving upon tilavonemab’s results.

TEP-PSP: preliminary results of a therapeutic education program in progressive supranuclear palsy

A. Camara, C. Painous, M. Baixauli, J. Herrero, S. Pelaez, I. Martin, I. Quiñoa, C. Torregrosa, M. Carrasco, JC. Lopez Reyes, L. Maragall, Y. Compta (Barcelona, Spain)

This report describes what might be called “PSP 101” for patients and caregivers.  Researchers in Spain have organized a registry for PSP in Catalonia, the region of the country that includes Barcelona, with 5.5 million inhabitants.  So far, they have enrolled 15 patients, each with a caregiver.  They have administered a course of instruction comprising 5 sessions covering general knowledge of the disease, nursing care, speech and physical therapy, and occupational, psychological, and social support.  Patients’ and caregivers’ satisfaction with the sessions was very high, as measured by a standard scale.  Enrollment is continuing and the researchers plan a follow-up to assess long-term benefits of the program.  This sort of program can fill a need for patients and caregivers who may not be inclined to read (or remember) printed or on-line material, and its interactive nature may prove an advantage over those more passive methods of instruction.  If further observations continue to demonstrate success in Catalonia, and if a comparison with more traditional means of lay education proves favorable, PSP organizations elsewhere may want to adapt such a course to other languages, cultures, and systems of medical care and to scale it up to larger patient groups.

Sniffing the air outside my burrow

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Sorry for the long absence – 25 days.  But I have two good reasons.  One is that the day after my last post, my wife and I flew to Norway and Denmark for a vacation.  I wasn’t going to blog from vacation and an enforcer was constantly at my side.  Reason Two is that  I was planning to stay for the Movement Disorders Society conference in Copenhagen, but we both came down with Covid five days into the trip, isolated in our hotel room for the next five days and skedaddled home before the MDS.  We’re both just about over the symptoms now, thanks, but it sure took long enough.  At age 70, you just don’t bounce back like you used to.

But I haven’t forgotten about you all.  I’ve categorized, counted, and reviewed the on-line abstracts of all 52 PSP-related poster presentations at the MDS:

  • Clinical phenomenology: 11
  • Physiology, chemistry and molecular biology: 7
  • Epidemiology, cohort studies, and care delivery: 8
  • Treatment: 4
  • Diagnosis (non-imaging): 5
  • Non-PET imaging: 8
  • PET imaging: 9

Over the next few days, I’ll crank out some summaries, opinions, and reasons for us all to hope.

The mighty-chondria

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When someone with PSP reports a feeling of “weak muscles” to their neurologist, the answer is typically, “yes, you’re weak, but the problem isn’t in your muscles – it’s in the messages to your muscles from your brain.”  But it turns out that in PSP, muscles can be a problem, too, and that opens up some treatment potential.

We’ve known for decades that the mitochondria aren’t working right in PSP and other neurodegenerative diseases.  You’ll recall that those are the tiny factories in almost all our cells devoted to the biochemical process of respiration – that where oxygen and sugar combine to produce energy for the cell’s many functions.  Besides that very important job, mitochondria are also involved in processes such as neural plasticity (the ability of brain cells to react to external influences), calcium regulation, electrical properties of the cell and synaptic transmission.

Here’s a electron microscope photo of a single mitochondrion (from this source).

What brain cells and muscle cells have in common is the need to maintain very different concentrations of potassium between themselves and the surrounding fluid (called a “gradient”), and that takes lots of energy.  So, any defect in mitochondria will tend to hurt brain cells and muscle cells first and worst.  In fact, childhood neurological dysfunction and muscle weakness are the two main features of a whole category of diseases caused by single-gene mutations affecting proteins used only by mitochondria.

In PSP, the mitochondrial problem is more subtle, but we don’t know exactly what it is or what causes it.  Here are some strands of evidence:

  • Brain cells growing in a dish that have had their own mitochondria destroyed and replaced by mitochondria isolated from blood cells of people with PSP don’t recover from various kinds of stress as well the same brain cells with replacement mitochondria from healthy people. 
  • Toxins damaging an important series of chemical reactions in the mitochondria called Complex I can cause a PSP-like condition in lab animals. 
  • Complex I and other components of mitochondria are also damaged by tau molecules with an abnormal number or location of attached phosphate molecules (“phospho-tau”), which we know occur in PSP.  The net effect is excessive levels of “free radicals,” which are toxic by-products of normal respiration.
  • While the most important gene mutation contributing to PSP risk is in MAPT, which encodes tau, the next-most important is PERK (protein kinase RNA-like endoplasmic reticulum kinase), which regulates the responses to stress in mitochondria.
  • Coenzyme Q-10, a nutritional supplement that assists Complex I, may help some of the immediate symptoms of PSP, as shown by at least one double-blind trial.

All the above is simply background justification to suspect that muscles and not just brain should be involved in PSP.  But there’s more direct evidence, too:

  • Muscle weakness and fatigue are more common in PSP than in others of the same age.
  • Weight loss is common in PSP and occurs early in the disease course.  The same is true for both in Parkinson’s, but not as markedly.
  • Grip strength is impaired in PSP.  That could be a result of changes in the brain, but the duration of the muscle fiber contractions is prolonged in PSP, a sign of muscle dysfunction.
  • Men (but, oddly, not women) with PSP have a reduced overall muscle mass relative to others of the same age. 
  • Muscle biopsy in people with PSP shows modest evidence of the same severe change in mitochondria (called “ragged red fibers”) that occur in the genetic mitochondrial diseases of childhood.

So, what’s the take-home for people with PSP? 

  • First, EXERCISE – including low-intensity muscle-building exercises.  Discuss the details first with your neurologist or physical therapist, and probably also with your primary care physician to make sure your heart and lungs are up to the task. 
  • Second, HAVE HOPE that insights into the mitochondrial role in PSP will bring new treatment or neuroprotection targeted at those cellular processes in the brain.  In fact, one such medication, called AMX-0035 (a combination of taurursodiol and sodium phenylbutyrate) will be entering a Phase 3 trial for PSP in the next few months.  The combination under the brand name “Relyvrio” was approved last year by the FDA for Lou Gehrig disease, where there’s a similar mitochondrial problem, so I have very high hopes that the same will happen for PSP.