Monthly Archives: December 2023

Dizzy

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Dizziness is a common but poorly understood symptom in PSP.  That word can mean at least three things:

  • a lightheadedness that seems a prelude to fainting, usually caused by a drop in blood pressure
  • a sensation of movement of the body or the environment (usually spinning, but sometimes rocking or gliding)
  • a vague sensation of being off balance. 

Impairment of autonomic function is common in the Parkinsonian disorders such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy (in ascending order of likelihood).  There’s less evidence for, and research on, autonomic dysfunction in PSP. 

As background: The autonomic system is divided into sympathetic and parasympathetic portions.  Generally, the sympathetic system performs “fight or flight” functions such as raising blood pressure and heart rate in response to stress and the parasympathetic the “vegetative” functions such as powering the intestines to digest food.  When the sympathetic portion is damaged by a neurodegenerative disease, the most common symptom is lightheadedness upon standing.  We’ve all experienced this to a mild degree, but when severe, the result can be fainting, falls and injuries.

A well-designed project reported in the current issue of an obscure journal called The Polish Journal of Neurology and Neurosurgery has now compared PSP with PD and MSA with regard to various aspects of autonomic function including drops in blood pressure upon standing, or “orthostatic hypotension.”  The authors are Drs. Jakub Malkiewicz and Joanna Siuda of the Medical University of Silesia, in Poland.  (Disclosure: One of the two co-editors of the journal is an old friend and colleague of mine, Dr. Zbigniew Wszolek of the Mayo Clinic Jacksonville, who has special expertise in the atypical Parkinsonisms.)

The blood pressure was recorded in a very careful, standardized way:  It was measured after 15 minutes flat on a tilt table and then 5 minutes after being raised to a 60-degree angle.  The result was that none of the 25 patients with PSP or 20 healthy, age-matched controls experienced systolic blood pressure drops of more than 20 points.  However, this did occur in 20 (26%) of the 76 patients with PD and in 7 (58%) of the 12 with MSA.

This result is consistent with my own experience, where an office version of this test in my patients with early or moderate PSP experiencing dizziness rarely elicited much drop in blood pressure or intensification of the symptom.

How can this guide the care of people with PSP?  It means a few things:

  • In people with early PSP, the possibility of low blood pressure is highly unlikely as a cause of dizziness.
  • If the neurologist can rule out an inner-ear disturbance by the absence of a sensation of movement, nausea, a change in hearing, or a rhythmic, abnormal eye movement called nystagmus.  That leaves the possibility of a brain disturbance – either the PSP itself or an unrelated issue with the balance mechanism.
  • A neurologist whose patient with known PSP reports dizziness should provide the same careful assessment as anyone else with the same symptom, rather than simply to diagnose low blood pressure due to dehydration or an excessive dosage of antihypertensive medication. 

A “brain disturbance” causing vague dizziness could be things like:

  • a chronic subdural hematoma from a fall (which could be drained surgically)
  • a minor stroke (which could prompt the addition of stroke prevention measures and a workup for treatable arterial narrowing)
  • a small tumor (which could potentially be removed or irradiated)
  • the effects on the brain of a medication (which could be reduced or discontinued)
  • unusual seizures (which could be prevented with medication) – the most distant possibility

Nevertheless, in someone with advanced PSP (not the group studied by Malkiewicz and Siuda), it’s also important to seriously consider hypotension as the cause of dizziness.  Here’s why:

  • When you can’t swallow comfortably or get up for a glass of water on on your own, it’s easy to become dehydrated.  
  • Limiting fluids to avoid nighttime incontinence or bathroom trips can do the same. 
  • Dopamine-enhancing drugs for Parkinson’s prescribed for PSP can reduce the blood pressure. 
  • Some drugs for urinary incontinence can do the same by dilating the blood vessels. 
  • Diabetes, even if undiagnosed, can damage the sympathetic nerves (“autonomic polyneuropathy”). 
  • Diuretics prescribed for swollen ankles can reduce blood pressure.

Sorry to give you all these things to worry about, but use them to question your doctors about whether they’re doing everything they can to diagnose and maybe treat your dizziness.

My thanks to Drs. Malkiewicz and Siuda for directing our attention to this still-understudied issue.

Wired

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With a nice handful of medications for PSP approaching clinical trials, it would be great to be able to assess the participants’ movement ability not just every few weeks to months at the research center, but also much more frequently at home.  The reduced need for clinic visits would ease participation for patients who for whatever reason have difficulty tolerating or obtaining travel.  It could also provide a more “real-world” picture of how the patient is doing in their home environment.

One relatively easy step in that direction arose from a project published last year (in which I, full disclosure, was senior author).   It modified the 28-item PSP Rating Scale, omitting the exam items that might not work well by video and used existing databases of PSPRS scores over time to assess the correlation between the modified and unmodified scores.  In short, the correlation was excellent.

But a PSP Rating Scale modified for video still requires a video connection, and that can be tough for the PSP age group and their caregivers, especially those where cell service is spotty.  Besides, video visits can’t happen every day or even close to it.  So, some other gadget would be nice.

Now, a group led by Dr. Alexander Pantelyat of Johns Hopkins and Dr. Anne-Marie Wills of Mass General (the co-senior authors) with Dr. Mansi Sharma of Mass General (the first author) have published a first-blush look at a simple gait monitoring system in PSP and Parkinson’s. 

Other versions of the same idea for PSP have had to be used in a lab at a research facility and required a complex array of sensors pasted to various parts of the body.  But this one is used in the patient’s home and requires only three sensors: one strapped to the lower back with a belt and one fastened to each shin by what looks like an old-fashioned garter strap like my father used to wear.  For reasons of safety, only patients with histories of very few falls and ability to walk unassisted qualified for this early trial.  Patients with PSP and Parkinson’s were compared on their performance of four standard gait tasks.  They received instructional videos and the three sensors communicated with an app on a tablet provided.

Of the 22 patients who qualified and consented, only two (both with Parkinson’s) couldn’t manage the technical requirements.  For the others (10 with PD and 10 with PSP), the device proved able to quantify and time the movements well and to differentiate PSP from Parkinson’s. Most important was that managing the experimental hardware and software while avoiding falls or other complications was perfect.

The next step will be to assess the device over a period of several months for its ability to track PSP progression.  This should be successful because the Spearman correlation coefficients of the three gait measures with the modified PSP Rating Scale, were pretty good: 0.62, 0.64 and 0.84; and we know that the PSPRS tracks PSP progression well.  (Correlation of 1.0 is perfect and 0 is random.) 

Another reason to be optimistic about the device to track progression is that it’s already been accomplished, although with a more complex, six-electrode device implemented in a research lab.

A reason for caution is that not every patient in a drug study walks unassisted at home as safely as these 20 hand-picked participants, especially toward the end of a one-year trial period.  Furthermore, using this device at home in routine clinical practice would involve patients at all levels of gait instability.  But for people in remote areas or whose caregiver can’t afford to take time off from work for a clinic visit, this could be the ticket to research trial participation.

The hindbrain steps forward

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The cerebellum is gradually being understood as a contributor to cognitive and behavioral function in both in health and disease.  A new publication has teased out MRI changes in the cerebellum that differentiate PSP from other dementing disorders early in the disease.  This pattern could be developed into a diagnostic test and as a marker of disease progression and even as a guide to rehabilitation measures.

The cerebellum is classically thought of as a regulator of movement.  In its most simplistic essence, its job is to put a brake on voluntary movement instructions from the cerebrum.  The cerebellum is guided in this task by perception of the position and motion of the trunk, head and limbs, by the effect of gravity, all complemented by visual input.

More recently, the cerebellum has demonstrated a memory function when it comes to movement regulation (making “muscle memory” more than just a metaphorical expression), and damage to certain parts of the cerebellum can cause a behavior disinhibition and cognitive impulsivity similar to the frontal lobe damage seen in PSP. In that sense, the cerebellum still functions as a “brake,” but on behavior and cognition rather than just on movement.

Now, researchers from the University of California San Francisco have carefully analyzed routine MRI scans from people with dementia arising from a variety of neurodegenerative conditions including PSP.  They specifically quantified gray matter damage.  (Gray matter is brain tissue composed mostly of cell bodies — as opposed to white matter, which is mostly axons.  In the cerebellum, unlike the cerebrum, the gray matter is the deeper layer and the white matter is superficial.)

The figure below shows the principal results. Illustration from Chen Y, et al. Alzheimer’s & Dementia, 2023. The senior author is Dr. Katherine Rankin. Each MRI image has been reconstructed by computer from routine scans to show the cerebellum splayed out flat.  The randomly assigned colored areas represent a loss of gray matter relative to non-demented people of similar age (“Controls”).  Note that the pattern for PSP differs in obvious ways from the other diseases, though at present the differences are only between the averages for groups, not individual differences useful for diagnosis in routine care. 

Notes: The small type abbreviations are the sub-areas of the cerebellum.  AD=Alzheimer’s disease; CBD=corticobasal degeneration; LBD=Lewy body dementia; TDP=frontotemporal dementia with TDP-43 protein aggregation.  It comes in 3 types. “Pick’s” is a form of frontotemporal dementia.  LBD is combined with AD because at autopsy, the former is always accompanied by some of the latter.  This paper did not include Parkinson’s disease or multiple system atrophy, as those diseases rarely include dementia early in the course, the focus of the present study.

The authors conclude, “These findings suggest the potential for cerebellar neuroimaging as a non-invasive biomarker for differential diagnosis and monitoring.”  They hasten to add that to understand the reasons for these different patterns of cerebellar loss, future studies will have to image the areas of the cerebrum where brain cell activity has been lost and to correlate that with corresponding loss of activity in the cerebellum.  That’s called “functional neuroimaging” as opposed to the “structural neuroimaging” of the current study.   

These insights, aside from their qualitative and quantitative diagnostic value, could provide guidance for electrical or magnetic transcranial stimulation (i.e., delivered across the scalp and skull rather than by inserting hardware onto or into the brain) as symptomatic treatment for PSP and the other dementing disorders. 

Flashes and rumbles

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One of this blog’s more frequent and thoughtful readers/commenters, “Mauraelisabeth3,” has asked a good question about the possibility auditory and visual sensory gamma-frequency stimulation as a treatment for PSP.  I responded by promising a blog post on the subject, and here it is:

As always, some scientific background first:  An electroencephalogram (EEG) is a recording of electrical waves emanating from the surface of the brain, as measured by wires pasted to the scalp.  The various brain waves are classified by their frequencies.  The ones relevant to ordinary patient care range from the slowest (i.e., lowest frequency), called “delta,” at 1-4 cycles per second (or “Hertz” or “Hz), to “theta” (4-8 Hz), “alpha” (8-13 Hz) and “beta” (13-30 Hz).  Most of the EEG activity in a healthy, relaxed but awake adult with eyes closed is alpha, and with increasing alertness or with eye opening, there’s more beta.  Theta and delta are important in normal sleep and in many kinds of brain diseases. 

But there’s a higher frequency called “gamma,” which can be found mainly in deeper areas of the brain not usually detected by routine EEG, or if it is detected, it’s hard to distinguish from artifact caused by scalp muscle activity.  It turns out that in people with Alzheimer’s disease, there’s a reduction in gamma activity in the areas deep in the brain that are the headquarters of the memory problem. 

Now to the matter at hand:  There’s a way to “entrain” the EEG activity of those memory-related areas to increase their gamma activity.  An AD mouse model called 5XFAD (with 5 mutations in 2 genes relevant to AD: amyloid precursor protein and presenilin 1) improves in multiple ways after such stimulation, including reducing its load of beta-amyloid, the main component of the amyloid plaques of AD.  A mouse with a mutated form of the tau protein shows improvement in some measures as well, and tau, of course, is the protein central to PSP. Here’s a technical review article on the topic, but it’s from 2018.

A company called Cognito Therapeutics, based in Cambridge, MA, was started by scientists at MIT who have performed much of the early lab work.  So far, the company has sponsored one small, controlled trial showing some improvement in people with AD, but it’s not published other than in very cursory form on the company’s website.  A year ago, in December 2022, Cognito started a Phase 3 trial in AD, meaning a large trial of the sort that, if successful, could win FDA approval for the device for AD.  It’s scheduled to conclude in 2025.  For one hour a day, participants wear glasses flashing a light at 40 Hz (the most relevant point in the gamma range) and headphones playing a tone at the same frequency.  A 40 Hz flash is just barely perceptible as flashing (50 Hz is the standard “fusion frequency”) and a 40 Hz tone is a low rumble.

Some caveats about the treatment: 

  • The most recent literature I found is far from unanimous on whether AD consistently has reduced gamma activity in relevant brain regions, and I found no evidence at all that PSP does. 
  • Although the small clinical trial to date found no adverse effects, there is evidence from the mouse experiments that the gamma stimulation increases the activity of the microglia, the brain’s main inflammatory cells.  That could be a good thing if it enhances the scavenging of unwanted, aggregation-prone protein. But it could be a bad thing if it aggravates the inflammation thought to comprise an important part of the pathogenetic process in many neurodegenerative diseases, including AD and PSP.
  • In the few clinical trials to date, an hour’s stimulation provides only about one day of measurable benefit.  Such a regimen might prove impractical in the real world.

Bottom line:  Would I recommend volunteering for a trial of 40-Hz sensory stimulation in PSP . . .

  • . . . if some more lab data in mice, or very early phase human data supported the benefit and safety of such a treatment in PSP, and
  • . . . if such a trial fully communicated the scientific uncertainties and safety concerns? 

Yes, I probably would.

Keep in mind that devices producing 40-Hz light and/or sound are already commercially available as meditation aids.  No clue here if they help, harm or neither, but until I know more, I’ll categorize them along with all the other placebos out there.

You gotta know when to fold ’em

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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

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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 . . .

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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

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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.