A peek at research coming down the pike

The American Academy of Neurology’s annual conference is the world’s largest clinical neurology meeting, with a combination of preliminary, cutting-edge research presentations and educational updates for clinicians.  This year’s event will take place in Boston from April 22 to 27, 2023. 

Each year, the meeting includes over 1,000 presentations of research in the form of brief, published summaries and in-person posters.  At the meeting, one of the authors has to stand next to the poster during a specified interval to field questions and criticism.  The presentations are subjected to a lower peer-review bar than are full papers in good journals, but on the upside, they are usually published months before the corresponding full paper.  Many researchers use the reactions of the conference attendees to improve their manuscripts before submission to a journal.

Here are the ones from the AAN’s website yielded by my search on “progressive supranuclear palsy,” along with my brief editorial comment on some.

Anti-IgLON5 disease is a very rare autoimmune disease that can mimic PSP, though it usually progresses much faster and occurs in younger patients than PSP (see my previous post for a bit more explanation).  Dr. Yoya Ono and et al tested for anti-IgLON5 antibodies in a group of 223 patients with PSP enrolled to date in the Japanese Longitudinal Biomarker Study in PSP and CBD (JALPAC).  They found the antibodies in none of them, providing additional confirmation that anti-IgLON5 disease is extremely rare, even in the population with apparent PSP.

Startle response: It has long been known that PSP weakens the startle response as measured by electrical responses of muscles in the face, but the location of the defect in the nervous system has been unclear.  Now, Dr. Peter Pressman et al at UCSF administered a 115-decibel burst of white noise through headphones to 33 people with PSP and 38 healthy controls.  The PSP group failed to react with much of an increase in heart rate or sweating.  The authors point out that because PSP is known not to include an important peripheral sympathetic nervous system defect, their result is probably explained by degeneration of the startle response circuit in the pons.

Diagnosis by AI. Neuropathologists and informatics researchers at the Mayo Clinic Jacksonville have taught an artificial intelligence system to diagnose tau-based diseases on brain tissue through the microscope.  Dr. Shunsuke Koga et al used a technique called “clustering-constrained-attention multiple instance learning” to differentiate PSP from Alzheimer’s, CBD, globular glial tauopathy and Pick’s disease.  This initial version of the system had 87% agreement with human neuropathologists and is being refined.

“Incidental” PSP. My 2019 book on PSP mentions that the lifetime incidence of PSP in autopsies in persons who died with no symptoms suggesting PSP was much greater than that based only on diagnosis in living persons. That data, from 2011, was from a group at Barrow Neurological Institute in Arizona led by Dr. Thomas Beach.  Now, the same group, with Dr. Erika Driver-Dunckley as first author, has updated their case series.  They found the lifetime incidence in the population to be about 780 cases per 100,000 persons per year, about 50 times the rate as diagnosed only in living persons.  I’ll get into the implications of this in a future post.  (They’re huge.)

Wearable monitors. Efforts to collect information on abnormal movement from home using wearable devices started years ago and was accelerated by the pandemic.  A project of that sort in PSP started last year under the leadership of my research colleagues Drs. Alex Pantelyat and Anne-Marie Wills of Johns Hopkins and Harvard, respectively.  An interim report on the first 7 patients to complete 12 months of observation, with the lead author Dr. Mansi Sharma of Massachusetts General Hospital, shows that the remote measurements correlate well with the PSP Rating Scale and PSP Quality-of-Life Scale.  The eventual goal is to find ways to efficiently measure PSP progression for the purpose of evaluating large numbers of drug study subjects who live far from the study center or have difficulty traveling.

Sex difference. Clinical drug trial designers are always looking for ways to eliminate sources of “statistical noise” that could obscure an effect, good or bad, of the drug being tested.  A group led by Dr. Leonardino Digma of UCSD and the Carlos III Institute of Health in Madrid used data from the TAUROS study, published in 2014, which found that the drug tideglusib failed to slow the progression of PSP over its 12 months of double-blind treatment.  The new analysis found that while the men and women had similar verbal fluency at the start of the TAUROS study, that ability declined faster in men.  This suggests that future drug trial designers should take sex of the participants into account in calculating whether their experimental treatment has slowed the rate of decline of verbal fluency.

Amantadine. Way back in 1993, I published a review of the records of the 87 patients with PSP I had seen up to that point with regard to their responses to all the drugs they had received for that condition.  An unexpected result was that amantadine, one of the standard drugs for Parkinson’s disease back then, helped at least as much as anything else.  That publication prompted me and many other neurologists to routinely try amantadine in their patients with PSP.  Now, Dr. Nikolaus McFarland et al at the University of Florida have reviewed records of their 350 patients with PSP to tabulate amantadine responses.  Of the 42 patients who received the drug and had an adequate record of the results, 5 improved, 30 had no benefit or a worsening, and 7 were unsure.  The most common side effect, occurring in 6 patients, was confusion or hallucinations.  So, about 10-15% of patients with PSP will benefit and a similar number or a bit more will have important side effects that will abate after discontinuation of the drug.  That’s why I recommend that amantadine be tried – with close observation and follow-up – in everyone with PSP who does not already have important cognitive difficulties or other symptoms, such as constipation, that amantadine could exacerbate. 

Tau PET. A positron emission tomography (PET) tracer variously called 18F-PM-PBB3, 18F-APN-1607 or 18F-florzolotau has successfully undergone small, preliminary studies and will soon enter a larger, more definitive, “pivotal” trial.  As a supplementary method of validation, Dr. Hironobu Endo et al of Chiba University and Niigata University in Japan obtained PET images using that tracer in a patient with far-advanced PSP.  After the patient died a year later, his brain autopsy showed that the locations and intensities of abnormal tau in the autopsy tissue as revealed by traditional anti-tau antibody staining correlated very well with those in the PET images.  This result, albeit in only a single patient, provides additional support for the utility of this tracer as a diagnostic tool for PSP. (Disclosure: I’m a consultant for Aprinoia, the company developing this tracer in the US.)

Anatomic origin. Dr. Edoardo Spinelli et al of San Raffaele University in Milan and Mayo Clinic Rochester report their use of functional MRI to map out the anatomical origin and subsequent pathway of spread of the PSP process in the brain.  They found the origin to be the left midbrain tegmentum.  (The tegmentum is covered by the tectum, or “roof,” site of the vertical gaze centers, and in turn, covers the base, or “peduncles, ” site of the main motor control tracts.  I assume that the specific spot in the tegmentum is the substantia nigra, which has long been known to be one of the three nuclei in the brain where PSP first appears.)  Furthermore, they found that as the disease progressed, areas became involved in order of directness of connectivity to the left midbrain tegmentum.  I, for one, was surprised to learn that the origin had such a clearly asymmetric origin starting on the left in all, or most, patients.

Could calcium be the key?

A powerful way to find causes and cures for diseases that occur in its common, non-familial pattern (which we call “sporadic”) is to find and study the genetic mutation(s) causing the same disease to occur in a rare, familial pattern.  The protein(s) encoded by those genes can then be investigated for a non-genetically-determined role in the sporadic form of the disease.

I know this from my own experience studying Parkinson’s disease.  In 1990, I found and worked up a large Italian-American family that, long story short, proved to have 61 members with PD over 5   generations.  My colleagues and I found the mutation, which was in the gene encoding alpha-synuclein, a protein not previously suspected of a relationship to PD.  That protein then proved to have a central role in sporadic PD even though virtually no one with that form of the disease has a mutation in that gene.  Now, treatments and diagnostics aimed at that protein are being tested.

That’s one reason I was excited to see a paper published this week by researchers mostly at Washington University in St. Louis, with contributions from UCSF, the University of Sao Paulo, Brazil, and the Neural Stem Cell Institute in Rensselaer, NY.  The first author was Miguel Minaya, PhD, a molecular geneticist working at WUStL in the lab of Celeste Karch, PhD, with whom I’ve collaborated in the past.  Her lab is a world leader in using stem cells to model neurodegenerative diseases.

There are 50 mutations in the MAPT gene (which encodes tau protein) that produce a hereditary disease that looks a lot like PSP at all levels and is called “frontotemporal lobar degeneration with mutations in the tau gene” or FTLD-tau.  The researchers divided those mutations into 3 logical groups based on their mechanism of action and chose one mutation from each group to test.  To do that, they used stem cells derived from skin biopsies of people with one of the three chosen mutations.  They measured those cells’ “expression” of all the other genes.  (Gene “expression” means how active a gene is in actually encoding its protein, as measured by levels of its specific messenger RNA.)  They created control group of stem cells by using the gene editing tool CRISPR to correct the PSP-causing mutation.  That way, the disease cells and the controls were genetically identical except for that one mutation.

They found that the expression of 275 of the 20,000 human genes differed in the uncorrected stem cells compared to the corrected stem cells.  What many of those 275 had in common, they discovered, was that they helped control calcium levels inside the cells.

The experimenters next did the obvious and looked at calcium levels in the two sets of stem cells, finding lower levels in the uncorrected group.  That showed that these genes known to affect calcium were actually doing so, as opposed to only theoretically doing so.  They obtained additional confirmatory evidence by imaging calcium in the cells and analyzing gene expression in mice carrying mutated versions of the human tau gene.

Next, and here’s the real payoff, they did the 2020s version of what was done with our alpha-synuclein discovery back in the 1990s: They used an existing database of gene expression measurements from autopsied brains with sporadic PSP and from autopsied brains with no neurodegenerative disease.  The database showed that for 63 of the 275 genes, there was an alteration similar to what was found in the stem cells from the people with FTLD-tau.

What does it all mean?  It means that drugs regulating the calcium content of brain cells may be candidates for things that might slow the degenerative process in PSP.  Such drugs would likely be convenient oral meds, including some mentioned by Dr. Minaya and colleagues that are already on the market for other conditions.  These include tramadol (for pain), ethosuximide and oxcarbazepine (for seizures), levodopa (for Parkinson’s) and nicotine* (for enriching tobacco companies).

Something else it means is that this innovative (because of its use of stem cells and large arrays of expression data) experimental approach can now be used to study any sort of brain disease that’s strongly hereditary or where there’s a rare hereditary form.

*I know what you’re thinking.  Don’t.

A bit of help with prognosis

A paper of mine just hit the streets today.  Actually, the idea and most of the work came from an old friend and colleague at the University of Chicago, Dr. Tao Xie.  (His last name is somewhere between “she” and “chee” and his first name is perfect for a PSP researcher.)  Here’s the story of that project, from the beginning.

From 1994 to my retirement from practice in 2020, I kept a careful record of the PSP Rating Scale (PSPRS) results in all 526 patients I saw with PSP.  The database includes each patient’s sex, birth year, month/year of PSP symptom onset, and death month/year (if deceased).  For each visit, I recorded the month/year and each of the 28 PSP Rating Scale item scores.  Back in 2020, some other colleagues and I published a paper on how to use the raw PSPRS scores to help predict prognosis in individual patients.

Tao asked if he could use my database, with my formal collaboration, to find a better way of predicting long-term survival.   He said he didn’t just want to look at raw scores – he wanted to look at their magnitude and rate of progression at one critical point: the time when the person first developed difficulty looking down.  That’s easily approximated by finding the date of the visit when the score on the PSPRS item for downgaze first exceeded zero.  He would then correlate those “input variables” with, as “output variable,” the patient’s overall survival.  The progression rate would be calculated as the raw item score divided by the number of years since PSP onset.  I said, “great idea.”  

Why choose the onset of downgaze palsy as the benchmark?  That’s when the insidious pathological process of PSP has first broken out of its three places of origin in the brain: the substantia nigra, the subthalamic nucleus and the globus pallidus.  Why it starts in those three places is a mystery, but from there the abnormally folded tau protein molecules travel along the axons to other places, and pretty much their first stop is the area where downgaze is controlled, in the dorsal midbrain.  (Perhaps relevantly, downgaze palsy is by far the most “specific” feature of PSP, meaning that of all of the disease’s features, that’s the one shared with fewest other diseases.)

So, Tao figured that once the process gets to the downgaze area, it has emerged from its birthplaces and is on its unfortunate way to other parts of the brain, probably at whatever speed is specified by the individual’s particular chemical and genetic makeup.  Because that rate of transmission varies among individuals with PSP, it makes sense to measure the progression rate of PSP as of that stage of the disease rather than at a one-point-fits-all stage such as a set number of years after symptom onset.

Here’s what we found:  The shorter survival is associated with older onset age and, as of the time of initial downgaze palsy, the PSPRS item scores for 1) difficulty swallowing liquids and 2) difficulty arising from a chair.

So, what does this mean?  For care of an individual patient, the neurologist’s recommendations might be shaded to an extent by the knowledge that the patient’s future course will be more – or less – favorable than the published averages for PSP.  In a large clinical trial, the statistician analyzing the data might want to achieve a more valid comparison of the active drug and placebo groups by weighting the progression data according to these factors. 

Yes, research proceeds in small steps, but proceed it does.

A rescue operation

It’s been 26 days since my last post.  Sorry.  I’ve been very busy with some consulting for drug companies and with co-authoring a research paper.  You’ll hear more about the fruits of those labors before too long.  But for now, I have some good news about a new drug:

Back in 2015, I reported to you on a conference presentation by the CEO of a tiny Swiss company called Asceneuron (“uh-SEH-nu-ron”).  They had a promising group of nearly identical drugs for PSP that were just entering the mouse testing stage.  Since that time, one drug has emerged from among its littermates as the leading candidate and has acquired the code name, “ASN90.”  Here’s that blog post’s maybe too-technical explanation of its mechanism of action:

All of the OGA inhibitors being developed are small molecules suitable for oral administration. . . . [These drugs reduce] tau aggregation by inhibiting OGA (O-GlcNAcase; pronounced “oh-GLY-na-kaze”). That enzyme removes the sugar N-acetyl-beta-D-glucosamine from either serine or threonine residues of proteins. The opposing reaction, catalyzed by O-GlcNAc transferase, like other post-translational modifications, is a common way for cells to regulate proteins. In the case of tau, having that sugar in place reduces aggregation.

In other words, ASN90 works via the ancient drug mechanism of inhibiting the action of an enzyme.

Since 2015, ASN90 has emerged from its littermates as Asceneuron’s favored OGA inhibitor.  It has passed its tests for efficacy in animals and for safety in three small trials in healthy humans and now it’s ready to be tested in people with PSP.  But Asceneuron has had trouble finding the multiple millions in funding for that, so for the past few years, poor ASN-90 has been languishing. 

But now, Asceneuron has announced that it has licensed ASN90 to a big Spanish drug company called Ferrer, which is ready to start a Phase II trial!  Cool!  That’s all I know so far, except that the drug also has potential in Alzheimer’s disease. I also know that Phase II trials in PSP typically need 6 months to organize, 6 months to fully recruit, 12 months as the double-blind treatment duration and another few months to organize the data’s loose ends and analyze the results. That’s about 2 to 2½ years — and then it takes a few months for the FDA has to scrutinize the results and issue its decision, and then it takes more time for the company to ramp up production and distribution.

Hope matters.

In case you don’t know, Phase II trials may be open-label or double-blind and serve mostly to test the safety and tolerability of the drug in people with the target disease, as opposed to healthy volunteers.  Such trials also help establish the optimal dosage needed to minimize side effects while keeping the dosage high enough to accomplish its job in the brain, based on previous lab and animal data.  Phase II trials often have a “multiple ascending dose” phase to establish the optimal dosage before proceeding with the main part of the trial using that dosage. When a Phase II trial is double-blind and sufficiently large, it can also serve as a test of efficacy.  In the past, the FDA has indicated that when it comes to PSP and other serious, rare diseases without existing treatment, a moderate-size (i.e., about 200-400 patients) Phase II trial with highly favorable safety and efficacy results would be enough for it to approve the drug. Ordinarily, for drugs targeting conditions that already have good treatments on the market, the FDA demands at least one larger Phase III trial, sometimes two.

I’ll report back the moment I know more, including the locations of study sites for Ferrer’s drug trial.

The sincerest form of flattery

A reader just commented, “What other diseases can mimic PSP?” Below is a pretty exhaustive list of things that can cause vertical gaze palsy*, the most specific** diagnostic hallmark of PSP. Most of these disorders don’t mimic the whole classic PSP syndrome, but even PSP doesn’t do that in many cases. Keep in mind that most of these mimics have other features besides the gaze palsy, occur at much younger ages than PSP, or are exceedingly rare. For all those reasons, a good neurologist is unlikely to confuse these conditions with PSP in practice.

The disorders with specific treatment (though maybe not cures) have three asterisks ***.

*”Palsy” in general means weakness (not tremor, as popularly thought). In the setting of PSP, palsy refers to a limitation of the range of voluntary eye movements.

**The “specificity” of a diagnostic sign is technically the fraction of the people without the disease who don’t have the sign. In other words, specificity = [true negatives] divided by [true negatives + false positives].




  • Amyotrophic lateral sclerosis
  • Corticobasal degeneration
  • Dementia with Lewy bodies
  • Frontotemporal dementia with tau staining
  • Frontotemporal dementia with ubiquitin staining
  • Globular glial tauopathy
  • Lytico-bodig
  • Motor neuron disease with congophilic angiopathy
  • Multiple-system atrophy
  • Pallidal degeneration
  • Parkinson disease (only upgaze affected)***
  • PSP


  • Normal-pressure hydrocephalus***
  • Pineal region masses***
  • Third ventricular enlargement***

Metabolic / Genetic          

  • B-12 deficiency***
  • Huntington disease
  • Neuronal intranuclear inclusion disease
  • Niemann-Pick disease type C***
  • Spinocerebellar ataxia type 8
  • Tay-Sachs disease, adult-onset (hypometric vertical saccades)
  • Wernicke encephalopathy***
  • Wilson disease***


  • Anti-phospholipid syndrome***
  • Anti-IgLON4 disease***
  • Paraneoplastic syndromes***
  • Postencephalitic parkinsonism***


  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  • Lacunar states (“vascular PSP”)***
  • Post-aortic surgery


  • Whipple disease***
  • Neurosyphilis***


  • Guadeloupean tauopathy


  • Creutzfeldt-Jakob disease


This morning I received an email from a CurePSP support group leader in Texas forwarding a local newspaper clipping about a young girl in Taiwan with a genetic metabolic defect of the brain who had received a form of gene therapy.  She asked if that approach could be of potential use against PSP.

Here’s my answer:

For decades, a routine neuroscience laboratory tool has been to inject the brain with a harmless virus, called a “vector,” carrying a gene to induce brain cells to manufacture that gene’s protein product.  This has been useful in PSP research. Before long, the same idea could become a treatment for patients with neurodegenerative diseases.  The main drawback is that it requires a neurosurgical procedure to inject the virus with the therapeutic gene into the specific spot(s) in the brain where it’s needed. 

This approach has worked in early-phase trials in people with Parkinson’s disease, where cells that make dopamine are degenerating, and is continuing safety studies in PD.  The gene in those trials encodes the enzyme AADC (aromatic amino acid decarboxylase), which controls dopamine’s rate of production.  AADC mutations do not occur in PD, but the girl in Taiwan who received the gene therapy was suffering from an inherited deficiency of AADC, causing delayed neurological development. 

This sort of gene therapy, but using MAPT, the gene for the tau protein, has been used in PSP research to produce a rat model for use in testing new treatments.  The company sponsoring the AADC deficiency trial in Taiwan is developing an MAPT gene therapy for the rare form of frontotemporal dementia caused by mutations in MAPT, called FTDP-17.  Unfortunately, PSP, unlike AADC deficiency or FTDP-17, is not caused by a single mutation in a known gene, so it would not be amenable to having that gene replaced by this sort of gene therapy.  It’s true that PSP, like PD, includes a dopamine deficiency, but PSP would not respond to AADC gene therapy for the same reason it doesn’t respond to L-DOPA (which is converted by the body into dopamine): the brain cells on which dopamine acts degenerate in PSP. 

The hopeful note, however, is that if a compound such as a growth factor protein or an anti-sense oligonucleotide (ASO) is found to help PSP, a gene for that compound could, in theory, be inserted into a viral vector and injected into the brain.  That could provide a steady, lifetime supply of the compound.



Today is Martin Luther King Day, and here’s one of his best quotes, from 1968:

“We must accept finite disappointment, but never lose infinite hope.”

Fast-forward to the 1980s, early in my career as a neurologist mostly for patients with incurable movement disorders.  I rapidly learned that besides objective diagnosis and treatment, my agenda at patient visits should include an old-fashioned pep talk along with an update on research.  Now, I had grown up in a culture where such “touchy-feely,” subjective things were far subservient to scientific thinking, and my medical education was no different.  So, once I was out in the real world of patient care, it was kind of a revelation to discover that a simple, subjective appeal to hope could sometimes alleviate more suffering than any medication, therapy or surgery I could prescribe.

Fast-forward again to 2004, at which point I had been CurePSP’s Clinical and Scientific Director for 14 years, and a new CEO named Richard Zyne arrived.  He was an ordained minister who spent his career mostly with non-sectarian, non-profit organizations.  As a clergyman, he well knew the value of hope in helping people deal with adversity, and he quickly made “Because Hope Matters” CurePSP’s tagline.

I’ll admit I was skeptical at first.  I thought that providing hope was the doctor’s job at an individualized, “retail” level in the exam room and that CurePSP should support research, educate patients and clinicians, and help find ways to bring the best available care to all who need it.  But working with CurePSP showed me the value of a national organization with multiple communication platforms in reassuring patients and families that scientific understanding of PSP is advancing, that similar diseases are slowly yielding to new treatment, that more researchers and journal articles are devoted to PSP than ever, and that a well-run non-profit organization is in their corner. In other words, I again discovered that hope matters, but now at a more “wholesale” level.

The idea for this blog post entered my mind from the proximity of MLK Day and my post from four days ago, where I reported the failure of one PSP drug candidate but offered hope for five others currently in clinical trials.  In fact, regular readers of this blog know that I try to infuse hope into every post rather than merely reporting the news objectively.  For the ability to understand the value in that, I thank my patients, Richard Zyne – and Dr. King.

We just have to keep trying

I have some bad news.  Another experimental drug has failed to slow the progression of PSP.  The double-blind Phase 2 trial of RT-001 in 40 participants took place in Munich, Germany.  The company, BioJiva, has given me permission to discuss this ahead of their press release.

RT-001 has a unique mechanism of action.  It’s based on the ample evidence that a major part of the problem in PSP is an attack on brain cells’ membranes by “reactive oxygen species.”  ROS, a product of dysfunction of the mitochondria, damage the fatty acids, a major component of cell membranes.  The drug is one of those fatty acids, linoleic acid, but with a twist.  Two of the hydrogen atoms in the molecule are replaced by deuterium, which is hydrogen with an extra neutron in its nucleus.  (Water made with deuterium instead of hydrogen is called “heavy water.”)  The drug is incorporated into the membranes as if it were ordinary linoleic acid, but the two deuteriums protect it against attack by the ROS. 

Sound crazy, you say?  Naïve, maybe? Well, it may actually work in another disease with too much ROS activity, amyotrophic lateral sclerosis!  BioJiva announced last year that an early-phase trial in ALS gave favorable, albeit undramatic results, with a 23% slower rate of decline relative to the placebo group.  So, the company will continue to pursue work with RT-001 in ALS, but not in PSP.

But take heart, PSP community.  There are still five PSP neuroprotection trials in progress using fasudil, TPN-101, NIO-752, sodium selenate, and AZP2006.  Then, of course, there are multiple trials of “symptomatic” treatment.  See my recent post for details.

Which of those five PSP neuroprotection candidates is most likely to work?  I wish I (or anyone) knew enough about the molecular and cellular abnormalities underlying PSP to answer that question.

Disclaimer:  I don’t own any stock in BioJiva or have any other financial relationship with them.  Their Chief Medical Officer gave a presentation on the then-ongoing trial at CurePSP’s “Neuro2022” symposium in New York in October, where I was one of the organizers and moderators.

Great PR, so-so accuracy

Two full weeks since my last post – holiday activities, don’t you know, starting on December 21 with a solstice party at the home of an eccentric friend.   I see that my blog viewership has declined precipitously in the past week, so I’m happy that you all have better things to do at holiday time than to read about PSP.  Don’t we all wish that the disease itself would take a few days off, too?

My re-emergent thought is about the famous “hummingbird sign.”  On an MRI scan in the sagittal plane – that’s as if you sliced someone down the middle and looked at the cut surface – the brainstem sort of looks like a side view of a hummingbird. 

In the MRIs above, the nose is on the left.  In the lower images, the arrows stop just short of the indicated structures so as not to obscure them.  Note the progressively thinner, sleeker midbrain (the hummingbird’s head and beak) with retention of the plump pons (the belly, which is plumper than than that of a real hummingbird). 

Now here’s the issue.  The appearance of the hummingbird sign isn’t as closely related to PSP as has been implied by many.  There are just too many false positives and false negatives. 

The false positives mostly occur in people with normal-pressure hydrocephalus, a condition where the fluid-filled spaces in the brain (the “ventricles”) enlarge because of an obstruction in the re-absorption of the fluid into the bloodstream.  This stretches the fibers adjacent to the ventricles, impairing control of gait, cognition and the bladder.  It also presses down on the midbrain, producing the hummingbird sign.  Then there are those individuals with corticobasal degeneration where the features resemble PSP (“CBS-PSP”).  They can also have a hummingbird sign.

The false negatives occur in the first couple of years after the initial symptoms.  They also occur if the MRI is mis-aligned on the brain or the head is a little rotated, producing an allegedly midline cut that’s actually a couple of millimeters to one side.  That means that the thinnest part of the midbrain, which is in the midline, isn’t shown in the image. 

You should also know that the hummingbird sign isn’t just about a thin midbrain.  A normal pons is also part of the sign.  That’s because in multiple system atrophy and a few rarer disorders, both the midbrain and pons become thinner.  But in PSP, it’s mostly the midbrain that does so.

I think that in the next year or two, a test of the tau protein in spinal fluid, blood or a tiny punch biopsy of skin will provide a much more accurate diagnosis of PSP than the hummingbird sign.  Soon thereafter we will probably have a PET technique that does the same. Then, clinical treatment trials can be accomplished faster because they won’t have to compensate for the statistical noise produced by participants with a false positive diagnosis.  In fact, all sorts of research on PSP will become much more powerful if people without PSP can be excluded. 

All my best for the New Year.