What’s good for the goose . . . ?

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Biogen is currently testing an anti-sense oligonucleotide drug called BIIB-080 in patients with mild cognitive impairment and very mild Alzheimer’s disease. The goal would be to slow or prevent their conversion to full-blown Alzheimer’s disease. Today someone posted a comment asking if I thought this could work for PSP. I thought this could make a good, brief post:


Biogen has an early-phase trial of BIIB080 in Alzheimer’s, and there’s no reason to think it wouldn’t work as well in PSP.

Actually, the Alzheimer’s trial is mostly for people with “mild cognitive impairment” and the measure of success would be preventing progression (“conversion,” as it’s called) to full-blown Alzheimer’s. They are also enrolling some patients with mild AD, hoping to prevent progression to moderate stages. If the people at Biogen feel that BIIB080 should first be tested in such an early disease phase, that could be why they chose Alzheimer’s over PSP: there is no known equivalent of mild cognitive impairment for PSP.

Another reason Biogen might be starting with AD is the ready availability of a test for beta-amyloid in the brain in the pattern specific for that disease. It’s called an Amyvid scan, and participants in the BIIB080 trial have to show an AD pattern on the scan to qualify. There is no equivalent, road-tested, sensitive and specific diagnostic test for PSP, which means that a much larger trial would be necessary to overcome the “statistical noise” caused by people with a false-positive diagnosis of PSP.


The diagnostic criteria for PSP do define a state called “suggestive of PSP,” but there are still no data on what fraction of those individuals eventually progresses to probable or definite PSP, or how long it takes. On the other hand, there are excellent such data on the conversion of MCI to Alzheimer’s.


A couple of examples of symptoms that would result in a diagnosis of “suggestive of PSP” are repeated falls and slow downward eye movements. As you can tell, such symptoms in isolation are not very specific for PSP, so a trial enrolling such patients would have to have many hundreds of particicpants for a statistically useful fraction of them to convert to possible, probable of definite PSP, especially over only a 12-month period. Furthermore, the size of the trial would have to be large enough for the conversion rate among the recipients of the active drug to be validly compared to the rate among those on placebo.


So, my guess is that if BIIB080 works in mild cognitive impairment and very mild AD, Biogen will test it in PSP. But if a good pre-clinical marker for PSP becomes available, then it would much more practical to try such treatments in pre-clinical PSP.

But there are other drug companies with other anti-tau ASOs. One, from Novartis, is already enrolling patients. Others are approaching clinical trials.

A downside to the back-door approach

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Someone wrote asking if they should seek a fecal microbiota transplant (FMT) for their spouse with PSP. (See yesterday’s post, which reports on a favorable double-blind trial.) Of course, I replied that I can’t give individualized medical advice, but it occurred to me to write this post to mention two downsides that I didn’t mention yesterday.

One problem is that drinking the huge volume of fluid for the 3 bowel preps could be very difficult for someone with PSP. It typically requires drinking a 8 full 8-ounce glasses of a salty-tasting stuff over 2 hours (i.e., one glass every 10-15 minutes) the night before the procedure and then repeating the same thing on the morning of the procedure. That’s 64 ounces twice, which totals one gallon. That has to be repeated at 4 weeks and again at 8 weeks for the other 2 coloscopies/transplants. All those fluids could invite aspiration. I don’t know if using a thickener would be permitted, but that’s not a full guarantee against aspiration, and the mere exertion of the swallowing muscles might not be possible for someone with more than mild PSP.

The other issue is finances. Colonoscopies are expensive — my survey on line suggests an average professional fee of $2,000, another fee for the facility and another for the bacteria to be transplanted. Then, multiply by 3 for the 3 steps in the FMT. I doubt that any public or private insurer would pay for this for someone with PSP, where it’s not FDA-approved. The insurers know that quacks offer FMT for many medical conditions with no proper double-blind trials as evidence of benefit and safety. The insurers may simply lump PSP in with those conditions despite the one small positive trial from China, and it’s hard to argue with them on that.

So, I’ll leave this to the judgment of my commenter’s spouse’s own doctor and to that of the gastroenterologist who would be doing the procedures.

A back-door approach

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For the past few years, fecal microbiota transplantation (FMT) has been part of mainstream medicine’s treatment for a nasty, antibiotic-resistant intestinal infection by the bacterium Clostridium difficile.  Essentially, the idea is to replace the person’s colonic bacteria with a new set obtained from the stool of healthy people.  The new bacteria are introduced to the junction between small and large intestines via coloscopy after a standard bowel prep.  

On the theory that immune-related diseases could be a result of some poorly-characterized problem in the colonic bacteria, clinics have sprung up to use FMT for things like inflammatory bowel disease and multiple sclerosis.  PSP is a disease for which evidence of abnormal immune function has been accumulating.  Furthermore, constipation occurs in PSP to a far greater degree than abnormalities in other autonomic nervous system abnormalities such as urinary incontinence or low blood pressure.  This vaguely suggests that an abnormality of intestinal bacteria could underlie PSP in some way.

A trial of FMT in PSP appears in the current issue of the prestigious British journal The Lancet from a research group at Zhengzhou University in Zhengzhow, China led by Dr. Haiyan Tian with senior author Dr. Xuejing Wang. They randomly assigned 68 people with newly-diagnosed PSP (averaging 2.6 years since onset) to receive identical bowel preps followed by either FMT or placebo transplant, which was a colored saline solution.  Neither the patients nor the researchers performing the transplantations or evaluations knew the treatment assignments.  That is, it was a proper randomized, double-blind trial. 

Each patient received 3 such transplantation procedures – at 0, 4 and 8 weeks.  The patients were examined periodically over 36 weeks using the PSP Rating Scale (PSPRS) at 16 weeks as the “primary outcome measure.” They also received a long list of other standard tests and chemical measures in the stool as secondary outcome measures. 

The result was that at Week 2 (i.e., 2 weeks after the first procedure), the PSPRS, which averaged 40.1 in each group at the start, improved by 1.5 points in the FMT group and worsened by 0.2 points in the placebo group (as expected), for a total “treatment effect” of 1.7 points.  At Week 7, the treatment effect was 2.8 points; at Week 12, 4.8 points; at Week 16 (the “primary” outcome), 4.3 points; and at Week 36, 3.8 points. 

The researchers confirmed that the FMT group’s post-treatment stool had lower levels of inflammation-related compounds than that of the placebo group.  Side effects, all of them minor and transient gastrointestinal symptoms, occurred in 3 patients in the FMT group and 2 in the placebo group.

Taken at face value, this is good news – the primary outcome measure reduced the PSPRS by 4.3 points relative to placebo, which is (4.3 / 40.1 =) a 10.7% improvement. 

Let’s keep several things in mind:

  • As a comparison, the average person with PSP worsens about 11 PSPRS points per year, so a 4.3-point improvement is the equivalent of erasing about 5 months’ progression.  In these 68 patients, the progression before the trial was much faster, averaging 15.4 points per year, possibly because they all had PSP-Richardson syndrome, the most rapidly-progressing form of PSP.  So for them, a 4.3-point improvement is the equivalent of only 3.4 months of progression.
  • This is not a trial of neuroprotection, where the treatment is attempting to slow the long-term progression of the underlying disease process.  Although FMT, in theory, could do that, this particular trial measured only short-term improvement in outward signs and symptoms. We call that “symptomatic treatment,” and that’s what all existing treatments for PSP do for specific symptoms with various degree of success.
  • As you can see from the PSPRS scores above, the benefit started to wane at about Week 12, which was about 2 months after the third transplant.  We only have subsequent measurements at Weeks 16 and 36, so we don’t know how soon another round of 3 transplants would have to be repeated in order to maintain an acceptable degree of improvement.  Hopefully, these researchers are continuing to observe and examine these 68 patients and will report longer-term results.

Bottom line:  I interpret this as a “proof-of-concept” study.  That means that even though the trial’s procedure might not be practical as routine treatment, the results (assuming they’re confirmed by studies elsewhere) show that revising the colonic bacteria can do good things for PSP, at least in the short term. 

Next steps are to:

  • Measure the duration of benefit from the three FMTs;
  • Devise an orally-administered capsule of bacteria that is safe and can accomplish the same thing;
  • Mount a neuroprotection trial, which requires about 200 patients on FMT and another 200 on placebo to detect a 25% slowing of progression.
  • And most importantly, figure out what biochemical action the old bacteria were doing wrong that the new bacteria are doing right, and accomplish the same effect in a simpler way.

Then there’s this minor question: How and why do some people acquire a set of colonic bacteria that increase PSP risk and how can that be prevented?

A peek at research coming down the pike

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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?

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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

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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

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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

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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].

———

DISORDERS WITH VERTICAL GAZE PALSY IN AT LEAST SOME CASES

Degenerative

  • 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

Structural           

  • 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***

Immune              

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

Vascular              

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

Infectious          

  • Whipple disease***
  • Neurosyphilis***

Toxic    

  • Guadeloupean tauopathy

Prion

  • Creutzfeldt-Jakob disease