Anti-sense oligo update

CurePSP asked me to write up something on ASOs for their website ( Thought I’d give my loyal blog readers a sneak peak:

Probably the single biggest story in the world of PSP right now is NIO752.  That’s an antisense oligonucleotide (ASO) being tested for safety and tolerability in people with PSP.

ASOs interrupt the process by which a specific gene’s DNA is transcribed into RNA, thereby reducing the production of the encoded offending protein.  The ASO itself is a short stretch of RNA whose genetic code is a mirror-image of part of the DNA whose translation is to be suppressed.  The ASO’s genetic sequence and that of the offending DNA recognize each other and stick together, preventing the corresponding protein from being produced. In this case, the targeted DNA is the MAPT gene, which encodes the tau protein. Other ASOs operate by targeting slightly different stages of the transcription/translation process.

In the US, the FDA has approved several kinds of ASO, the best-known being nusinersin (brand name “Spinraza”) for spinal muscular atrophy, a progressive and usually fatal condition that typically starts in infancy but in mild forms can start at any age.  In the pivotal trial of nusinersen, 21 of 51 infants receiving the drug were improved after 6 months, while that was true for none of the 27 infants receiving sham treatment.  If we can achieve similar results for NIO752, it would be by far the best news ever for PSP.

ASO molecules are too large to cross the blood-brain barrier, which means that for a brain disease, they must be administered by injection directly into the spinal fluid.  This is performed as for a diagnostic spinal tap.  In the current trial, NIO752 is given once monthly over a period of 3 months and the participants are examined periodically for an additional 9 months.  The 64 participants are at 4 sites in the US (La Jolla, CA; Boca Raton, FL; Rochester, MN and Nashville TN), 2 in Canada (both in Montreal), 5 in Germany and 1 in the UK. This safety and tolerability trial is expected to end in May 2024.  Its sponsor is Novartis Pharmaceuticals, co-headquartered in Basel, Switzerland and Cambridge, MA. For more information: 1-888-669-6682 or

A trial can detect important safety issues with only 64 participants but detecting actual benefit requires more.  The standard “primary outcome measure” for clinical treatment trials in PSP is the PSP Rating Scale.  Assuming that is still the case in 2024, when a treatment trial would begin, and half of the participants receive placebo, the minimum number of participants needed would be 276.  That number also assumes that the study is designed to detect at least a 30% difference between the two groups’ rates of progression.  Detecting less of a difference would require more participants and detecting a greater difference would require fewer.  A new outcome measure with less variability than the PSPRS would reduce the number of participants required.

From the standpoint of those with PSP and their families hoping to enter a trial of NIO752, the most important number isn’t a number, but a date: A trial starting in mid-2024 would probably end in 2027. Another important number is the eventual price of the drug.  NIO752 would have to be injected every month, lifelong. Nusinersen’s price is $125,000 per injection.  So, if the price of NIO752 is anything like that, the cost to Medicare, Medicaid and private insurors would present an impossible situation.  CurePSP estimates that about 20,000 people in the US have PSP at any given time.  If even half of them received a $125,000-per-month drug, the total annual cost would be $15 billion plus the doctors’ fees for the monthly injection procedure.  Clearly, something would have to give. 

But first, let’s hope that NIO752 actually works.

Executive dysfunction, as it were

A major announcement: There’s now evidence that an important factor in the cause of PSP are variants in two “regulatory genes” called PLEKHM1 and KANSL1, both of which are very near the MAPT (tau) gene on chromosome 17. 

Regulatory genes are not encoded into protein.  Rather, they affect the rate at which other genes are transcribed into protein, kind of like business executives or military officers directing the activities of others.  Such proteins are called “transcription factors.” The project identified the gene being regulated in this case as SP1, which encodes the protein called Sp1 (note the lowercase p; the fewer abbreviations in science, the better, I always say). SP1 is located on chromosome 12 and works in tandem with a group of other genes to regulate many cellular processes. 

As a comparator, the researchers used samples from people with Alzheimer’s disease, finding that it involved a different set of regulatory genes that did not interact with SP1.  This result could allow drugs that regulate the Sp1 protein or gene-directed therapy for the PLEKHM1 or KANSL1 genes to be developed as treatment or prevention for PSP. The new finding’s significance is underscored by its publication in Science, one of a small handful of top general scientific journals. 

The research was a collaboration between the highly productive neurodegenerative genetics groups at UCLA and UCSF, with Drs. Daniel Geschwind and Martin Kampmann, respectively, as senior members.  The first author was Yonatan Cooper, an MD/PhD student at UCLA.  In response to my email, Yonatan commented, “A key challenge in modern medicine has been interpreting genetic risk factors [for diseases of complex causation] and translating them to understand disease mechanisms. This is especially true for the 17q tau locus, which is the major genetic risk factor for PSP.  The approach that we used was crucial to allowing us to identify these new genes in that region.” 

The “approach that we used” in Yonatan’s quote is called a “massively parallel reporter assay” (MRPA).  It assesses thousands of single-nucleotide DNA variants for their ability to regulate other genes’ protein expression levels.  For this study, the researchers chose the region close to the two variants in or near the MAPT gene found in 2011 by the PSP Genetics Consortium and funded by CurePSP.  That region comprises hundreds of genes, any of which could be actual source(s) of the PSP risk in that region of the genome.

That 2011 study used “single-nucleotide polymorphisms (SNPs)” in DNA from autopsy-confirmed PSP brain tissue and control subjects.  Even now, 11 years later it remains the most informative single study on the genetics of PSP.  (Disclosure: I was a minor co-author.)  It identified a handful of regions across the genome where a marker differs between the two groups, implying that a gene near each marker contributes to the cause of PSP.  Two of those markers were in or near MAPT.  But that technique can’t positively incriminate which of the hundreds of genes in that region of chromosome 17 actually cause(s) the disease.  The current study did that by testing all of the thousands of variants in those genes for their ability to alter protein production in a way that could help cause PSP. 

One next step is to look for drugs or other treatments to counter the effect of these two regulatory abnormalities on the function of the SP1 protein and/or a protein with which it interacts.  Another next step is to use the same technique to look for other regulatory genes near the other PSP-related markers identified in the 2011 SNP study and more recently and to look for drug targets in the protein products of the genes they regulate.

I don’t know about you, but I’m nerdy enough to be very excited about this!

Thinking out loud

I’m making a list of clinical topics to be covered in CurePSP’s next annual scientific conference.  That task made me think carefully about what’s important to clinicians seeking to stay current on PSP and CBD.  So, I thought I’d share that list with you all, for what it’s worth.  Keep in mind that the laboratory research end of things will be a separate list.

  • Clinical spectrum and its pathology
  • Clinical aspects of genetics and epigenetics
  • Fluid biomarkers             
  • PET biomarkers
  • MRI biomarkers
  • Clinical outcome measures (rating scales, wearables, eye movement, gait measures, etc)
  • Gene therapy
  • Tau-directed drug trials
  • Mitochondria-directed drug trials
  • Gait retraining
  • Current best practices in symptomatic care

Plug and play

My last post was about an on-line tool to assist in reading MRI scans to differentiate PSP from some other diagnostic possibilities.  But the formal diagnostic criteria for PSP are still based on traditional history and neurological exam, with MRI as a confirmatory adjunct. This post is about an on-line tool to assist physicians in using those formal criteria.

Starting in the 1980s, a number of researchers, including me, published diagnostic criteria for PSP.  Although these were later validated by autopsy results, they were not so at the time of publication.  Just as important, they tended to be either insufficiently sensitive or insufficiently specific (see my preceding post for definitions of those).  You want sensitivity if you’re trying to measure the prevalence of the disease and don’t want to miss any cases.  You want specificity if you’re trying to recruit a group of people with PSP for a study of causes or treatments and don’t want to risk including anyone without actual PSP.

So, in 1986, Dr. Irene Litvan, now at UCSD, then at the NIH, organized an international group of leading PSP experts to create new criteria.  They produced two sets for living patients: “possible PSP” was more sensitive and “probable PSP” was more specific.  “Definite PSP” was reserved for autopsy-confirmed cases, and the project also included a new set of criteria for that, which served as the “gold standard” by which to validate the first two. 

The new sets were called the NINDS-SPSP Criteria after the National Institute of Neurological Disorders and Stroke (the part of the NIH involved) and the Society for PSP (the former name of CurePSP), which provided a grant for the project. 

The NINDS-SPSP criteria were a hit and remained the world’s standard until researchers realized that those criteria took no heed of the clinical variants of PSP that were starting to be described in 2005.  The classic form of PSP now received the name “PSP-Richardson syndrome” after the leader of the group in Toronto who first described the disease in 1963.  It turns out that PSP-RS explains only about half of all PSP!  The most common of the newly-described variants is PSP-parkinsonism, accounting for about 25% to 40% of all PSP.  Six other much less common ones have been reported, each of which starts with and emphasizes one of the features that starts later in the course of PSP-RS.  Towards the later stages, all of the variants acquire most of the classic features of PSP-RS and all tend to look the same by that point. 

Sorry for that digression.

So in 2015, Dr. Guenter Höglinger, then in Munich, now in Hannover, convened a group to devise a new set of criteria to tease out the different types of PSP and to identify PSP in its earliest stages.  Of course, there aren’t yet enough autopsied cases to provide the stastistical power needed to validate their criteria for the less common PSP types, but that’s changing.  In any event, the new criteria were published in 2017 and dubbed the “MDS PSP Criteria” to recognize the support of the Movement Disorder Society.

Just one problem: they’re very complicated, occupying 7 pages of tables in the journal. To remedy that, Dr. Hoglinger and colleagues have created an on-line form that performs the same diagnostic algorithm as all those tables.  It’s free and it’s at  I’d suggest that you try it out, but many of the data fields require the results of a neurological exam performed by an experienced neurologist.  Furthermore, many of the questions ask things like whether the patient has any evidence of certain alternative diagnoses, and that’s not something that a layperson is likely to know.  But feel free to forward the link to your favorite neurologist for their use.  The different PSP subtypes have different rates of progression, so identifying one’s subtype could be useful.

Mail-order diagnosis

You may have noticed that I’ve been bullish on the ability of ordinary MRI scans to help diagnose PSP.  Now there’s an on-line, automated resource to allow anyone anywhere to upload MRI images and receive an answer – for free.

We’ve known for over a decade that very careful, standardized measurement of the size of various parts of the brain can track the progression of PSP over the 1-year course of treatment trial better than the PSP Rating Scale or any other “bedside” measure.  But more recently, MRI has been found to be highly useful in the differential diagnosis of PSP – that is, telling PSP from normal aging, Parkinson’s, Alzheimer’s, and other conditions. 

For an excellent, technical, open-access review of simple MRI measurements in the diagnosis of PSP, click here. The leading authors are Dr. Aldo Quattrone and his son Dr. Andrea Quattrone at Universita Magna Graecia in Catanzaro, Italy, who pioneered most of the discoveries described.

Such MRI-based measurements use only routinely obtained images like those from your local radiologist.  But actually doing the measurements requires some experience.  The Catanzaro group has created a Web portal onto which anyone can upload de-identified MRI images from a CD.  An answer returns in a few days.  The site is

The black-and-white images below show the inputs into the automated algorithm.  Sorry if these close-up brain images look like abstract expressionism.  The drawings here may help orient you.

MRI images A and B are sagittal (A is in the midline and B is a few mm to one side), images C and D are in the coronal plane and image E is in the horizontal (or axial) plane.

from: Quattrone, et al. Brain Science, 2022.

A: midbrain area (upper outline; Amb) and pons area (lower outline; Apons) (In PSP, atrophy of the midbrain is marked but atrophy of the pons is mild.)

B: middle cerebellar peduncle diameter (This atrophies only a little in PSP.)

C: superior cerebellar peduncle diameter in a slice parallel to the midline (“parasagittal” slice; This atrophies moderately in PSP.)

D: third ventricle diameter (averaging the diameters of the front, middle and back thirds) (This enlarges markedly in PSP.)

E: maximum distance between anterior horns of lateral ventricles (This atrophies moderately in PSP.)

The number derived from these measurements is called the magnetic resonance parkinsonism index (MRPI).  Its value is (Apons/Amb) x (B/C).  Values above 13.88 indicate PSP-RS with 89% sensitivity*, 95% specificity* and 94% accuracy*. This works best in separating PSP-Richardson syndrome from Parkinson’s disease. 

The MRPI 2.0 is (MRPI) x (D/E).  This works better than the original MRPI in separating PSP-Parkinson and other non-Richardson PSP variants from Parkinson’s disease.  Values above 2.70 indicate PSP with 86% sensitivity, 92% specificity and 90% accuracy.

*Sensitivity is the fraction of people with the disease who have a positive test. 

Specificity is the fraction of people without the disease who have a negative test. 

Accuracy is the fraction of people with an accurate test, whether positive or negative. 

In this case, “the disease” means PSP and “without the disease” means PD, some other disease or no disease.

The really valuable part is that this technique works well even in early, mild cases, where a diagnosis could not be made by other means.  In a few studies, such patients were followed for years until they showed more definitive signs, which were then used to validate the initial, image-based diagnoses.

This technique has not been shown effective in differentiating PSP-P from multiple system atrophy of the parkinsonian type (MSA-P), which is a common dilemma for movement disorder specialists seeing a patient with mild symptoms.  But the MRPI and MRPI 2.0 could be combined with other supplementary tests such as supine and standing blood pressure (usually abnormal in MSA-P, normal in PSP) and still-experimental tests such as blood levels of tau, phosphorylated tau and neurofilament light chain (all elevated in PSP, not in MSA) to refine its abilities.

Another important caveat:  Sometimes PSP can be mimicked by rare cases of common diseases like Alzheimer’s or dementia with Lewy bodies, or by some rare diseases like corticobasal degeneration, frontotemporal dementia with parkinsonism, or pallidopontonigral degeneration.  There haven’t yet been enough patients with those things subjected to the MRPI or MRPI 2.0 to prove those formulas able to separate those conditions from PSP.  After all, the MRI only looks for atrophy of certain brain structures, regardless of whether that atrophy is related to tau aggregation or something else.

Bottom line:  As my medical students don’t appreciate hearing, no diagnostic test short of autopsy is ever going to be definitive on its own.  Any test will have to be combined with old-fashioned history and exam and with other imaging, fluids or physiological tests.  Knowing which of those to choose for a given patient and how to interpret the results will keep humble, human neuro-diagnosticians in business for a while longer.


In my next post: another on-line tool for the diagnosis of PSP.

Sleep treatment study seeks participants

One of the top PSP research centers in the world is at the University of California San Francisco.  Two researchers there, Drs. Christine Walsh and Thomas Neylan, are leading a study of sleep in PSP and asked me to help them find suitable participants.

The goal is to test the effect of two sleep medications on the treatment of sleep disruption in PSP.  No in-person visits to San Francisco are required and no study staff would need to come to your home. 

Both medications, zolpidem (Ambien) and suvorexant (Belsomra), are approved by the FDA for sleep in general, but their benefit and side effects in people specifically with PSP remain unclear.  This study uses a crossover design so that each participant will receive the two medications and placebo over the 6-week course of the study. Sleep will be monitored by questionnaire and by two small, wearable devices to record movement and brain waves, respectively. All of the questionnaires will be done over the phone or by Zoom, with 1 to 3 calls each week for 6 weeks.

Participants must have a diagnosis of PSP, live anywhere in the United States, and have an available care partner to help provide information during the interviews.

You can find more information about the study by viewing a video here: or by emailing Dr. Walsh at: Click here for the listing in

Near-term genetic PSP-ology

Remember the Human Genome Project?  It cost about $3 billion and took 13 years (1990 to 2003) – and that was with 20 labs around the world working in parallel.  A commercial lab can now sequence your whole genome in a few days for about $600.  Now the problem is how to recognize a “abnormal” result and what to do with that information.  We all have mutations that our parents don’t, and most of those have no health implications.  The problem is knowing which ones do.  This makes it medically and ethically tricky to interpret the results of a whole-genome sequence. 

Until that knowledge base improves, whole-genome sequencing will probably be useful mainly in assaying for known mutations in well-studied genes.  It is also possible to roughly predict the health implications of a never-before-seen mutation in a well-studied gene by working out the amino acid substitution that would result in the protein being encoded.  Then, using the physical and chemical principles of protein structure and function, one could roughly predict how that amino acid substitution might affect the function of the protein.  But that’s still an inexact science.  Besides, a lot of the genome doesn’t encode proteins at all – it has regulatory functions, which sometimes involves encoding small stretches of RNA that in turn regulate protein production.

So, with those challenges in mind, here’s a bit of speculation as to what might be in store, near-term, for genetic testing in the routine clinical care of PSP.  Thanks go to my friend and colleague Alex Pantelyat, MD of Johns Hopkins for his input.

  • Once effective treatments for PSP arrive, we may find that people with different variants in the gene encoding tau (or other gene) respond differently to specific medications.  This might be especially true for treatments targeting the process where the information in the DNA is encoded into proteins (called “transcription”).  Right now, short stretches of DNA or RNA called “antisense oligonucleotides” (ASOs) that interfere with the encoding of the normal form of tau are in clinical trials.  As you’d imagine, this risks side effects caused by a lack of normal tau protein.  But if we knew what gene mutation was causing PSP in an individual, an ASO could be specifically tailored for it. 
  • It will become standard practice for clinical trials of any sort of treatment to be designed for people with, or without, specific gene variants.  Or if a trial doesn’t try to restrict enrollment in that way, it will at least do the sequencing at the time of enrollment and apply the genetic information retrospectively to check if the treatment works in people with specific gene variants. 
  • As discussed in my last post, variants in the LRRK2 gene help determine the duration of survival of people with PSP, though they don’t affect the risk of developing the disease to begin with. There are bound to be other genes with similar effects.  Sequence data from such genes could be useful to people with PSP and their families in preparing for the future financially and emotionally.
  • The last point, about prognostic genetic markers, is about single-gene variants.  But the same point could apply to combinations of variants in multiple genes where no single variant has a measurable effect. 
  • Using a battery of gene variants as a high-accuracy diagnostic test for PSP (as opposed to prognosticating a rate of progression or what symptoms might develop next) seems unlikely to come to pass, as the list of genes already linked to PSP probably are the most informative ones, and they are insufficient as a diagnostic test.  But if that list is coupled with other non-genetic tests such as MRI, PET and blood tests for tau or neurofilament light chain, a highly accurate test battery could result. 

Beyond the $600 lab fee are the bills for the necessary interpretation and counseling, which add about $2,000.  While the lab fee has been declining because of technological improvements, the other services are provided by human beings and are only likely to rise.  Insurance companies, Medicare and Medicaid don’t presently cover any of this unless it’s for someone with cancer or a very ill newborn.  I assume this is because we don’t yet have enough use for the data in terms of alterations in management.  But what are the financial implications if my above predictions come true and actionable uses do become available?  PSP is a rare disease, but what if similar uses of whole-genome sequencing are developed for Alzheimer’s, atherosclerosis, depression and the many other diseases where genetic variants, or combinations thereof, affect disease risk or prognosis?   Even if we manage to reform the medical payment in the US and improve access to that system for those presently under-served, who will provide all that counseling? And who will respond to patients’ demands for preventive treatment? And who will pay for that treatment? Scary.

Is PSP genetic? An update

Last week, someone wrote to CurePSP asking if PSP was genetic. I took a look at what I had previously provided CurePSP on that topic to post on its website, and decided it wasn’t nearly detailed enough. So I decided to write up the following. A version of it appears, or will soon appear, at

PSP only very rarely runs in families.  Fewer than one in 20 people with PSP knows of even one other family member with PSP, even counting distant cousins. 

But when multiple genetic variants confer only small risks of developing a disease and some sort of non-genetic factor is also necessary, it will be rare for more than one member of a family to have the unlucky co-occurrence of enough of those factors to produce outward signs of the disease. 

That’s basically how PSP works, but then things get a little more complicated:

The gene on chromosome 17 that encodes the tau protein is called MAPT, for “microtubule-associated protein tau.”  The MAPT gene has two variants that are more common in PSP than in the rest of the population.  One of them is called the H1 haplotype and actually consists of a section of the chromosome that is reversed relative to adjacent sections.  About 95 percent of people with PSP have this variant on both of their copies of chromosome 17, while this is true for only about 60 percent of the rest of the population.  So the H1 haplotype is (nearly) necessary but far from sufficient to cause the disease. 

We’re still not quite sure how the H1 haplotype increases PSP risk.  It may simply increase the amount of tau produced, which causes that protein to stick together, even if it’s structurally normal.  But more recent work shows that it causes too many methyl groups to stick to the MAPT gene, altering its function. This is exciting because drugs can be developed to alter DNA methylation. Other recent evidence supports the idea that the H1 haplotype reduces the fraction of tau molecules that include the fragment encoded by the MAPT gene’s exon 2. 

The other MAPT variant associated with PSP is statistically independent of the H1 haplotype and its function is unknown.

Over the past two decades a handful of other gene variants not on chromosome 17 have been found to be slightly more common in people with PSP than in those without PSP.  These genes help control a variety of critical processes such as disposal of damaged proteins, inflammatory mechanisms, operation of synapses, and integrity of the brain cells’ insulating sheaths.  However, the effect of these genes, individually or together, is too small to serve as a diagnostic test for the disease or to produce more than one case in a family.   

A gene called LRRK2 has been found to influence (in a rough way) not the likelihood of PSP, but the age at which it starts.  CurePSP is presently supporting a project to pursue this clue to try to find a blood test that might predict the individual’s rate of progression.  As it happens, mutations in LRRK2 are the most common cause of familial Parkinson’s disease and the occasional person with that mutation will have the pathology of PSP at autopsy despite having had the outward appearance of PD during life.  Wonders never cease.  Drugs that suppress the action of abnormal (and normal) LRRK2 are in trials for Parkinson’s.

Despite all I’ve said about the genetic component of PSP being subtle, a small fraction of people with PSP do have a relative with the same diagnosis, raising questions about the risk to their siblings and children.  A few points of advice about that:

  • When a disease occurs in several members of a family in a pattern consistent with either a dominant or a recessive mechanism, it’s easy nowadays to identify that gene.  Despite the dozens of families alleging multiple members with PSP, such a gene has never been reported in the literature. 
  • False-positive diagnoses of PSP are common.  This may account for most of the reports of multiply-affected families, even if one of them had autopsy confirmation.  However, in most situations where two or more relatives have been diagnosed with PSP, there have been no autopsies.
  • A strongly familial disorder called frontotemporal dementia with parkinsonism (FTDP) can mimic PSP, even at autopsy, but the special features of PSP such as balance loss and trouble with downgaze are mild or absent.  Many of the mutations causing this disorder are in the MAPT gene, but those mutations do not occur in non-familial PSP.  Furthermore, FTDP is associated with the MAPT’s H2 rather than H1 haplotype.  Both of these points cast additional doubt on FTDP being real PSP.  The FTDP-associated mutations can be detected by a commercially available blood test with a doctor’s prescription, but they are very rare, with only about 100 such families having been reported in the medical literature world-wide.
  • Despite those caveats, there actually are two or three families world-wide having several members with ordinary PSP (i.e., not FTDP) both during life and at autopsy, with no mutations in the MAPT gene.  Such families can be highly valuable for PSP research, as the gene causing their disease could be encoding a protein that might be key to all PSP.

Bottom line: 

Familial PSP is so rare that people with that condition need not be concerned for their children or siblings.  This advice even accounts for the possibility that what has been diagnosed as PSP may in fact be its rare, familial imitator, FTD with parkinsonism.  Most PSP experts advise their patients’ healthy relatives to make no changes to plans for career, children or finances because of one person with PSP in the family. 

However, when there is a clear indication of two or more close relatives with PSP, one should consider testing one affected person for FTDP by sequencing either the MAPT gene or a battery of genes associated with various dementing neurodegenerative diseases.  This should be done only with the guidance and participation of a genetics counselor or neurologist well-versed in interpreting genetic testing.  If the affected patient has one of those mutations, then another affected relative can be tested as confirmation and healthy relatives can be tested for the same specific mutation if they so choose.  However, a positive result would not predict the age of symptom onset, so there is little or no actionable information to be gained through testing healthy relatives.

Further research results in the near term could change these recommendations, so keep an eye on for updates.  But if you want me to speculate right now, take a look at the next post.