My last two posts summarized the portions of the PSP Study Group’s October 4 meeting on imaging, markers and longitudinal observational studies.  This one’s on the current state of neuroprotective clinical trials.  The information is from presentations by Adam Boxer and Günter Höglinger and from informal contributions by other attendees.

First, some background

“Neuroprotective” means slowing or maybe halting the progression of the underlying disease process without improving the current symptoms or disability.  It is to be distinguished from “symptomatic” treatment, which only helps the symptoms or disability, typically transiently, while the underlying process continues. 

The four most recent failed neuroprotective treatments have been davunetide, a neurotrophic (i.e., neuron growth-promoting and repair) agent; tideglusib, a kinase inhibitor (that works by preventing abnormal attachment of phosphate groups to tau), tilavonemab and gosuranemab (both monoclonal antibodies directed against the “first,” or N-terminal, end of the tau molecule). None of these four slowed PSP progression as measured by the PSP Rating Scale or any other bedside test, although there’s controversial evidence that tideglusib slowed the progression of atrophy in relevant brain areas on MRI.  

Other hopeful PSP neuroprotective agents that have failed to work in double-blind trials in recent years.  These, in no particular order, are salsalate, an approved non-steroidal anti-inflammatory drug that reduces tau phosphorylation; TPI-287, an anti-cancer drug that improves microtubule function; coenzyme Q-10, a nutraceutical that enhances mitochondrial energy production; Juvenon, an antioxidant; pyruvate, creatine and niacinamide, other antioxidants; riluzole, a drug with multiple mechanisms that is approved for neuroprotection in ALS, where its benefit is minimal; rasagiline, an inhibitor of monoamine oxidase-B, an enzyme that produces toxic free radicals from dopamine; lithium, an approved drug in psychiatry that reduces tau phosphorylation; valproate, an approved drug in psychiatry and for epilepsy that does the same; and methylene blue, an approved drug for multiple medical problems that inhibits tau aggregation.

Monoclonal antibodies

We don’t know why the antibodies have failed to date.  Maybe tau’s the N-terminal isn’t consistently present or accessible to antibodies in whatever form of tau is relevant to the spread of PSP through the brain.  Maybe the trials started too late in the course of the disease.  Maybe not enough of the antibody was able to cross the blood brain barrier, even though the tau content of the spinal fluid as measured in the lumbar space (not near the brain) was dramatically reduced.  Maybe tau is protected from antibodies as it moves between neurons by some sort of bubble-like or bridge-like membrane structure.  Maybe the cell-to-cell transmission of tau isn’t the most critical or rate-limiting step in the pathogenesis of PSP. 

A promising bit of support for N-terminal antibody treatment comes from three patients who participated in the gosuranemab trial’s site at the University of Pennsylvania who later died and were autopsied.  Their brains showed changes in the glial cells suggesting that the antibodies had incited a clear anti-tau reaction that was absent in untreated patients with PSP.  Although the neurofibrillary tangles and other visible, insoluble tau deposits were unchanged by the antibody, the authors of the paper (and I) conclude that maybe all that’s required for clinical efficacy is some tweaking to the antibody, to its dosage, to its ability to cross the blood-brain barrier, or to the stage in the course of PSP when it’s given.               

Despite the failure of the two antibodies so far and our shortage of explanations, drug companies have continued to develop monoclonal antibodies against tau.  These are being tested (almost) exclusively in Alzheimer’s for the near future.  Zagotenemab (LY3303560, from Lilly) and semorinemab (RO7105705, from Roche) are both directed against tau’s N-terminal.  BIIB076 (from Biogen) and JNJ-63733657 (from Johnson & Johnson) are directed against tau phosphorylated at position 217.  Bepranemab (UCB0107 from UCB) and E2814 (from Eisai) target the mid-portion of tau.  Lu AF87908 (from Lundbeck) targets phosphorylated amino acid 396, near the C-terminal.  The lone PSP trial of any of these is a Phase 1b (i.e., double-blind but designed to test safety, not efficacy) trial of beprenamab at one center in Germany.  Even if the drug does well in that trial, further efforts are planned only for Alzheimer’s for the time being.

Anti-sense oligonucleotides

A Phase 1, double-blind trial of NIO752, an ASO from Novartis, is in progress at 7 sites in the US, 2 in the UK, 2 in Canada and 5 in Germany.  The 48 patients on active drug will be divided into three groups, each with a different dosage level, and 12 patients will receive placebo.  The lowest dosage level will start first and the next will start only if there is no immediate safety issue with the first. The drug must be given by intrathecal injection, which means directly into the spinal fluid by injection into the thecal sac at the base of the spine.  The procedure is identical to a diagnostic “spinal tap” except that that’s a fluid removal for diagnosis and this is a fluid administration for treatment.  This will be performed 4 times at 1-month intervals followed by another 3 months of observation.  More info is here.

ASOs are short strands of RNA with multiple mechanisms of action, each at a different step in the process of translating information from the MAPT (microtubule-associated protein tau) gene into the tau protein.  Many experts feel that this approach, being far “upstream” in the pathogenetic process, is the most promising of the current neuroprotective ideas for the tauopathies.  Obviously, the issues of safety and convenience of monthly spinal taps are potential obstacles.  ASO neuroprotection against Huntington’s disease, where the aggregating protein is “huntingtin,” was reported in June 2021 to have failed, but so little is known of the mechanisms of ASOs that this is not necessarily bad news for the tauopathies.

OGA inhibitors

To self-plagiarize from a 2015 post, a class of experimental drugs for the tauopathies “reduce tau aggregation by inhibiting OGA (O-GlcNAcase; pronounced “oh-GLIK-na-kaze”). That enzyme removes the sugar N-acetyl-beta-D-glucosamine from either serine or threonine residues [amino acids] 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.”  Got all that? A major plus for the OGA inhibitors is that they, like most enzyme-inhibiting drugs, are small molecules, which means they can be taken orally.

Trials of OGA inhibitors for PSP have not yet begun and there’s no clue in the grapevine as to when that might happen.  But a first-in-human study of ASN-51 (from Asceneuron) in 40 patients with Alzheimer’s is under way in Australia. 

My sources tell me that Merck has another OGA inhibitor that has not yet started clinical testing.  It’s not even listed as a pre-clinical candidate in the latest revision of Merck’s publicly available, on-line pipeline info, which was last updated on July 27, 2021.

Although salsalate failed to slow PSP progression, another approved non-steroidal anti-inflammatory called tolfenamic acid reduces tau production. A single-center, Phase 2a trial had planned to start enrolling 24 patients with PSP at the Cleveland Clinic in Las Vegas in early 2021, but the trial start is delayed indefinitely.  The drug is available by prescription for migraine in the UK and some other countries but not in the US. 

Finally, AZP2006 (from AlzProtect) activates secretion of progranulin in the brain, reducing inflammation, and also has an independent action as a tau anti-aggregant.  It is given as an oral solution.  A Phase 1 trial in progress at three centers in France and a Phase 2 trial at the same three sites is planned.

For more technical details on neuroprotection (and symptomatic treatment) in PSP, see the excellent recent review by Lawren VandeVrede and colleagues from UCSF.

Our CurePSP Centers of Care review is mostly on symptomatic PSP treatment but includes a section on neuroprotection.

Markers: the longitudinal approach

We got plenty of candidate PSP treatments.

We got drug companies willing to risk their resources on trials for a rare disease.

We got clinical trial sites with proven records of efficiency. 

We got patients willing to make the sacrifices demanded by clinical trials. 

What ain’t we got? 

We ain’t got markers. 

(Deepest apologies to Rodgers and Hammerstein.)

Markers in this context are simply diagnostic tests, and there are two kinds – trait markers and state markers.  Trait markers allow us to distinguish people with from those without the disease, preferably in a very early stage, where treatments designed to prevent further decline would be most likely to occur and most useful to the patient.  Trait markers also allow us to exclude from a PSP trial any people who don’t actually have PSP.  State markers, on the other hand, quantify the amount of damage that’s already occurred and the degree of benefit of the experimental treatment. 

The best trait marker for PSP to date is purely clinical, meaning that it does not require any sort of imaging, automated measurements of movement, gene testing or chemical testing of body fluids.  That’s the MDS-PSP Criteria, published in 2017. Other types of tests can help exclude from consideration other conditions such as Alzheimer’s, Parkinson’s, MSA, normal-pressure hydrocephalus and vascular parkinsonism, but they are only helpful in those cases where a specific alternative diagnosis is plausible.  They don’t positively diagnose PSP; they only rule out other things.

Two up-and-coming trait markers for PSP are spinal fluid levels of tau with a phosphate group on amino acid 181 (Ptau181) and neurofilament light chain (NfL).  Ptau181 levels are below normal, on average, in all forms of PSP except for the gait-freezing type (PSP-PGF).  This contrasts with Alzheimer’s disease, where that marker is elevated, on average.  The average level of neurofilament light chain (NfL) in the spinal fluid is much higher in PSP and CBS than in controls or Alzheimer’s but is also elevated in many other neurodegenerative disorders.  So the ratio of NfL divided by Ptau181 in the spinal fluid is an good marker for PSP, but cannot distinguish it from CBD, and for PSP-Richardson, it may not be as accurate as the bedside clinical criteria. For ordinary clinical use, a blood test would be easier than a spinal tap, and the utility of these levels as a state marker has not been adequately studied, even for CSF.  That requires a longitudinal study over a period of at least a year.  So the NfL/Ptau181 ratio isn’t ready for prime time as a PSP trait marker, much less as a state marker.

The most widely used state marker for PSP is still the PSP Rating Scale, which is also purely clinical. (Disclaimer: I developed the PSPRS starting in 1995 and published it in 2005 along with my statistician colleague Pam Ohman-Strickland.)   It takes 15 minutes to administer and requires no equipment other than an armless chair, a cup of water to test swallowing — and the apparatus between the neurologist’s ears.  In recent years, modifications of the PSPRS have been shorter, easier to administer by laypersons, or more directly reflective of the patient’s daily activities.  Although all of these revisions are valid and have been shown to correlate well with the full, original PSPRS, none has been widely tested in the field, and the PSPRS remains the standard for now.  But it’s not good enough.  Its score is affected by common non-PSP conditions such as injuries, arthritis or strokes, or by PSP-related conditions; for example, orientation testing can be affected by apathy, gait testing by muscle rigidity, blepharospasm by Botox and everything by dehydration or malnutrition.  So there’s a lot of variance in the PSPRS as measured from one visit to the next.  This dictates that trials be large enough and long enough to cancel out the “statistical noise,” and that costs money.

A longitudinal study is observational – it includes no treatment.  It enrolls patients with the disease of interest, or sometimes also healthy people with histories suggesting a high risk of developing that disease.  Many longitudinal trials also enroll control subjects with no apparent risk for the disease — typically spouses, relatives or friends of those in the first two groups.  All of the subjects undergo tests at entry using whatever diagnostic procedures are being evaluated as markers, some of which are repeated periodically.  The study follows the patients through their course, at least with interim histories and physical exams.  If feasible and appropriate, autopsies are obtained to verify the diagnosis and to correlate specific autopsy features with diagnostic test results during life.  The goal is to identify which, if any, of the diagnostic tests prove able to accurately identify people with the disease in the earliest stages and which can track their subsequent course with precision.

There are presently at least 8 PSP longitudinal studies in progress: 2 in Germany and 1 each in India, Italy, Japan, Luxembourg, the US/Canada and the UK.

At the PSP Study Group meeting on October 4, James Rowe of Cambridge updated the group on the longitudinal PROSPECT-M-UK study, which is headed by Huw Morris of University College London. (“M” is for MSA, a late addition.) It now includes 21 academic clinic sites in the UK and about 700 patients, of whom about 100 have made more than the initial visit.  They have found that using MRI measures of atrophy of certain regions of the cerebrum is more precise than the PSPRS, reducing the number of patients needed for a treatment trial by nearly half.  The measures were atrophy of frontal and temporal lobes and enlargement of the lateral ventricles, an indirect sign of diffuse cerebral atrophy.  This confirms and extends the findings in the two trials of monoclonal antibodies that failed to help PSP, where MRI at the start and end of the studies provided a sharper picture of the patients’ progression than the PSPRS.  The reduction of the sample size was even more marked for CBD, but in fairness, the PSPRS was not designed for that disease.  One of the PROSPECT-M-UK study’s specimen collections is skin biopsies.  These can be used to look for tau aggregation in nerve endings, a potential early-stage, only slightly invasive trait marker.  Skin biopsies can also be used to create stem cells, which are then converted into neuronal cultures in which experimental treatments can be tested.  In this case, each such “brain in a dish” will come with a detailed, standardized clinical record.  Even more important, that lab model is not a mouse with a PSP-like condition, but a human being with real PSP.

LK Prashanth of Vikram Hospital in Bangalore described the longitudinal PSP study being conducted by the Parkinson Research Alliance of India. The Pan-India Registry for PSP (PAIR-PSP) includes 15 centers with 68 patients, with a goal of 1,000 over the next 2 years.  They are performing whole genome sequencing along with more conventional measures.  They have found that PSP-Richardson syndrome, the classic form, exists in only 25% of their group.  Next is PSP-parkinsonism with 22% and PSP-CBS with 18%.

Martin Klietz of Hannover Medical School updated the group on the two German studies, DESCRIBE and ProPSP.  The first has enrolled 400 patients, the second, 276.  Each study covers the entire country, although one is based in the north, at Hannover and the other in the south, at Munich.

Rejko Krüger of the University of Luxembourg mentioned that his institution’s longitudinal Parkinsonism study, which recruits from that small country as well as nearby areas of France, Germany and Belgium, has recruited 80 patients to date, and is collecting skin biopsies and spinal fluid in addition to the usual imaging and clinical markers.

Takeshi Ikeuchi of Niigata University, Japan, described the Japanese Longitudinal Biomarker Study in PSP and CBD (JALPAC).  It has accumulated 337 patients with at least one visit, of whom 257 have had at least two.  They found PSP-Richardson in a slightly higher percentage, 35%, than did the study in India.  They found a good correlation of the PSPRS with disease duration but, as expected, wide range of velocities of progression across patients. 

No one at the meeting provided an update on the US/Canada study, which focuses not specifically on PSP or CBD, but on a much more inclusive disease category called frontotemporal dementia (FTD).  PSP and CBD are often classified within the category of the FTD’s because they usually feature dementia of frontal lobe origin.  The protein aggregating in the brain cells is different in the various FTD diseases – tau, TDP-43 and FUS are the most common.  The study, called “ALL-FTD,” is headed by Brad Boeve at the Mayo Clinic Rochester and Adam Boxer and Howard Rosen at UCSF.  It presently includes 21 sites in the US and 2 in Canada. The longitudinal arm has a goal of 1,100 patients and the biofluid-focused arm, with just one visit apiece, aims for 1,000 patients.  I’ll let you know about current PSP enrollment once I can squeeze that out of someone, but for more info, try their website.

Gabor Kovacs of the University of Toronto described a project based in Japan to study “incidental PSP.”  This is early brain changes of PSP that had not yet started to cause symptoms by the time of death.  It is found in specimens donated by families whose loved one died without known neurological illness.  One such collection, at Banner Health in Arizona, found very mild PSP pathology in 5% of their autopsied brains.  This means that 5% of the elderly population may be incubating PSP.  Of course “may” is the critical word, but analyzing the medical, genetic, and toxin exposure backgrounds of such a large group of people, even in retrospect, could provide valuable clues to the cause of PSP.

Solving our image problem

Günter Höglinger of Hannover University in Germany is probably the world’s most productive PSP researcher right now.  A few years ago, he organized a PSP Study Group as part of the International Parkinson and Movement Disorder Society.  Most of the 51 members are European – I’m one of the 11 US members.  The PSPSG’s main accomplishment to date is developing and publishing a new set of diagnostic criteria for PSP.  The group meets for a couple of hours in person every year in conjunction with the IPMDS’s conference, but of course, the past two meetings have been on Zoom.  The agenda is to informally discuss our recent research activities and ideas.

This year’s meeting was held on October 4, 2021.  Here’s a boiled-down, edited and explicated version of the proceedings.  The topics were classified into imaging, longitudinal studies, fluid markers and treatment.  As per last week, it will be the installment plan: Each of those four topics will be a separate post here on PSP Blog.


James Rowe of Cambridge University, a legitimate rival to Günter as the world’s current leading PSP researcher, described the value that 7-Tesla MRI brings to PSP research.

Most standard MRI scans for medical care use a magnetic field strength of 1.5 Tesla and a growing number use 3 T for additional resolution.  But about 100 research MRI machines world-wide are capable of 7 T imaging.  This provides, for the first time, a clear image of the locus ceruleus (LC), a cylindrical cluster of blue pigmented cells in the brainstem that uses noradrenaline as its neurotransmitter.  It averages 14.5 mm in length but only 2.0 mm in diameter, making it difficult to see with conventional 1.5 T or 3.0 T MRI.  It supplies input to many other brain areas and degenerates in PSP and other neurodegenerative disorders.  Dr. Rowe hopes that the rate of worsening of atrophy of the LC on 7 T MRI may be usable as an outcome measure in PSP neuroprotective treatment trials.

A technique called magnetic resonance spectroscopy (MRS) uses existing MRI machines to provide not an anatomical image, but a measure of levels of some kinds of chemicals in specified areas of brain tissue.  It’s currently used mostly in brain tumor diagnosis. (Side note: MR spectroscopy long antedates MR imaging, which essentially takes MRS measurements of multiple pencil-shaped volumes of tissue sharing a slice of brain and then uses a computer to reconstruct those numbers into a two-dimensional image.) 7T MRI provides greater resolution here as well.  Dr. Rowe reported that he is studying the effects on circuits in the cortex of tiagabine (brand name Gabitril), an approved epilepsy drug that increases levels of the inhibitory neurotransmitter gamma-amino-butyric acid (GABA).  A similar drug is atomoxetine (brand name Strattera), which is approved for attention-deficit hyperactivity disorder.  Dr. Rowe is leading a clinical trial of that drug for disinhibited behavior, apathy and impulsivity in PSP.  A secondary outcome measure in that PSP trial, i.e., one that will not be critical to the study’s conclusions because it’s still an experimental test, is using 7T MRS to assess GABA levels in selected brain areas.   

Adam Boxer of University of California San Francisco, yet another very prolific PSP researcher, described the progress of his NIH-supported project, “4-repeat tau neuroimaging initiative,” or 4RTNI (pronounced “Fortney”).  The study is following patients with PSP or CBS every 6 months using MRI to track atrophy and tau PET to track tau aggregate accumulation.  The study also includes clinical evaluations, plasma levels of Ptau217 (tau with a phosphate group attached at amino acid number 217) and PET scans for beta-amyloid to detect Alzheimer’s disease (AD), which in an atypical form is the pathology underlying many cases of CBS.  The goal is to develop better diagnostic tests and progression markers for use in future PSP and CBD treatment trials.  While the Richardson syndrome clinical picture is almost always explained by underlying PSP pathology, an especially pressing issue is to distinguish CBS caused by CBD pathology (CBS-CBD) from CBS caused by AD pathology (CBS-AD).  Plasma levels of Ptau217 are very high in people with AD pathology, either as classic clinical AD or as CBS-AD, but normal in CBS-CBD and CBS with other pathologies.  A commonly used statistical measure of accuracy, the “area under the receiver operating characteristic (AUC),” for plasma Ptau217 in distinguishing CBS-AD from CBS-CBD is 0.96, very close to the theoretical ideal of 1.0.  However, that’s for advanced cases.  The test’s utility in early cases, where it’s likely to be needed most, is much less so far.  Dr. Boxer tentatively concludes that in distinguishing CBS-CBD from CBS-AD, plasma Ptau217 is almost as accurate as amyloid PET, the current standard, a much more difficult and costly procedure.

Dr. Boxer discussed another project in progress within the 4RTNI umbrella to help distinguish CBS-AD from CBS-CBD or CBS-PSP (i.e., to allow patients with CBS to participate in anti-tau treatment trials).  His research group combined a measure of cortical atrophy with one of midbrain atrophy using a Bayesian logistic regression.  That’s a technique that allows one to create a statistical “model” of a phenomenon, or to dissect its component parts, by successively trying different solutions and tweaking each based on the previous result.  This is different from traditional statistical models, which use event frequencies rather than successive refinements of an a priori hypothesis.  Look it up.  They were able to achieve an AUC for CBS-CBD vs. CBS-PSP to 0.95 for patients presenting with motor signs and 0.91 for those presenting with non-motor signs. 

Next post: Longitudinal PSP studies

The tao of tau: Part 2

As promised, here’s the second of two installments on the latest in tau-ology, at least as of the Tau2020 conference, held in February 2020. Yesterday’s post covered treatment, and today’s, everything else. There was no Tau2021, but Tau2022 is planned for February.

Tau structure and function

More is becoming known about the N-terminal domain of tau, where exons 2 and 3 are alternatively spliced (i.e., some forms of tau have the amino acid sequence encoded in the MAPT gene’s exon 2, others have those of exons 2 and 3).  This end of the protein is now suspected of controlling the spacing between microtubules, which comprise the cell’s internal skeleton and transport system.  Next to that is the “proline-rich domain,” which interacts with enzymes and with other proteins that include the WW domain.  That’s where a protein includes the amino acid tryptophan occurring in a string that regulates signaling between proteins. This is part of the new body of evidence that tau is partly a signaling protein.  (Fun fact: The single-letter amino acid abbreviation system (allegedly) assigned “W” to tryptophan because T was taken and part of the tryptophan’s molecule has a W shape.)  

The highlight of the conference was probably the keynote talk from Dr. Michel Goedert describing his group’s work on high-resolution imaging of tau using cryo-electron microscopy. (See my recent post, “A frozen treat” for details and an update.)  The bottom line was that each tauopathy has its own, very different, pattern of tau misfolding that is uniform across patients with that disorder.  That’s true even for disorders with the same isoforms, like PSP and CBD, which are both 4R (i.e., 4-repeat; having 4 microtubule-binding areas) but have radically different tau misfolding patterns.  Better understanding of these structures may point to disease-specific diagnostic and therapeutic innovations.  This starts to undermine the hope that PSP will provide the key to all tauopathies, including Alzheimer’s. For this and his other work, Dr. Goedert was awarded the $250,000 Rainwater Prize at this conference.

Post-translational modifications of tau

You know about tau phosphorylation, and the textbooks say that it can result from “stress.”  But more recent research has identified some specific causes such as brain ischemia, as from atherosclerosis; brain trauma; and excessive sodium intake.  The last works through activation of the immune system.

A recently-identified role for tau is to protect DNA in the cell’s nucleus from oxidative stress, which can result from certain toxins or from mitochondrial dysfunction.  Tau seems to help the histone proteins in the nucleus do their job of regulating access to the genome.

Abnormally phosphorylated tau in the cytoplasm can indirectly affect the function of DNA in the nucleus in many ways.  These include deranging the function of actin and microtubules, which maintain the structure of the nucleus, damaging DNA, damaging the protein portion of chromosomes, affecting RNA handling, reducing ribosome stability and encouraging DNA code rearrangements.  The next problem is to determine exactly which PTM’s do what and to develop drugs specifically targeted at those that actually cause neurodegenerative diseases. In fact, we don’t yet even know for sure that hyperphosphorylated tau causes tau aggregation in humans.

Although we know of 50 different mutations in the MAPT (i.e., the tau) gene that cause or increase risk of tauopathies, none of them is known to act via causing PTM’s.  This confirms that the pathogenesis of PSP is multifactorial and that the combination of factors differs across individuals.

Tau genetics

It has been known since 1999 that PSP is associated with a genetic variant called the H1 haplotype.  This consists of a section of chromosome 17, comprising the MAPT gene and about 15 others, that is reversed relative to the rest of the chromosome.  More recently, variants, especially the H1c subhaplotype, have been discovered that associate more strongly and specifically with PSP. The mechanism may be to allow the protein transcription machinery access to other areas of the genome where the handful of other genes associated with PSP have been identified. 

A project under the aegis of the Tau Consortium and the scientific leadership of Celeste Karch, Alison Goate and Sally Temple has created a collection of cells from 140 (and counting) volunteers with pure tauopathies such as PSP and some of their family members.  Some of the cells are fibroblasts taken from skin biopsies, others are stem cells (i.e., induced pluripotent stem cells, IPSCs) made from such fibroblasts and still others are neural cells made from those stem cells.  Some of the volunteers had single-gene causes of their illness and others had a single genetic variant that increases risk for PSP but is insufficient to cause it.  Some of the cells from the latter group with a single, identifiable mutation have had that mutation corrected using CRISPR, leaving a cell culture with only the poorly-understood genetic “background” necessary to cause the disease.  This represents a valuable tool for studying garden-variety, “sporadic” (i.e., apparently with no familial clustering) PSP. The cells are offered as a resource to carefully vetted researchers worldwide.

Mutated versions of a gene called LRRK2 (“lark-two”) are known as a group to be the strongest genetic contributors to Parkinson’s disease.  But strangely, a few people with some of LRRK2 mutations, including the most common one, develop PSP rather than PD. Now, Drs. Edwin Jabbari, Huw Morris and colleagues used samples from the UK’s Parkinson’s Disease Society Brain Bank to find that a genetic marker close to LRRK2 is associated with more rapid progression of PSP.  LRRK2 is known to affect disposal of dysfunction or excessive protein, possibly including tau. It also is involved in neuroinflammation. Both mechanisms are at or near the top of the current list of contributors to the pathogenesis of PSP.  The logical next step is to develop drugs suppressing the toxic activity of the enzyme produced by the LRRK2 gene.

The significance of the extreme predominance of 4-repeat tau in the tangles of PSP and CBD remains unclear.  (Most other tauopathies have an equal combination of 3-repeat and 4-repeat tau “isoforms,” mimicking tau in normal human brain, and a few tauopathies have predominantly 3-repeat tau.)  At Tau2020, The Rainwater Charitable Foundation awarded its early-career award to Dr. Patrick Hsu of the Salk Institute for a new technique that allows researchers to control the number of repeats in tau.  It’s based on the same general type of RNA-manipulating technology as CRISPR-Cas9, but in this case it’s called CRISPR-CasRx. It can be adapted to manipulate “alternative splicing” not only of tau, but also that of many other proteins that, like tau, have multiple isoforms. So far, the technique is only for neuronal cell cultures, but it opens up a world of potential experiments to fix the molecular variation in tau underlying PSP and CBD.

Prion-like tau propagation

We know that in cells growing in a researcher’s dish or in a mouse’s brain, misfolded tau introduced into the system can travel cell to cell, templating new copies of itself along the way.  But the details of the process and its relevance to the human tauopathies remain unclear.  In fact, in no human tauopathy has such a process been conclusively demonstrated, although it has been clearly observed in the prion protein disorders such as Creutzfeldt-Jacob disease or mad cow disease.  So, as we try to confirm the prion-like hypothesis in the tauopathies, we do have to remain open to alternative ideas to explain the spread of the disease within the brain.

A clue to why tau is secreted by brain cells could be its recently-discovered role as a local hormone or signaling molecule, to regulate the activity of brain cells and the sleep-wake cycle. However, even here the mechanisms are unclear.  There is recent evidence that tau is released from cells encapsulated in tiny membrane bubbles called vesicles.  In that case, the tau may be protected from therapeutic antibodies designed to slow the spread of tauopathies.  Additional recent evidence has found tau receptors on brain cells consisting of heparan sulfate proteoglycans, low-density lipoprotein receptor-related protein and even amyloid precursor protein.  For now, the science of tau spread remains, like most embryonic sciences, a collection of disconnected observations.

Independent of the specific molecular form or transit vehicle used by tau, imaging studies have recently shown that a prediction of the next brain region to become involved in a progressing tauopathy can be based on the involved area’s concentration of abnormal tau, its synaptic connections and its areas of direct non-synaptic contact with other cells.  Both of the latter two routes operate via active mechanisms; passive diffusion is no longer considered a factor.

Why are tau aggregates toxic?

This is a large, complicated issue, but one recently discovered clue is that brain cells containing tau aggregates, when finding themselves under stress for some other reason, signal the brain’s immune cells to come and engulf them, but without killing them. If this has the effect of protecting the tau-containing cells without preventing them from secreting their tau, then it could mean that a new tau-directed treatment could work better if coupled with a drug that inhibits the brain’s immune function.

Tau-based brain imaging

Positron emission tomography (PET) imaging using a radio-labeled glucose analog as a tracer for energy production is a standard way to help distinguish the frontotemporal disorders such as PSP, CBD and FTD from Alzheimer’s disease.  PET using a dopamine analog can distinguish the atypical parkinsonisms from Parkinson’s disease but is only available for research use.  But we have no PET-based technique to specifically identify PSP or CBD.  PET using a tau tracer is showing excellent results in distinguishing AD from other dementias, but it works poorly for PSP.  One problem is that the spatial resolution of PET is insufficient to show the tau deposits because it sticks to some other normal and abnormal molecules in the same set of neurons.  But many drug companies are developing many tau tracers and a few of them are starting to show more validity for PSP.  One, called [3H]CBD-2115, has shown good accuracy but doesn’t cross the blood-brain barrier.  However, some tweaks to the molecule or to the BBB might solve that problem.  Hopefully, it will be safe to administer and once broken down in the brain, won’t leave any radioactive remains behind for any length of time.

An exciting but early-stage development is that Genentech and AC Immune are developing an anti-tau antibody called semorinemab in tandem with a tau-directed PET tracer called [18F]-GTP1.  The PET tracer, in addition to tracking any slowing of tau aggregation, may also be useful in allowing a measurement of tau aggregation at the study baseline to predict the individual’s disease progression absent any intervention.  That, in turn, could allow a more individualized interpretation of the neuroprotective drug’s benefit.  Although that seems a good model for drug testing, it was announced in September 2021 that in prodromal and mild AD, semorinemab failed to slow progression in most of the outcome measures but did slow progression by 44% in one critical bedside test, the ADAS-Cog11.  The sister trial in moderate AD continues.  The companies have not announced plans for testing in PSP.

The NIH and the Rainwater Charitable Foundation have each created consortia to develop tau-based PET tracers for non-AD tauopathies.  The RCF effort involves the Michael J. Fox Foundation in its efforts to distinguish PD from PSP and CBD.

The tao of tau: Part 1

Our knowledge of the tau protein and the tauopathies is expanding faster than ever.  In February 2020, just before the lockdown, the Alzheimer Association, the Rainwater Charitable Foundation and CurePSP hosted an international conference in Washington, DC to discuss the latest in tau-ology.  “Tau2020” drew 650 people from 21 countries – academic researchers, government regulators, lay organization leaders, philanthropists, and key players in the pharmaceutical and biotech industries. 

A 12,000-word article summarizing the two days of talks appeared last week in the journal Alzheimer’s and Dementia.  In this post and the next, I summarize that summary – with an eye in particular on PSP and CBD, though much of the conference’s attention, understandably, was on Alzheimer’s disease and frontotemporal dementia. What follows is not a textbook article nor literature review or even a summary of one, but only a list of recent advances presented at the Tau2020 conference.

Today’s post will cover treatment issues and tomorrow’s will cover everything else. Dickens, Dostoevsky, Hemingway, Joyce, and Nabokov published in installments – why can’t I?  


The failure in clinical PSP trials of two monoclonal antibodies directed against tau’s N-terminal (i.e., the “beginning” or left end of the molecule as conventionally depicted) has not prevented researchers from developing antibodies against other parts of the tau molecule. Antibodies against (in conventional left-to-right order) the proline-rich region, the microtubule binding region or the C-terminal region are all under investigation. We now know that antibodies directed against the central regions of tau are more effective in preventing tau spread in cultured human neurons.  In fact, administering a mixture of antibodies directed against more than one of these regions is being contemplated. 

The two trials that ultimately failed in PSP chose the N-terminal as the target for their antibodies because in Alzheimer’s disease, misfolding starts in that area and because fragments of tau that include the N-terminal increase beta-amyloid production, an observation irrelevant to PSP.  Perhaps for these reasons, the two companies have continued their AD programs for their N-terminal-directed antibodies while discontinuing their PSP programs.  In my opinion, this is another potential difference between AD and PSP that weakens the hypothesis that a tau-directed prevention of either will be a prevention for both.

Several conference speakers emphasized that going forward, our ability to detect a neuroprotective benefit of any tau-based drug will improve if the clinical trials can manage to exclude non-tauopathy patients with disorders mimicking a tauopathy.  Such patients include those with dementia with Lewy bodies, multiple system atrophy, TDP-43-based frontotemporal dementia, normal-pressure hydrocephalus and vascular parkinsonism.  The speakers also agreed that new diagnostic markers will have to detect disease at a much earlier stage to give patients the greatest likelihood of responding while still able to live a good-quality life.  They also felt that future trials should avoid subjects taking many concomitant medications that could obscure the benefit of the drug being tested.  A further recommendation was to tailor the specific outcome measure to each patient’s combination of deficits and that the various subtypes of PSP, each of which may have its own mode of tau spread, are unlikely to respond equally to the same neuroprotective agent.  Finally, they noted that we do not yet know how far tau must be reduced to achieve slowing of disease progression, and that this may vary across patients.

Another active area, but so far applied only to AD, is active anti-tau vaccines.  This is where a person with or without disease receives an inactive fragment or form of tau, inducing the immune system to make antibodies directed against disease-causing tau that persist for months, years or decades.  This is the mechanism for most vaccines in common use.  It differs from the monoclonal antibody-based passive “vaccination,” where antibodies themselves are infused from the outset and typically wear off in a month or so.  Probably the active vaccine furthest down the clinical pipeline is ACI-35, from Axon Neuroscience.  Again, trials so far are in AD and no plans to extend them to PSP have been announced.

Anti-sense oligonucleotides (ASOs) have entered early clinical trials in both PSP and AD.  ASOs are short, single-stranded synthetic DNA molecules.  They bind to the messenger RNA that that assists in the production of tau, in turn inducing the enzyme RNase H1 to degrade that mRNA.  Unfortunately, ASOs can only be given by injection into the spinal fluid, as they cannot cross the blood-brain barrier.  The procedure must be repeated every three months. Another potential drawback is that ASOs reduce production of normal tau as much as they do abnormal tau. A Phase 1 safety and tolerability trial in 64 patients is being conducted at Mayo Clinic Rochester, Vanderbilt University and at two sites in Canada, three in Germany and one in the UK. For more information, visit ( Identifier: NCT04539041).

A highly innovative solution to the problem crossing the blood-brain barrier that limits utility of the ASOs and many other potential new neurological drugs.  Denali Therapeutics is testing a “transport vehicle,” a molecule that can escort a variety of drugs across the BBB.  It works by binding to an antibody with the “transferrin receptor” protein genetically engineered into its structure.  The therapeutic drug is then bound to this complex, which can penetrate the BBB.  Denali is experimenting with attaching anti-tau antibodies or tau-directed ASOs to this vehicle. Trials in humans have not yet begun.

Another approach that sounds like science fiction is “proteolysis-targeting chimeras (PROTAC) molecules, first developed in 2001.  These are hybrids of two small molecules, one of which can bind to, in this case, tau, and the other that is recognized by the brain cells’ internal garbage disposal called the ubiquitin-proteasome system.  Unlike antibodies, PROTACs can easily enter brain cells.  Their only human application so far has been in oncology, but experiments in mouse tauopathy models are proving successful.

A new methodology in clinical trial design is the “basket study,” common in oncology, where several rare types of cancer are tested as a group.  We still know too little about the differences among the tauopathies to insist that in evaluating a new drug, each disease must have its own trial.  The one basket study to date that included PSP was performed at UCSF for the drug TPI-287, which stabilizes microtubules.  AD, PSP and CBS were included.  Unfortunately, the drug proved inefficacious, but the trial method proved practical.

Reports from the front

Last week the International Parkinson and Movement Disorder Society held its annual meeting – by Zoom, natch.  (A pity – in normal times, that meeting is held each year in a different, interesting international city, letting us append a culturally-oriented vacation to a consistently great conference.  But COVID has done far worse to others, so I shouldn’t complain, and the Zoom format allowed clinicians working in remote or poor countries to participate, a major plus.)

There were 1,320 original research presentations, all in the form of posters.  Of those, 37 came up in my search on “progressive supranuclear palsy.” Presented now for your delectation, in random order, are summaries of the top five presentations of original research in PSP along with my own take on their importance and implications: 

  • Imaging/Gait Correlates: 

A group from the Mayo Clinic led by Dr. Irene Sintini performed detailed gait analysis in 19 people with PSP and imaged their brains in three ways: non-contrast MRI (looking for atrophy in specific areas), diffusion tensor imaging (an advanced MRI technique showing fibers connecting the various parts of the brain and the speed of fluid slowly flowing through in them), and flortaucipir PET (showing tau aggregation, a research technique not quite ready for routine clinical diagnostic use in PSP, but working quite well for Alzheimer’s).  Then they looked for associations among the gait and imaging measures.    

They identified two general patterns of association:  One was that better gait velocity, stride length, and gait stability were associated with larger frontal lobe volumes and less flortaucipir uptake in the precentral gyrus, which is a part of the frontal lobe that controls movement.  The other was that worse postural imbalance was related to greater flortaucipir uptake in the left paracentral lobule, which helps control movement and sensation on the right side as well as bowel and bladder function.

Admittedly, this was kind of a “fishing expedition,” an unkind term we use for a research project that’s just looking for patterns of abnormalities without a specific hypothesis in mind.  But that’s how the process leading to eventual breakthroughs can begin.  In this case, associating specific gait-related abnormalities of PSP with specific brain regions could point the way to deep-brain stimulation techniques, cell replacement therapies, or transcranial (i.e., non-invasive, painless) magnetic or electrical stimulation treatment.  Besides, who knows what gene therapy might come along in a few years to take advantage of this groundwork in some still-undreamt-of, anatomically-directed way?

  • Diagnostic MicroRNA:

Dr. Ravi Yadav and colleagues at India’s National Institute of Mental Health and Neurosciences in Bangalore compared microRNA in plasma (blood without its cells) from 18 patients with PSP and 17 healthy controls matched for age and sex.  They used a type of polymerase chain reaction (PCR) test that, unlike PCR for forensic purposes or COVID testing, provides quantitative measurements.  MiRNA regulates many things in cells, acting much like enzymes.

They found five kinds of miRNA where the difference between PSP and controls was large enough to serve as a diagnostic test.  A commonly used measure of the ability of a diagnostic test to work well at the individual level rather than merely to distinguish groups by their averages is called the “area under the receiver operating characteristic curve” (AUC).  A good AUC is at least 0.8, with a perfect test being 1.0.  These five miRNAs’ AUC’s ranged from 0.78 to 0.86. 

This is promising, and if refined and perhaps combined with another moderately accurate test, could provide an excellent test for PSP.  But first, we need replication in a larger study and a different lab; PSP has to be compared by this test to other neurodegenerative disorders, not just to healthy controls; and cases with early, diagnostically-equivocal signs of PSP should receive this test and then be followed until a diagnosis declares itself.

  • Astrocyte Proteomics:

Astrocytes are the main type of glial cells in the brain.  They are largely non-electrical but perform many supportive functions for the neurons and may actually process information.  They are where the abnormalities of PSP start.  These cells don’t normally make tau but they can accumulate it in the tauopathies, and their resulting appearance, called “tufted astrocytes,” is the pivotal diagnostic feature of PSP through the microscope. 

Dr. Felipe Ravagnani and co-workers from the University of São Paolo, Brazil were interested in what genes are expressed into protein more intensively in such cells from patients with PSP relative to the same cells from healthy controls.  You can’t take astrocytes from a living person’s brain, so they created them in a dish by taking fibroblast cells from the lowest layer of a skin biopsy from each subject and treated them with various things to first remove their skin specializations and to become stem cells.  Then they treated with other things to turn them into astrocytes and compiled and compared the proteins in PSP-patient-derived astrocytes to those from controls.

Such a technique ordinarily produces a long list of differences that’s hard to draw any conclusions from.  So it pays to classify the proteins that differ between the two groups into the kinds of cellular and biochemical pathways in which they participate.  This incriminated two pathways.  One was for cell cycle activation, which is how the cell decides when to divide and to stop dividing.  The other was for one of the chaperone pathways, in this case CTT/TriC, which is important to axonal transport and to degradation of abnormal or excessive proteins.  Both pathways involve tau.

It’s still too early to know what to make of this, and proteomics research is notoriously subject to methodologic variables.  But the chaperone pathways, which are important in regulating protein folding, have been suspected for many years as part of the cause of PSP.  Cell cycle abnormalities are critical to cancer, but the opposite problem – insufficient cell division – could contribute to glial pathology and start the more general neurodegenerative process.  If the new results are confirmed, they would present new targets for drug development.

  • CBD Diagnostic Accuracy:

Just as PSP has multiple variants, so does corticobasal degeneration (CBD).  The most common and the classic form is called CBD-corticobasal syndrome (CBD-CBS).  Other common ones are CBD-PSP syndrome, CBD-frontal behavioral/spatial syndrome (CBD-FBS) and CBD-nonfluent/agrammatic variant aphasia (CBD-NAV).  A set of clinical diagnostic criteria for CBD was published in 2013. 

Now, Drs. Danielle Lux and colleagues at University College London have evaluated the accuracy of the CBD criteria in predicting actual CBD pathology at autopsy in 133 cases.  They found the positive predictive value (PPV) of the “probable CBD” criteria was only 33% and the PPV for the “possible CBD” criteria was only 51%.  (PPV is equal to the number who actually have the disease on autopsy divided by the number who have tested positive during life by satisfying the clinical criteria.)  They also found that CBD-NAV had a better PPV than the other variants.  As an aside, CBD-PSP had the most rapid course of all of the variants assessed.

These results confirm and extend previous reports in the literature using smaller sample sizes.  They better elucidate CBD’s wide variety of clinical presentations. This variety is the main reason why almost all of the clinical trials so far testing tau-directed treatment enroll people with PSP-Richardson syndrome, not CBD — the PSP-RS diagnostic criteria have a much greater PPV for actual PSP pathology at autopsy.  We hope that tau PET imaging and fluid biomarkers in CSF or blood will soon correct this situation for folks with CBD.

  • A Survival Model:

Until the fine day comes when we can prevent or slow the progression of PSP, predicting survival is important.  Patients and families need to plan psychologically and financially.  Designers of long-term treatment trials need to know the likely dropout rate due to death. 

Dr. Tao Xie and colleagues at the University of Chicago have added usefully to the considerable existing literature on this topic.  In 23 patients who had died with PSP, they recorded the time from onset of the first PSP symptom to onset of downgaze palsy; the severity of downgaze palsy at that point using a scale ranging from 10 to 100; sex; age at PSP onset; motor function; and use of medication for parkinsonism or for pulmonary or cardiovascular diseases.  They used those data to create a formula by which to calculate survival from onset to death.

They found that total survival duration in years can be predicted by the equation: 5.76 + (1.11 x disease duration at the assessment) – (0.03 x downgaze palsy severity at the time of the assessment) – (0.03 x the age of onset).  The result predicted total survival duration reasonably accurately, with an average error of 0.82 (standard deviation 0.67) years.

The method of measuring the downgaze palsy was not described in the brief presentation and may be somewhat subjective, so an even more accurate prediction may be feasible using other measures.  Also, it’s not clear from the material presented that other features of PSP might perform as well as downgaze palsy as a predictor of survival.  For example, last year my colleagues and I published a very different method of estimating PSP survival that works about as well as this new one but requires administration of the whole 28-item PSP Rating Scale. 

At the scientific level, it’s interesting that in the mathematical model of Xie et al, downgaze palsy is an important factor in predicting death despite involving only a small portion of the total brain pathology.  I say that because in PSP, death is not particularly related to visual problems, but is usually the result of overall immobility, poor nutrition, aspiration and bladder infections.  But even if the measure of downgaze palsy only provides the model with an easily-measured proxy for those other disabilities, the model would still be a convenient and useful service for patients and families. 


Keep in mind that despite clearing the bar for acceptance at this conference, these research reports have not been subjected to a detailed peer-review process.  In fact, most original presentations at most conferences are never published in anything like the same form.  But I chose to relay these five to you because I think that in the end, they’re likely to stand up to scrutiny and to influence scientific thinking or bedside practice. 

Post-post modifications

Since yesterday’s post about the discovery of the detailed pattern of tau misfolding in the various tauopathies went live, some discussions with colleagues and laypersons have prompted me to bang out the following Q/A:

Q: Does the newly discovered, major difference in tau folding between PSP and CBD mean that CurePSP and researchers interested in PSP will devote fewer resources to CBD going forward?

A: Absolutely not.  The two diseases still have a lot more commonalities than differences and each will continue to benefit from research and patient care insights into the other.

Q: Does this new information mean that PSP has less value as a test bed for treatments aimed at Alzheimer’s disease?

A:  Only very slightly.  All of the tau-based treatments in the research pipeline are aimed at tau in general, not any specific folding pattern.  Over time, it may emerge that the parts of the tau molecule that are more “buried” within the folding structure are less able to interact with antibodies or drugs.  If that inaccessible section is different in PSP compared with in Alzheimer’s, then a drug company or researcher interested in AD may decide to direct their efforts accordingly.  But most of the tau molecule will probably prove to be equally accessible, for practical purposes, in all of the folding conformations, in which case, PSP will remain as valid as ever as a test bed.

Q: How definite is the new discovery?

A: Like any scientific discovery, it needs to be confirmed by different researchers in different labs using slightly different techniques. 

Q: Will the new discovery accelerate finding a prevention or cure*?

A: Possibly, and it’s hard to say by how much.  An effective prevention or cure may not care about the specific tau folding pattern.  For example, a very promising type of prevention now entering clinical trials is anti-sense oligonucleotides (ASO’s), which are small strands of RNA that prevent the genetic code for tau from being translated into tau protein.  The misfolding occurs at a later stage, so an ASO directed at tau should help reduce tau production in any tauopathy.  (Whether the amount of tau production is the key to the disease is another question.)

*Technically, a “cure” requires not only halting of the disease progression but also repair of the existing damage.  Those are two different things, and the latter is more difficult to achieve for a complex structure like the brain.  If we can find a way to diagnose PSP in its earliest stages, before there’s enough damage to cause symptoms, then all we need is a way to prevent further damage.

Q: What determines the tau folding pattern in the first place?

A: Any of several things that we know of, and there are undoubtedly more that we don’t yet know of.  The leading candidate is the attachment of small molecules to the tau protein that affect its ability to bend and to stick to itself.  The most common such molecule by far is phosphate (one phosphorus atom and three oxygen atoms) but others are various sugars, lipids, acetyl groups, sulfyl groups, methyl groups and dozens of others (Wikipedia has a nice list). These are called “post-translational modifications” (PTMs) and they’re normal, but like any normal biological process, they can go awry.

Other things causing protein misfolding in some disorders are environmental toxins and genetic abnormalities.  We don’t yet know the relevance of these to PSP or CBD, but there are some indications that it’s not zero.

We don’t know why certain diseases have abnormalities of PTMs.  We don’t even know, in most cases, if the abnormal PTMs are a cause of the tissue damage or a collateral effect of the same toxic process that causes that damage.  The new information about tau folding patterns will certainly intensify the already intense search for those answers.

A frozen treat

I wish I could report on some breakthrough in the treatment or prevention of PSP, but that hasn’t happened yet. But what I can do is to report on a major advance in understanding an “upstream” step in the process that’s killing brain cells in PSP. The abnormal tau molecule in PSP has now been imaged.

The prevailing, and probably correct, theory is that brain cells are damaged somehow by tau protein that has folded upon itself, causes its healthy sibling tau molecules to similarly misfold via a templating process. The tau then forms stacks like checkers, called “fibrils,” which are toxic to the cells. Tau doesn’t normally have any folding pattern at all – if it’s not attached to the cells’ internal skeleton, doing it’s normal job, it’s floating around in the cytoplasm (the cells’ internal fluid) like overcooked spaghetti in boiling water. We’ve known for decades that through the electron microscope, the fibrils of PSP look different from those of Alzheimer’s, which in turn are different from those of corticobasal degeneration, which are different from those of Pick’s disease, and so on. We’ve hypothesized that this is because the pattern of misfolding determines the geometry of the stacks of tau, and those stacks determine which cells are attacked, and that determines the patient’s symptoms. But we had no details.

Well, now we do, thanks to a new lab technique called “cryo-electron microscopy” or “cryo-EM.” That’s where the sample is imaged at a temperature cold enough to keep it from wiggling around as much, allowing a far greater visual resolution than was possible using other methods. It still does wiggle a bit, which is why the technique starts by making a video of a tau molecule and then computer-averages the image. The resulting still photo shows the protein molecule’s pattern of loops and folds; even the individual amino acids are visible as fuzzy bumps on the chain. The resolution of the images was 2.7 Angstroms, about the same as the diameter of a water molecule.

Over the past couple of years, researchers applied cryo-EM to tau in a few tauopathies including AD, CBD and Pick’s disease. Only now has PSP been studied by this technology, along with a bunch of much less common tauopathies. The new paper is from an international team led by Michel Goedert, Sjors H. W. Scheres, Yang Shi and Wenjuan Zhang, all of Cambridge University. It was published in Nature, probably the world’s most prestigious and selective biomedical journal.

Misfolded tau from a patient with PSP (Shi Y., et al. Nature 2021)

They imaged tau from 11 diseases, a number large enough to justify a classification system using a few different features such as the number of layered folds and hairpin turns. They found that the folding patterns of the various PSP subtypes were identical except for one case of a rare type, PSP-F, a variant with disproproportionate frontal lobe behavior and cognitive problems. Under the new classification system based on tau folding, the tauopathy most similar to PSP was globular glial tauopathy, a rare cause of dementia diagnosable only at autopsy.

They found the folding pattern of Alzheimer’s tau to be identical to that of primary age-related tauopathy (PART), familial British dementia (FBD) and familial Danish dementia (FDD). The pattern in chronic traumatic encephalopathy (CTE) was similar but not identical to that. Corticobasal degeneration (CBD) was similar to argyrophilic grain disease (AGD) and aging-related tau astrogliopathy (ARTAG). Finally there was Pick’s disease, which was similar to none of the other ten.


Why is all this important? I’ll let the authors themselves explain:

“The presence of a specific tau fold in a given disease is consistent with its formation in a small number of brain cells, followed by the prion-like like spreading of tau inclusions. This may underlie the temporo-spatial staging of disease. Knowledge of the tau folds in the different diseases provides a framework for studying tauopathies that will lead to a better understanding of disease pathogenesis. At a diagnostic level, our findings will inform ongoing efforts to develop more specific and sensitive tau biomarkers.”


By “temporo-spatial spreading,” they mean where in the brain the damage spreads and how fast. So the next big step is to figure out just how the molecular structure presented on the surface of each kind of misfolded tau interacts with healthy brain structures. Once we do that, we can find a monkey wrench to throw into that process – one monkey wrench for PSP and globular glial tauopathy; another for AD and its pals PART, FBD and FDD and possibly CTE; one for Pick’s; and yet another for CBD, AGD and ARTAG.

I’ll try to keep you updated on this, and soon I’ll opine on the collateral question of whether this new work casts doubt on our long-held position that PSP, as a “pure tauopathy,” is a good test-bed for all of the tauopathies, including AD.