A paradigm shift?

You already know that PSP and CBD are “pure tauopathies,” meaning that tau is the only protein consistently aggregating in the degenerating brain cells.  You also know that Alzheimer’s disease has two such aggregating proteins, beta-amyloid and tau, and that problems in the former seem to induce the problems in the latter.  But now there’s evidence that in PSP there’s a second protein causing the tau problem. It’s called “filamin-A” and if the evidence is correct, it’s a very big deal. 

A research group from several centers in Japan led by Dr. Koyo Tsujikawa of Nagoya University encountered a pair of identical twins with PSP.  They found that each man had multiple copies of a normal region of their X chromosome where 16 different genes reside.  One of those 16, called “FLNA” because it encoded the protein filamin-A, was previously known to play a role in the brain cell’s internal skeleton.  Of course, tau is also involved with the cytoskeleton, so the scientists focused on filamin-A before the other 15 proteins. 

The paper lists 31 authors.  I know two of the senior guys and can vouch that they have produced consistently excellent work for decades. 

Their lab experiments showed that this mutation in the twins and their PSP are cause-and-effect rather than just coincidental. Sorry, but this gets a little tech-y:

  • Autopsied brain cells from the twins with PSP showed not only the excess tau expected in PSP, but also excess filamin-A, and the two proteins aggregated into insoluble clumps in the same brain cells.
  • The twins had tufted astrocytes, a tau-laden feature of PSP brain tissue found in no other disease, and those same cells had abundant filamin-A. This means that this is real PSP, as best we can define it, and not some imitator.
  • Filamin-A levels were normal in autopsied brain samples from people with no brain disease and from brains of patients with CBD, AD, Parkinson’s and dementia with Lewy bodies.
  • In cultured human cells, excessive filamin-A produced by adding an extra copy of the FLNA gene increases the production of tau; and reducing filamin-A production with “silencing RNA” directed at FLNA prevented excessive tau production.
  • Mice engineered to over-produce tau (called “MAPT knock-ins”) did not develop high filamin-A levels, showing that in the direction of causality goes from filamin-A to tau, not the reverse.
  • FLMA knock-in mice produced tau that was not only over-abundant, but qualitatively abnormal as well, with excessive attachment of phosphate groups (“hyperphosphorylation”), an important known driver of neurodegeneration in PSP and the other tauopathies.
  • The genetic abnormalities in FLNA appear to damage tau by interacting with a third protein called F-actin. Genetic abnormalities in F-actin have not been found in PSP, but the function of that protein is impaired by mutations in the gene LRRK2 (“lark-two”), which are over-represented in PSP.  (It was previously known that lab-induced abnormalities in F-actin can cause tau to malfunction in a way that damages brain cells, but there was no reason to think this was relevant to human tauopathies until now.)
  • Among 312 patients with non-familial PSP analyzed in the new paper, none had the same mutation found in the twins (i.e., extra copies of FLNA) but there were 12 patients (4%) with other kinds of mutations in FLNA.  Much lower percentages of FLNA mutations were present in patients with CBD, AD and healthy individuals. 

So, what does this mean?

At the superficial level, it means that some sort of abnormalities in filamen-A could explain tau misbehavior in PSP, just as abnormalities in beta-amyloid abnormalities explain tau misbehavior in AD.  Only a small minority of people (in Japan) with PSP actually have a mutation in the gene for filamen-A, but like any protein, its function may be impaired by many other things such as toxins, trauma, inflammation, and genetic or non-genetic defects in proteins with which it interacts. 

At a more profound level, this new insight could mean that finding the ultimate cause of PSP should start with filamin-A or F-actin even though effective treatments for the diseases could act elsewhere, like with tau itself.  Attacking a disease “upstream,” where the problem starts, is theoretically better than downstream, though the latter is closer to the actual loss of brain cells.

There are a couple of caveats:

  • Mutations in FLNA have long been known to cause a developmental brain abnormality with cognitive delay.  Both twins’ brains had subtle forms of that.  So their PSP may not be a good model for ordinary, non-familial PSP occurring in developmentally normal individuals. 
  • The frequency of FLNA mutations in the 312 Japanese patients with non-familial PSP may not apply to other populations.  The genetic studies of PSP in non-Japanese populations to date have not found a relationship with FLNA, but there are technical reasons for false negatives in that sort of study. 

But these caveats aren’t dealbreakers at all:  Regarding the second issue, remember that rare, atypical, genetic forms of neurodegenerative diseases have in the past provided very valuable insights into the cause of the common, typical, non-familial form of a disease.  For example, in Parkinson’s, 20 members of an extended Italian-American family kindred with young-onset, rapid-progressive PD were found to harbor a mutation in the gene for alpha-synuclein.  On further scrutiny, that protein proved to be central to all PD and trials of anti-alpha-synuclein treatments are under way.  A similarly huge advance in understanding Alzheimer’s disease arose from analyzing the extra chromosome 21 in individuals with Down syndrome (trisomy 21).  A search of that chromosome pointed to the amyloid precursor protein, the source of beta-amyloid, critical to all AD.  In neither PD nor AD does more than a tiny fraction of patients have a mutation in their genes for alpha-synuclein or amyloid precursor protein.

Could we be at the threshold of a similarly radical advance in our understanding of PSP?  Could such a paradigm shift provide targets for a drug to prevent, slow or halt PSP?  We’ll find out — and I hope soon.

Get out those rulers

Everyone with a suspected diagnosis of PSP should have a brain MRI.  It can find more-readily-treated things such as strokes, tumors or normal-pressure hydrocephalus.  But the MRI is not all that useful in differentiating PSP in its early, diagnostically-uncertain, stages from other neurodegenerative conditions such as Parkinson’s, MSA, Alzheimer’s, CBD, dementia with Lewy bodies, and the several forms of FTD.  Even the famous hummingbird sign of PSP doesn’t appear until the middle stages of the disease, by which time a neurologist can make the diagnosis by history and physical exam anyway.  Besides, any disorder that causes atrophy of the midbrain will produce a hummingbird sign.

But now, researchers at the University of California, San Francisco and the Universitat Autònoma de Barcelona have used an automated system to measure the degree of atrophy of several areas of brain as seen on MRI.  The system, called “FreeSurfer,” is in standard use in research requiring MRI measurements. The lead author was Ignacio Illán-Gaia and the senior author was Adam Boxer.  All of their 326 subjects had been evaluated at UCSF’s Memory and Aging Center between 1994 and 2019.  The diagnosis in each case was later established at autopsy – a major scientific strength of this study.  Autopsy showed PSP in 68, CBD in 44, various forms of FTD in 144, Alzheimer’s in 45, and PD, MSA or DLB in only 11.

The four brain areas chosen for analysis were all previously known to atrophy in PSP: cerebral cortex, midbrain, pons and superior cerebellar peduncle.  (The midbrain and pons are in the brainstem and the SCP is one of three tracts connecting the cerebellum to the rest of the brain.)  They used not only the size of each, but also a previously reported index called the “magnetic resonance parkinsonism index” (MRPI), a formula involving the size of the midbrain, pons, SCP and middle cerebellar peduncle. (See note below for details.) The MRPI does very well in distinguishing PSP from PD, but has not been adequately evaluated against all possible alternative diagnoses.  Actually, an updated version called “MRPI 2.0” can distinguish PSP from MSA because it takes into account atrophy of the thalamus, but it’s too new to have an automated version, so this project satisfied itself with the MRPI.

The result was that the MRPI showed an excellent ability to distinguish PSP from the other diseases as a group.  The area under the receiver operating curve (AUROC; see my previous post for an explanation) was excellent: 0.90 of a possible 1.00.  But the AUROC for distinguishing PSP from CBD was only moderate at 0.83.  A more sophisticated statistical analysis, a “multiple logistic regression model” (MLRM), worked even better, distinguishing PSP from the others with a superb AUROC of 0.98.  The CBD- vs-others comparison also benefited from the MLRM, rising to 0.86.

To put the AUROC into more-relatable terms: The AUROC of 0.98 in this case corresponds to an “accuracy” of 95%.  That means that the MLRM got the diagnosis correct (i.e., PSP or not PSP) in 95% of patients.  But that simple calculation can be misleading, which is why the AUROC is used by researchers. 

As mentioned above, the total number of patients with PD, DLB and MSA was only 11.  That’s because the study was performed at a memory center, not a movement center.  While the MRPI has proven its utility in distinguishing PSP from PD, the same can’t be said for the PSP vs DLB or the PSP vs MSA comparisons.  So we need more work with a statistically robust number of patients with DLB and MSA.

For an admittedly biased assessment of the importance of this study, here’s Dr. Illán-Gaia in emailed comments in response to my request for a couple of quotable blurbs:

Our study demonstrates in a large autopsy-proven cohort that combining a set of cortical and subcortical measures of cerebral atrophy could represent a powerful diagnostic tool. These measures can be obtained with a simple MRI and could be combined with other biomarkers to improve the diagnosis of patients with PSP or CBD.

More work needs to be done to ensure the translation of our method to clinical practice and we are now working to validate our results in other large multicenter studies.

Notes: 

The MRPI is calculated as follows: (area of pons on mid-sagittal section / area of midbrain on midsagittal section) X (diameter of middle cerebellar peduncle on parasagittal section / diameter of superior cerebellar peduncle on coronal section). 

The MRPI 2.0 multiplies the MRPI by the (maximum width of the third ventricle / maximum width of the frontal horns of the lateral ventricles).

Skin is now in the game

Researchers led by Dr. Elena Vacchi of Lugano, Switzerland report new data on the utility of skin biopsies in the diagnosis of PSP and CBS.  This diagnostic approach is further along for Parkinson’s, where the fibers of alpha-synuclein are not difficult to detect in the tiny nerves in skin. The same technique, but for tau, has not been particularly successful for PSP so far, but these researchers did more sophisticated molecular tests. 

They recruited 11 patients with PSP and 4 with CBS, along with 31 with PD, 14 with MSA and 24 healthy controls.  They obtained two cylindrical plugs of skin 3 mm in diameter from the back of the neck and another two from just above one ankle.  They measured the amount of normal and abnormal tau protein and the forms of RNA encoding the most common abnormal tau forms found in PSP and CBD (the 2N4R isoform). 

Comparing the group with PSP or CBS with the group with PD, there was a 90% sensitivity (i.e., the fraction of the patients with PSP or CBS whose biopsy showed an excess of abnormal tau) but only 69% specificity (the fraction of those without PSP or CBS with a normal result) and 0.812 AUC (see the note below).  For the comparison of PSP/CBS versus MSA, the results were better: 90% sensitivity, 86% specificity and 0.900 AUC.  I assume that that’s because of PD’s known tendency to have a little tau aggregation along with its alpha-synuclein, while that happens little in MSA.  For some reason the comparison of PSP/CBS with healthy controls was only moderate, with an AUC of 0.774.  The neck skin proved more informative than the ankle skin. 

The authors point out that their patients’ diagnoses were not autopsy-confirmed.  One solution might be to obtain the skin samples from deceased patients undergoing brain autopsy.  They also point out that the pattern of excessive phosphorylation of tau, which is known to be critical to disease causation, was not considered at all in their otherwise-thorough lab procedures.  So that might improve their results.

An interesting upshot is the authors’ observation that in PD and MSA, there was a reduction of nerve fibers in the skin, while this did not occur in PSP/CBS.  Together with evidence from many other sources, this suggests to them that in PD and MSA, the disease starts in the peripheral tissue (i.e., in non-brain organs such as the skin) and spreads to the brain, while in PSP and CBD, the problem starts in the brain and spreads outwards.

Note: Per Wikipedia, “A receiver operating characteristic curve, or ROC curve, is a graphical plot that illustrates the diagnostic ability of a binary classifier system as its discrimination threshold is varied.”  In other words, how well does a simple positive/negative diagnostic test do in distinguishing true positives from true negatives?  This allows you to optimize the definition of “positive” and “negative” test.  The curve’s vertical axis is the sensitivity or the true positive rate (0 to 1.0) and the horizontal axis is 1 minus specificity or the false positive rate.  The area under that curve (AUC) has a theoretical maximum of 1.0.  Excellent diagnostic tests have an AUC of 0.90 or more, and moderate tests, 0.80 to 0.89.  A coin flip’s AUC is 0.50.

Hello darkness my old friend

One of the most troublesome symptoms of PSP is photophobia.  That sounds like a psychiatric condition, but it’s when bright light is uncomfortable or even painful, and it occurs sooner or later in nearly everyone with PSP.  In a few, it’s one of the first symptoms, manifesting in some cases as difficulty watching a brightly spot-lit performer on an otherwise dark stage and progressing to an intolerance even for standard indoor lighting. 

The explanation that I’ve long accepted starts with insufficient blinking, then drying of the surface of the eye, then inflammation, then pain when the pupil attempts to constrict to light.  But I’ve recently learned that it also may be a direct neurological effect of the PSP disease process.  https://pubmed.ncbi.nlm.nih.gov/18328771/  Supporting this theory is the observation that photophobia is a very consistent symptom of benign essential blepharospasm.  That’s where the eyes blink or clench shut involuntarily, with no other neurological issues.  Blepharospasm also occurs as a very frequent component of PSP, suggesting that blepharospasm itself, whether part of PSP or not, includes photophobia without implicating eye surface drying.

Whatever the cause, photophobia can be a very early and important feature of PSP.  But someone with PSP experiencing photophobia should still look for other, more easily treated, causes.  An article by Dr. Thomas Buchanan and colleagues at the University of Utah reviews the diagnosis and treatment of photophobia in the Journal of Neuro-Ophthalmology. (I know you all await each issue eagerly.)

They reviewed the records of every patient with photophobia seen at their center over a 9-year period, finding that 10 patients (9% of the 111 adults) had PSP.  The only disorders accounting for larger percentages were migraine (54%), dry eye syndrome (36%) and eye trauma (8%).  (These total more than 100% because some patients had more than one cause listed by their physicians.)

The article provides a thorough list of disorders causing photophobia.  I’m not going to define these for you, but I suggest you look through the list, hopefully with the advice of your doctor, as some of them have specific treatment.  Of course, in the population of those who already have PSP, the likelihood of any of these other conditions as the cause of their photophobia is very low. 

This list is adapted from: Buchanan TM, Digre KB, Warner JEA, Katz BJ. The unmet challenge of diagnosing and treating photophobia. Journal of Neuro-Ophthalmology: 3/25/2022. 10.1097/WNO.0000000000001556 

Causes of Photophobia

Seeking a treatable primary cause is all well and good, but that takes time, so aggressive treatment at the symptomatic level is the place to start.  The best shaded glasses for photophobia aren’t standard, green sunglasses, but FL-41 tinted glasses.  Those are rose-colored, and you’ll just have to endure jokes about your new outlook on life.  If for some reason you find the green glasses more comfortable, don’t wear them indoors, as your eyes will adapt to the dark and become extra painful when you return to the outdoors. 

Just in case your photophobia is caused by eye drying, lubricant drops, especially those with forms of cellulose, may provide relief.  More aggressive measures include certain medicated eye drops, gel tables inserted in the lower lid, or petrolatum-based lubricants.  Surgical options are available as well, though none of them has been formally tested in people with PSP. 

There’s a specialty, believe it or not, called “neuro-optometry.”  Those folks are usually easier to get an appointment with than a general ophthalmologist or neuro-ophthalmologist and may be more comfortable managing chronic, PSP-related problems like photophobia.  Furthermore, they don’t do surgery themselves, so they are a good source of unbiased advice on that score.

Long PSP

For several years, one of CurePSP’s public-facing taglines has been, “Because Hope Matters.”  Last week, the CurePSP staff decided to make that advice part of the organization’s actual logo, replacing “Unlocking the Secrets of Brain Disease” at that position. 

In trying to help patients with PSP, CBD and many other still-incurable diseases over four decades, I’ve found that hope really does matter.  It’s not just a bit of quackery arising from medical impotence.  No matter how thin that thread of hope may be, a person’s stress level, and their motivation to work with their physician to do what can be done, are greatly enhanced by some measure of hope:  hope that a cure, or at least a way to halt the disease’s progress, may be found in their lifetime; hope that they will be among the minority spared some of the most disabling symptoms; and hope that their survival will beat the average.

That’s why I was most glad a few days ago to see a report from the Rossy Program for PSP Research at the University of Toronto of four patients with clinical diagnoses of PSP surviving 11, 12, 18 and 20 years after symptom onset.  The average figure is typically reported as between 6.7 and 7.5 years.

Three of the four Toronto patients had confirmation of PSP at autopsy.  The fourth had a very rare condition called pallido-nigro-Luysian atrophy (PNLA), a tauopathy that often mimics PSP and is equally resistant to treatment, but has a much slower course. 

Sidebar:  I first learned about PNLA in 2004, when I was invited by the journal Movement Disorders to discuss a “clinicopathological correlation.”  That’s a teaching exercise where the organizer selects a patient whose diagnosis was difficult or impossible to make during life but whose autopsy gave the answer.  The organizer sends a clinical summary to a recognized outside expert or two with no previous knowledge of the patient.  They each submit a written discussion and a diagnostic conjecture to be published alongside the autopsy results.  The case I was invited to discuss was someone with a clinical picture that looked exactly like PSP except for a 26-year survival.  The other discussant and I each independently concluded that the patient had PSP with a long survival was statistically plausible for that condition.  But the autopsy showed “primary pallidal degeneration,” of which this was the eighth case ever reported in the medical literature.  The pathologist mentioned PNLA as a similarly rare, closely-related condition that he considered as an alternative, but it did not fit the autopsy results quite as well.  Now back to business:   

Whenever I discuss expected survival duration with a person with PSP or their family, I tell them the truth – as gently as possible.  But I also point out that they could beat the average survival figures, especially if they get treatment to help protect from falls, aspiration, infections, malnutrition, and emotional stress.  That measure of hope provides a kind of lifeline to grasp, one now corroborated by the medical literature.  So here are four more patients proven to have beaten the odds – four more reasons for hope. 

Common thread, silver bullet, naïve hope?

There’s a great place on the Internet called bioRxiv (“bio archive”), where researchers can post their papers without benefit of peer review.  Users know that they’re reading the latest, but the greatest?  Maybe only its authors and their mothers think so.  But when a paper is from a group of researchers with stellar reputations, it’s probably the real deal.

Such is the case for “Age-dependent formation of TMEM106B amyloid filaments in human brain,” posted on the bioRxiv website in November 2021.  Most of the 29 authors, including the leading ones, are from University of Cambridge or elsewhere in the UK, but many are from various institutions in Japan, with a few from the Netherlands, Canada, Austria and the US.

The paper found that the brains of healthy elderly persons have abnormal aggregates of a misfolded form of the protein TMEM106B. This stuff is known to be a component of healthy lysosomes and endosomes, components of the cell’s garbage disposal mechanism.  Variants in the gene encoding TMEM106B elevate one’s risk of developing the TDP-42 type of frontotemporal dementia.  The term “amyloid” in the paper’s title doesn’t refer to the beta-amyloid of Alzheimer’s disease but to its more generic sense of any protein aggregated into insoluble clumps.  Tau in PSP, for example, is an amyloid. 

Not only did the bioRxiv paper discover amyloids of TMEM106B in normal aging, it found them even more abundantly in a raft of neurodegenerative diseases: Alzheimer’s, CBD, multiple types of FTD, Parkinson’s, dementia with Lewy bodies, multiple system atrophy and multiple sclerosis.  Notice that PSP isn’t on the list.  That’s because none of their 22 brain samples were from people with PSP. 

So last week, into the breach rides a paper that has actually been peer-reviewed and published — in Cell, no less.  (A very prestigious, selective journal.)  Those authors, from Columbia University, Mayo Clinic Jacksonville and a number of other places in the US, Canada and Belgium, found the same TMEM106B aggregates in both of the brains they examined from people with PSP.  They knew of the bioRxiv paper and cited it.  (That’s how I found the bioRxiv paper.  Technically unpublished, it didn’t appear in my daily electronic searches of the PSP literature via Pub Med.   I doggedly tracked it down on the bioRxiv website only after I saw it cited in the new Cell paper.  See what I do for you, my dear readers?)

An interesting finding is that unlike tau, TMEM106B misfolds the same way in all the diseases analyzed so far.  This may have huge potential implications: if (and this is a big “if”) the misfolded TMEM106B plays an important role in the formation of the misfolding and toxicity of tau and the other disease-specific proteins, and if (another big “if”) this misfolding is the rate-limiting step in the loss of brain cells in the neurodegenerative disorders, THEN preventing TMEM106B from forming or from misfolding, or targeting it with antibodies or drugs could be the silver bullet that prevents all of these diseases, PSP included.

That could be a naïve hope, but I’ll ask some hard-bitten old lab codgers bearing the scars of past failed grand theories what they think.

Pushing the envelope a little more

Three more clinically relevant, PSP-related reports from last month’s Tau 2022 symposium:

Barring entry to tau.  The way tau enters healthy cells in its spread through the brain has recently been found to be “receptor-mediated endocytosis.”  The same mechanism is used by many viruses, including influenza A,  Zika . . . and coronavirus.  Work is ongoing to identify genes encoding protein components of that process.  Then, inhibiting the production of such proteins could slow the spread of tau (not to mention those other diseases).  One of the proteins found to be involved in receptor-mediated endocytosis is LRRK2, which is mutated in a common, hereditary form of Parkinson’s disease.  The uptake of tau, at least by cells growing in a lab, is slowed by drugs that inhibit the most common PD-associated LRRK2 mutant, called G2019S (because a glycine at amino acid position 2019 is replaced by serine).  So this raises the possibility that such drugs, presently in trials for PD, could slow progression of tauopathies such as PSP.

PSP as a seizure disorder?  Some new evidence suggests that tau participates in the causation of PSP not by invading and destroying brain cells directly, but by getting a few brain cells too excitable.  This, in turn, could attract attention from the immune system, which over-reacts and causes slight damage to those and other brain cells, which causes more hyper-excitability, and so on in a vicious cycle.  This implies that a way to slow the progression of PSP could be anti-seizure drugs, which calm down hyper-excitability in brain cells.

Iron could be key. It turns out that in brain tissue from people with PSP, abnormal deposition of iron occurs in the same cells as the disease process.  It’s most pronounced in astrocytes, the type of cell in which PSP appears, based on several decades’ evidence, appears to start.  The researchers identified genes that are disproportionately “expressed” (i.e., actively coding their proteins) in the iron-laden cells.  This offers multiple new targets for drugs to act upon.

A few tidbits from Tau 2022

Here are some very quick research updates from the Tau 2022 meeting of February 22-23.  Most of this is unpublished, so I can’t get into much detail.

Oral tau expression modulators. Drugs that modulate the production of the tau protein are currently in clinical trials but are administered by injection, typically directly into the spinal fluid.  Not very practical.  But now, orally administered drugs that do much the same thing are being developed and have drug company interest.

New drug trial?.  A drug called lonafarnib, which inhibits an enzyme called farnesyl transferase, is FDA-approved for one form of pathologically early ageing in children.  It has also been known for a couple of years to slow progression in a mouse model of tauopathy by enhancing the action of lysosomes, which break down excessive tau.  Now, it’s being studied in healthy human volunteers and a trial in people with tauopathies may not be far off.

A tau inflection point.  In Alzheimer’s disease, positron emission tomography (PET) scanning for tau has shown that in the first few years, before the symptoms become very troublesome, the tau burden in the brain is increasing slowly.  But then, at about the time the symptoms bring the person to medical attention, the tau burden dramatically increases and continues to do so thereafter.  That tipping point has been informally and perhaps disrespectfully called a “ca-tau-strophe” beyond which the process may not be amenable to slowing by any treatment.  We don’t know if the same thing happens in PSP, but it seems likely.  This is further justification for improving the sensitivity of diagnostic methods and for better educating health professionals about PSP.

New gene “knock-in” models. Frontotemporal dementia is strongly hereditary in about a third of cases.  Of these, 4% have a PSP-like picture, 5% are PD-like and 2% are CBD-like.  The average onset age of hereditary FTD is only 50, compared with about 65 for true PSP.  (True PSP occurring in a familial pattern is much rarer and no mutation for that has been identified.)  So far, 71 different mutations in the tau gene have been found as causes of hereditary FTD.  A few of those have individually been inserted into mice to create commonly used models for PSP and Alzheimer’s research.  Those mouse models have taught us a lot, but drugs that slowed progression of the tauopathy in such mice have uniformly failed in human clinical trials of AD or PSP.  However, many mutations in other genes have been found to confer a small degree of risk for AD or PSP.  Presumably, someone with AD or PSP must harbor at least two such mutations.  Now, researchers have created mice with multiple such mutated genes, hoping that they will provide a more faithful mimic of human tauopathy for use in screening drugs before embarking on human treatment trials. 

PSP blood test challenges.  Tau protein with abnormal attachment of phosphate groups in certain positions is increased in the blood of people with Alzheimer’s disease.  This can serve as a diagnostic tool.  But the same isn’t true for PSP, unfortunately.  This may be because there’s less abnormal tau in the brain in PSP.  But in PSP, unlike in AD, the glial cells of the brain have more abnormal tau than the neurons, and a new type of blood test can differentiate between tau from the two brain cell types.  This requires measuring tau in tiny, membrane-bound droplets in the blood called “exosomes.”  Work to assess the diagnostic potential of exosomes in PSP is ongoing.

PSP as an immune disorder. The tauopathies have been found to involve changes in immune function and the part of the immune system involved is different in the various disorders.  In PSP and CBD, for example, the “natural killer” (NK) lymphocytes are more involved, while in Alzheimer’s, it’s more about the microglia.  PSP has been found to have a set of gene variants related to glial function and another related to NK lymphocytes that tend to be suppressed to the similar degrees, meaning that the disease may result, in part, from simultaneous insufficiency of these two functions.

Another set of dispatches from the Tau 2022 meeting soon — I promise.

Handwriting analysis?

I spent most of last week attending two virtual conferences.  One was the semiannual investigators’ meeting of the Tau Consortium.  That’s a group of a few dozen researchers funded by the Rainwater Charitable Foundation.  Attendance is limited to funded researchers, their trainees, and invited guests from organizations that work with the RCF.  I got in as a representative of CurePSP.  They keep attendance private so that speakers will feel free to share their work long before publication without fear of plagiarism. The other was Tau 2022, a biannual conference sponsored by the Alzheimer’s Association, the Rainwater Charitable Foundation and CurePSP, with help from a few drug companies.  Registration was open to the public and I was on its Steering Committee, again representing CurePSP.  Both conferences were stuffed with cutting-edge work by some of the world’s top researchers.  I’m working on summarizing for you, dear reader, some of the things that I’m allowed to share, and that will take a few more days.

Meanwhile, I saw a cool paper in a journal called Sensors.  Paula Stępień, a biomedical engineer at Silesian University and colleagues from multiple other institutions in Poland created an app that analyzes a commonly used, pen-and-paper neuropsychological test called the Luria Alternating Series Test.  The examiner draws a series of connected triangles (actually inverted V’s) and squares (without the bottom side) an inch or two at the left of a sheet of paper.  The patient then has to continue the series the rest of the way.  Here are examples for someone with PSP (top), PD (middle) and a healthy control.  The examiner’s model is the first five figures on the left of each line:

The algorithm looks at 35 possible error features and can label subjects as having PSP, PD or neither with 70.5% accuracy.  While that’s not as good as MRI or a formal, in-person history and exam by a neurologist, it does have the advantage of being a lot easier and cheaper and can be performed remotely.  Perhaps coupling it with some other tests similarly compatible with telemedicine could raise that accuracy figure.  That could allow treatment trials to screen people with suspected PSP before bringing them in for the standard hours-long, in-person initial evaluation visit.

The article doesn’t mention how long the patients had PSP or PD or the severity of their outward signs, so perhaps the same diagnostic information could have been obtained by casual observation by video call.  But like any diagnostic test, you first have to make sure it works in people with an existing diagnosis before you test it in those with early-stage or diagnostically equivocal symptoms.

A distinction with a difference

Apathy and depression are among the most disabling non-motor features of PSP, and they’re not the same thing.  To quote the opening lines of an excellent 1998 paper from Morgan L. Levy and colleagues from UCLA, University of Iowa and the NIH,

“Apathy is defined as diminished motivation not attributable to decreased level of consciousness, cognitive impairment, or emotional distress.  Depression involves considerable emotional distress, evidenced by tearfulness, sadness, anxiety, agitation, insomnia, anorexia, feelings of worthlessness and hopelessness, and recurrent thoughts of death.”

That article, entitled, “Apathy Is Not Depression,” focused on Alzheimer’s, frontotemporal dementia, Parkinson’s, Huntington’s and PSP. It pointed out that while apathy is traditionally considered to be one of the many possible features of depression, it can also be analyzed separately.  So that’s what they did.  

They found that among their 22 patients with PSP, 77% had apathy without depression, 5% had depression without apathy, 14% had both and 5% had neither.  In the 154 patients overall, there was no correlation between apathy and depression. (Among the 22 with PSP, there were too few with depression to calculate the correlation specifically for that disease.)  Apathy was more common and severe in AD, FTD and PSP, while depression was more common and severe in PD and HD.  In the overall group, apathy was associated with disinhibition, but depression was associated with anxiety, agitation, irritability and hallucinations.

The prevalence of depression and apathy in PSP vary wildly across studies, depending on definitions and sources of patients.  For example, fast-forward to a December 2021 study from Sarah M. Bower and colleagues at Mayo Clinic Rochester.  In their 97 patients with PSP, depression was present in 55% and apathy in only 12%.  This proportion was roughly the same for each of the nine PSP subtypes evaluated except for PSP-speech/language, where depression was much less frequent.

Why should we care about the distinction between apathy and depression?  Because they’re both treatable and the treatments differ. Here’s a compilation of recommendations from experts at UCSF and from the CurePSP Centers of Care.  Keep in mind that these recommendations are generally based on experience and record reviews rather than on randomized trials.

  • Depression in PSP is typically treated with selective serotonin reuptake inhibitors (SSRIs) (except for paroxetine because of its anticholinergic side effects), serotonin-norepinephrine reuptake inhibitors (SNRIs) or bupropion.  Non-drug treatments include cognitive-behavior therapy, mindfulness yoga, professionally guided meditation, and in very severe cases, electroconvulsive therapy.

  • Apathy in PSP, on the other hand, is treated with one of the amphetamine-like drugs methylphenidate or modafinil, or sometimes an SNRI.  Apathy can be worsened by SSRIs.  Regular conditioning exercise is also useful.

So, add this to the long list of reasons why it’s so wrong for a doctor to tell someone with PSP, “Sorry, but there’s nothing I can do for you.”