Bad for the goose, good for the gander?

A disturbing piece of news this week about an influential 2006 paper in Nature about Alzheimer’s disease.  Turns out it was likely that some of the data in the published version were deliberately faked.  The paper was about beta amyloid, which is not an issue in PSP.  In fact, this could actually be good news for PSP research.  Here’s why:

In the experiments reported in the 2006 paper, researchers at the University of Minnesota Twin Cities used mice carrying a copy of the human amyloid precursor protein (APP) gene with a mutational variant known to cause AD in humans.  (In the normal human brain, the protein product of the APP gene is cut to form beta-amyloid, abbreviated, “A-beta.”)  The researchers allowed the mice to develop cognitive deficits, analyzed their brains, and found a type of small A-beta aggregates never before seen, dubbing them “A-beta*56.”  They extracted the small aggregates, called “oligomers,” and injected them into the brains of genetically normal (“wild-type”) rats, which proceeded to develop AD-like cognitive disabilities. 

Ever since A-beta was identified as a critical player in AD in 1984, researchers had been trying to nail down just what form that protein takes in the process of causing, or contributing to, the disease.  The 2006 paper seemed finally to answer that question and formed the basis for innumerable subsequent experiments world-wide and hundreds of millions of dollars spent by the NIH, philanthropies and drug companies to build upon it in pursuit of an AD treatment. 

The 2006 Nature paper used a commonplace lab technique called Western blot to separate out different proteins from a mixture.  A bit of the mixture is placed on a flat layer of absorptive material and subjected to an electrical field.  The heavier proteins move more slowly than the lighter ones.  The resulting array is exposed to an antibody-based stain that allows it to be seen.  The positions and sizes of the individual protein spots are then analyzed. 

A sample Western blot unrelated to the research discussed here. The numbers on the left are the molecular weights of the proteins in kiloDaltons (one Dalton is the weight of one proton). The leftmost column shows the separation of a standard mixture of proteins of known weight as a benchmark. The other two columns show components of a protein mixture before (middle) and after (right) the addition of an enzyme that cuts proteins.

But now, a whistleblower has reported evidence that some of the Western blot images in the publication and many others from the same lab were placed where they didn’t belong, citing faint lines between blots that could result from cutting-and-pasting.  There was also an instance of two blots with identical size and shape, something with a likelihood approaching zero absent a copy-and-paste operation.  The journal Science hired two scientists unconnected to the Minnesota team to take a look.  They confirmed that deliberate falsification is highly likely, though there’s no smoking gun, which would require access to the original Western blot images or to the original data readouts. Nor, so far, has there been a confession. 

Meanwhile, what’s the upshot?  For the AD field, it means that the treatment trials of anti-A-beta drugs were based on much less laboratory evidence than was thought, possibly explaining why they all failed.  (Aducanumab, the antibody approved in 2021 by the FDA, targets A-beta, but its clinical benefit is highly controversial, Medicare refuses to cover the treatment, and most neurologists opt not to prescribe it.)  That means that by default, anti-AD treatments addressing tau, the other protein aggregating in AD, deserve more attention.

Some experts have questioned the importance of A-beta in AD for decades, but only in the last 15 years or so has AD research into tau as the alternative received serious support.  In PSP, tau is the only protein that consistently aggregates and there’s no evidence of A-beta misbehavior at all.  PSP is therefore considered by many scientists to be a good test bed for anti-tau treatments for AD.  That’s why I think that if these new doubts about A-beta in AD direct attention to tau, an intensification of tau-based PSP research could result, and that could, by extension, benefit AD as well. 

While two anti-tau antibodies have failed to slow the progression of PSP in clinical trials, there are many other ways to address tau in PSP, including one trial currently recruiting and at least two more set to start in the next year. 

So, let’s hope that this week’s revelation gives PSP research a boost and AD research a long-overdue redirection.


Here’s a detailed editorial in Science explaining all of this (without my own speculation about the possible benefit for PSP research). But it’s behind the journal’s paywall and I didn’t want to post the pdf I have access to through my university. That would be another form of dishonesty.

Dr. John Steele, fondly remembered

The PSP community mourns the passing of neurologist John C. Steele, MD on May 21, 2022, surrounded by his children in Bali, Indonesia, his most recent home. He was 87.

Dr. Steele was one of the physicians at the University of Toronto who in 1963 and 1964 published the defining clinical and pathologic descriptions of PSP.  The eponym, “Steele-Richardson-Olszewski syndrome” predominated in the medical literature for decades and is still used by some writers to honor the accomplishment. At the time, Dr. Steele was a neurology resident, Dr. J.C. Richardson was his mentor and department chief, and Dr. Jerzy Olszewski was a neuropathologist. Their 1964 paper in Archives of Neurology remains today the most frequently cited article on PSP not just for its primacy, but also for the thoroughness of its clinical and pathologic details.

Son and grandson of physicians, Dr. Steele was born in Toronto in 1934. He earned undergraduate and medical degrees at the University of Toronto and completed a neurology residency at Toronto General Hospital in 1965. He married Margaret Porter, an artist and writer who authored a children’s book on PSP.  Dr. Steele is survived by children Alex, Erica and Julia and grandchildren Jonathan, Sophia and Sean.

After his training, Dr. Steele won the prestigious McLachlan Fellowship, allowing him to pursue studies in Britain and France for two years. From that point on, his career was unconventional. He spent a year practicing and teaching in Thailand, returning in 1968 to the University of Toronto as a pediatric neurologist. In 1972, he moved to the Pacific, where he would spend the rest of his life.

He first worked as a general physician on the remote atoll of Majuro in the Marshall Islands doing everything from delivering babies to removing fishhooks, sailing on small freighters to deliver medical care on even more remote atolls.  After six years in Majuro, Dr. Steele spent a year at the London School of Hygiene and Tropical Medicine for fellowship training in clinical tropical medicine. He then moved to the island of Pohnpei in the Eastern Caroline Islands, where he trained local doctors and nurses under a clinical appointment on the faculty at the University of Hawaii Medical School.  From Pohnpei he also continued his work of practicing medicine in remote islands.

In 1982 he settled on the island of Guam as the neurologist at the US Navy’s base hospital and medical director of the local VA clinic. On Guam and nearby islands Dr. Steele cared for and studied individuals with a neurodegenerative disorder endemic to the indigenous Chamorro people. It was called lytico-bodig or the ALS-parkinsonism-dementia complex (PDC). Over the years, Dr. Steele invited and hosted multiple scientists to study this geographically and ethnically specific disorder. He spoke at numerous international medical and epidemiological conferences to create interest in PDC among researchers. Perhaps his most famous scientific guest on Guam was Dr. Oliver Sacks, whose 1997 book “The Island of the Colorblind” features a detailed portrait of Dr. Steele and his work. (The title refers not to Guam, but to the atoll of Pingelap, 1,000 miles east, where a different disease is endemic.)

Despite the lack of formal research facilities on Guam, Dr. Steele found ways to collaborate with other scientists in state-of-the-art inquiries into the cause of PDC. His warm relationship with the community as a local physician provided access to information on traditional practices, helping to elucidate risk factors for the development of the disease. He assisted in constructing detailed family trees to couple with modern molecular genetics performed by collaborators.  Those relied on Dr. Steele’s having accomplished the difficult and delicate task of securing consent for blood samples and brain autopsies. Those studies ultimately showed that mutations in genes previously known as risk factors for other neurodegenerative diseases are over-represented in the PDC population but do not fully explain its cause. This raises the possibility of as-yet-unsuspected genes or of toxic or infectious contributors.

Dr. Steele’s insights into the Chamorro’s dietary habits helped form the hypothesis that PDC was caused by a toxin in the fruit of a cycad tree, the “false sago palm,” by consuming fruit bats (“flying foxes”) that eat the fruit and bioconcentrate its toxins. One such toxin, beta-Methylamino-L-alanine (BMAA), is produced by cyanobacteria in the trees’ roots. The toxic mechanism of this amino acid remains unclear but may rely on its mis-incorporation into proteins in place of serine, thereby encouraging misfolding of the resulting protein. Another compound in the same fruit, beta-D-glucoside, acts as an excitotoxin at glutamate receptors, another mechanism known to cause brain degeneration.

Favoring the fruit bat hypothesis is the observation that PDC has slowly disappeared over the decades since World War II, as traditional dietary practices gave way to Westernization of the Chamorros’ lifestyles. Dr. Steele’s indefatigable work with the Chamorro population was instrumental in this idea, which today remains one of the leading non-genetic hypotheses explaining PDC.

A major inspiration for Dr. Steele in his work on Guam was the similarity between PDC and PSP. In 1963, during his neurology residency in Toronto, his department hosted visiting lecturer Dr. Asao Hirano, a leading neuropathologist who had studied PDC in the 1950s. At that visit, Dr. Hirano examined the brain specimens from the original PSP patients and was struck by the similarity with PDC. Twenty years later, soon after arriving on Guam, Dr. Steele saw a similarity of the impaired downward eye movement and other outward features in the two diseases. Although PSP occurs world-wide and differs from PDC in important molecular details, Dr. Steele recognized that their similarities could prove key. He approached the puzzle of PDC by continually probing the rapidly accumulating knowledge of PSP and by collating the theories and data of a wide array of specialists. As he pointed out many times, the comparative study of PSP and PDC may shed light not only on those two disorders, but also on all neurodegenerative diseases. He framed his life’s work and scientific aspirations in that way.

Few of us can claim to have set so worthy a goal or to have accomplished as much in its service.

Simple but effective

A chance re-encounter

A 2019 article I came across this week dragged me back into blog posting after a month-long break (sorry, fans — I have no excuse).  I remember seeing the paper at the time but blew it off as mere confirmation of previous publications.  But it actually may provide a way to diagnose PSP years before symptoms appear. 

The problem is a familiar one

As you know from my constant harping on the subject, what we really need are two things: a way to diagnose PSP in its earliest stages, preferably before it causes any disabling symptoms (or any symptoms at all); and a way to prevent the disease process from progressing further than that.  In official lingo: a marker and neuroprotection. 

All sorts of marker proposals are showing promise: leading the pack right now are tests of blood or spinal fluid for neurofilament light chain or tau, PET scans for tau, and various MRI techniques.  Two of the more distant contenders are smartphone-based eye movement measurements and skin biopsies for tau aggregates. The problem is to differentiate very early PSP from normal aging and from competing diagnostic possibilities such as Parkinson’s, MSA and dementia with Lewy bodies. 

Get out your rulers

MRI measurements of the volume of the cerebrum is a very sensitive way to track the progression of PSP and is used in drug trials routinely to compare the rate of brain loss in the treatment group to that in the placebo group.  But it doesn’t work for diagnosing the disease in the first place.  For that, you need to image a part of the brain that, unlike the cerebrum, is involved early in the course of the disease.  It also has to be easy to image using standard MRI machines.  The dorsal midbrain does both. 

As an internal comparator, the study also measured the size of the pons, which is the segment of brainstem just below the midbrain.  It atrophies little in PSP.  For both measures, they used the area in square centimeters of the structure on a mid-sagittal MRI cut (one that slices the head perfectly into left and right halves).  See the image below.

MRI in the mid-sagittal plane, with nose at left of each. The left image shows the dorsal midbrain and the right, the pons. a radiologist drew the outlines by hand with a mouse. The MRI machine’s software calculates the area with each outline in square centimeters. (From Cui et al BMC Neurology 2020)

Now, while the dorsal midbrain is where vertical eye movement, the hallmark of PSP, is situated, it’s not where PSP starts.  That happens in subthalamic nucleus, the globus pallidus and the substantia nigra.  But the dorsal midbrain gets involved soon enough, is much easier to image than those things, and is consistently involved in the classic form of PSP, Richardson syndrome. 

History is not bunk

So, with that as background, Dr. Jong Hyeon Ahn and colleagues from six university hospitals in South Korea found 27 patients with PSP with brain MRIs not only after their PSP symptoms began, but also before they began.  The scans had been performed for non-PSP symptoms such as transient dizziness, fainting, suspected stroke, or headache.  In fact, the article says that elderly South Koreans often request — and receive — brain MRIs as part of their routine checkups.  (Who knew?)  The MRIs were routine, with none of the standardization across radiology sites that are commonplace in multi-center drug studies.  In other words, these were “real world” MRIs.

The pre-symptomatic MRIs were performed an average of 28 months (range: 12-48 months) before PSP symptoms began and the researchers pored over their records to make sure there were no symptoms at the time suggestive of PSP.  They rejected MRIs done within 12 months of symptom onset to further reduce the chance that the symptoms prompting the scan were part of PSP.

They compared these pre-symptomatic MRIs to the same patients’ post-onset MRIs and to those of 27 patients with Parkinson’s and another 27 with no known brain disorder.  The 27 with PSP all had the classic PSP-Richardson syndrome, where the vertical eye movement problem is more prominent than in the less common PSP subtypes. 

I few paragraphs ago, I mentioned that the pons was also measured.  In some diseases, both the midbrain and pons atrophy together, but only in PSP is the midbrain affected far worse.  So they divided the areas of the pons by that of the midbrain, expecting that ratio to be higher in PSP than in competing diagnostic possibilities. 

The results

The graph below compares the four subject groups by their pons area, midbrain area and pons/midbrain ratio. There’s some overlap between groups, but the averages (the means) differ both for the midbrain alone and for the pons/midbrain ratio.  The horizontal bars with asterisks indicate a statistically significant difference between the means of two groups at the ends of the bar.  The pons alone showed no differences, as expected, but the midbrain alone did show a difference and the pons/midbrain ratio did even better than that.

Areas of dorsal midbrain and pons as measured on mid-sagittal MRI. The horizontal brackets with asterisks indicate statistically significant differences between groups. P=pons, M=midbrain, RS=Richardson’s syndrome, PD=Parkinson’s disease (from Ahn et al Park Rel Dis 2022)

Those differences weren’t just at the level of the group means, which would be scientifically interesting but close to useless for patient care.  For the pons/midbrain ratio, the accuracy (the fraction of subjects correctly classified by the test) for pre-symptomatic PSP vs PD was 89% and for pre-symptomatic PSP vs controls, it was 93%.  A more critical statistic from the standpoint of avoiding false positives is the specificity, which for the pons/midbrain measurement comparing PSP and PD, was an amazing 100%.  It was the same for the PSP vs controls. 

Receiver operating curves showing the trade-off between the sensitivity and specificity of the midbrain area (blue) with pons/midbrain ratio (green) in distinguishing patients with PSP from those with Parkinson’s disease (left two graphs) or controls (right two graphs). The two upper graphs compare pre-symptomatic PSP with PD or controls. The two bottom scans compare post-onset PSP with PD or controls. (From Ahn et al. Park Rel Disord 2022)

Now — for the green eyeshades

A strength of the study is that all the pre-symptomatic MRIs were more than 1 year before symptoms began.  Any shorter than that would raise questions of whether very subtle PSP features might have been present.  Another strength is that the MRIs were performed on ordinary machines available in any radiology office.

One caveat is that all 27 PSP patients had the PSP-Richardson form, and the findings may not apply to PSP-Parkinsonism or the other atypical forms.  Another is that the patients were alive and not autopsy-confirmed in their diagnoses and a third is that the neurological evaluations had been performed by general neurologists rather than by movement disorder specialists.

The take-home

So, we await confirmation by other researchers with larger subject numbers and comparisons of PSP with MSA and DLB.  We also need to standardize the measurement of the pons and midbrain areas to strengthen the real-world diagnostic value of this painless, harmless and apparently highly accurate test.  Coupling this test with other simple ones may create an even more accurate diagnostic battery.

This could be a keeper.  Then all we’ll need is a way to keep everyone pre-symptomatic.

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.