I’m making a list of clinical topics to be covered in CurePSP’s next annual scientific conference. That task made me think carefully about what’s important to clinicians seeking to stay current on PSP and CBD. So, I thought I’d share that list with you all, for what it’s worth. Keep in mind that the laboratory research end of things will be a separate list.
My last post was about an on-line tool to assist in reading MRI scans to differentiate PSP from some other diagnostic possibilities. But the formal diagnostic criteria for PSP are still based on traditional history and neurological exam, with MRI as a confirmatory adjunct. This post is about an on-line tool to assist physicians in using those formal criteria.
Starting in the 1980s, a number of researchers, including me, published diagnostic criteria for PSP. Although these were later validated by autopsy results, they were not so at the time of publication. Just as important, they tended to be either insufficiently sensitive or insufficiently specific (see my preceding post for definitions of those). You want sensitivity if you’re trying to measure the prevalence of the disease and don’t want to miss any cases. You want specificity if you’re trying to recruit a group of people with PSP for a study of causes or treatments and don’t want to risk including anyone without actual PSP.
So, in 1986, Dr. Irene Litvan, now at UCSD, then at the NIH, organized an international group of leading PSP experts to create new criteria. They produced two sets for living patients: “possible PSP” was more sensitive and “probable PSP” was more specific. “Definite PSP” was reserved for autopsy-confirmed cases, and the project also included a new set of criteria for that, which served as the “gold standard” by which to validate the first two.
The new sets were called the NINDS-SPSP Criteria after the National Institute of Neurological Disorders and Stroke (the part of the NIH involved) and the Society for PSP (the former name of CurePSP), which provided a grant for the project.
The NINDS-SPSP criteria were a hit and remained the world’s standard until researchers realized that those criteria took no heed of the clinical variants of PSP that were starting to be described in 2005. The classic form of PSP now received the name “PSP-Richardson syndrome” after the leader of the group in Toronto who first described the disease in 1963. It turns out that PSP-RS explains only about half of all PSP! The most common of the newly-described variants is PSP-parkinsonism, accounting for about 25% to 40% of all PSP. Six other much less common ones have been reported, each of which starts with and emphasizes one of the features that starts later in the course of PSP-RS. Towards the later stages, all of the variants acquire most of the classic features of PSP-RS and all tend to look the same by that point.
Sorry for that digression.
So in 2015, Dr. Guenter Höglinger, then in Munich, now in Hannover, convened a group to devise a new set of criteria to tease out the different types of PSP and to identify PSP in its earliest stages. Of course, there aren’t yet enough autopsied cases to provide the stastistical power needed to validate their criteria for the less common PSP types, but that’s changing. In any event, the new criteria were published in 2017 and dubbed the “MDS PSP Criteria” to recognize the support of the Movement Disorder Society.
Just one problem: they’re very complicated, occupying 7 pages of tables in the journal. To remedy that, Dr. Hoglinger and colleagues have created an on-line form that performs the same diagnostic algorithm as all those tables. It’s free and it’s at https://qxmd.com/calculate/calculator_567/diagnosis-of-progressive-supranuclear-palsy-psp I’d suggest that you try it out, but many of the data fields require the results of a neurological exam performed by an experienced neurologist. Furthermore, many of the questions ask things like whether the patient has any evidence of certain alternative diagnoses, and that’s not something that a layperson is likely to know. But feel free to forward the link to your favorite neurologist for their use. The different PSP subtypes have different rates of progression, so identifying one’s subtype could be useful.
You may have noticed that I’ve been bullish on the ability of ordinary MRI scans to help diagnose PSP. Now there’s an on-line, automated resource to allow anyone anywhere to upload MRI images and receive an answer – for free.
We’ve known for over a decade that very careful, standardized measurement of the size of various parts of the brain can track the progression of PSP over the 1-year course of treatment trial better than the PSP Rating Scale or any other “bedside” measure. But more recently, MRI has been found to be highly useful in the differential diagnosis of PSP – that is, telling PSP from normal aging, Parkinson’s, Alzheimer’s, and other conditions.
For an excellent, technical, open-access review of simple MRI measurements in the diagnosis of PSP, click here. The leading authors are Dr. Aldo Quattrone and his son Dr. Andrea Quattrone at Universita Magna Graecia in Catanzaro, Italy, who pioneered most of the discoveries described.
Such MRI-based measurements use only routinely obtained images like those from your local radiologist. But actually doing the measurements requires some experience. The Catanzaro group has created a Web portal onto which anyone can upload de-identified MRI images from a CD. An answer returns in a few days. The site is https://mrpi.unicz.it/.
The black-and-white images below show the inputs into the automated algorithm. Sorry if these close-up brain images look like abstract expressionism. The drawings here may help orient you.
MRI images A and B are sagittal (A is in the midline and B is a few mm to one side), images C and D are in the coronal plane and image E is in the horizontal (or axial) plane.
A: midbrain area (upper outline; Amb) and pons area (lower outline; Apons) (In PSP, atrophy of the midbrain is marked but atrophy of the pons is mild.)
B: middle cerebellar peduncle diameter (This atrophies only a little in PSP.)
C: superior cerebellar peduncle diameter in a slice parallel to the midline (“parasagittal” slice; This atrophies moderately in PSP.)
D: third ventricle diameter (averaging the diameters of the front, middle and back thirds) (This enlarges markedly in PSP.)
E: maximum distance between anterior horns of lateral ventricles (This atrophies moderately in PSP.)
The number derived from these measurements is called the magnetic resonance parkinsonism index (MRPI). Its value is (Apons/Amb) x (B/C). Values above 13.88 indicate PSP-RS with 89% sensitivity*, 95% specificity* and 94% accuracy*. This works best in separating PSP-Richardson syndrome from Parkinson’s disease.
The MRPI 2.0 is (MRPI) x (D/E). This works better than the original MRPI in separating PSP-Parkinson and other non-Richardson PSP variants from Parkinson’s disease. Values above 2.70 indicate PSP with 86% sensitivity, 92% specificity and 90% accuracy.
*Sensitivity is the fraction of people with the disease who have a positive test.
Specificity is the fraction of people without the disease who have a negative test.
Accuracy is the fraction of people with an accurate test, whether positive or negative.
In this case, “the disease” means PSP and “without the disease” means PD, some other disease or no disease.
The really valuable part is that this technique works well even in early, mild cases, where a diagnosis could not be made by other means. In a few studies, such patients were followed for years until they showed more definitive signs, which were then used to validate the initial, image-based diagnoses.
This technique has not been shown effective in differentiating PSP-P from multiple system atrophy of the parkinsonian type (MSA-P), which is a common dilemma for movement disorder specialists seeing a patient with mild symptoms. But the MRPI and MRPI 2.0 could be combined with other supplementary tests such as supine and standing blood pressure (usually abnormal in MSA-P, normal in PSP) and still-experimental tests such as blood levels of tau, phosphorylated tau and neurofilament light chain (all elevated in PSP, not in MSA) to refine its abilities.
Another important caveat: Sometimes PSP can be mimicked by rare cases of common diseases like Alzheimer’s or dementia with Lewy bodies, or by some rare diseases like corticobasal degeneration, frontotemporal dementia with parkinsonism, or pallidopontonigral degeneration. There haven’t yet been enough patients with those things subjected to the MRPI or MRPI 2.0 to prove those formulas able to separate those conditions from PSP. After all, the MRI only looks for atrophy of certain brain structures, regardless of whether that atrophy is related to tau aggregation or something else.
Bottom line: As my medical students don’t appreciate hearing, no diagnostic test short of autopsy is ever going to be definitive on its own. Any test will have to be combined with old-fashioned history and exam and with other imaging, fluids or physiological tests. Knowing which of those to choose for a given patient and how to interpret the results will keep humble, human neuro-diagnosticians in business for a while longer.
In my next post: another on-line tool for the diagnosis of PSP.
One of the top PSP research centers in the world is at the University of California San Francisco. Two researchers there, Drs. Christine Walsh and Thomas Neylan, are leading a study of sleep in PSP and asked me to help them find suitable participants.
The goal is to test the effect of two sleep medications on the treatment of sleep disruption in PSP. No in-person visits to San Francisco are required and no study staff would need to come to your home.
Both medications, zolpidem (Ambien) and suvorexant (Belsomra), are approved by the FDA for sleep in general, but their benefit and side effects in people specifically with PSP remain unclear. This study uses a crossover design so that each participant will receive the two medications and placebo over the 6-week course of the study. Sleep will be monitored by questionnaire and by two small, wearable devices to record movement and brain waves, respectively. All of the questionnaires will be done over the phone or by Zoom, with 1 to 3 calls each week for 6 weeks.
Participants must have a diagnosis of PSP, live anywhere in the United States, and have an available care partner to help provide information during the interviews.
You can find more information about the study by viewing a video here: https://pspsleepstudy.com or by emailing Dr. Walsh at: Christine.Walsh@ucsf.edu. Click here for the listing in clinicaltrials.gov.
Remember the Human Genome Project? It cost about $3 billion and took 13 years (1990 to 2003) – and that was with 20 labs around the world working in parallel. A commercial lab can now sequence your whole genome in a few days for about $600. Now the problem is how to recognize a “abnormal” result and what to do with that information. We all have mutations that our parents don’t, and most of those have no health implications. The problem is knowing which ones do. This makes it medically and ethically tricky to interpret the results of a whole-genome sequence.
Until that knowledge base improves, whole-genome sequencing will probably be useful mainly in assaying for known mutations in well-studied genes. It is also possible to roughly predict the health implications of a never-before-seen mutation in a well-studied gene by working out the amino acid substitution that would result in the protein being encoded. Then, using the physical and chemical principles of protein structure and function, one could roughly predict how that amino acid substitution might affect the function of the protein. But that’s still an inexact science. Besides, a lot of the genome doesn’t encode proteins at all – it has regulatory functions, which sometimes involves encoding small stretches of RNA that in turn regulate protein production.
So, with those challenges in mind, here’s a bit of speculation as to what might be in store, near-term, for genetic testing in the routine clinical care of PSP. Thanks go to my friend and colleague Alex Pantelyat, MD of Johns Hopkins for his input.
Once effective treatments for PSP arrive, we may find that people with different variants in the gene encoding tau (or other gene) respond differently to specific medications. This might be especially true for treatments targeting the process where the information in the DNA is encoded into proteins (called “transcription”). Right now, short stretches of DNA or RNA called “antisense oligonucleotides” (ASOs) that interfere with the encoding of the normal form of tau are in clinical trials. As you’d imagine, this risks side effects caused by a lack of normal tau protein. But if we knew what gene mutation was causing PSP in an individual, an ASO could be specifically tailored for it.
It will become standard practice for clinical trials of any sort of treatment to be designed for people with, or without, specific gene variants. Or if a trial doesn’t try to restrict enrollment in that way, it will at least do the sequencing at the time of enrollment and apply the genetic information retrospectively to check if the treatment works in people with specific gene variants.
As discussed in my last post, variants in the LRRK2 gene help determine the duration of survival of people with PSP, though they don’t affect the risk of developing the disease to begin with. There are bound to be other genes with similar effects. Sequence data from such genes could be useful to people with PSP and their families in preparing for the future financially and emotionally.
The last point, about prognostic genetic markers, is about single-gene variants. But the same point could apply to combinations of variants in multiple genes where no single variant has a measurable effect.
Using a battery of gene variants as a high-accuracy diagnostic test for PSP (as opposed to prognosticating a rate of progression or what symptoms might develop next) seems unlikely to come to pass, as the list of genes already linked to PSP probably are the most informative ones, and they are insufficient as a diagnostic test. But if that list is coupled with other non-genetic tests such as MRI, PET and blood tests for tau or neurofilament light chain, a highly accurate test battery could result.
Beyond the $600 lab fee are the bills for the necessary interpretation and counseling, which add about $2,000. While the lab fee has been declining because of technological improvements, the other services are provided by human beings and are only likely to rise. Insurance companies, Medicare and Medicaid don’t presently cover any of this unless it’s for someone with cancer or a very ill newborn. I assume this is because we don’t yet have enough use for the data in terms of alterations in management. But what are the financial implications if my above predictions come true and actionable uses do become available? PSP is a rare disease, but what if similar uses of whole-genome sequencing are developed for Alzheimer’s, atherosclerosis, depression and the many other diseases where genetic variants, or combinations thereof, affect disease risk or prognosis? Even if we manage to reform the medical payment in the US and improve access to that system for those presently under-served, who will provide all that counseling? And who will respond to patients’ demands for preventive treatment? And who will pay for that treatment? Scary.
Last week, someone wrote to CurePSP asking if PSP was genetic. I took a look at what I had previously provided CurePSP on that topic to post on its website, and decided it wasn’t nearly detailed enough. So I decided to write up the following. A version of it appears, or will soon appear, at http://www.curepsp.org.
PSP only very rarely runs in families. Fewer than one in 20 people with PSP knows of even one other family member with PSP, even counting distant cousins.
But when multiple genetic variants confer only small risks of developing a disease and some sort of non-genetic factor is also necessary, it will be rare for more than one member of a family to have the unlucky co-occurrence of enough of those factors to produce outward signs of the disease.
That’s basically how PSP works, but then things get a little more complicated:
The gene on chromosome 17 that encodes the tau protein is called MAPT, for “microtubule-associated protein tau.” The MAPT gene has two variants that are more common in PSP than in the rest of the population. One of them is called the H1 haplotype and actually consists of a section of the chromosome that is reversed relative to adjacent sections. About 95 percent of people with PSP have this variant on both of their copies of chromosome 17, while this is true for only about 60 percent of the rest of the population. So the H1 haplotype is (nearly) necessary but far from sufficient to cause the disease.
We’re still not quite sure how the H1 haplotype increases PSP risk. It may simply increase the amount of tau produced, which causes that protein to stick together, even if it’s structurally normal. But more recent work shows that it causes too many methyl groups to stick to the MAPT gene, altering its function. This is exciting because drugs can be developed to alter DNA methylation. Other recent evidence supports the idea that the H1 haplotype reduces the fraction of tau molecules that include the fragment encoded by the MAPT gene’s exon 2.
The other MAPT variant associated with PSP is statistically independent of the H1 haplotype and its function is unknown.
Over the past two decades a handful of other gene variants not on chromosome 17 have been found to be slightly more common in people with PSP than in those without PSP. These genes help control a variety of critical processes such as disposal of damaged proteins, inflammatory mechanisms, operation of synapses, and integrity of the brain cells’ insulating sheaths. However, the effect of these genes, individually or together, is too small to serve as a diagnostic test for the disease or to produce more than one case in a family.
A gene called LRRK2 has been found to influence (in a rough way) not the likelihood of PSP, but the age at which it starts. CurePSP is presently supporting a project to pursue this clue to try to find a blood test that might predict the individual’s rate of progression. As it happens, mutations in LRRK2 are the most common cause of familial Parkinson’s disease and the occasional person with that mutation will have the pathology of PSP at autopsy despite having had the outward appearance of PD during life. Wonders never cease. Drugs that suppress the action of abnormal (and normal) LRRK2 are in trials for Parkinson’s.
Despite all I’ve said about the genetic component of PSP being subtle, a small fraction of people with PSP do have a relative with the same diagnosis, raising questions about the risk to their siblings and children. A few points of advice about that:
When a disease occurs in several members of a family in a pattern consistent with either a dominant or a recessive mechanism, it’s easy nowadays to identify that gene. Despite the dozens of families alleging multiple members with PSP, such a gene has never been reported in the literature.
False-positive diagnoses of PSP are common. This may account for most of the reports of multiply-affected families, even if one of them had autopsy confirmation. However, in most situations where two or more relatives have been diagnosed with PSP, there have been no autopsies.
A strongly familial disorder called frontotemporal dementia with parkinsonism (FTDP) can mimic PSP, even at autopsy, but the special features of PSP such as balance loss and trouble with downgaze are mild or absent. Many of the mutations causing this disorder are in the MAPT gene, but those mutations do not occur in non-familial PSP. Furthermore, FTDP is associated with the MAPT’s H2 rather than H1 haplotype. Both of these points cast additional doubt on FTDP being real PSP. The FTDP-associated mutations can be detected by a commercially available blood test with a doctor’s prescription, but they are very rare, with only about 100 such families having been reported in the medical literature world-wide.
Despite those caveats, there actually are two or three families world-wide having several members with ordinary PSP (i.e., not FTDP) both during life and at autopsy, with no mutations in the MAPT gene. Such families can be highly valuable for PSP research, as the gene causing their disease could be encoding a protein that might be key to all PSP.
Familial PSP is so rare that people with that condition need not be concerned for their children or siblings. This advice even accounts for the possibility that what has been diagnosed as PSP may in fact be its rare, familial imitator, FTD with parkinsonism. Most PSP experts advise their patients’ healthy relatives to make no changes to plans for career, children or finances because of one person with PSP in the family.
However, when there is a clear indication of two or more close relatives with PSP, one should consider testing one affected person for FTDP by sequencing either the MAPT gene or a battery of genes associated with various dementing neurodegenerative diseases. This should be done only with the guidance and participation of a genetics counselor or neurologist well-versed in interpreting genetic testing. If the affected patient has one of those mutations, then another affected relative can be tested as confirmation and healthy relatives can be tested for the same specific mutation if they so choose. However, a positive result would not predict the age of symptom onset, so there is little or no actionable information to be gained through testing healthy relatives.
Further research results in the near term could change these recommendations, so keep an eye on http://www.curepsp.org for updates. But if you want me to speculate right now, take a look at the next post.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.