Great PR, so-so accuracy

Two full weeks since my last post – holiday activities, don’t you know, starting on December 21 with a solstice party at the home of an eccentric friend.   I see that my blog viewership has declined precipitously in the past week, so I’m happy that you all have better things to do at holiday time than to read about PSP.  Don’t we all wish that the disease itself would take a few days off, too?

My re-emergent thought is about the famous “hummingbird sign.”  On an MRI scan in the sagittal plane – that’s as if you sliced someone down the middle and looked at the cut surface – the brainstem sort of looks like a side view of a hummingbird. 

In the MRIs above, the nose is on the left.  In the lower images, the arrows stop just short of the indicated structures so as not to obscure them.  Note the progressively thinner, sleeker midbrain (the hummingbird’s head and beak) with retention of the plump pons (the belly, which is plumper than than that of a real hummingbird). 

Now here’s the issue.  The appearance of the hummingbird sign isn’t as closely related to PSP as has been implied by many.  There are just too many false positives and false negatives. 

The false positives mostly occur in people with normal-pressure hydrocephalus, a condition where the fluid-filled spaces in the brain (the “ventricles”) enlarge because of an obstruction in the re-absorption of the fluid into the bloodstream.  This stretches the fibers adjacent to the ventricles, impairing control of gait, cognition and the bladder.  It also presses down on the midbrain, producing the hummingbird sign.  Then there are those individuals with corticobasal degeneration where the features resemble PSP (“CBS-PSP”).  They can also have a hummingbird sign.

The false negatives occur in the first couple of years after the initial symptoms.  They also occur if the MRI is mis-aligned on the brain or the head is a little rotated, producing an allegedly midline cut that’s actually a couple of millimeters to one side.  That means that the thinnest part of the midbrain, which is in the midline, isn’t shown in the image. 

You should also know that the hummingbird sign isn’t just about a thin midbrain.  A normal pons is also part of the sign.  That’s because in multiple system atrophy and a few rarer disorders, both the midbrain and pons become thinner.  But in PSP, it’s mostly the midbrain that does so.

I think that in the next year or two, a test of the tau protein in spinal fluid, blood or a tiny punch biopsy of skin will provide a much more accurate diagnosis of PSP than the hummingbird sign.  Soon thereafter we will probably have a PET technique that does the same. Then, clinical treatment trials can be accomplished faster because they won’t have to compensate for the statistical noise produced by participants with a false positive diagnosis.  In fact, all sorts of research on PSP will become much more powerful if people without PSP can be excluded. 

All my best for the New Year.

Genetic testing advice

I’ll plagiarize myself again. CurePSP asked me to write up a piece in response to someone asking if a person with PSP or CBD (or suspected PSP or CBD) should have genetic testing. The short answer is mostly “no,” but here are the details:

People with an established diagnosis of PSP or CBD and a close relative with one of those conditions (or a strong suspicion thereof) should consider having their MAPT gene sequenced.  That’s the gene encoding the tau protein.  But the vast majority of those with PSP or CBD have no similarly affected relatives, and for them, genetic testing is neither necessary nor useful.

The test should sequence the entire MAPT gene and not merely check for the ten mutations, all of them very rare, that have been associated with PSP (seven with CBD) in the past.  If the person with the disorder (called the “proband”) proves to have a mutation in MAPT, then other family members with similar symptoms can be tested as well. 

Variants in eight genes other than MAPT have been associated with PSP and five with CBD, but each of these raises the disease risk only slightly and testing for them is not useful in an individual or even in a family.  That’s because these are only “marker associations,” not specific mutations altering a protein known to be involved in the PSP process. The markers are called “single-nucleotide polymorphisms” or “snips” and unlike the MAPT mutations, they incriminate a span of about 100 or so genes, not a specific gene, much less a specific mutation that can be tested for.

We must keep in mind that many mutations, even in genes like MAPT, are harmless and do not cause disease.  Sixty MAPT mutations have been reported in humans so far, and only ten of them are known to cause PSP. So having a mutation in MAPT and having PSP doesn’t necessarily mean that one caused the other.  If a relative with the same symptoms has the same mutation, it may still not be cause-and-effect, but if that relative is distant, or the proband and two or more relatives share symptoms and a mutation, then the likelihood of cause-and-effect is greater. 

Even if there’s a good statistical likelihood that the proband’s mutation is the cause of their disease, and a healthy relative proves to have the same mutation, one still would not be able to predict how soon the relative might start to develop symptoms.  That information could be available soon from some other type of “pre-symptomatic” or “predictive” testing, but no such test has yet proven to be sufficiently accurate in such a situation.

People with suspected PSP or CBD with no relatives with similar symptoms have no need for genetic testing.  Even if one of the known PSP/CBD-causing mutations were found, it would not contribute much to the likelihood of PSP or CBD as the diagnosis explaining the symptoms.  The same is true for the healthy relatives of someone with established PSP/CBD.

So, as you can tell, estimating disease risk from genetic testing can be complicated.  That’s why a professional genetics counselor or a physician with expertise in adult neurogenetics should advise anyone considering having family genetic testing for PSP or CBD. Don’t just rely on the simple report supplied by 23andMe.

I’ll update this as necessary.

More fun than a spinal tap

A diagnostic tool routinely used in psychology is the Rey-Osterreith Complex Figure:

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The patient is timed while copying the figure.  The figure and copy are removed and the patient re-copies the figure from memory immediately and again after 30 minutes.  It’s a sensitive measure of visuospatial recall, visuospatial recognition, response bias, processing speed, and visuospatial constructional ability.

Although the test has existed in its current form since 1944, there has been no publication on its utility in PSP.  Now, an Italian research group at the University of Pisa led by Dr. Luca Tommasini gave the test to 30 people with PSP-Richardson syndrome, 30 with Parkinson’s disease and 30 healthy persons matched to the others on age, gender and educational attainment. 

It was previously known that people with Parkinson’s make errors on the test related to planning and impulsivity.  The new study found that in PSP, those errors are more severe than in Parkinson’s, with the added problems of disinhibited repetition of some elements and “vertical expansion” of the figure.  The latter could be related to the difficulty in moving the eyes vertically or to an underlying difficulty in accurately conceptualizing vertical space.  In my own experience with people with PSP, there is disproportionate difficulty attending to objects and events at the upper and lower extremes of the visual space even if the eyes were still able to move adequately in those directions.

These results could help distinguish PSP-RS from PD diagnostically.  We await results for the other disorders with which PSP can be confused such as multiple system atrophy-parkinsonism and corticobasal degeneration.  We also await results from very early-stages of the disease, when such a diagnostic test would be most useful, and from variant forms of PSP such as PSP-parkinsonism and PSP-progressive gait freezing, where cognitive abilities are not usually as impaired as in PSP-Richardson syndrome.

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.


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).

Marker development: anarchy vs plutocracy?

You’ve heard me whining that we need a diagnostic “trait marker” for PSP. In other words, we need to be able to accurately distinguish PSP – during life — from such mimics as Parkinson’s, multiple system atrophy, Alzheimer’s, corticobasal degeneration, normal-pressure hydrocephalus and others. Only in that way can we create “pure” groups of patients in which to study the disease and test specific treatments.
Right now, the best diagnostic test we have is the MDS-PSP Diagnostic Criteria, which requires only traditional history-taking and a hands-on neurological exam. Those criteria work well for PSP-Richardson syndrome after the first couple of years but not quite well enough for earlier-stage PSP-RS nor for the “minority” or “atypical” types, which together account for 60 to 75 percent of PSP.

The most promising markers using laboratory or imaging data are levels of phosphorylated tau and neurofilament light chain (NfL) in the spinal fluid and blood; and perhaps MRI measurements of the size of the midbrain, pons and related areas at the base of the brain. But these are far from ready for prime time. NfL is a protein component of brain cells that has been shown to occur at about a two-fold higher level, and to increase faster over time, in PSP and MSA than in PD, Alzheimer’s and other neurodegenerative diseases. MRI changes don’t occur in the early stages. Positron emission tomography is coming along, but won’t be ready for use in PSP for another few years, and even then will be costly and not widely available.

Last week, my routine surveillance of new PSP-related research papers in the literature yielded two interesting hits — both about PSP trait markers, both using new lab techniques, and both from Italy.

Corinne Quadalti and colleagues at the University of Bologna measured NfL and alpha-synuclein in spinal fluid and blood. They found that plasma NfL alone worked very well in distinguishing PD from PSP, with an accuracy of 0.94. (“Accuracy” in this context is the area under the receiver operating characteristic curve, which compares sensitivity with specificity. Perfect accuracy is 1.0 and a useless test’s accuracy is 0.5, where a coin flip would work as well.)

Alpha-synuclein is the main protein aggregating in Parkinson’s, dementia with Lewy bodies and multiple system atrophy. It is to those diseases what tau is to PSP and CBD. To measure it, they used a new technique called “real-time quaking-induced conversion” (RT-QuIC; pronounced, “R-T quick”), which measures that protein in its misfolded and aggregated forms. This prevents that abundant protein in its normal form from swamping the measurement. The result was positive in 91% of their patients with PD and in none of their 58 patients with PSP or CBD.

Now, if you have a nose for statistics, you’ll raise your hand and say, “But those 9% of PD patients with a negative test comprise more people in the general population than all the patients with PSP or CBD, so a negative test doesn’t mean much.” and you’d be right. So, while the sensitivity of the test for PD is excellent, the specificity is low, rendering the overall accuracy in a real-world situation insufficient.

For that reason, the authors combined two measurements – spinal fluid NfL and serum alpha-synuclein, with a resulting improvement in distinguishing PD from PSP/CBD to a sensitivity of 97.4% and specificity of 100%. That’s more like it, but keep in mind a few issues: They combined PSP and CBD into one group, and we don’t know if the results apply as well to each disease alone. They had no autopsy confirmation of the diagnoses, which means that these patients were already at a stage that was possible to diagnose using traditional clinical criteria; this means that patients with earlier-stage illness will be needed in a follow-up study. Finally, and as always, the results have to be confirmed at other centers using other techniques.

The other eye-catching paper was from Ida Manna and colleagues at the University Magna Graecia in Catanzaro, Italy. They use exosomal micro-RNA (miRNA) in blood to distinguish among PSP, PD and healthy controls.

Exosomes are tiny bubbles of brain cell membrane enclosing whatever cell contents were there when the bubble pinched itself off and floated free. They often find their way into the bloodstream. MicroRNAs are stretches of RNA averaging only about 22 nucleotides. They do not encode proteins as messenger RNA (mRNA) does, but instead bind to mRNAs to regulate their translation into protein. They are specifically encoded in the DNA of the genome and about 2,000 of them are known to exist.

Dr. Manna et al measured levels of 188 miRNAs for which there is evidence of association with some neurodegenerative disease. They found a set of 6 miRNAs that together yielded an accuracy in distinguishing PSP from PD of 0.91. The accuracy for distinguishing PSP from controls was 0.90.
Of course, many of the same caveats that I listed for the other paper apply to this one. Plus, PSP mimics other than PD were not included in the analysis. Just as important is that there were only 25 patients with PSP and they were a mixed bag of 20 with PSP-Richardson and 5 with PSP-Parkinson. In applying a marker for the purpose of excluding patients with PD from a study of PSP, it is critical to be able to distinguish PD from PSP-P. It is unlikely that those 5 patients with PSP-P constituted a statistically valid sample for that purpose. That will be a project for another day.

What do I take away from these two papers? Neither of them alone provides a marker just yet, and each has its drawbacks given the current early stage of work. But perhaps, with some refinement, combining them with other non-invasive markers could create a diagnostic panel with enough accuracy to distinguish PSP from all of its mimics. After all, in medicine in general, multiple diagnostic tests (several tests of body fluids, some imaging, a physiologic test such as an EKG) must be combined to produce an actionable diagnosis. Why should PSP be any different?

I think the problem (and it’s a good problem to have) is that new candidate markers are being identified all the time, as are ever more sophisticated technology for measuring them, with RT-QuIC, miRNA and exosomes as prime examples. That means as researchers turn their attention to early-phase development of newer ideas using newer technology, ideas that looked potentially useful if pursued further may be neglected and not developed into practical tests. What to do? Do we just let scientific nature take its course in its traditional, anarchical way, waiting for research groups to take techniques with good initial data to the next level? Or should a group of experts with an iron fist issue some sort of “white paper” listing which markers with good preliminary evidence, perhaps like the ones I describe here, should be nurtured with funding and collaborations? If so, who chooses those experts? And once the experts are chosen, how can we prevent them from favoring the ideas in which they’ve invested their own time, resources and reputations?

You know where the “comment” button is.

Knowing one’s limitations

As promised, here’s the next installment in my series on impactful posters on PSP from the annual conference of the International Parkinson’s and Movement Disorders Society that is winding up today on line.  This poster, like the one in my last post, is from Japan.

Most of you know that corticobasal degeneration (CBD) is very similar to PSP in many ways, though only about a tenth as common.  The most common typical clinical syndrome of PSP, called PSP-Richardson syndrome, correlates extremely closely with the typical pathological autopsy appearance that we call PSP.  But for CBD, the most common clinical syndrome, called corticobasal syndrome (CBS) has a much looser correspondence with the typical autopsy picture called CBD.  Only about half of all people with CBS have CBD at autopsy.  Of the rest, the most common autopsy picture is PSP, then Alzheimer’s disease, with a half-dozen or so others comprising the rest.  Unfortunately none are more treatable at present than CBD.  Here’s an up-to-date, authoritative, technical description of that for you to chew on if you want the details.

Here’s some more background:  One of the ways that PSP can present itself clinically is with the corticobasal syndrome.  In other words, about 3 percent of people with PSP in the brain look outwardly like they have the typical appearance of CBD.  How to tell if those folks have PSP-CBS or CBD-CBS itself?

The leading clinical PSP expert in Japan, in my biased opinion, is my friend Ikuko Aiba, MD.  She and her colleagues in Nagoya compared the medical records of 12 autopsy-proven patients with CBD with those from eight with autopsy-proven PSP-CBS.  The only clinical feature that was more common in the CBD-CBS patients was urinary incontinence and the only one more common in PSP-CBS was limitation of vertical gaze and slowed eye movements (“saccades”) in general.  The CBD-CBS patients tended to progress a little more quickly with regard to overall loss of mobility.

The take-home is that in the absence of specific treatment for either condition (i.e., treatment directed at the cause rather than the symptoms) this information could be useful in refining recruitment in clinical trials, in prevalence studies and diagnostic biomarker development, each of which would like to be able to create a patient series consisting purely of the disease under study.

The other take-home is that it’s actually next to impossible to distinguish PSP-CBS from CBD-CBS in the living patient.  Neurologists who claim to be able to do so, even with this bit of new information, are just kidding themselves — and their patients.  They should just diagnose “corticobasal syndrome” and leave it at that. Thanks to Ikuko Aiba and colleagues for pointing that out.