Tag Archives: quantitative susceptibility mapping

PSP’s top 10 of 2025: part 2 of 2

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Happy New Year, all!

Yesterday’s post was the first five of my top ten PSP news items of 2025. Here are the rest, again in approximate and subjective descending order of importance.

  1. New ways of interpreting standard MRI images have gained ground as diagnostic markers for PSP. One is a test of iron content in brain cells called “quantitative susceptibility mapping” (QSM). Nine papers on that topic appeared in 2025, four in 2024 and none previously. It’s looking like combining QSM data from ordinary measurements of atrophy of PSP-related brain regions could be the ticket, as both measures come from the same test procedure, unpleasant though it may be, and they measure different things.
  2. Positron emission tomography (PET) imaging of PSP’s type of tau (“4-repeat tau”) has made advances in 2025. This test requires intravenous injection of a “tracer” with a radioactive component that enters the brain tissue,sticks to the target molecule and is then imaged. It can distinguish PSP from non-PSP, distinguish among various PSP subtypes, and quantify the disease progression. The leading such tracer in terms of readiness for submission to the FDA is [18F]PI2620 and a distant second is [18F]APN-1607 ([18F]-PM-PBB3; Florzolotau). A tau PET tracer called Flortaucipir is on the market as a test for Alzheimer’s disease, but it performs poorly for PSP.
  3. There’s brain inflammation in PSP, but it’s not clear whether it’s a cause or a result of the loss of brain cells, or both. Regardless, measuring the quantity and type of inflammation using blood or PET could shed light on the cause of the disease, identify new drug targets, and serve as a diagnostic marker. A good example of 2025 research on blood markers of inflammation in PSP is here and on PET imaging of inflammation is here .
  4. We know of variants in 21 different genes, and counting, each of which subtly influences the risk of developing PSP or its age of onset. The area of the genome most important to PSP is the one that includes the gene encoding tau (called “MAPT”) on chromosome 17. The most important PSP genetic advance in 2025 was probably the discovery that some PSP risk is conferred by extra copies of a stretch of DNA, not the sequence itself. This news could inspire investigation of other places in the genome for other copy-number variants, which are much trickier to find than sequence variants. Here’s a great review of the latest in PSP genetics.
  5. And lastly, a disappointment: a negative result of a double-blind trial of the combination of two drugs already approved for other conditions: sodium phenylbutyrate (“Buphenyl”) and taurursodeoxycholic acid (“TUDCA”). Blog post here. Sponsor’s press release here. Buphenyl protects the endoplasmic reticulum, which helps manufacture proteins and TUDCA protects the mitochondria, which provide the cells’ energy. The pair were theorized to act synergistically. The upside is that the trial’s placebo group data can be used to provide better statistical support for future innovations in clinical trial design.

Imaging in the diagnosis of PSP

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A very active area of research right now is how various imaging techniques (“scans” in English) can and cannot assist in distinguishing the atypical Parkinsonian disorders from other conditions and from one another.  Yes, this is important for clinical care and counseling.  But even more important right now is that until we have specific treatments for these diseases, we need accurate diagnosis in living people.  This is important for laboratory researchers who want to know the true diagnosis of the patient who supplied a fluid sample, and to the designers of clinical trials who want to make sure the patients in their trials have the disease for which the treatment was designed. 

Dr. Jennifer L. Whitwell, a radiology researcher at the Mayo Clinic in Rochester, MN has just published a very helpful review of that topic in Current Opinion in Neurology.  It gets pretty technical, but here are the takeaways with, of course, my own editorial contributions:

  • Measurement of atrophy by MRI: 
    • The magnetic resonance Parkinsonism index (MRPI), especially its updated version, the MRPI 2.0, gives excellent differentiation of PSP from non-PSP, with an area under the receiver operating curve of 0.98. (That statistic is 1.00 for perfect accuracy and 0.50 for no better than a flip of a coin. For a bit more explanation of the AUROC and a graph, see this post from last year.) 
    • Routine MRI can also be used to compare the various PSP variants with regard to atrophy of specific brain structures.  Atrophy of the brainstem is worse in PSP-Richardson syndrome, PSP-CBS and PSP-frontal than in the others.  This information could be useful in treatment trial design because some PSP variants progress faster than others. So, a trial of a disease-slowing treatment could potentially determine which patients have which variants and adjust the statistical analysis of the treatment outcomes accordingly.
    • MRI shows that atrophy in PSP-Richardson’s syndrome starts in the midbrain, (the upper part of the brainstem where the substantia nigra and the vertical gaze centers reside), followed by a succession of other areas of the brainstem, cerebellum and basal ganglia, before finally reaching the cerebral cortex.  But two PSP subtypes involving relatively more cortical function (the frontal behavioral type and the corticobasal syndrome type) spread into the frontal cortex much earlier in the process, although like PSP-RS, they start in the midbrain.  These observations could help guide designers of other imaging-based diagnostic tests for PSP.
  • Measurement of metabolism by fluorodeoxyglucose positron emission tomography (FDG PET):  The pattern of reduced brain tissue metabolic activity in PSP can be distinguished from normal with an AUROC of 0.99.  Distinguishing PSP from corticobasal syndrome, multiple system atrophy and Parkinson’s disease is more difficult but still useful at 0.90.
  • Measurement of tau deposition by PET:  A PET technique that reveals the location of abnormal tau in Alzheimer’s is already in standard clinical use for AD, but it doesn’t work well for other tauopathies.  Two techniques designed for PSP are expected to enter pivotal clinical trials in the next few months.  In small studies, the two ligands called PI-2620 and APN-1607 (formerly called PM-PBB3) have shown good results in distinguishing PSP from the other tau disorders and Parkinsonian disorders.  (A PET ligand is the chemical injected intravenously that sticks to the brain chemical of interest, allowing its location to be mapped.) But these two ligands can occasionally give conflicting results when given to the same patient, so the AUROCs from the upcoming trials are eagerly awaited.
  • Measurement of iron deposition by MRI: This technique, called quantitative susceptibility mapping (QSM), is not part of a routine MRI, but it can be performed with the same machine.  Its PSP-diagnostic results are not quite as accurate of the ones above, with an AUROC of 0.83 for distinguishing PSP-Richardson’s syndrome from Parkinson’s disease.  I assume the AUROCs for other kinds of PSP, especially PSP-Parkinsonism, are worse, but work continues on this technique.
  • Functional MRI: The spread through the brain of abnormal tau, and with it the damage of PSP, proceeds along “functional networks.”  That means that after first affecting the substantia nigra in the midbrain, the damage proceeds to areas most closely yoked to it in terms of simultaneous electrical activity.  Those physiological relationships have been delineated by “functional MRI” technique, where a person is given various mental or motor tasks to perform while in the MRI machine.  The MRI software is set to measure not physical or chemical structure as for routine MRI, but blood flow, which correlates exquisitely with brain tissue electrical activity.  These observations could potentially allow researchers to assess the effects of experimental drugs on the immediate or longer-term pattern of brain cell activation in people with PSP.

Exciting developments all, and I apologize for nerding out on you yet again.  But as one of this blog’s commenters said a few years ago, “Thanks, Dr. Golbe, for respecting our intelligence.”  Still, I’ll try softer stuff next time.