Günter Höglinger of Hannover University in Germany is probably the world’s most productive PSP researcher right now. A few years ago, he organized a PSP Study Group as part of the International Parkinson and Movement Disorder Society. Most of the 51 members are European – I’m one of the 11 US members. The PSPSG’s main accomplishment to date is developing and publishing a new set of diagnostic criteria for PSP. The group meets for a couple of hours in person every year in conjunction with the IPMDS’s conference, but of course, the past two meetings have been on Zoom. The agenda is to informally discuss our recent research activities and ideas.
This year’s meeting was held on October 4, 2021. Here’s a boiled-down, edited and explicated version of the proceedings. The topics were classified into imaging, longitudinal studies, fluid markers and treatment. As per last week, it will be the installment plan: Each of those four topics will be a separate post here on PSP Blog.
James Rowe of Cambridge University, a legitimate rival to Günter as the world’s current leading PSP researcher, described the value that 7-Tesla MRI brings to PSP research.
Most standard MRI scans for medical care use a magnetic field strength of 1.5 Tesla and a growing number use 3 T for additional resolution. But about 100 research MRI machines world-wide are capable of 7 T imaging. This provides, for the first time, a clear image of the locus ceruleus (LC), a cylindrical cluster of blue pigmented cells in the brainstem that uses noradrenaline as its neurotransmitter. It averages 14.5 mm in length but only 2.0 mm in diameter, making it difficult to see with conventional 1.5 T or 3.0 T MRI. It supplies input to many other brain areas and degenerates in PSP and other neurodegenerative disorders. Dr. Rowe hopes that the rate of worsening of atrophy of the LC on 7 T MRI may be usable as an outcome measure in PSP neuroprotective treatment trials.
A technique called magnetic resonance spectroscopy (MRS) uses existing MRI machines to provide not an anatomical image, but a measure of levels of some kinds of chemicals in specified areas of brain tissue. It’s currently used mostly in brain tumor diagnosis. (Side note: MR spectroscopy long antedates MR imaging, which essentially takes MRS measurements of multiple pencil-shaped volumes of tissue sharing a slice of brain and then uses a computer to reconstruct those numbers into a two-dimensional image.) 7T MRI provides greater resolution here as well. Dr. Rowe reported that he is studying the effects on circuits in the cortex of tiagabine (brand name Gabitril), an approved epilepsy drug that increases levels of the inhibitory neurotransmitter gamma-amino-butyric acid (GABA). A similar drug is atomoxetine (brand name Strattera), which is approved for attention-deficit hyperactivity disorder. Dr. Rowe is leading a clinical trial of that drug for disinhibited behavior, apathy and impulsivity in PSP. A secondary outcome measure in that PSP trial, i.e., one that will not be critical to the study’s conclusions because it’s still an experimental test, is using 7T MRS to assess GABA levels in selected brain areas.
Adam Boxer of University of California San Francisco, yet another very prolific PSP researcher, described the progress of his NIH-supported project, “4-repeat tau neuroimaging initiative,” or 4RTNI (pronounced “Fortney”). The study is following patients with PSP or CBS every 6 months using MRI to track atrophy and tau PET to track tau aggregate accumulation. The study also includes clinical evaluations, plasma levels of Ptau217 (tau with a phosphate group attached at amino acid number 217) and PET scans for beta-amyloid to detect Alzheimer’s disease (AD), which in an atypical form is the pathology underlying many cases of CBS. The goal is to develop better diagnostic tests and progression markers for use in future PSP and CBD treatment trials. While the Richardson syndrome clinical picture is almost always explained by underlying PSP pathology, an especially pressing issue is to distinguish CBS caused by CBD pathology (CBS-CBD) from CBS caused by AD pathology (CBS-AD). Plasma levels of Ptau217 are very high in people with AD pathology, either as classic clinical AD or as CBS-AD, but normal in CBS-CBD and CBS with other pathologies. A commonly used statistical measure of accuracy, the “area under the receiver operating characteristic (AUC),” for plasma Ptau217 in distinguishing CBS-AD from CBS-CBD is 0.96, very close to the theoretical ideal of 1.0. However, that’s for advanced cases. The test’s utility in early cases, where it’s likely to be needed most, is much less so far. Dr. Boxer tentatively concludes that in distinguishing CBS-CBD from CBS-AD, plasma Ptau217 is almost as accurate as amyloid PET, the current standard, a much more difficult and costly procedure.
Dr. Boxer discussed another project in progress within the 4RTNI umbrella to help distinguish CBS-AD from CBS-CBD or CBS-PSP (i.e., to allow patients with CBS to participate in anti-tau treatment trials). His research group combined a measure of cortical atrophy with one of midbrain atrophy using a Bayesian logistic regression. That’s a technique that allows one to create a statistical “model” of a phenomenon, or to dissect its component parts, by successively trying different solutions and tweaking each based on the previous result. This is different from traditional statistical models, which use event frequencies rather than successive refinements of an a priori hypothesis. Look it up. They were able to achieve an AUC for CBS-CBD vs. CBS-PSP to 0.95 for patients presenting with motor signs and 0.91 for those presenting with non-motor signs.
Next post: Longitudinal PSP studies