The American Academy of Neurology’s annual conference is the world’s largest clinical neurology meeting, with a combination of preliminary, cutting-edge research presentations and educational updates for clinicians. This year’s event will take place in Boston from April 22 to 27, 2023.
Each year, the meeting includes over 1,000 presentations of research in the form of brief, published summaries and in-person posters. At the meeting, one of the authors has to stand next to the poster during a specified interval to field questions and criticism. The presentations are subjected to a lower peer-review bar than are full papers in good journals, but on the upside, they are usually published months before the corresponding full paper. Many researchers use the reactions of the conference attendees to improve their manuscripts before submission to a journal.
Here are the ones from the AAN’s website yielded by my search on “progressive supranuclear palsy,” along with my brief editorial comment on some.
Anti-IgLON5 disease is a very rare autoimmune disease that can mimic PSP, though it usually progresses much faster and occurs in younger patients than PSP (see my previous post for a bit more explanation). Dr. Yoya Ono and et al tested for anti-IgLON5 antibodies in a group of 223 patients with PSP enrolled to date in the Japanese Longitudinal Biomarker Study in PSP and CBD (JALPAC). They found the antibodies in none of them, providing additional confirmation that anti-IgLON5 disease is extremely rare, even in the population with apparent PSP.
Startle response: It has long been known that PSP weakens the startle response as measured by electrical responses of muscles in the face, but the location of the defect in the nervous system has been unclear. Now, Dr. Peter Pressman et al at UCSF administered a 115-decibel burst of white noise through headphones to 33 people with PSP and 38 healthy controls. The PSP group failed to react with much of an increase in heart rate or sweating. The authors point out that because PSP is known not to include an important peripheral sympathetic nervous system defect, their result is probably explained by degeneration of the startle response circuit in the pons.
Diagnosis by AI. Neuropathologists and informatics researchers at the Mayo Clinic Jacksonville have taught an artificial intelligence system to diagnose tau-based diseases on brain tissue through the microscope. Dr. Shunsuke Koga et al used a technique called “clustering-constrained-attention multiple instance learning” to differentiate PSP from Alzheimer’s, CBD, globular glial tauopathy and Pick’s disease. This initial version of the system had 87% agreement with human neuropathologists and is being refined.
“Incidental” PSP. My 2019 book on PSP mentions that the lifetime incidence of PSP in autopsies in persons who died with no symptoms suggesting PSP was much greater than that based only on diagnosis in living persons. That data, from 2011, was from a group at Barrow Neurological Institute in Arizona led by Dr. Thomas Beach. Now, the same group, with Dr. Erika Driver-Dunckley as first author, has updated their case series. They found the lifetime incidence in the population to be about 780 cases per 100,000 persons per year, about 50 times the rate as diagnosed only in living persons. I’ll get into the implications of this in a future post. (They’re huge.)
Wearable monitors. Efforts to collect information on abnormal movement from home using wearable devices started years ago and was accelerated by the pandemic. A project of that sort in PSP started last year under the leadership of my research colleagues Drs. Alex Pantelyat and Anne-Marie Wills of Johns Hopkins and Harvard, respectively. An interim report on the first 7 patients to complete 12 months of observation, with the lead author Dr. Mansi Sharma of Massachusetts General Hospital, shows that the remote measurements correlate well with the PSP Rating Scale and PSP Quality-of-Life Scale. The eventual goal is to find ways to efficiently measure PSP progression for the purpose of evaluating large numbers of drug study subjects who live far from the study center or have difficulty traveling.
Sex difference. Clinical drug trial designers are always looking for ways to eliminate sources of “statistical noise” that could obscure an effect, good or bad, of the drug being tested. A group led by Dr. Leonardino Digma of UCSD and the Carlos III Institute of Health in Madrid used data from the TAUROS study, published in 2014, which found that the drug tideglusib failed to slow the progression of PSP over its 12 months of double-blind treatment. The new analysis found that while the men and women had similar verbal fluency at the start of the TAUROS study, that ability declined faster in men. This suggests that future drug trial designers should take sex of the participants into account in calculating whether their experimental treatment has slowed the rate of decline of verbal fluency.
Amantadine. Way back in 1993, I published a review of the records of the 87 patients with PSP I had seen up to that point with regard to their responses to all the drugs they had received for that condition. An unexpected result was that amantadine, one of the standard drugs for Parkinson’s disease back then, helped at least as much as anything else. That publication prompted me and many other neurologists to routinely try amantadine in their patients with PSP. Now, Dr. Nikolaus McFarland et al at the University of Florida have reviewed records of their 350 patients with PSP to tabulate amantadine responses. Of the 42 patients who received the drug and had an adequate record of the results, 5 improved, 30 had no benefit or a worsening, and 7 were unsure. The most common side effect, occurring in 6 patients, was confusion or hallucinations. So, about 10-15% of patients with PSP will benefit and a similar number or a bit more will have important side effects that will abate after discontinuation of the drug. That’s why I recommend that amantadine be tried – with close observation and follow-up – in everyone with PSP who does not already have important cognitive difficulties or other symptoms, such as constipation, that amantadine could exacerbate.
Tau PET. A positron emission tomography (PET) tracer variously called 18F-PM-PBB3, 18F-APN-1607 or 18F-florzolotau has successfully undergone small, preliminary studies and will soon enter a larger, more definitive, “pivotal” trial. As a supplementary method of validation, Dr. Hironobu Endo et al of Chiba University and Niigata University in Japan obtained PET images using that tracer in a patient with far-advanced PSP. After the patient died a year later, his brain autopsy showed that the locations and intensities of abnormal tau in the autopsy tissue as revealed by traditional anti-tau antibody staining correlated very well with those in the PET images. This result, albeit in only a single patient, provides additional support for the utility of this tracer as a diagnostic tool for PSP. (Disclosure: I’m a consultant for Aprinoia, the company developing this tracer in the US.)
Anatomic origin. Dr. Edoardo Spinelli et al of San Raffaele University in Milan and Mayo Clinic Rochester report their use of functional MRI to map out the anatomical origin and subsequent pathway of spread of the PSP process in the brain. They found the origin to be the left midbrain tegmentum. (The tegmentum is covered by the tectum, or “roof,” site of the vertical gaze centers, and in turn, covers the base, or “peduncles, ” site of the main motor control tracts. I assume that the specific spot in the tegmentum is the substantia nigra, which has long been known to be one of the three nuclei in the brain where PSP first appears.) Furthermore, they found that as the disease progressed, areas became involved in order of directness of connectivity to the left midbrain tegmentum. I, for one, was surprised to learn that the origin had such a clearly asymmetric origin starting on the left in all, or most, patients.
2 thoughts on “A peek at research coming down the pike”
Dear Dr Golbe,
My husband has been diagnosed with PSP since October 2021, which actually began as PPAphasia-non-fluent. He was a very active person and now uses a walker with difficulty. He takes Galantamine, Sinemet and Amytriptilin. Do you have any thoughts or experience on supplements of Glutathion and Cysteine treatments? Thank you for your blog which I follow very closely from the Canary Islands, Spain.
Dear Ms. Schumann: There have been no adequate trials of glutathione or cysteine in PSP. Nor have there been publications reporting informal observations of improvement in a series of patients that might suggest more than just a placebo effect. So, I can’t recommend those drugs.