A new paper has analyzed data from 863 people with PSP from the failed Biogen and AbbVie monoclonal antibody trials from the late 2010s.  The purpose was not to re-sift the data for signs of benefit, but to characterize the participants’ cognitive deficits in detail and to measure their rate of cognitive worsening over the 12 months of the trials. 

This sort of thing has been done before, but not with as many patient or using those trials’ main cognitive measure, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a 12-component test that has become the standard cognitive test in drug trials of PSP and other diseases.  It includes tests of:

• Immediate memory
• Delayed memory
• Visuospatial/constructional ability
• Language
• Attention. 

The present analysis also included four timed tests that other work has shown to be affected early in PSP and to be sensitive to its progression:

• Phonemic and semantic fluency (saying as many words as possible in one minute meeting a condition such as things starting with the letter T or things found in a supermarket)
• Wechsler Letter-Number sequencing test (connecting randomly arranged letters and digits in order: A-1-B-2, etc.)
• Color Trails Test 1 (connecting small, randomly arranged circles in order of their enclosed numbers, ignoring their two background colors)
• Color Trails Test 2 (similar, but alternating the background colors)  

Other features of this analysis worth noting:

• A lot of other data about the participants’ PSP was gathered in standardized fashion, per the two trials’ protocols.  As you’d imagine, a test requiring writing and drawing could be affected by PSP’s motor and ocular deficits.  So, the statistical analysis adjusted each participant’s cognitive performance by their scores on the eye movement and/or limb movement PSP Rating Scale sections.
• These participants were in the early-to-middle stages of PSP, at a mean of 3.3 years since symptom onset, with a standard deviation of only 1.4 years. So, one cannot assume that the conclusions of this study apply to people in earlier or later stages.  The same applies to their average age of 68.7 (sd 6.9) years.
• The analysis combined the placebo and active-drug groups; it did not compare them to each other.  The authors felt that this would be fine because the original study’s comparison between the two groups’ responses to the drugs showed no differences, unfortunately.

The results showed that all scores worsened to a statistically significant degree over the 12 months except for story memory (immediately after the story), story recall (after a delay), list recall (immediate recitation of a word list) and list recognition (indicating after a delay which words on a second list were also on the first).

The most rapidly progressing tasks were complex figure copying (with the original visible) and coding (where nine geometric symbols are presented along with corresponding digits from 1 to 9; with this “code” on the same page, the person must then draw the symbols corresponding to a list of random digits.)

The take-home for patients and families is that memory is relatively preserved in PSP, at least through the first four or five years.  This despite the habit of many laypersons of referring to any cognitive deficit as a “memory problem.”  So, cognitive activities relying on memory such as listening to music, comedy or stories may remain a source of entertainment and satisfaction for those with PSP well into the disease journey.  On the other hand, puzzles, crafts, drawing and strategy games are likely to prove frustrating.

Another use of these results is in the design of future clinical treatment trials.  The RBANS is a time-consuming, fatiguing test for both patient and clinician, requiring 45-60 minutes for those with PSP.  If the RBANS can be reduced to its most rapidly progressing, most informative, components, the same (or better) information on the subject’s progression might be obtainable in a fraction of that time, without the fatigue.  This could improve the quality of the data not only on the cognitive test, but on the other study-related tests as well.  An excellent start at this was made a few years ago by scientists at Biogen.

The new paper’s first author was Zoë Cappella Cooper, a Harvard undergraduate headed for a stellar career.  (I know this because I’ve worked with her on other projects.)  The senior author was her mentor, Anne-Marie Wills, MD, a long-time colleague of mine at Harvard Medical School and Massachusetts General Hospital.