The fourth of the five PSP-related research papers to land in PubMed on a single day this week is from Ulm, Germany.   It compared PSP with ALS with regard “small involuntary fixation saccades” or SIFSs.  Here’s what that means and why it’s important: (Red alert: serious, nerdy neuroscience is coming.)

When we stare at a small visual target, we all have small, fast, irregular, eye movements away from the target.  Each is rapidly corrected by an equal and opposite movement and their size ranges from 0.01 degrees to 2 degrees.  (The normal full range of voluntary eye movement in each of the four directions is about 50 degrees.)  In PSP, these SIFSs become larger and more frequent in the horizontal plane (i.e., left and right), ranging up to 3 degrees and occurring up to twice per second.  The largest of these are called “square wave jerks.” They are so common in PSP, even in the earliest stages, that a neurologist finding signs of PSP but no square wave jerks must strongly consider some other diagnosis.  As you’d imagine, SWJs degrade vision by making it difficult to aim the most sensitive, central part of the retina at a target.

Square wave jerks and milder forms of SIFSs also occur in amyotrophic lateral sclerosis (ALS or Lou Gehrig disease).  ALS and PSP both include frontal cognitive loss and affect overall body movement, especially speech and swallowing, have frontal cognitive loss and have a similarly rapid course, but are otherwise not at all similar.  In ALS, the average age of onset is 10 years younger; the cognitive loss is a late occurrence; it affects the spinal cord worst; and the protein aggregating in the cells is TDP-43 rather than tau.  As eye movement are controlled, in part by the frontal lobes, it seems reasonable that the frontal damage is the source of SWJs in both diseases. 

Now, Drs. Wolfgang Becker, Anna Behler, Olga Vintonyak and Jan Kassubek have compared people with PSP and ALS with regard to the details of their SIFSs, including their square wave jerks.  In addition to making some new observations about SIFSs in general, they found that in ALS, the size and frequency of SIFSs are correlated, while such a relationship is absent in PSP. 

The researchers explain this result by suggesting that the basal ganglia, where the substantia nigra, globus pallidus and subthalamic nucleus are the first three nuclei affected in PSP, are the most likely source of SWJs in that disease, while in ALS, the SWJs probably arise from damage to the frontal cortex.  They suggest that in PSP, the amplitude and frequency of the SWJs are regulated by different sites in the basal ganglia, explaining their observed lack of correlation.  More work will be needed to confirm that suspicion, but some support comes from the observation in this paper that the severity of vertical eye movement loss, the cardinal feature of PSP, correlates closely with the amplitude of the (horizontal!) square wave jerks.

Why should anyone care?  First of all, a general point: One never knows when a “basic science” observation may lead to broader insights that could allow treatments to be developed.  More specifically, finding that a feature of PSP arises from multiple parts of the basal ganglia reduces the appeal of targeting just one allegedly critical or rate-limiting area of basal ganglia damage with a preventative or restorative treatment.  Such approaches have been proposed using injection of viral vectors to deliver gene therapy or growth factors.  Non-invasive targeting of the basal ganglia has been proposed using focused ultrasound.  This new paper suggests that a more general approach reaching the whole brain, or at least all the basal ganglia, might work better.