Tag Archives: PSP-parkinsonism

Jesse Jackson

Posted on by

The Rev. Jesse L. Jackson, Sr., the civil rights leader and political activist, has announced that his 2017 diagnosis of Parkinson’s disease has been changed to PSP.

I have no inside information on the details of Rev. Jackson’s condition, but I can tell you that this is a common scenario for people with the second-most-common type of PSP, called PSP-Parkinsonism (PSP-P).  It accounts for about 15% to 35% of all PSP, depending on the source of the data, and starts out looking like Parkinson’s disease (PD), typically with asymmetric stiffness of the limbs and often a tremor, without much cognitive, eye movement or balance difficulty.   The symptoms, like those of PD, usually respond to levodopa, though not quite as well or for as many years. 

PSP-P progresses at a rate typical for PD, not the faster rate for most types of PSP.  The average lifespan of PSP-Richardson syndrome (PSP-RS), which accounts for about 45% to 55% of PSP, is about 6 years, while for PSP-P, it’s 9 years and for PSP overall, 7 years.  (The lifespan of people with PD receiving modern treatment averages about 16 years, but many neurologists today don’t know that before levodopa became available in 1970, it was about 9 years, like PSP-P.)

The typical journey of someone with PSP-P starts with a satisfactory response to levodopa.  But the dosage requirement increases more rapidly and balance problems develop sooner than in PD.  After a few years, the neurologist may suspect one of the “atypical Parkinsonian disorders,” examine the patient more closely than at the previous follow-up visits, find the eye movement problem and frontal cognitive issues of PSP, and change the diagnosis.  Often, this re-evaluation is performed by a second neurologist whose opinion was sought by the patient or family member worried about the atypical symptom course and unsatisfactory levodopa response.

So, if Rev. Jackson does have PSP-P, he would now be at about the average (i.e., the median) survival duration.  Of course, about half of all people with PSP-P survive past the median, some for as long as a total of 20 years or even more.

A scientific comment: Keep in mind that PSP-P wasn’t described in the medical literature until 2005 and formal criteria to distinguish among the various (now 10) different PSP subtypes didn’t appear until 2017.  Before then, most people with PSP-P would not have fulfilled the existing formal criteria for PSP, which were published back in 1996.  Therefore, pre-2017 statistics on the prevalence or lifespan of people with PSP refer mostly to PSP-RS, which is the name given in 2005 to what was defined as “PSP” by the 1996 criteria.

Another scientific comment: PSP-RS, PSP-P and the other 8 subtypes all have the same set of microscopical changes in the brain, featuring neurofibrillary tangles of tau protein and tufted astrocytes.  It’s just the sets of locations around the brain that differ to some extent.  We don’t yet know what causes this “cell-type specificity,” but the best theory is that it’s slight differences in the mis-folding pattern of tau, caused by slightly different locations of abnormal attachment of phosphate groups on the protein.

And finally, an editorial comment: Almost all clinical drug trials in PSP only accept participants with PSP-RS.  There are several good reasons for that, but that policy excludes half of all those with PSP, raising the theoretical possibility that any resulting treatment may work only in that sub-type.  I’ll discuss potential solutions in a future post.

Meanwhile, my deepest gratitude to Rev. Jackson for sacrificing some degree of personal medical privacy in the service of increasing public awareness of PSP and my best wishes to him in the journey forward.

Not your father’s PSP

Posted on by

As it turns out, PSP comes in many clinical flavors. Back in the 80s I remember some patients whose illness looked like Parkinson’s until I realized that they weren’t responding to my levodopa prescriptions, at which point I repeated a careful ocular motor exam and found square wave jerks and slow downward saccades. I also remember one member of my first series of 41 patients with PSP from 1988 with severe gait apraxia and freezing as his most disabling feature.
Then, in 2005, David Williams and colleagues, mentored by Andrew Lees at Queen Square, published what is probably the most important clinical paper on PSP in the half-century since Steele, Richardson and Olszewski. That work delineated and named PSP-Richardson syndrome (PSP-RS ) and PSP-parkinsonism (PSP-P). This wasn’t just a new way to slice a clinical spectrum sharing the same basic pathology; the two variants actually had statistical differences by cluster analysis. This suggests that they differ at the pathoanatomic level. They even differed in the ratio of 4R/3R tau. (It turns out that the predilection of PSP’s tangles for 4R tau is driven by RS.)

Since then, a cornucopia of low-frequency clinical variants meeting pathoanatomic criteria for PSP has been described. In approximate descending order of prevalence after RS and PSP-P are corticobasal syndrome, postural Instability, pure akinesia with gait freezing, frontotemporal dementia, ocular motor predominance, progressive non-fluent aphasia, semantic dementia, and a cerebellar variant.
The clinicopathologic studies are only starting to appear, but it’s likely that they will all turn out to emphasize different cells, nuclei and brain regions. We will also probably see some subtle molecular differences among them (presaged by the 4R/3R difference between RS and PSP-P).

That sounds like different diseases to me. Different diseases shouldn’t be combined in treatment trials, genetic analyses or descriptive studies. What a mess.

Or is it? Maybe we don’t need to find causes and cures for each PSP variant individually. As they’re all tau aggregation disorders, maybe they will all yield to the same prevention. Maybe the mechanism of prion-like spread, by now pretty much a textbook verity, will apply not only to all of the “pure tauopathies” (and it’s not yet clear that all of the PSP variants are in fact pure tauopathies) but to all of the protein-aggregation-based neurodegenerative disorders. If it does, then poisoning that process could be the grand unified answer to Alzheimer’s, Parkinson’s, ALS, and PSP in all its malign variety.