Is PSP the route to not just Alzheimer’s but also Parkinson’s?

We’ve known for many years that Parkinson’s disease, which the textbooks call an α-synucleinopathy, has some aggregated tau as well. It appears that each of the two proteins, once misfolded, not only induces its own normal brethren to misfold, it also induces copies of the other to misfold.
The first demonstration of this synergistic misfolding and resulting aggregation came in a series of three papers between 2002 and 2004 from the lab of John Trojanowski and Virginia Lee at Penn. The first authors were John Duda, Bernard Giasson and Paul Kotzbauer. (Disclaimer: I was one of their co-authors on all three.)

Now, Julia Gerson, a grad student in the lab of Rakez Kayed at the University of Texas Galveston, has presented work at the Society for Neuroscience that harnesses that finding of a PD/tauopathy overlap for therapeutic purposes. (Another disclaimer: Kayed has a related grant from CurePSP, where I chair the grant review.)

Gerson and friends created antibodies directed at oligomeric tau, which is tau in small aggregates of maybe 20 or 30 molecules, which are still small enough to remain in solution in the cytoplasm and therefore invisible to light microscopy, unlike mature neurofibrillary tangles. They didn’t want to target normal, non-aggregated tau for fear of disrupting the normal function of that protein, which is to stabilize microtubules.

They injected those anti-tau antibodies into mice that had a copy of a variant of the human gene encoding α-synuclein. The variation was an G209A mutation, producing an A53T alteration in the resulting protein. This is the mutation that my colleagues and I found in 1997 as the cause of PD in a large Italian-American family with autosomal-dominant PD, a finding that first linked PD with α-synuclein. (That’s Disclaimer #3. You’re starting to see why I’m so interested in this new finding.)

The antibody protected the mice against the loss of dopaminergic neurons that the α-synuclein mutation caused in the untreated mutant mice. Mice that received antibody against normal tau did even more poorly than the controls.

So here’s the take-home: Developing an anti-tau antibody for treatment of PSP may also help Parkinson’s. We already expect that it may help Alzheimer’s because that’s clearly a tau disorder. But now, the synergistic toxicity of tau and α-synuclein could also allow a single anti-tau antibody to protect against both Parkinson’s and dementia with Lewy bodies (which also has aggregation of both proteins).

If I were the drug companies, I’d be sitting up and taking notice. Two companies, Bristol-Myers Squibb and AbbVie (licensing an antibody from C2N) have already started anti-tau antibody trials in people with PSP. Others have anti-tau programs in progress.

This new report, which may extend the utility of those products to Parkinson’s, should give that snowball an extra push.

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PSP markers in CSF? Not yet

As a PSP-ologist, it takes a lot to discourage me, but the excellent review of CSF markers in the diagnosis of PSP did it. Nadia Magdalinou, Andrew Lees and Henrik Zetterberg of University College London, writing in the JNNP, point out that no CSF measure has been consistently or reproducibly found to differentiate PSP from all of the relevant competing diagnostic considerations.
An excellent study cited in the review found low levels of CSF α-synuclein in Parkinson’s, DLB and MSA relative to PSP and other brain disorders. A value less than 1.6 pg/μl had good (91%) positive predictive value for any synucleinopathy but higher concentrations had poor (20%) negative predictive value.  So that measure is of some small value.
Neurofilament light chain in CSF is elevated in PSP, MSA and CBD, according to another study, with an area under the ROC curve of 0.93. This has been confirmed by others since. This is useful in distinguishing PSP from PD, but when your patient has a poor levodopa response and downgaze problems, PD isn’t really the issue; PSP, MSA and CBD are.
One study of neurofilament heavy chain found that it can differentiate PSP from CBD but not from MSA. That study was published in 2006 and we’re still awaiting confirmation.
You’d think that tau would be the object of intense scrutiny in the differential diagnosis of PSP by CSF, but there’s been relatively little on that. One good study found that the ratio of phospho-tau to total tau is lower in PSP and MSA than in PD. The other studies of phospho-tau in PSP have been negative.
So the winner so far for PSP, limping across the finish line, seems to be neurofilament light chain. It’s not available commercially as far as I can tell; nor should it be, without further study.
Adding to this discouraging picture is the fact that most or all of the studies of CSF markers in PSP have sampled patients in a stage of PSP that allowed clinical diagnosis. By that time, the CSF picture may be more diagnostic than in the earlier stages, when a state marker would be most useful. In other words, the studies were retrospective rather than prospective.
For now, I’m putting my money on imaging.