A How-To Guide for Doctors

Educating health care providers about PSP and CBD has long been a goal of mine and of CurePSP.  Most of my patients relate unfortunate stories of bothersome or even disabling symptoms for years before any physician suspected the correct diagnosis.  During those years, they may have endured futile, expensive, and potentially harmful diagnostic tests and treatments.  Even after PSP or CBD is correctly diagnosed, attempts to manage the symptoms are often unsupported by evidence, prescribed at an inappropriate dosage, or continued after any benefit has disappeared — while their side effects continue.

All too often, the neurologist tersely informs the patient that no treatment is available for PSP or CBD and that they should just go home, do the best they can and maybe get some physical therapy.  While it’s true that there’s no “specific” treatment or way to slow the underlying disease process, there are treatments that ease most of the symptoms as symptoms.  This is called “palliative” or “symptomatic” management and it’s up to the neurologist and other clinicians to understand and offer it.

These management measures are not unique to PSP or CBD – they are standard drugs and therapies used for symptoms regardless of their underlying cause.  Having said that, it’s also true that patients with PSP may differ from others in their reactions to common medications. 

You may recall that in 2018 a brief single-author book appeared that described management of PSP for clinicians.  For better or worse, the author (that would be me) relied heavily on his own experience, his own reading of the literature and his own philosophical point of view to recommend diagnostic and therapeutic approaches.  That was great as far as it went, but it didn’t reach much of an audience.  The book’s cover price — $75 for the paperback or digital editions – deterred many, and the publisher didn’t advertise it at all.

But now we have a new resource – the CurePSP Centers of Care.  In 2017, when CurePSP organized this network of highly-qualified academic centers in the US and Canada, the mission was to have a list of geographically well-distributed centers providing first-rate care for PSP and CBD.  The network has now grown to 30 sites with plans for 10 more in the next few years.  But besides providing care, the CoC’s are also uniquely positioned to work collaboratively to improve care.  

So in 2019, I and the other three members of the CoC Steering Committee (Drs. Irene Litvan, Brent Bluett and Alexander Pantelyat) organized the other 21 (at the time) CoC site directors to write a “best practices” document on the symptomatic management of PSP and CBD.  We divided the topic into 12 section and for each, created a writing committee from the list of site directors and any institutional colleagues whom they chose to recruit as collaborators.  Each committee submitted a 2- or 3-page draft that the Steering Committee edited and stitched together into a coherent article.  We returned that to the whole group so that every co-author could have some input into the whole document and then submitted the result for publication.

We chose Frontiers in Neurology, an “open-access,” on-line journal, meaning that viewing and downloading articles does not require a subscription or a per-article fee.  Such journals cover their expenses by having advertising and by charging a fee to the authors; in our case CurePSP paid the $2,950 bill.

Here’s the link to the article and here’s the URL: https://www.frontiersin.org/articles/10.3389/fneur.2021.694872/full

Please consider sending the link (or a hard copy) to any clinician you know who takes care of people with PSP or CBD.  That’s not only neurologists, but also primary care physicians and nurse practitioners, ophthalmologists, optometrists, rehabilitation medicine specialists, neuropsychologists, physical therapists, speech/swallowing therapists, and occupational therapists.  Maybe keep a copy in your “go-bag” to provide to your doctors and nurses in a hospital or emergency room.  CurePSP will soon start a North America-wide campaign to distribute the link along with a series of videos of experts discussing and enlarging on points raised in the publication.

I think the authors of the paper did a great job, if I do say so myself.  But now begins the real work of broadcasting our advice so that clinicians can be competent and comfortable taking care of people with PSP and CBD.

He said he was just going out to buy cigarettes . . .

Yeah, yeah.  I know I haven’t posted anything in the past two years other than responses to questions.  No, I don’t know why.  But those who stray can be redeemed, I’m told.  So here’s the first installment of a quick and dirty summary of most of the important news in the world of PSP from 2018 and 2019:

I’ve mentioned with breathless hope the two large trials of monoclonal antibodies directed against the tau protein, one sponsored by Biogen, the other by AbbVie.  Both were designed to detect slowing of the progressive decline in function as measured by the PSP Rating Scale.  Bad news.  Back in July 2019, AbbVie ended its study prematurely after an interim analysis showed no benefit and that continuing the study would be futile.  Biogen completed its study in October and announced in early December that its results were no better than AbbVie’s.  In each case, there were no important adverse effects.  But each company is continuing development of its respective antibody for Alzheimer’s disease.  Those results won’t be available for a few years.

But there’s still hope for anti-tau antibodies in PSP.  Both the Biogen and the AbbVie antibodies were designed to recognize the “N terminal,” so-called because of its unattached amino group, which is based on nitrogen.  (The other end is called the “C terminal” because of its unattached acid group, which is based on carbon.)  But other drug companies are developing antibodies targeting other parts of the tau molecule, and they haven’t announced any intention to abandon those programs.  Next out of the gate will be the big Belgian company UCB, whose antibody targets the “microtubule-binding domain” of the tau molecule, which is much closer to the C terminal.  Its Phase 1 trial has started at selected centers in Europe and in the works is a larger, Phase 3 trial that will include sites in the US.  Still other anti-tau antibodies are being tested in Alzheimer’s by Lilly, Roche/Genentech and Johnson & Johnson, and there’s no reason to think that those antibodies couldn’t work just as well against PSP.

Other treatment ideas are approaching clinical trials as well.  The closest are the “OGA inhibitors,” which I described in a 2017 post.  Three companies are working on those: Asceneuron, Merck, and Lilly, though the last is just targeting Alzheimer’s so far.  I hope that Asceneuron’s trials will start in 2020, though my PSP treatment hopes have been dashed before. Also on deck are the “anti-sense oligonucleotides,” or ASOs, which prevent the tau molecule from being manufactured in the first place.  Such drugs are already on the market for Duchenne muscular dystrophy, spinal muscular atrophy and hereditary transthyretin amyloidosis, each of which affects the muscles or nerves rather than the brain and are not tau disorders.

You’ll recall that a new set of diagnostic criteria for PSP was published in 2017.  It’s called the MDS-PSP Criteria after the Movement Disorder Society (now renamed the “International Parkinson and Movement Disorder Society” for obscure reasons), which sponsored the project.  New criteria were necessary to recognize early stages of PSP, when enrollment in treatment trials (and later, in treatment) would be most advantageous, and also to recognize the recently-described PSP subtypes.  In the past two years, a few studies have validated the criteria to some extent by comparing autopsy results with how closely patients satisfied the criteria during life.  Just last month, researchers in the UK found that applying the new criteria allowed them to expand their population with PSP by 74%.  The new patients were those with the “atypical” forms of PSP that went unacknowledged by the older criteria published in 1996.  The thing is, most of the “atypical” PSP patients will evolve to also satisfy the criteria for typical PSP, which we call PSP-Richardson syndrome, or PSP-RS.  So they would eventually have been recognized as PSP, but usually after years of erroneous diagnoses, unnecessary tests and futile, expensive and inconvenient treatments.

Quite enough for now.  I’ll continue these updates more faithfully, only next time it will get more technical.  Careful what you wish for.

PSP treatments in or near human trials

When a patient or caregiver asks me if anything can be done for PSP aside from palliative measures, my ready answer is that there’s a lot of research now into specific treatments that might slow or halt disease progression. I never have time to get into details in the time available, so I’m not sure my assurance is credible. So, putting my keyboard where my mouth is, here is a pretty thorough list of treatments that are in human trials for PSP or will enter such trials this year:

Anti-tau antibodies: BMS-986168 (Phase 1), C2N-8E12 (Phase 1). Both are in early stages of recruitment at multiple North American sites. The rationale is to bind and destroy abnormal tau en route between brain cells. (Disclosure: I’m a consultant to Bristol-Myers Squibb and a site investigator .) Other drug companies and academic labs are also working on anti-tau antibodies, but at an earlier stage.

Tau anti-aggregants: Leucomethylthioninium (LMTX). This is a derivative of methylene blue in Phase III for Alzheimer’s and frontotemporal dementia; If successful, PSP could be next. But beware the hype that has accompanied methylene blue and its derivatives.  The results from earlier-phase trials have not been published, which is curious.

Microtubule stabilizer: TPI-287 (Phase I). This is closely related to the taxane group of cancer drugs. In cancer, stabilizing microtubules helps prevent cells from dividing. In the brain, it compensates for the loss of tau, which normally stabilizes microtubules as the cells’ transport and skeletal system.

Tau acetylation inhibitor: Salsalate (Phase 1); This is being tested at UCSF, UCLA and UCSD in an open-label “futility” design. In other words, the study will determine not if the drug works, but if it deserves to be tested further. The same drug is being tested for multiple other disorders and has long been on the market as a non-steroidal anti-inflammatory drug.

Tau aggregation inhibitors: ASN-561, an O-GlcNAcase inhibitor. This will probably enter Phase I in 2016. It acts by promoting the attachment of a sugar molecule, N-acetyl glucosamine, to the tau protein, thereby inhibiting its aggregation. Such “OGA” inhibitors are also being tested for other conditions, including cancer.

Anti-sense oligonucleotides: These are RNA molecules designed to inhibit the production of 4-repeat tau, which is over-produced in PSP relative to 3-repeat tau. That imbalance could be contributing to tau aggregation. These have not reached human trials.

Anti-microglial agent: FK506 reduces the activity of microglia, inflammatory cells in the CNS. Evidence is increasing that such inflammation is a cause, rather than an effect, of cell loss in many of the neurodegenerative diseases. In fact, several immune-response-related genes were among the top 10 “hits” in the 2011 study of genetic risk factors in PSP.

Young plasma: Only in 10 patients, non-controlled and only at UCSF, this study will give plasma from healthy men younger than 30 to patients with PSP. The primary outcome issue is safety and tolerability, but efficacy measures will also be applied. Recruitment is under way. The theory is that some unknown blood-borne molecule in young people prevents them from developing PSP and could slow the process in someone with the disease.

Mitochondrial nutrient: Coenzyme Q-10 (Two small double-blind studies, one published and one unpublished) show similar modest improvement in PSP Rating Scale scores. This is a symptomatic treatment but the above items on this list are all potentially neuroprotective.

For more information on any of these, see http://www.clinicaltrials.gov.

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.