The elusive limelight

No rare disease advocate wishes illness on anyone, but we do all hope that one of PSP’s inevitable sufferers will happen to be a celebrity. 

When Michael J. Fox announced his diagnosis, awareness of Parkinson’s disease and fundraising for its research took off.  Amyotrophic lateral sclerosis, its prevalence no more common than that of PSP, would still languish in obscurity without Lou Gehrig.  Awareness that Alzheimer’s disease was not “accelerated aging” nor a circulatory problem was boosted early on by the plights of Rita Hayworth and more recently of Ronald Reagan, Glenn Campbell and Pat Summitt.  Robin Williams brought Lewy body dementia to popular consciousness for the first time.

PSP has never had a celebrity advocate who was an affected person.  The only real candidate emerged in 1999, when British comic actor Dudley Moore announced his diagnosis.  Shortly thereafter, a profile of Mr. Moore on the TV newsmagazine “20/20” brought the disorder some degree of attention.  In fact, at least a couple of new patients came to me after recognizing their own neurological deficits in the 20/20 piece.  A few months later, Mr. Moore himself became my patient.  He told me that he appreciated that PSP needed a celebrity spokesperson and offered to help in fundraising, but declined to become its “poster boy” (his words, not mine).  He did participate in one fundraiser before his death in 2002 and I never tried to wheedle any video clips, interviews or other forms of publicity out of him.

CurePSP did attract as its spokesperson for a number of years a celebrity whose father had PSP.  Starting in about 2005, Patricia Richardson, an accomplished actor who in the 1990s had played opposite Tim Allen in the TV sitcom “Home Improvement,” joined CurePSP’s Board of Directors.  When we appeared at events together, she was admirably persistent in prodding me to translate my scientific presentation into language appropriate to the audience.  She was generous with her time for CurePSP’s outreach and support services.  But in 2015, she and CurePSP parted ways. 

About a year ago, Linda Ronstadt announced that she had been diagnosed with PSP.  The CurePSP leadership immediately attempted to propose a spokesperson relationship, but were unable to establish contact at all.  In a September 2019 “New Yorker” magazine profile ahead of the release of the new documentary, “The Sound of My Voice”, she said, “I’ve just accepted it. There’s absolutely nothing I can do. I have a form of Parkinsonism that doesn’t respond to standard Parkinson’s meds, so there’s no treatment for what I have. It’s called P.S.P.—Progressive Supranuclear Palsy.”  But the documentary itself mentions only “Parkinson’s disease.”  (A digression: Perhaps, like many patients and caregivers, Ms. Ronstadt is under the misimpression that PSP is only a more severe form of PD, in which case she may think that someone with PSP could be said have both, one being a subset of the other.  I won’t share my own diagnostic impression on PD vs PSP based on her current speech, facial movement and eye movement as they appear in the documentary.  I’ve been around long enough to know that diagnoses relying of such fragmentary data are risky.) 

So PSP still struggles to enter public consciousness. A glimmer of hope appeared on major network TV on January 7, with the premiere of the NBC series, “Zoey’s Extraordinary Playlist.”  The star hallucinates that others communicate their feelings in the form of impromptu song-and-dance numbers.  Her father, with advanced PSP, is played with admirable accuracy by Peter Gallagher.  Sure enough, in one of the pilot episode’s musical scenes, the father, aware of his daughter’s multiple professional and personal anxieties, breaks out of his immobile, mute state into a tender song of encouragement.  The script does not include the term “PSP” or “progressive supranuclear palsy” but press blurbs and cast interviews do so.  Of course, this does not provide a real-life celebrity spokesperson, but at least it’s publicity.

Of course, I hope that no celebrity – or anyone else – ever comes down with PSP.  But once the inevitable happens, perhaps he, she or a loved one will be willing to sacrifice some time, energy and privacy to the cause. 

Your own one- or two-year crystal ball

You may know that for many years one of my jobs at CurePSP is to chair the grant review. Twice a year we have a deadline for researchers in either academia or the private sector to apply for up to $100,000 for work related to PSP or CBD. It’s very competitive, as we receive about 20-25 applications a year from some top research groups and fund only about 5-7 of them. We welcome purely clinical projects as well as laboratory work. The term of the grants is 1 or 2 years. Here are the 4 successful awardees from our Fall 2019 grant cycle:

Lukasz Joachimiak, The University of Texas Southwestern Medical Center, Dallas: Structural basis for tau strain conformation in CBD and PSP

In the brain, the tau protein can form an altered shape that clumps together in an aggregated form.  This study will isolate the tau protein from healthy, PSP, and CBD patient brain tissues. Specialized research tools will be applied to determine how the abnormally folded shape of tau differs from the tau from healthy brains. Understanding the fine details of how the tau protein changes from a normal shape to the different “bad” forms found in disease will provide the blueprint for designing new methods to detect and prevent these devastating diseases in patients.

David Butler, Neural Stem Cell Institute, Rensselaer, NY: Bifunctional intrabodies to lower tau

The goal of this project is to develop therapeutic agents that will prevent tau accumulation and associated death of brain cells with novel antibody-based reagents (termed intrabodies). Intrabodies are antibodies expressed within brain cells, while antibodies produced by the immune system or administered by vein do not penetrate brain cells.   These antibodies are highly selective for tau, and they have been engineered to target tau for degradation using the cell’s normal clearing process. The study’s central hypothesis is that targeted degradation of tau protein will reduce the amount of tau available to misfold and thus reduce cell death.

J. Mark Cooper, University Hospital, London, UK: The influence of TRIM11 on tau, aggregation, release, and propagation

In 2018 this research group identified the TRIM11 gene as a risk factor for PSP. This study will investigate the effects of a the protein encoded by that gene on toxic tau protein aggregation in the brain. It is believed to play a role in regulating the levels of some proteins within the cell, in particular proteins that may form aggregates. The study will use models of brain cells grown in the laboratory to focus on how changes to TRIM11 influence tau protein regulation, in particular its tendency to aggregate. These findings may help to identify potential therapeutic targets to modify PSP disease progression.

K. Matthew Scaglione, Duke University, Durham, NC: Small-molecule regulation of a protein quality-control E3 to treat PSP

The protein Hsc70 or “CHIP” accelerates the removal of tau from the brain. This project intends to identify compounds that stimulate CHIP functions.  One important such function is as an “E3” enzyme, which is an important part of one of the brain cells’ “garbage disposal” mechanisms called the ubiquitin-proteasome system (UPS).  E3 allows the UPS to recognize specific proteins for appropriate disposal.  Finding new compounds to stimulate this function is an important first step toward developing small (that is, orally dosable) molecules to slow or prevent the progression of PSP and CBD.

(If those descriptions sound like they’re not my own writing style, it because each was provided by the researchers themselves and then edited by me to fit what I think, based on little evidence, to be the technical background of this blog’s readers.)

I’ll update you on the progress of those projects once they’re publicly presented or published over the next 2 or 3 years.

A sidebar about PubMed: If you didn’t already know, you can see these, or any, researchers’ previously published work by typing a name into the search line at PubMed. Enter the last name, then the initials. To narrow it down, add a topic (like tau or neurodegenerative disease). The initial display lists papers satisfying the search terms in reverse chronological order. Clicking on one of them brings up the authors, institutions and a half-page, technical-language summary. There’s always a stack of links to related papers, including subsequent ones that cite it. Clicking an author’s name will produce a list of his/her other publications. Plus, for some articles, the whole text is available via a clickable link, sometimes for free, usually for an exorbitant fee. Have fun!

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.

This orphan has many parents

The Orphan Drug Act of 1983 was a game-changer for rare diseases.  A result of lobbying by patient-led groups such as NORD with bipartisan political support, its principal author was the liberal Democratic Congressman Henry Waxman and its signer was President Reagan.  The rate of FDA approval of drugs for orphan diseases increased from fewer than one per year before 1983 to an average of 13 per year over the ensuing decades.  The ODA provided drug companies 7 years of new patent protection, financial subsidies in the form of grants, a fast-track approval process and last but not least, a tax credit for 50% of the development costs.

A disorder qualifies for “orphan” designation under the ODA if its point prevalence in the US is fewer than 200,000.  PSP easily meets that criterion, with about 5,000 diagnosed cases or 20,000 if you count those who undiagnosed but potentially diagnosable.

PSP’s transition from an orphan to an object of loving care has been remarkable.  There are several reasons:

First, a drug that works for PSP may also work for other tauopathies, including Alzheimer’s disease.  Of course, a huge potential market exists in the ascendancy of AD as a major epidemiologic challenge for the Boomer Generation and beyond.

Second, the disappointing results of clinical trials of drugs addressing the beta-amyloid aggregation of AD turned the research world’s attention to tau aggregation as the key to AD prevention.

Third, PSP, as a “pure tauopathy” offers a good, clean “test bed” for anti-tau agents.  (We now know it’s not so pure, but close enough for present purposes.)

Fourth, neuroprotective trials are easier in PSP than in AD despite the recruitment difficulty arising from the disease’s rarity.  One reason is that PSP, unfortunately, progresses more quickly than AD.  (Aside: A “neuroprotective” trial attempts to reduce the rate of worsening of the disease, usually without improving the existing symptoms.  A “symptomatic” trial attempts to improve existing symptoms without regard to the long-term progression or outcome.)  Demonstrating that a drug slows a disease’s progression requires fewer patients and a shorter treatment period when the untreated disease progresses more rapidly.  This translates into cheaper development costs and less development time.

Fifth, in the absence of a proven biomarker for AD, clinical trials must rely on neurological exams and reports of daily activities by patients and caregivers.  No such clinical scale accomplishes this adequately for AD, but the PSP Rating Scale does so for PSP.  (Bragging point disguised as a disclaimer: I developed the PSPRS.)

But the House of Representatives’ version of the new tax reform bill eliminated the tax credit in the Orphan Drug Act.  The thinking was that drug companies often charge prices for those drugs far in excess of their development costs, thereby defeating the original intent of the ODA to support development of drugs without a reasonable expectation of profitability.  The drug companies can usually get away with those prices because the patients are desperate and because the insurance companies providing prescription coverage want to avoid lawsuits and public-relations disasters.  Besides, the insurors can just raise their premiums to spread the cost over their other subscribers.

The other concern in the House was that drugs developed under ODA protection may then find use against more common conditions with highly profitable results.  Some examples are Cialis (developed for pulmonary hypertension, then for erectile dysfunction), Botox (dystonia, then wrinkles) and Provigil (narcolepsy, then off-label as a cognitive enhancer) .  A PSP drug subsequently used for AD could become another example, as pointed out above.

The final tax reform law is a compromise.  It reduces the fraction of the development costs that can be taken as a tax credit from 50% to 25%, not to zero.  How will this affect the drug companies’ calculations regarding future orphan drug development?  I haven’t a clue.  But my attitude toward this complicated situation is that patients with PSP should be glad that their disease is of interest to drug companies, even if that’s only a by-product of their interest in AD or some other way to game the ODA.

Some think tank now needs to figure out just how much credit the ODA deserves for recent decades’ abundance of new drugs for orphan diseases.  Maybe it’s not an economic issue at all.  Maybe it’s just that recent basic scientific breakthroughs have created more drug targets.  Or maybe the drug companies have figured out that they can charge tens or hundreds of thousands of dollars per year for a drug and get away with it.  Either way, maybe the ODA is unnecessary or needs to be radically revised.  One can hope that if the current work on PSP results in a mega-expensive AD drug that strains our present health care model, maybe the result will be a truly universal health care system in the US.

PSP by the Bay

Just returned from the annual CurePSP International Research Symposium, held this year in on the campus of University of California San Francisco on October 27.  About 120 researchers attended, many from Europe and Japan.  The first keynote speaker was Bruce Miller from UCSF, perhaps the country’s leading behavioral neurologist, who gave an overview of PSP/CBD research with an emphasis on activity of the Tau Consortium, the multi-institutional research group that he directs.  The other keynoter was Robert Stern, a neuroscientist at Boston University who directs clinical research at BU’s Chronic Traumatic Encephalopathy Center.

Bruce’s talk touched on many topics — from the nosology and pathology of the various cognitive/behavioral syndromes in the tauopathies to the sleep disturbance in PSP (hyperarousal is common in PSP, while hypoarousal predominates in CBD).  Perhaps most interesting was his up-to-the minute summary of the state of tau PET imaging in PSP diagnosis (not nearly ready for prime time, though potential exists).

Bob’s lecture summarized the story of CTE.  He emphasized that the most important frequent cause isn’t concussions, but the continual sub-concussive blows to the head such as those suffered by football players during routine blocking and tackling.  He was too smart to speculate much about a relationship between the tauopathy of CTE and that of PSP, but I’m not:  I’ll say that in both cases, individuals with a genetic predisposition to tau aggregation are exposed to a precipitating factor – repeated brain tissue stretching for one, some sort of toxin for the other.  If we can find the genetic background for one, we may find it for the other.

Perhaps the genetic answers will emerge from the whole-exome sequencing project that is complete and in the writing phase or the whole-genome sequencing project that is well under way. But as pointed out in another Symposium talk by Jerry Schellenberg, the U Penn geneticist who heads those efforts for the PSP Genetics Consortium, there’s a lot of “genetic dark matter” in the form of genomic deletions, undetectable by mere sequencing.

Maybe in future posts I’ll get more into the other excellent CurePSP Symposium talks – and the 18 concomitant poster presentations.  Or maybe I’ll get distracted by a random shiny object I find somewhere else.

You’ve dragged me back, or: an anti-tau antibody update

Yeah, yeah.  I know it’s been 15 months since my last post.  I’m fine, thanks – just busy with other things.  But today a kind reader from Canada named Maureen posted a comment asking where I was all this time and threw in a little flattery just to get me going.  I’m a sucker for that.

So here’s the latest on the hottest topic in PSP-ology, the antibody trials.  Right now, five drug companies have anti-tau antibodies in the pipeline.  Two have started human trials and are in Phase 2.  The others are still in laboratory phases or in the early planning for human trials.  As a reminder, these antibodies are directed at the tau protein and are given by intravenous infusion, typically at intervals of a month.  The idea is to intercept the misfolded, abnormally aggregated tau as it passes through the intercellular fluid between brain cells. (We still don’t know if it’s between neurons or glia or both.)  The hope is to slow the spread of the disease process through the brain.  This treatment would probably not improve any existing deficits, just slow the rate at which they worsen going forward.

The first drug company out of the blocks, in 2015, was Bristol-Myers Squibb, which sold its neurodegeneration division to Biogen in April 2017.  This Phase 1 trial was designed only to assess safety and comprised only 48 patients, a quarter of whom received placebo.  The antibody passed with flying colors, with no important side effects over the 12 months of treatment.  The patients (including the 12 assigned to placebo for the first year) are continuing to receive active drug and are generating more data along the way.  The protocol did include measures of efficacy, the principal one being the ability of the treatment to slow the progression of the disease relative to placebo as measured by the PSP Rating Scale.  But that effect would have to have been huge to be statistically noticeable in so small a study.

That’s the purpose of the Phase 2 studies, of which 2 are in progress.  The one that Biogen bought from Bristol-Myers Squibb will include 396 patients, a third of whom will receive placebo infusions.  The study will take place at about 35 sites in the US, Europe and Japan.  Recruitment has begun and the double-blind phase will last a year for each patient, though it will probably take about 6 months to get all of the patients entered.  This study has been dubbed the “PASSPORT” study.  (It looks like an acronym, but it doesn’t really abbreviate anything except that the letters “PSP” are in there somewhere.)

The one by AbbVie, another big drug company, comprises 180 patients, of whom 60 will get placebo.  It will take place at 18 sites around the US plus 3 in Canada, 2 in France and one in Australia.   About half of the sites are presently recruiting patients.  This study is called “ARISE.”  When I find out what that’s supposed to abbreviate, I’ll let you know.

You can find more info about both trials, including contact information for prospective participants, at clinicaltrials.gov.  Here’s the listing for the BMS/Biogen study and here’s the link for the AbbVie study.

Maybe a future post will regale you with my random thoughts about whether anti-tau antibodies are actually likely to help.

[Full disclosure: I consult on an hourly basis for both BMS/Biogen and AbbVie in matters regarding the PSP Rating Scale, which I published in 2007 and is the principal outcome measure for both studies.  I have no personal financial interest in the studies’ outcome.]

Express yourself, or better yet, don’t.

An original and interesting observation just appeared that might help explain how the known genetic variants associated with PSP might cause the disease.  It has to do with regulating gene expression.

Mariet Allen, PhD, a junior researcher at Mayo Clinic Jacksonville, and colleagues published the paper in the current issue of Acta Neuropathologica.  The senior author is Nilüfer Ertekin-Taner, PhD, who received a grant from CurePSP for this work.  The general idea of using such “endophenotypes” to assess the role of genetic variants in causing PSP has long been proposed by their mentor, Dennis Dickson, MD, a leading neuropathologist, who was also an author of this paper.

They used tissue from 422 brains from the CurePSP Brain Bank at Mayo that had been confirmed as having PSP.  They made three types of measurements in each brain: gene expression (measured as messenger RNA), epigenetic methylation of DNA (measured as CpG islands), and numbers of the various classic PSP micro-anatomic changes that have been known for decades.  They correlated those measurements with whether each case carried the major or minor allele of markers reported in  the genome-wide analysis (GWAS) of single-nucleotide polymorphisms published in 2011 by Hoglinger et al. (Disclaimer: I was a minor co-author on the 2011 paper.)

Without getting too much into the details, the results were that the genetic variants and increased DNA methylation at MAPT (the gene for tau protein) and/or MOBP (the gene for myelin-associated basic protein) were associated with increased expression levels of some proteins not previously associated with PSP.  One such protein was “leucine-rich repeat-containing protein 37A4” or LRRC37A, which is coded at chromosome 17q21.31-q21.32.  The genetic marker status at that location was also associated with increased expression levels and methylation levels in two other proteins encoded by genes at the same approximate location, ARL17A and ARL17B.  (Adenosine diphosphate ribosylation factor-like GTPases are involved in protein transcription and like LRRC37A, are located next to the MAPT gene on chromosome 17.)

LRRC37A appears to be involved in regulating interactions of proteins with other compounds.  Its upregulation is known to be harmful to cells.  Intriguingly, its gene produces a wide variety of alternatively spliced protein forms (where some exons’ protein products are included, others excluded, from the finished protein product) in different people and in different species.  This may suggest that this gene is unstable and could easily be induced to make an inappropriate variant of its protein by a subtle exposure to a toxin or a toxic effect of another gene.

Furthermore, the marker status at the MAPT locus correlated with more intense tau aggregates in the form of coiled bodies and tufted astrocytes, two of the standard diagnostic features of PSP.  This reinforces the idea that tau overexpression is part of the pathogenesis of PSP and that inhibiting that expression could provide prevention.

So as the authors modestly conclude, “MOBP, LRRC37A4, ARL17A and ARL17B warrant further assessment as candidate PSP risk genes.”  All of these associations may suggest new drug targets, but it’s a long slog from there to the clinic.  However, if someone screens a library of existing drugs for their ability to suppress overexpression of these proteins, the path to a treatment could be much, much shorter

Critique of pure prionopathy

If you follow the latest in neurodegenerative disease research, you’ve heard the “prion hypothesis” or “pathogenic spread hypothesis.”  For the past five or six years, it’s been widely claimed, and almost as widely accepted, that the proteins that mis-fold and aggregate in the brain cells in PSP, as well as in its big brothers Alzheimer’s and Parkinson’s and the rest, spread through the brain in a way similar to how prion protein spreads through the brain in the prion diseases such as Creutzfeldt-Jakob disease, mad cow disease and kuru.  A respectable body of experimental evidence supports — or at least is compatible with —  this idea.

But now a pair of highly respected Harvard neuroscientists, Dominic Walsh and Dennis Selkoe, have said not so fast.  In a very well-balanced and dispassionate review of the prion hypothesis in Nature Reviews / Neuroscience, they show that while the existing evidence is compatible with cell-to-cell spread of toxic protein aggregates, there is still plenty of room for a hypothesis that posits selective cell vulnerability with a more generalized toxic influence.  I won’t get into the technical weeds, but here are their major points:

  1. Even in the classical prion disorders, it is well-accepted that “cell-autonomous” factors, rather than just spread from nearby cells, determines which cells are and are not involved.  The salient example is that the asparagine-for-aspartate mutation at position 178 in the prion protein causes familial CJD when the person has a valine at position 129 in the same protein but causes fatal familial insomnia with there’s a methionine at 129.  (Neither of the latter substitutions by itself is pathogenic.)
  2. The “pathogenic spread” hypothesis rests in no small part on the observations of Braak and colleagues that early-stage Alzheimer’s or Parkinson’s pathology in people dying from other causes is confined to certain specific brain areas, suggesting that the process starts there and spreads.   But Walsh and Selkoe point out that those early sites of pathology may merely be the areas most sensitive to a generalized insult.  Furthermore, only about half of the cases of each of those diseases followed that pattern.
  3. Another buttress for the pathogenic spread hypothesis is the observation that 5-10% of fetal substantia nigra cells transplanted into the striatum of patients with Parkinson’s developed Lewy bodies themselves after a number of years. But this need not be the result of spread of pathogenic alpha-synuclein; it could be the result of a more generic insult such as inflammation in the injection site, where most of the injected cells have died.  They cite evidence that activation of microglia (the brain’s inflammatory cells) in other types of neural grafts can produce Lewy bodies in those grafts.
  4. The experiments showing that injected alpha-synuclein or tau protein can induce the formation of aggregates in host brain is incomplete because they do not adequately demonstrate actual cell loss or impairment of brain function in the host animal. We know from other lines of experiment that aggregates alone do not correlate well with neurological impairment in human or experimental neurodegenerative disease.
  5. The pathologic anatomy of rare, dominantly inherited forms of Alzheimer’s, Parkinson’s and frontotemporal dementia fits well within the spectrum of their corresponding sporadic conditions. A genetic cause, producing the same intense pressure for protein aggregation in many areas of the brain simultaneously, would not be expected to mimic the anatomic pattern of a single-anatomic-source process posited by the pathogenic spread hypothesis.
  6. There are still many questions left unanswered by the pathogenic spread hypothesis. This doesn’t directly contradict its other tenets, but it weakens its explanatory power. It cannot explain the initial protein misfolding; how the aggregates are released; how they remain aggregated in the interstitial fluid where the concentration of the protein is far less; why they don’t stick to the outsides of cells after being excreted, as their physical chemical characteristics suggest they should; how they choose only certain target cells to penetrate; and how the aggregates escape into the cytoplasm from the membrane vesicles that presumably would be the vehicles by which they penetrate their targets.

 

As a final point, Walsh and Selkoe make a case for avoiding the term “prion-like” or “prion-oid” with reference to neurodegenerative diseases unrelated to the prion protein itself.  They list several known features of prion protein spread in the known prion diseases that as far as we know are absent in PSP, Alzheimer’s, Parkinson’s, etc.  They also cite the absence of any known transmissibility of the non-prion-protein and point out that we don’t know enough about either group of diseases to equate them at that level of terminology.

Excellent scientists that they are, Walsh and Selkoe describe a set of experiments to undertake and new research tools to develop in order to strengthen or reject the pathogenic spread hypothesis.  Maybe I’ll get to that in another post.  But they end with the hope that the pathogenic spread hypothesis is true, for that would provide many potential therapeutic targets that would not otherwise exist.

A new definition of PSP

When you design a research project in PSP, it’s important to make sure that everyone in the subject group with PSP in fact has PSP. Otherwise, you degrade the statistical power of the trial to detect any benefit of the treatment. The standard diagnostic criteria for PSP (called the “NINDS-SPSP Criteria” and spearheaded by Irene Litvan, MD, now of UCSD) were published in 1996 and have worked well for that purpose; Their positive predictive value (the fraction of patients satisfying the criteria who actually have PSP) and specificity (the fraction of those without PSP who fail to satisfy the criteria) are close to 100%.
But as we now enter the new era of trials of experimental neuroprotective treatment for PSP, we would like to diagnose the disease at an earlier stage, when such interventions are most likely to be effective, and the NINDS-SPSP Criteria don’t do that so well, with a sensitivity of about 80% overall, certainly lower in early cases. Another shortcoming is that the various phenotypes of PSP that have been described since 2005 won’t in many cases satisfy the criteria, which were designed for the “original flavor,” now called PSP-Richardson’s syndrome.
So time has marched on and we need a new set of criteria. Günter Höglinger, MD, Professor at the German Center for Neurodegenerative Disorders in Munich and probably the world’s leading clinical researcher in PSP, organized an international effort to revise the criteria. I’m privileged to serve on the four-person Steering Committee. A year ago we started to hash things out by email and conference calls, using the published articles on clinical features of PSP that use either autopsy or the NINDS-SPSP Criteria as a gold standard. The group, comprising 33 people from 11 countries, met in Munich on March 9 and 10 to turn our rough draft into a final version suitable for submission to a journal for peer review.
The new criteria recognize the various phenotypes of PSP. They are PSP-Richardson syndrome (about 55% of all PSP), PSP-parkinsonism (30%), PSP-frontal dementia (5%), PSP-ocular motor (1%), PSP- pure akinesia with gait freezing (1%), PSP-corticobasal syndrome (1%), PSP-progressive non-fluent aphasia (1%), and PSP-cerebellar (<1%). The remaining few percent are combinations of these or still-unrecognized forms.
The new criteria also delineate various “oligosymptomatic” or “prodromal” (the wording remains unsettled) forms, which may or may not develop into one of the diagnosable phenotypes. For example, there is now evidence that someone in the PSP age group with gradually progressive gait freezing for several years and a normal MRI, even without other abnormalities, will almost always prove to have PSP. The same is true for someone with bilateral rigidity and bradykinesia who fails to respond to levodopa and has some sort of nonspecific, undiagnosable visual symptoms or dizziness. Neither of these patients would satisfy the proposed new criteria for any of the PSP phenotypes, but they may still be worth identifying for inclusion in a longitudinal cohort study of people who are at risk of developing PSP. Our new criteria do that.
I’ll keep you updated.