The sincerest form of flattery

A reader just commented, “What other diseases can mimic PSP?” Below is a pretty exhaustive list of things that can cause vertical gaze palsy*, the most specific** diagnostic hallmark of PSP. Most of these disorders don’t mimic the whole classic PSP syndrome, but even PSP doesn’t do that in many cases. Keep in mind that most of these mimics have other features besides the gaze palsy that make them very unlikely to actually be confused with PSP in practice.

The disorders with specific treatment (though maybe not cures) have three asterisks ***.

*”Palsy” in general means weakness (not tremor, as popularly thought). In the setting of PSP, palsy refers to a limitation of the range of voluntary eye movements.

**The “specificity” of a diagnostic sign is technically the fraction of the people without the disease who don’t have the sign. In other words, specificity = [true negatives] divided by [true negatives + false positives].

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DISORDERS WITH VERTICAL GAZE PALSY IN AT LEAST SOME CASES

Degenerative

  • Amyotrophic lateral sclerosis
  • Corticobasal degeneration
  • Dementia with Lewy bodies
  • Frontotemporal dementia with tau staining
  • Frontotemporal dementia with ubiquitin staining
  • Globular glial tauopathy
  • Lytico-bodig
  • Motor neuron disease with congophilic angiopathy
  • Multiple-system atrophy
  • Pallidal degeneration
  • Parkinson disease (only upgaze affected)***
  • PSP

Structural           

  • Normal-pressure hydrocephalus***
  • Pineal region masses***
  • Third ventricular enlargement***

Metabolic / Genetic          

  • B-12 deficiency***
  • Huntington disease
  • Neuronal intranuclear inclusion disease
  • Niemann-Pick disease type C***
  • Spinocerebellar ataxia type 8
  • Tay-Sachs disease, adult-onset (hypometric vertical saccades)
  • Wernicke encephalopathy***
  • Wilson disease***

Immune              

  • Anti-phospholipid syndrome***
  • Anti-IgLON4 disease***
  • Paraneoplastic syndromes***
  • Postencephalitic parkinsonism***

Vascular              

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  • Lacunar states (“vascular PSP”)***
  • Post-aortic surgery

Infectious          

  • Whipple disease***
  • Neurosyphilis***

Toxic    

  • Guadeloupean tauopathy

Prion

  • Creutzfeldt-Jakob disease

Re-programming

This morning I received an email from a CurePSP support group leader in Texas forwarding a local newspaper clipping about a young girl in Taiwan with a genetic metabolic defect of the brain who had received a form of gene therapy.  She asked if that approach could be of potential use against PSP.

Here’s my answer:

For decades, a routine neuroscience laboratory tool has been to inject the brain with a harmless virus, called a “vector,” carrying a gene to induce brain cells to manufacture that gene’s protein product.  This has been useful in PSP research. Before long, the same idea could become a treatment for patients with neurodegenerative diseases.  The main drawback is that it requires a neurosurgical procedure to inject the virus with the therapeutic gene into the specific spot(s) in the brain where it’s needed. 

This approach has worked in early-phase trials in people with Parkinson’s disease, where cells that make dopamine are degenerating, and is continuing safety studies in PD.  The gene in those trials encodes the enzyme AADC (aromatic amino acid decarboxylase), which controls dopamine’s rate of production.  AADC mutations do not occur in PD, but the girl in Taiwan who received the gene therapy was suffering from an inherited deficiency of AADC, causing delayed neurological development. 

This sort of gene therapy, but using MAPT, the gene for the tau protein, has been used in PSP research to produce a rat model for use in testing new treatments.  The company sponsoring the AADC deficiency trial in Taiwan is developing an MAPT gene therapy for the rare form of frontotemporal dementia caused by mutations in MAPT, called FTDP-17.  Unfortunately, PSP, unlike AADC deficiency or FTDP-17, is not caused by a single mutation in a known gene, so it would not be amenable to having that gene replaced by this sort of gene therapy.  It’s true that PSP, like PD, includes a dopamine deficiency, but PSP would not respond to AADC gene therapy for the same reason it doesn’t respond to L-DOPA (which is converted by the body into dopamine): the brain cells on which dopamine acts degenerate in PSP. 

The hopeful note, however, is that if a compound such as a growth factor protein or an anti-sense oligonucleotide (ASO) is found to help PSP, a gene for that compound could, in theory, be inserted into a viral vector and injected into the brain.  That could provide a steady, lifetime supply of the compound.

Larry

Hope

Today is Martin Luther King Day, and here’s one of his best quotes, from 1968:

“We must accept finite disappointment, but never lose infinite hope.”

Fast-forward to the 1980s, early in my career as a neurologist mostly for patients with incurable movement disorders.  I rapidly learned that besides objective diagnosis and treatment, my agenda at patient visits should include an old-fashioned pep talk along with an update on research.  Now, I had grown up in a culture where such “touchy-feely,” subjective things were far subservient to scientific thinking, and my medical education was no different.  So, once I was out in the real world of patient care, it was kind of a revelation to discover that a simple, subjective appeal to hope could sometimes alleviate more suffering than any medication, therapy or surgery I could prescribe.

Fast-forward again to 2004, at which point I had been CurePSP’s Clinical and Scientific Director for 14 years, and a new CEO named Richard Zyne arrived.  He was an ordained minister who spent his career mostly with non-sectarian, non-profit organizations.  As a clergyman, he well knew the value of hope in helping people deal with adversity, and he quickly made “Because Hope Matters” CurePSP’s tagline.

I’ll admit I was skeptical at first.  I thought that providing hope was the doctor’s job at an individualized, “retail” level in the exam room and that CurePSP should support research, educate patients and clinicians, and help find ways to bring the best available care to all who need it.  But working with CurePSP showed me the value of a national organization with multiple communication platforms in reassuring patients and families that scientific understanding of PSP is advancing, that similar diseases are slowly yielding to new treatment, that more researchers and journal articles are devoted to PSP than ever, and that a well-run non-profit organization is in their corner. In other words, I again discovered that hope matters, but now at a more “wholesale” level.

The idea for this blog post entered my mind from the proximity of MLK Day and my post from four days ago, where I reported the failure of one PSP drug candidate but offered hope for five others currently in clinical trials.  In fact, regular readers of this blog know that I try to infuse hope into every post rather than merely reporting the news objectively.  For the ability to understand the value in that, I thank my patients, Richard Zyne – and Dr. King.

We just have to keep trying

I have some bad news.  Another experimental drug has failed to slow the progression of PSP.  The double-blind Phase 2 trial of RT-001 in 40 participants took place in Munich, Germany.  The company, BioJiva, has given me permission to discuss this ahead of their press release.

RT-001 has a unique mechanism of action.  It’s based on the ample evidence that a major part of the problem in PSP is an attack on brain cells’ membranes by “reactive oxygen species.”  ROS, a product of dysfunction of the mitochondria, damage the fatty acids, a major component of cell membranes.  The drug is one of those fatty acids, linoleic acid, but with a twist.  Two of the hydrogen atoms in the molecule are replaced by deuterium, which is hydrogen with an extra neutron in its nucleus.  (Water made with deuterium instead of hydrogen is called “heavy water.”)  The drug is incorporated into the membranes as if it were ordinary linoleic acid, but the two deuteriums protect it against attack by the ROS. 

Sound crazy, you say?  Naïve, maybe? Well, it may actually work in another disease with too much ROS activity, amyotrophic lateral sclerosis!  BioJiva announced last year that an early-phase trial in ALS gave favorable, albeit undramatic results, with a 23% slower rate of decline relative to the placebo group.  So, the company will continue to pursue work with RT-001 in ALS, but not in PSP.

But take heart, PSP community.  There are still five PSP neuroprotection trials in progress using fasudil, TPN-101, NIO-752, sodium selenate, and AZP2006.  Then, of course, there are multiple trials of “symptomatic” treatment.  See my recent post for details.

Which of those five PSP neuroprotection candidates is most likely to work?  I wish I (or anyone) knew enough about the molecular and cellular abnormalities underlying PSP to answer that question.

Disclaimer:  I don’t own any stock in BioJiva or have any other financial relationship with them.  Their Chief Medical Officer gave a presentation on the then-ongoing trial at CurePSP’s “Neuro2022” symposium in New York in October, where I was one of the organizers and moderators.