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Less is more

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Have you ever heard of the PSP Quality of Life Scale (PSP-QoL)?  It’s widely accepted among researchers, but with 45 questions, each rated on a 0-4 scale plus one question rated on a 0-100 scale, the 30 minutes it takes to administer is just too long.  Still, the PSP-QoL is used in most clinical treatment trials, just not as the primary outcome measure.  Of its 45 items, 22 are motor (including eye movements) and 23 are cognitive and behavioral.  The total score correlates with the PSP Rating Scale (the usual primary outcome measure in clinical trials) to a high degree, with a correlation coefficient of 0.65, where 1.00 is perfect correlation and 0 indicates a random relationship.  That’s considered very good, because you don’t want the secondary measure to correlate perfectly with the primary – you want it to provide additional information.

Now, a group of German neurologists has figured out how to streamline the PSP-QoL down to 12 items:  7 motor and 5 cognitive/behavioral.  They call it the “PSP-ShoQoL.”

The correlation with the PSP Rating Scale is 0.51 (still a good figure) and the correlation with the original PSP-QoL is 0.93.  That means that the short version can be used in place of the original for most purposes.  The PSP-ShoQoL progresses over time just as the original does, which means that it can be used to help decide if a treatment slows the progression of PSP over a period such as a year.

Here are the items in the short version, each rated 0: no problem, 1: slight problem, 2: moderate problem, 3: marked problem, or 4: extreme problem.

MOTOR DIFFICULTY: Do you have difficulty . . .

Grooming, washing or dressing yourself?

Doing things around the house such as housework or do-it-yourself projects?

Using public transport?

Enjoying active leisure activities including gardening or walking?

Climbing stairs?

Using the toilet independently?

Walking?

COGNITIVE AND BEHAVIORAL DIFFICULTY: Have you . . .

Found your thinking is muddled?

Felt not motivated to do things?

Felt confused?

Felt anxious?

Felt your relationships with family members has changed?

I doubt that you will be designing a formal clinical trial any time soon, so why am I telling you about this scale?  So that in preparation for each visit with your neurologist, you can consider completing it on your own or with help (it’s designed for either).  Your neurologist could then get a nice, concise picture of the quality of your life and hopefully integrate that information into their recommendations.  It saves time for questions, emotional support and other critical things that are hard to fit into a 20- or 30-minute visit.

Sing, o muse!

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You’ll recall from my 7/4/24 post that Rep. Jennifer Wexton of Virginia announced last year that she has PSP.  Below is a new press release from her office.  My point relates to its final paragraph.

Wexton Marks Disability Pride Month on House Floor Using New AI Voice Model

Washington, July 25, 2024

Washington, DC — Today, Congresswoman Jennifer Wexton (D-VA) delivered a speech on the floor of the House of Representatives to recognize Disability Pride Month, celebrated each July. Wexton utilized her new AI voice model for the first time on the House floor to share how she has fought throughout her career for disability rights and accessibility issues, and how that has now become a personal fight for her since her Progressive Supranuclear Palsy (PSP) diagnosis last year.

“I hope that when people see me continuing to do all I can to keep living my life and doing this job I love as best I can, they understand and appreciate the courage, resilience, and spirit that so many Americans of differing abilities demonstrate each and every day. I hope I can be a voice — even an AI voice — for Americans facing accessibility challenges and other disabilities, because too often people only see us for that disability. And in truth we are so much more,” said Wexton.

The AI voice model was created through ElevenLabs, a software company that specializes in developing natural-sounding speech synthesis software using deep learning. The model was generated consensually using a collection of previous public speeches from Rep. Wexton provided by her team. Any additional questions about the ElevenLabs technology can be directed to press@elevenlabs.io.

More than the nominal topic of Disability Pride Month, the text mentions that she used an AI-based speech aid to deliver a speech on the floor of the House.  It used audio recordings of her public speeches before PSP’s dysarthria set in to train the AI software to translate a written text into speech in her own voice, not the electronic, synthetic voice we all recognize as “computer speech.”  This is important because the distinctive timbre of one’s speech provides an important emotional identifier. 

This technique, relying as it does on a prepared, written text, is not suitable for ordinary two-way conversations unless you can type extremely fast. Few people with PSP can do that, even with the help of word-completion software.  Besides, hardly anyone has a collection of old audio clips on which to “train” the AI software that Rep. Wexton used.  An audio bank deliberately created for this purpose in an early stage of illness is one potential solution.

I wanted to review the latest on this topic, mostly to help me advise CurePSP about what sort of programs or research it might support going forward.  So, I consulted my newest muse, ChatGPT.  Here’s what it had to say about voice banking and other solutions for severe dysarthria:

You can bank your own voice for future use in a speech generation app in case you become disabled. Voice banking involves recording a variety of phrases and sentences while your voice is still healthy. These recordings can later be used to create a synthetic version of your voice, allowing speech generation apps to produce speech that sounds like you.

Here are the general steps to bank your voice:

    Choose a Voice Banking Service: Select a service that offers voice banking. Some popular options include VocaliD, Acapela, and ModelTalker.

    Record Phrases: Follow the service’s instructions to record a set of phrases and sentences. The more you record, the better the quality of the synthesized voice.

    Submit Recordings: Upload your recordings to the voice banking service.

    Voice Synthesis: The service will process your recordings and create a synthetic version of your voice.

    Integration with Speech Generation App: Once your synthetic voice is ready, it can be integrated into a speech generation app. This allows you to communicate using your own voice even if you lose the ability to speak naturally.

Voice banking is a proactive step that can significantly improve the quality of life for individuals facing conditions that may affect their ability to speak.

Alternatives to voice banking?

If voice banking is not a suitable option for you, there are several alternatives that can help with communication if you become disabled. Here are a few options:

1. Voice Cloning

Voice cloning uses advanced AI to create a synthetic version of your voice with fewer recordings. Services like Respeecher and Descript can create high-quality voice models from a limited amount of audio data.

2. Text-to-Speech (TTS) with Customization

Text-to-speech technology can be customized with different voices, accents, and tones. Some TTS systems allow you to adjust parameters to make the voice sound closer to your own. Popular TTS engines include:

    Amazon Polly

    Google Text-to-Speech

    Microsoft Azure Speech Service

3. Pre-Recorded Messages

You can record common phrases and sentences that you might need. These recordings can be played back as needed. Devices like the GoTalk series or AAC (Augmentative and Alternative Communication) devices often support this feature.

4. Alternative and Augmentative Communication (AAC) Devices

AAC devices and apps provide various ways to communicate through symbols, text, and synthetic speech. Examples include:

    Tobii Dynavox

    Proloquo2Go

    TouchChat

5. Predictive Text Apps

Predictive text apps can assist in quicker communication by predicting the words and phrases you are likely to use. These apps learn from your typing habits to offer more accurate suggestions. Notable apps include:

    SwiftKey

    Gboard

6. Communication Boards and Books

Low-tech options such as communication boards or books with pictures, symbols, or letters can be very effective, especially in environments where technology might not be available.

7. Eye-Tracking Technology

For individuals with severe physical disabilities, eye-tracking technology allows communication through eye movements. Devices like the Tobii Eye Tracker can be used to control computers and AAC software.

8. Sign Language and Gestures

If you retain some physical ability, learning sign language or using a system of personalized gestures can be an effective way to communicate.

Each of these alternatives offers different advantages depending on your specific needs and circumstances. Exploring these options can help you find the most effective means of communication in the event of disability.

Now back to human me. 

It goes without saying that these solutions have to be tailored to the individual – no easy task considering that the disease itself worsens with time.  Another complication is that many of the techniques require manual dexterity or eye movement control beyond the abilities of many people with PSP.  (It also goes without saying that anything from ChatGPT can be incomplete or even wrong.)

Medicare pays most of the cost of some of these things if there’s a doctor’s prescription. Discuss with a speech pathologist, which you should be doing anyway for general PSP-related speech and swallowing issues.

If you consider me your PSP muse, whose mine? Now I know.

Quantifying love

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This audience does not have to be told that caring for a loved one with PSP can be a major burden.  Two CurePSP Centers of Care have now quantified this using the Zarit Caregiver Burden Scale completed from 2014 to 2022 by 139 caregivers of 131 persons with atypical Parkinsonian disorders.  The results are published in Clinical Parkinsonism & Related Disorders.  Here’s the scale:

Ninety (65%) of the caregivers were women.  Of the 131 patients they were caring for, 59% had PSP, 28% MSA and 13% CBS.  The patients were on average about 4.5 years into their illnesses.  (All three disorders have about the same average rate of progression and survival duration.)  Here are the salient statistically significant results, adjusted for potential confounders as necessary:

  • The average (i.e., mean) total score was 28.8 of a possible 88.
  • Of the four disorders, PSP, CBS and MSA-cerebellar gave similar average scores, but scores for MSA-Parkinson were milder by a margin of about 8 points.
  • Female patients regardless of diagnosis involved a greater caregiver burden than males, regardless of the caregiver gender.
  • Female caregivers reported greater burden than males regardless of the patient’s gender or diagnosis.

The authors list several weaknesses of the analysis and propose a prospective study to avoid these.  They include the absence of consideration of:

  • the relationship between patient and caregiver
  • age and any chronic illness of the caregivers
  • changes in the score over time
  • measures of the patient’s disability, especially falling frequency

The authors’ subjective opinion is that the patient’s cognitive and behavioral deficits are perhaps the most important determinant of the caregiver’s burden.  A future study should examine this hypothesis in a formal way.

Adding these variables to the analysis would require a larger number of patient/caregiver pairs.  This might be best accomplished in the context of a large treatment trial, where “secondary” and “exploratory” measures always accompany the “primary” measure of the drug’s efficacy.  Alternatively, all 36 CurePSP Centers of Care could undertake such a project outside of any treatment trial, assuming adequate funding is available.

The first author of the new paper is Jessica Shurer, a medical social worker who serves as CurePSP’s Director of Clinical Affairs and Advocacy.  The two senior authors are neurologists Alexander Pantelyat and Miriam Sklerov, directors of the Centers of Care at Johns Hopkins and the University of North Caroline at Chapel Hill, respectively, The three are credited with having conceptualized the study along with the second-named author, Margaret Ivancic, a medical social worker at UNC.

The Feds pitch in

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I’m happy to report that the National Plan to End Parkinson’s Act was signed into law by President Biden this week. It covers not only Parkinson’s disease itself, but also “all other neurodegenerative Parkinsonisms, including multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, and Parkinson’s-related dementia.”

The bill is named after two people: Dr. Emmanuel Bilirakis, who died with PD last year and was the brother of the act’s original sponsor, Rep. Gus Bilirakis, Republican of Florida; and Rep. Jennifer Wexton, Democrat of Virginia, who announced in September 2023 that she has PSP. Both representatives have been critical proponents of the act throughout the legislative process. Here’s the President signing the act on July 2, 2024, seated between Rep. Wexton and Rep. Bilirakis.

Here’s a copy of the act. It requires the Department of Health and Human Services to develop and periodically update a coordinated Federal plan to find the causes and cures of the Parkinsonisms and to make recommendation for future Federal support of those efforts. The act requires the DHHS to appoint an Advisory Council of at least 23 members from multiple stakeholders to meet at least quarterly. It also requires the DHHS to organize an annual research conference on its efforts in this area. Both conferences are to be open to the public. Although the act itself provides no funding — not even for the conferences it requires — the Advisory Council and DHHS are tasked with generating recommendations for future Federal funding.

I’m not sure that this is a step forward for PD, where there’s already excellent public awareness, plenty of research conferences, and robust, ongoing programs in the academic, lay-led non-profit, philanthropic, and pharmaceutical sectors. I don’t know that “coordination” by a Federal agency is going to improve on the current system, which is driven by the inherently powerful, albeit messy, force of our capitalist system and by the collective voices of the 1 million Americans with PD.

But for PSP and the other atypical Parkinsonisms, it’s a different story. With only about 5,000 to 10,000 diagnosed affected people in the US and no major celebrity as its champion, PSP could benefit greatly from the awareness this act could bring. That could help turn the attention of all of those existing PD-interested players toward the atypicals.

And another thing: For years — no, decades — I’ve felt frustration over how promising preliminary findings in PSP often can’t gain traction because of personalities, scientific “fashion,” funding issues or other immediate practicalities. A potentially longer-term view of the Advisory Council could help change that, but only if the group avoids the traditional pressures hampering progress for the atypical Parkinsonisms up to this point. The potential, however, is definitely there.

Walk this way

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Sorry for the seven-week hiatus since my last post, but I’ve been busy.  In that interval, I took a vacation (Finger Lakes and Niagara Falls); had a major fundraiser for a charity I lead (my high school’s alumni association, which funds educational improvements at the school); did the usual spring yard work (which gets harder each year for some reason); and most time-suckingly, I’ve been writing an invited review article on clinical trial design in PSP.

The authorial invitation came from the editor of a journal with the unwieldy name, Alzheimer’s & Dementia: Translational Research & Clinical Interventions.  I don’t know — maybe whoever proposed that refused to shorten it but agreed to replace the “ands” with ampersands. 

Anyway, one topic touched upon in my manuscript is the possibility of using wearable, wireless motion sensors in PSP drug trials.  If such a thing could be used at home, the resulting reduction in trial site visit frequency could make life easier for travel-challenged patients and their accompanying caregivers.  It could also provide more frequent assessments than are possible with in-person visits, avoiding some sampling error and the artifact of an unfamiliar environment in which to walk.

My latest information, based on hearsay and the published literature, is that the most convenient and otherwise suitable motion sensor system for those with PSP is called Mobility Lab from a company called APDM. It can serve the purposes of gait monitoring in a PSP trial using only three wireless sensors, one strapped to each ankle and one on the lumbar area using a belt.  I read through the 46-page user’s manual, which is written for research personnel familiar with electronic data gathering.  The technician has to manipulate four electronic devices besides the sensors themselves. While a tech-savvy layperson would be able to do it just fine at home, most people would not. 

So, the device isn’t ready for prime time use at home in PSP trials.  But it could be used at the trial site to record a nice raft of gait measurements of potential research value that can’t be derived from a traditional neuro exam.  Besides, the precision of some of the device’s measurements exceed that of the PSP Rating Scale, allowing smaller and/or shorter trials. Downsides: The system only assesses gait, just one aspect of PSP, albeit the most important one according to many of those affected. Plus, there’s no built-in way to assess falling or freezing frequency, though those might theoretically be derivable from the data with some additional software.

Awareness is key

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The state of Virginia has just enacted a law declaring each May “PSP Month of Awareness.” Former Virginia State Senator and current US Representative Jennifer Wexton announced her diagnosis of PSP in September 2023 and has been working to help spread much-needed public awareness of the disorder. She still has many friends in the state legislature who stepped up to the plate for her and the approximately 20,000 others in the US with PSP.

It may sound like a mere charitable if toothless gesture to honor a respected, ill colleague. But if more doctors, researchers and members of the public were aware of PSP, there would be more rapid diagnosis, faster clinical trial enrollment and more attention from researchers, philanthropists and drug companies. PSP has a slightly greater population prevalence than Lou Gehrig disease (or amyotrophic lateral sclerosis or ALS), which enjoys much greater awareness. Reasons for that are that ALS has been known to neurologists for a century longer (1869 vs 1964), it’s much easier to diagnose (a neuro exam and an EMG), has a more rapid course (averaging three years vs. an average of seven years for PSP), can sometimes affect much younger people than PSP ever affects, and maybe most important, is named after a beloved athlete who famously retired at age 36 and died two years later.

I don’t wish PSP on anyone, but if someone had to get it, I’m glad it was someone with Representative Wexton’s courage, foresight and influence.

Get on this list

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Today I officially ended a 10-year stint on the Scientific Advisory Board of the Frontotemporal Dementia Disorders Registry (FTDDR).  It maintains a list of people with the “FTD disorders,” loosely defined to include PSP and corticobasal degeneration as well as the standard forms of FTD.  The FTDDR is the only widely-available registry for PSP and collaborates closely with CurePSP.  It is supported financially by the Rainwater Charitable Foundation, which provides generous funding and infrastructure support for research on tau-based disorders, especially PSP. 

Registering with the FTDDR would allow you to contribute information on your condition to a powerful tool for researchers, philanthropists, government policymakers and patient support organizations.  It could serve to introduce you to drug companies and academic researchers seeking patients for treatment trials or observational (i.e., non-treatment) research.  Of course, you can choose which information about yourself to include and not to include, and you can opt out of consideration for treatment trials if you like. 

The registry is designed to safeguard your confidentiality. When the registry personnel supply data to outside organizations , the registrants’ identifying and contact information is stripped away first. If an outside organization wishes to contact contact you about a research project, the registry office would manage that for them. In that way, you could decline without revealing your identity to the outside organization.

I highly recommend that you register.  Just go to https://ftdregistry.org/ and follow the instructions.

Vindaloo + hockey = PSP?

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Did you know that Toronto is the most ethnically diverse city in the world?  Besides, it’s a pretty big place, with about 6 million people in its metropolitan area.  Besides that, Toronto is home to one of the top PSP research institutions in the world, the Rossy Centre at the University of Toronto, and Canada has universal, free medical insurance, which removes financial impediments to diagnosis and treatment.  That’s why Toronto is a great place to answer the question as to whether the prevalence of PSP is uniform across groups of different ethnic backgrounds.

Dr. Blas Couto and colleagues have done just that, reporting their results in the current issue of Parkinsonism and Related Disorders.  They tabulated ethnicity for 135 patients with PSP living in the officially designated Toronto area and seen at their center as patients from 2019 to 2023.  The group proved unusual in that only 4.4% had the PSP-Parkinsonism variant, compared with figures elsewhere of around 25% to 40%.  The group with PSP-Richardson syndrome comprised 68% rather than the usual 45% to 55% and the other variants gave the expected percentages.

The ethnicities they considered were actually geographical areas, not exactly race, whatever that is. (“Race” has no scientific definition, anyway.)  The categories were — and this is directly copied/pasted from the paper:

  • East and southeast Asia, including China and Pacific Islands such as Philippines
  • Southern Asia, including India, Pakistan and middle east countries
  • Africa
  • South America, Central America and Mexico
  • West Indies, including Guyana, Haiti, Bahamas, Lesser Antilles such as Barbados, Trinidad and Tobago, Dominica, Grenada, Saint Kitts, Antigua and Barbuda, Santa Lucia
  • Europe, Australia and North America, excluding Mexico.

The analysis compared the frequencies of these demographics to those from the census for people aged 65 and older living in the Toronto metro area. 

The result was that the southern Asia group was moderately over-represented among the patients with PSP.  That group accounted for 11.5% of the general population but 25.2% of the PSP population at the researchers’ center.  That was statistically significant at the <.001 level, meaning that the chance of its being a false-positive fluke are less than 1 in 1,000.

They also compared the six groups to one another with regard to the PSP subtypes, finding the same southern Asia group to include more PSP-progressive gait freezing (17.7%) and PSP-corticobasal syndrome (14.7%) than the European-derived patients (6.4% and 9.5%, respectively). 

Couto et al mention the possibility of some sort of genetic effect, but the literature offers no clues as to what that might be, and they cite three previous papers from the UK showing no difference in PSP prevalence between whites and southern Indians there.  Could something in the food or water in Toronto affect Asians disportionately?  The title of this post offers an unserious possibility, but you get the idea.

Chin-stroking on that aside, now is when the rest of us try to poke holes in the findings.  Here are my efforts:

  • Do the ethnic percentages in their PSP practice or in medical institution as a whole accurately reflect those of the Toronto area?  That would be easy to measure.  I ask because in the US in recent years, the medical profession has acquired a disproportionate representation of people of southern Asian background.  Could that group therefore trust academic physicians more and seek their care more readily than do other ethnic groups? 
  • The patient mix of a highly specialized practice like that at the Rossy PSP Centre is subject to the referral habits of outside neurologists.  Neurologists who feel less comfortable with the atypical Parkinsonisms may be more likely to refer patients.  Perhaps that applies to a few neurologists practicing in heavily southern Asian neighborhoods in the Toronto area.
  • Despite the universal availability of free medical care in Canada, racially-based disparities in health and care access do exist there.  Couto et all cite this article. 
  • This is a univariate comparison, meaning that it didn’t correct for a hypothetical effect of other health issues that might be more common in the southern Asian population.  Not that I know what those might be.
  • Although the analysis age-matched the PSP group with the general population by confining itself to the over-65 group, that may not have been enough. Perhaps working-age people immigrating from southern Asia brought elderly parents with them more often than did those immigrating from elsewhere, thereby skewing the over-65 group towards the 80s and 90s and increasing the measured prevalence of an age-related disease like PSP.

An intriguing finding.  Hopefully this paper will stimulate others to dig deeper. That would be a victory for any scientific paper.

Mistaken identity

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I have some homework for you all: Make sure that the diagnosis of PSP has been accurately coded in the doctor’s records. 

Two researchers in Scotland, Diane Swallow and Carl Counsell, published a paper this week reporting that every single patient carrying the code for PSP (G23.1) did in fact have PSP on evaluation of their detailed records.  However, only 52% of the patients whose records showed clear PSP had that code recorded in their records.  In 45% of individuals with PSP, an incorrect code of G12.2 was recorded.  That’s the code for a condition called “progressive bulbar palsy,” which is a form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) that affects the muscles of the face, mouth and throat disproportionately.  (The “bulb” is another term for the medulla, the part of the brain from which most of the nerves to those structures arise. It does look sort of like a light bulb or tulip bulb.) PGP is much more rare than PSP and does not include most of its features, but the reason for the confusion is obvious.

Why is this important? Because accurate statistics on PSP’s prevalence are used by for scientific researchers, medical care planners, government regulatory agencies, insurance companies, pharmaceutical companies, granting agencies, and philanthropists. 

So, next chance you have, ask the neurologist’s office clerk if the diagnosis of PSP rather than progressive bulbar palsy is listed in the medical record’s formal problem list and if the code assigned to it is in fact G23.1.  If it’s not, and if the clerk tells you that they don’t have the access necessary to fix it, make sure that they pass the information along to whoever does have that access, and then it’s your job follow up to make sure it’s been taken care of.

Under the hood

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In response to a reader’s request, here’s a brief description of the mechanism of action of Relyvrio, which is a combination of two drugs, sodium phenylbutyrate and taurursodiol.  The text in bold italics below is copied verbatim from the supplementary material attached to the publication reporting the results of the first ALS trial.  The same explanation applies to PSP and other neurodegenerative diseases. You may feel that any treatment that claims to address all of those complex diseases is claiming too much, and you could be right. But stranger things have happened. If you want more scientific detail, see the five references below. Note that Reference 5 discusses release of cytochrome C from mitochondria. That’s a cell signalling compound that causes cells to start up their “suicide machine,” more formally called the apoptotic pathway. Cells undergo apoptosis when they’re not working well or as a normal “pruning” procedure during growth and development. Taurursodiol prevents that from happening as easily.

Endoplasmic reticulum stress or dysfunction associated with protein misfolding and aggregation has been implicated in the pathogenesis of ALS,[1] as has disruption of mitochondrial function and structure.[2] Sodium phenylbutyrate is a histone deacetylase inhibitor that has been shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress.[3,4] Taurursodiol recovers mitochondrial bioenergetic deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the apoptotic threshold of the cell.[5]

1. Jaronen M, Goldsteins G, Koistinaho J. ER stress and unfolded protein response in amyotrophic lateral sclerosis—a controversial role of protein disulphide isomerase. Front Cell Neurosci 2014;8:402.

2. Mehta AR, Walters R, Waldron FM, et al. Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: A systematic review and meta-analysis. Brain Commun 2019;1:fcz009.

3. Kaur B, Bhat A, Chakraborty R, et al. Proteomic profile of 4-PBA treated human neuronal cells during ER stress. Mol Omics 2018;14:53-63.

4. Suaud L, Miller K, Panichelli AE, Randell RL, Marando CM, Rubenstein RC. 4-Phenylbutyrate stimulates Hsp70 expression through the Elp2 component of elongator and STAT-3 in cystic fibrosis epithelial cells. J Biol Chem 2011;286:45083-92.

5. Rodrigues CM, Solá S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax- induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry 2003;42:3070-80.