A catalogue of autoimmune mimics

A post from two weeks ago describes a PSP-like condition caused by antibodies against a normal protein called IgLON5. Like most autoimmune disorders, it responded to immune-modulatory treatment.  Now, six cases of an MSA-like picture with antibodies against a different protein called Homer-3 has just been published by a research group in China. (See below for a downloadable pdf.)

Those patients’ conditions looked something like MSA in featuring ataxia, slowed movement and autonomic loss, and most of them responded to steroids or other immune modulation to some degree.  That report prompted an editorial by Eoin Mulroy, Bettina Balint and Kailash Bhatia of University College London summarizing what we know about immune disorders mimicking PSP, MSA and CBD.  I subscribe to that journal, Movement Disorders Clinical Practice, but I can’t upload the editorial to this public space without paying a hefty fee to the publisher.  So I’ll summarize it for you.

Drs. Mulroy and colleagues list 13 kinds of antibodies found in blood and/or spinal fluid that can produce some of the diagnostic features of one or more atypical parkinsonian syndrome. Each of the 13 antibodies attacks one of these proteins: CASPR2, CRMP5, DPPX, GAD, glycine receptor, Homer-3, Hu, IgLON5, Kelch-like protein 11, LGI1, Ma2, Ri and Sez612. 

  • The disorders mimicked by these syndromes are PSP (12 of 13), MSA (11 of 13) or CBD (3 of 13).
    • The one not reported to cause PSP symptoms is anti-Homer-3.
    • The two not reported to cause MSA symptoms are anti-DPPX and anti-MA2.
    • The three that have been reported to cause CBD symptoms are anti-GAD, anti-glycine receptor, and anti-IgLON5.
  • Only 4 of the 13 always start before age 60. 
  • Nine of 13 show evidence of inflammation on MRI in the form of high T2 signal in various spots.  
  • Routine tests on the spinal fluid (i.e., cell count, total protein, glucose) are normal in about half of cases.
  • A malignant tumor is commonly present in an organ outside the brain in 5 of the 13 and are “uncommon” in another 6.  Detection and removal of that tumor sometimes helps the neurological issue.
  • The good news is that in only 1 of the 13 is the response to immunomodulatory treatment described as “poor.”  It’s “good” in 2 and “partial” or “variable” in the other 10.

An important piece of advice is that the symptoms of these disorders develop from nothing to a state of some disability over weeks to months.  That’s called a “subacute” course. So there’s no point in doing these tests when the symptoms have developed over a period of years, a chronic course. 

None of the lab testing companies offers all of the antibody tests listed, and not everyone’s insurance covers tests from every company.  So the doctor (or patient/family/caregiver) will have to do some homework to figure out which tests are applicable to the specific symptoms, which companies offer the required tests and which testing companies work with that person’s insurance.   

Let’s bottle this

Far too often, physical therapy for the gait problem of PSP uses the techniques designed for Parkinson’s disease – targeting strength, flexibility, endurance and balance.  But much of PSP’s gait problem arises from the loss of monitoring by the visual sense.  The eyes can’t move well enough to maintain awareness of the spatial environment and to communicate that to the movement circuits in the brain.

Cris Zampieri, PT, PhD is a physical therapist at the NIH with an ongoing, published interest in PSP.  Since 2006, she has been a pioneer in devising special gait re-training for people with PSP by adding eye movement tasks to standard PT measures for Parkinson’s disease, in this case boxing, stepping and treadmill use.  

The patient reported now was a 63-year-old courtroom lawyer with a symptom duration of 11 years but a PSP Rating Score of only 24, where 0 is normal and 100 is the worst.  Such a mild score is typical of someone with PSP of only 2 or 3 years’ duration and to me suggests the subtype called PSP-parkinsonism.  The patient still enjoyed hikes in the woods and his specific goal for the therapy was to improve his ability to walk over rocks.  The regimen of one hour twice a week for a total of 15 hours produced satisfying improvements in formal measurements of gait and balance as well as in his subjectively reported ability to hike safely. A small but useful fraction of the benefit was still present at 6 months.

The novelty of this case report was that the patient was relatively high-functioning, allowing him to comply with more complicated instructions, and also that his treatment goals were different from those of the typical patient with PSP, who is merely seeking greater independence at home.  For me, the publication served as a reminder that there are specific PT measures for PSP that most physical therapists don’t know about.

Working with Dr. Zampieri on the current project were her NIH colleagues Earllaine Croarkin, Krystle Robinson and Christopher Stanley.  I emailed the lead author, Ms. Croarkin, to ask if this PT regimen could be applied at most PT practices.  Here’s her reply:

“The assessments and interventions we used for physical therapy in this case report can absolutely be repeated in typical physical therapy clinics . . . Our intent was to publish information in a manner that therapists could use to replicate the activities. For example, physical therapy interventions for gaze shifting, postural stability and step response employed low-cost equipment readily found in clinics, i.e.,  punching bag, laser light, stool, and treadmill.”

Citations of Dr. Zampieri’s earlier work on PT with accompanying eye movement retraining appear in my 2019 book on PSP management and in the 2021 Best Practices consensus document published by the CurePSP Centers of Care.  Now we need patients and caregivers to ask about it, neurologists to prescribe it, and physical therapists to know how to administer it.

John Q. Trojanowski (1946-2022)

John Trojanowski Other Specialty. Philadelphia PA

The world of neurodegeneration research was saddened this week by the death of John Q. Trojanowski, MD PhD, on February 8, 2022 at age 75.  He was a neuropathologist at the University of Pennsylvania. 

John’s work focused on protein aggregates and mechanisms of neurodegenerative disease spread.  Together with his life partner and research collaborator Dr. Virginia M-Y Lee, he played a central role in discovering the roles of tau protein in Alzheimer’s disease, of TDP-43 in frontotemporal dementia, and of alpha-synuclein in Parkinson’s disease and Lewy body dementia.  A major discovery John spearheaded was to extract abnormal tau protein from the autopsied brains of people with PSP and CBD and inject it into the brains of normal mice.  The animals developed PSP-like or CBD-like abnormalities, respectively, showing that the tau molecule is not a by-product of the degenerative process, but its specific cause.  He also showed that the tau from the human donor’s glial cells affects only the glial cells of the mouse, concluding that glial-acting tau differs from neuronal-acting tau.  That observation could have major implications for a treatment or prevention of PSP and CBD. 

My own research collaboration with John occurred back in the late 1990s.  I was the clinical leader of a group that in 1990 discovered the first family proven to have hereditary Parkinson’s disease. In 1997, my group collaborating with geneticists at the NIH showed that the disease in that family was caused by a mutation in alpha-synuclein, a gene not previously suspected of an association with PD.  But that didn’t mean that alpha-synuclein had any significance for PD in general.  Immediately after John saw our paper in Science, he got to work, finding that the Lewy bodies of ordinary PD were chock full of alpha-synuclein.  Although I was not a laboratory researcher, he then involved me in his research. That team showed that the brains from affected members of the family with the alpha-synuclein mutation had not only Lewy bodies, but also tau aggregates in the form of thread-like neurites.  Another paper of “ours” showed that alpha-synuclein and tau each promotes the aggregation of the other, implying that interrupting one process might interrupt the other. 

I wasn’t the only one whom John generously included in his projects.  He worked with top tau research groups world-wide and was welcomed as a collaborator not only for his scientific productivity, but also for his collegiality and his ability to explain difficult scientific concepts. His sense of humor and sense of style were icing on the cake.

All those fighting neurodegenerative diseases have lost a fine friend.

Appetizer, entrée and dessert

. . . and today, three news morsels:

First, sleep: Researchers at UCSF led by Jun Yeop Oh sought correlations between loss of specific areas of brain cells in the autopsies of 12 people with Alzheimer’s and 10 with PSP who during life had had detailed sleep studies.  They found relationships between several specific abnormalities of sleep with loss of neurons in two clusters of cells in the hypothalamus that use orexin and histamine, respectively, as their neurotransmitters.  A third area known to be related to sleep, the (dopamine-using) locus ceruleus in the midbrain, showed little or no such correlation.  The authors conclude that this line of inquiry “is crucial in designing the next generation of sleep medications [by boosting orexin or histamine] and even slowing down the progress of neurodegenerative disease through early interventions.”

Next, tau: A report from Michela Marcatti and colleagues at University of Texas Medical Branch in Galveston describes important differences between Alzheimer’s and PSP in the way their abnormal tau acts on the brain’s synapses.  They specifically looked at soluble oligomers – clumps of only a few tau molecules that remain soluble in the brain’s fluids, making them far more toxic than the larger, insoluble neurofibrillary tangles.  They found that in AD, tau oligomers displace beta-amyloid oligomers from the synapses after the initial disease stages, which may explain why treatments aimed at beta-amyloid have failed to date.  This bolsters our hopes AD and PSP could share a common treatment. The authors also suggest that the various tau oligomers’ different patterns of attack on the synapses might explain the different subtypes of PSP. 

Finally, a new drug: The oral drug AZP2006 is presently in a clinical trial for PSP in Europe. It acts by enhancing the effect of progranulin, a protein involved in multiple cell processes with potential relationships to neurodegeneration.  Researchers at Alzprotect, the French drug company sponsoring the trial, published the effects of AZP2006 in cultures of rat brain cells (neurons and microglia together) and in mice that had been genetically engineered to age quickly. It reduced abnormal tau phosphorylation and inflammation in the cultures and slowed the rate of cognitive decline in the mice.  It actually restored some of the animals’ lost cognitive abilities (!!), but we don’t know how long that benefit would last or if it resulted from rescue of sick cells or from some more ordinary drug action.

Rats join the fight

The best animal model we’ve had for PSP over the last 20 years has been a mouse genetically engineered to carry a mutated human tau gene.  The mutation is typically one of two single-nucleotide substitutions, each found in a form of hereditary frontotemporal dementia.  Such a model has been convenient and productive.  But it would be preferable for a PSP model that a) is in a species with a brain whose circuitry is a bit closer our own, and b) to more closely mimic the pathology of human PSP.  A vivid illustration of the inadequacy of the tau mouse has been the recent failure of two anti-tau antibodies to help human PSP after clear success in slowing progression of pathology in the tau mouse.  Dogs, cats or monkeys present practical and ethical difficulties.  Rats have been a candidate but attempts to create a tau rat have failed.  Until now.

A team at the State University of New York at Buffalo led by Dr. Stewart D. Clark has just created a rat with something resembling PSP.  The lead author was Dr. Gabriella King.  The title of the article, in the European Journal of Neuroscience, says it all: Human wildtype tau expression in cholinergic pedunculopontine tegmental neurons is sufficient to produce PSP-like behavioural deficits and neuropathology

The researchers took advantage of the fact that PSP involves a complex cluster of cell bodies in the brainstem called the pedunculopontine tegmentum (PPT; often called in the literature the pedunculopontine nucleus, or PPN).  The PPT uses acetylcholine as its neurotransmitter and provides input to many other brain areas involved in PSP.  A loss of acetylcholine-based connections is a major part of the pathology of PSP.  Damage to the PPT alone causes severe gait and balance problems, and loss of its acetylcholine input to other areas causes many other symptoms.  Attempts are ongoing to develop deep-brain stimulation to the PPT as treatment for the balance problems of PSP and Parkinson’s.

The researchers started with rats that were genetically engineered to readily incorporate any introduced gene into neurons that make acetylcholine.  Then, they put the gene for normal human tau into a kind of virus that readily and safely enters brain cells – called an adeno-associated virus.  It’s a commonly-used laboratory tool.  They injected those viruses into five spots in each PPT and three in a part of each thalamus that projects to the PPT, for a total of 16 injections into each rat’s brain.

A month later, the result was gait and balance difficulties and a loss of reactivity to loud noises (which occurs to a degree in human PSP).  Autopsy showed fewer acetylcholine-making neurons in the PPT, fewer dopamine-making neurons in the substantia nigra (presumably because of a loss of input from the PPT), and abnormal aggregates of tau protein in the brainstem resembling neurofibrillary tangles.  None of these abnormalities occurred in control rats receiving injections of adeno-associated virus carrying the gene for a harmless protein into the same 16 spots.

Clearly, this model is not as convenient as the tau mouse, which can be bred in colonies without a need for 16 carefully placed brain injections.  Another problem is that rats are more expensive to purchase and maintain than mice, mostly just because they’re larger.  But for smaller-scale projects, this is a major advance.  Let’s watch for commercialization of the model and for its utilization by other labs.

PSP doc tells all

The medical world must sell optimism because its researchers are competing with those in many other areas for limited grant money; its nonprofit organizations, including research universities, rely on donations that also pay their staffs’ salaries; and its physicians must maintain their patients’ hopes for a cure to prevent their sinking into despair and compounding their disabilities.

Today, a close colleagues asked me if I think there will really be a cure for PSP any time soon.  I knew that if I said no, she would have kept it to herself and not denounced me for disloyalty to the philosophy of optimism that rules the medical culture in which I live.  So, unafraid to say no . . . I said yes. 

I think that in the next few years, our ever-increasing knowledge of the far-upstream events in the process that kills brain cells in PSP will have yielded plenty of addressable drug targets.  Drug development is more fruitful than ever and will probably come up with something for at least one of those targets.  Some of those may be existing drugs for other conditions, allowing us to avoid most of the time-consuming safety testing required of new drugs.  New measures of drug efficacy in PSP will shorten the time required for drug trials.

The quest for early diagnostic markers will probably yield something along the lines of an easy blood test with which to screen people in their 50’s and 60’s and more difficult and expensive, but specific, imaging tests to evaluate those with a positive blood test.  This means that the treatment could be prescribed very early in the course of the disease, when it’s most likely to work.

I caution that this isn’t the same as discovering the cause of the disease and avoiding it, as we can do for many conditions of infectious, toxic or traumatic cause.  What I see for PSP is more like what we do for many cancers these days – detecting it early, killing or removing it before it spreads, and keeping an eye out for recurrence.  Another example of the same idea is diabetes, where without knowing or fixing the underlying cause of the disease, we can prescribe medication and lifestyle modifications that allow a normal lifespan rather than the few years’ survival common a century ago.

Keep in mind that this type of “cure” would not repair damage that has already occurred.  Once the disease process has destroyed a lot of brain cells, it may be impossible to replace them good as new.  There certainly are ongoing efforts to do that – it’s called regenerative neurology.  But the complexity, number and physical length of the brain cells’ connections disrupted in PSP are daunting.  Once they’re lost, things like growth factors or stem cells probably won’t bring them back without breakthroughs in basic scientific knowledge that I don’t see coming soon.  If I’m right, the best that a person with established PSP could hope for in the next few years would be a way to halt the ongoing progression.  But that alone would be a triumph.

So, yes, even among trusted friends, I’m an optimist about curing PSP in the near term.

A treatable PSP mimic

Yesterday’s post updated my diagram showing relationships between PSP/CBD and the other major neurodegenerative diseases.  The only substantive change was the addition of a tauopathy called “anti-IgLON5 syndrome,” which we’ll call “AIS.”  It’s not “major” in the sense of “common,” but in the sense of “important to know about because it’s treatable, especially if diagnosed early.” 

AIS sits on the border between the autoimmune and the neurodegenerative diseases.  (In fact, multiple sclerosis does that, too, but unlike most neurodegenerative diseases, it has no known protein aggregates in the affected brain cells.)  In AIS, the blood and/or spinal fluid have antibodies directed against one type of the “cell adhesion molecules” on the surface of brain cells.  Those molecules assist in the function of the microtubules, which are the cell’s internal skeleton and transport system, and also where tau normally works.  The problem is that we don’t yet know for sure whether the antibody attack causes the cell damage or if the antibodies are merely the immune system’s reaction to damage caused by something else.

The classic symptoms of AIS are major difficulties in the control of sleep and involuntary movements called “chorea.”   But more recently, four different types of AIT have been described, and one of them mimics PSP, with severe loss of balance and milder cognitive loss and predominantly vertical eye movement problems.  As in ordinary PSP, sleep problems are present as well, but with more dream enactment and obstructed breathing than occur in PSP. 

About a quarter of those with AIT have the PSP type.  The other three types emphasize problems with sleep (the most common); speech and swallowing; and cognitive problems, respectively.  All four types also display autonomic disturbances in a majority of patients, including episodes of sweating, incontinence, and slow or fast heartrate.  Oddly, only a few have low blood pressure. Otherwise, the autonomic features are similar to those of MSA, and of course the motor features of MSA, like those of PSP, can be similar to those of AIS, but without the chorea.

An important difference between AIT and PSP, CBD or MSA is that AIT has no muscle rigidity, movement slowness or tremor. Those three things are collectively called “parkinsonism.”

AIS’s average onset age of 64 plants it firmly in the range of most neurodegenerative diseases, rather than in the younger range typical of autoimmune diseases.  Furthermore, the female predominance of most autoimmune diseases does not exist for AIS.  Also, only one case in the literature has been reported to spontaneously improve, and the course is slowly progressive rather than fluctuating.  These points favor a neurodegenerative origin.

On the other hand, all patients with AIS have a specific genetic variant in one member of a set of genes on chromosome 6 associated with autoimmune disease.  It’s called the human leukocyte antigen, or HLA system.  And here’s the most important point favoring an autoimmune origin: treatment with standard immune modulating drugs such as steroids, intravenous immunoglobulin and azathioprine, helps about two-thirds of the patients.  

It’s interesting that the classic form of AIT, where sleep disturbances predominate, is much less responsive to immune modulatory drugs than the more recently-described variants.  So maybe the different types sit slightly on one side or the other of the autoimmune/neurodegenerative fence.

Here’s a colorful (but blurred – sorry) diagram showing features in 22 patients with AIS.  It’s from the research team in Barcelona that and first described AIS in in 2014 and is probably the world’s leader in neuro-autoimmune disorders.

The four subtypes appear in the second column (where “bulbar” means speech and swallowing), the intensity of each of seven features is represented by the shade of color in the boxes, and the immunological and genetic findings are on the right. From: Gaig C, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017 May 2; 88(18): 1736–1743. PMID: 28381508

This diagram doesn’t mention that some patients with AIS exhibit hyperexcitability in the form of muscle cramps, muscle jerks and easy startle. 

I must emphasize that while AIS is a tauopathy, it’s not PSP or CBD.  It affects different parts of the brain, has both 3R and 4R tau (PSP and CBD have only 4R), it has a longer survival untreated, and it has anti-IgLON5 antibodies.

So here’s the take-home: 

  1. People in the early stages of an illness suspected of being PSP, CBD or MSA should make sure their doctor knows about AIS so that testing for the antibody can be considered.  If it’s positive, immunomodulating treatment may make a big difference, especially if two or more such drugs are used together, and if treatment is started in the first two years of the illness.  Often, rheumatologists know more about the treatment of autoimmune disorders than neurologists, especially movement disorder specialists.
  2. Even if there’s no response to immunomodulatory treatment, finding anti-IgLON5 antibodies should prompt a search for small but growing cancer. While none of the publications on AIS has examined this issue thoroughly, other autoimmune disorders in the nervous system are very often associated with cancer.  Most of the published case series either didn’t work up the patients for cancer or lost follow-up before a small cancer would have revealed itself.  Detection and removal of a small, early cancer could help the AIS, and even more important, save a life.

Infographics march on

Here’s an update of my diagram showing the relationships of PSP and CBD to other major neurodegenerative diseases. I’ve added anti-IgLON5 tauopathy-PSP type and created an “Autoimmune” category just for it. This required a little rearranging of other things, and I’ve cleaned up some redundant blue lines, too.

Attention, t-shirt designers: Licensing deals are available.

I’ll have more to say about anti-IgLON5 tauopathy soon.

A new drug out of the gates

My post on December 19 mentioned that an early-phase trial of a drug called TPN-101 in PSP was about to start recruiting participants at two sites – one in Florida and one in Michigan.  I just learned that recruitment has begun and there are now five sites.  They’re in Boca Raton, Florida; Gainesville, Florida; Farmington Hills, Michigan; Las Vegas, Nevada; and Englewood, Colorado.  Contact information is available here.

The drug, whose new generic name is “censavudine,” is an inhibitor of the enzyme reverse transcriptase.  As you’d guess, it was originally developed for the treatment of AIDS.  The mechanism of action against PSP is via reducing levels of hyperphosphorylated tau.  It’s administered as an oral tablet.  This trial is designed to test safety.  With only 40 participants and less than six months of placebo-controlled treatment (followed by the same period of open-label observation), it isn’t large/long enough to assess benefit unless the magnitude of that benefit is improbably huge.

Figure that it will take six months to fully recruit, which means that the last patient will finish in mid-2023.  So I’d expect results in late 2023.  Let’s hope that this is safe and well-tolerated and that a Phase 2b or Phase 3 trial of hundreds of patients at dozens of sites will start soon thereafter.

A sneak preview

The Tau2022 Global Conference is coming up soon — on February 22 and 23!  It was all set for a hybrid format, with most of the speakers having committed to attend in person.  I’m on the meeting’s leadership committee representing CurePSP, one of the organizers along with the Alzheimer’s Association and The Rainwater Charitable Foundation.  Last week we decided to go entirely virtual.  It wasn’t a slam dunk, as we all ache to return to in-person, informal interactions with colleagues from around the world.  

Here’s a rundown of a few of the original presentations.  I’m keeping these blurbs very brief and vague so as not to steal anyone’s thunder:

  • A new organoid model grown from skin cells of a patient with PSP mimics PSP brain tissue closely.
  • New incrimination of disordered iron metabolism in the pathogenesis of PSP.
  • New evidence that hyperphosphorylated tau induces the misfolding and aggregation of normal tau.
  • A PET ligand for tauopathies has new evidence for utility in PSP and CBD.
  • A new technique, single-nucleus RNA sequencing, has identified two new glial cell types involved in PSP, offering possible new drug targets.
  • An FDA-approved AIDS drug reduces tau pathology in a PSP mouse model in a newly-discovered way and will soon enter clinical trials.

I’ll report back after the conference.