Monthly Archives: February 2022

Handwriting analysis?

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I spent most of last week attending two virtual conferences.  One was the semiannual investigators’ meeting of the Tau Consortium.  That’s a group of a few dozen researchers funded by the Rainwater Charitable Foundation.  Attendance is limited to funded researchers, their trainees, and invited guests from organizations that work with the RCF.  I got in as a representative of CurePSP.  They keep attendance private so that speakers will feel free to share their work long before publication without fear of plagiarism. The other was Tau 2022, a biannual conference sponsored by the Alzheimer’s Association, the Rainwater Charitable Foundation and CurePSP, with help from a few drug companies.  Registration was open to the public and I was on its Steering Committee, again representing CurePSP.  Both conferences were stuffed with cutting-edge work by some of the world’s top researchers.  I’m working on summarizing for you, dear reader, some of the things that I’m allowed to share, and that will take a few more days.

Meanwhile, I saw a cool paper in a journal called Sensors.  Paula Stępień, a biomedical engineer at Silesian University and colleagues from multiple other institutions in Poland created an app that analyzes a commonly used, pen-and-paper neuropsychological test called the Luria Alternating Series Test.  The examiner draws a series of connected triangles (actually inverted V’s) and squares (without the bottom side) an inch or two at the left of a sheet of paper.  The patient then has to continue the series the rest of the way.  Here are examples for someone with PSP (top), PD (middle) and a healthy control.  The examiner’s model is the first five figures on the left of each line:

stepien-luria-alternating-series-testDownload

The algorithm looks at 35 possible error features and can label subjects as having PSP, PD or neither with 70.5% accuracy.  While that’s not as good as MRI or a formal, in-person history and exam by a neurologist, it does have the advantage of being a lot easier and cheaper and can be performed remotely.  Perhaps coupling it with some other tests similarly compatible with telemedicine could raise that accuracy figure.  That could allow treatment trials to screen people with suspected PSP before bringing them in for the standard hours-long, in-person initial evaluation visit.

The article doesn’t mention how long the patients had PSP or PD or the severity of their outward signs, so perhaps the same diagnostic information could have been obtained by casual observation by video call.  But like any diagnostic test, you first have to make sure it works in people with an existing diagnosis before you test it in those with early-stage or diagnostically equivocal symptoms.

A distinction with a difference

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Apathy and depression are among the most disabling non-motor features of PSP, and they’re not the same thing.  To quote the opening lines of an excellent 1998 paper from Morgan L. Levy and colleagues from UCLA, University of Iowa and the NIH,

“Apathy is defined as diminished motivation not attributable to decreased level of consciousness, cognitive impairment, or emotional distress.  Depression involves considerable emotional distress, evidenced by tearfulness, sadness, anxiety, agitation, insomnia, anorexia, feelings of worthlessness and hopelessness, and recurrent thoughts of death.”

That article, entitled, “Apathy Is Not Depression,” focused on Alzheimer’s, frontotemporal dementia, Parkinson’s, Huntington’s and PSP. It pointed out that while apathy is traditionally considered to be one of the many possible features of depression, it can also be analyzed separately.  So that’s what they did.  

They found that among their 22 patients with PSP, 77% had apathy without depression, 5% had depression without apathy, 14% had both and 5% had neither.  In the 154 patients overall, there was no correlation between apathy and depression. (Among the 22 with PSP, there were too few with depression to calculate the correlation specifically for that disease.)  Apathy was more common and severe in AD, FTD and PSP, while depression was more common and severe in PD and HD.  In the overall group, apathy was associated with disinhibition, but depression was associated with anxiety, agitation, irritability and hallucinations.

The prevalence of depression and apathy in PSP vary wildly across studies, depending on definitions and sources of patients.  For example, fast-forward to a December 2021 study from Sarah M. Bower and colleagues at Mayo Clinic Rochester.  In their 97 patients with PSP, depression was present in 55% and apathy in only 12%.  This proportion was roughly the same for each of the nine PSP subtypes evaluated except for PSP-speech/language, where depression was much less frequent.

Why should we care about the distinction between apathy and depression?  Because they’re both treatable and the treatments differ. Here’s a compilation of recommendations from experts at UCSF and from the CurePSP Centers of Care.  Keep in mind that these recommendations are generally based on experience and record reviews rather than on randomized trials.

  • Depression in PSP is typically treated with selective serotonin reuptake inhibitors (SSRIs) (except for paroxetine because of its anticholinergic side effects), serotonin-norepinephrine reuptake inhibitors (SNRIs) or bupropion.  Non-drug treatments include cognitive-behavior therapy, mindfulness yoga, professionally guided meditation, and in very severe cases, electroconvulsive therapy.

  • Apathy in PSP, on the other hand, is treated with one of the amphetamine-like drugs methylphenidate or modafinil, or sometimes an SNRI.  Apathy can be worsened by SSRIs.  Regular conditioning exercise is also useful.

So, add this to the long list of reasons why it’s so wrong for a doctor to tell someone with PSP, “Sorry, but there’s nothing I can do for you.”

A catalogue of autoimmune mimics

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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.   

liu-homer-3-abs-mimicking-msa-orig-paperDownload

Let’s bottle this

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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)

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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

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. . . 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

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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

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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.