Great PR, so-so accuracy

Two full weeks since my last post – holiday activities, don’t you know, starting on December 21 with a solstice party at the home of an eccentric friend.   I see that my blog viewership has declined precipitously in the past week, so I’m happy that you all have better things to do at holiday time than to read about PSP.  Don’t we all wish that the disease itself would take a few days off, too?

My re-emergent thought is about the famous “hummingbird sign.”  On an MRI scan in the sagittal plane – that’s as if you sliced someone down the middle and looked at the cut surface – the brainstem sort of looks like a side view of a hummingbird. 

In the MRIs above, the nose is on the left.  In the lower images, the arrows stop just short of the indicated structures so as not to obscure them.  Note the progressively thinner, sleeker midbrain (the hummingbird’s head and beak) with retention of the plump pons (the belly, which is plumper than than that of a real hummingbird). 

Now here’s the issue.  The appearance of the hummingbird sign isn’t as closely related to PSP as has been implied by many.  There are just too many false positives and false negatives. 

The false positives mostly occur in people with normal-pressure hydrocephalus, a condition where the fluid-filled spaces in the brain (the “ventricles”) enlarge because of an obstruction in the re-absorption of the fluid into the bloodstream.  This stretches the fibers adjacent to the ventricles, impairing control of gait, cognition and the bladder.  It also presses down on the midbrain, producing the hummingbird sign.  Then there are those individuals with corticobasal degeneration where the features resemble PSP (“CBS-PSP”).  They can also have a hummingbird sign.

The false negatives occur in the first couple of years after the initial symptoms.  They also occur if the MRI is mis-aligned on the brain or the head is a little rotated, producing an allegedly midline cut that’s actually a couple of millimeters to one side.  That means that the thinnest part of the midbrain, which is in the midline, isn’t shown in the image. 

You should also know that the hummingbird sign isn’t just about a thin midbrain.  A normal pons is also part of the sign.  That’s because in multiple system atrophy and a few rarer disorders, both the midbrain and pons become thinner.  But in PSP, it’s mostly the midbrain that does so.

I think that in the next year or two, a test of the tau protein in spinal fluid, blood or a tiny punch biopsy of skin will provide a much more accurate diagnosis of PSP than the hummingbird sign.  Soon thereafter we will probably have a PET technique that does the same. Then, clinical treatment trials can be accomplished faster because they won’t have to compensate for the statistical noise produced by participants with a false positive diagnosis.  In fact, all sorts of research on PSP will become much more powerful if people without PSP can be excluded. 

All my best for the New Year.

Low-tech solutions

I know that some of my posts are too technical for some of my readers, so I’ll make amends right now. An important paper just appeared in the journal Neurology and Therapy called “The Lived Experiences of People with Progressive Supranuclear Palsy and Their Caregivers.” 

The nine authors were led by Dr. Gesine Respondek, a well-published PSP expert formerly at Hannover Medical School in Germany and now at Roche Pharmaceuticals.  The others are a diverse group from five different European medical institutions, two patient advocacy organizations and the study’s sponsor, the Belgian drug company UCB Biopharma.  They performed one-hour interviews of 21 patient/caregiver pairs, 7 patient organization representatives, 21 nurses and 42 neurologists in France, Germany, Italy, Japan, Spain, the UK and the US.  The patients and caregivers also completed smartphone-based, 7-day diaries with photos and formal daily questionnaires.  The analysis used a qualitative approach rather than attempting to fit the subjective information into a standard statistical model used in most medical research.

The study identified barriers to optimal care, the emotional responses to being a patient or a caregiver, and major “pain points.” The areas identified as important were:

  • delays in seeking medical advice for the initial symptoms because of apathy or misattribution of the symptoms by the patient or family
  • lack of awareness of PSP by non-neurologists
  • delays in even the neurologist suspecting PSP because of delayed appearance of downgaze difficulty or other hallmarks
  • a feeling of being overwhelmed by the diagnosis and its implications
  • delays in being referred by the general neurologist to a movement disorders specialist
  • diagnostic uncertainty even by the movement disorders specialist because of the overlaps between PSP and other candidate diagnoses
  • absence of objective diagnostic tests
  • a lack of empathy by the neurologist
  • frustration in having to settle for symptomatic treatment rather than disease-modifying treatment
  • the problem of being “no longer you”
  • the loss of independence in daily activities
  • lack of consistency in the rating and monitoring of symptoms
  • lack of guidelines and quality care standards for PSP management
  • stresses in confronting the end of life
  • caregivers feeling frustrated, sad, lonely, guilty and unsupported

The most important stresses among these related to the delays in receiving a correct diagnosis.  The countries differed in some areas with Japan offering the best support, information and home care. 

The authors concluded with these recommendations:

  • More countries should create patient organizations dedicated to PSP.
  • Time allotted for consultations should be longer to allow the clinician to better educate the patient/caregiver.  If this is not possible, then providing formal follow-up time by phone or video would be a good substitute.
  • To assist in the above, one of the shorter versions of the PSP Rating Scale should be widely adopted by neurologists in order to provide patients with an quantitative measure of their status within the time allotted at the visit.
  • At-home follow-up by a nurse specialized in parkinsonism, when financially feasible, would help.
  • Closer collaboration between patient organizations and clinicians should be facilitated.
  • More information should be available on “financial support, life expectancy, nutrition and tube feeding, and preparation for end-of-life.”
  • There should be better access to support for patient and caregiver in the form of adult day programs, support groups, respite care, home health care, social work, caregiver training and psychological support.
  • Tele-health forms of occupational therapy should be available.
  • Clinicians should be honest and open with the patient and caregiver about the unpleasant truths and the uncertainties.
  • The needs of the caregiver should be as important as those of the patients to clinicians, support organizations, insurors and policymakers.

As my own editorial response, I’ll say that:

  • Many of these recommendations are for services already available in the US via CurePSP and in the UK via the PSP Association.  But funding limitations at these charities limit their reach. 
  • CurePSP and the PSPA already offer many forms of layperson and professional education where funding is not an issue. They just have to get it to the right people.
  • Creating new or more educational materials for clinicians who can read English is not a priority.  We just need to grab their attention and convince them to devote some time and energy from their busy schedules to learning the material. Providing the materials in other languages would also help.
  • CurePSP’s Centers of Care network, which is only just getting started in earnest, is attempting to address many of the deficiencies on the part of professional education and access to care.  The best example is its “Best Practices” paper advising on treatment options and published last year.
  • I hope that there can be a radical change in how most physicians and insurers see PSP.  The current, “Oh, PSP is just a disease that old people get, and you’ve got to go sometime, and there’s nothing to be done.” has to change to, “PSP is a disease that reduces the quality and quantity of one’s retirement years and its sufferers and their families can benefit in many ways — both psychological and physical — from better access to care, faster diagnosis, and delivery of well-informed and empathetic symptomatic management.”

What’s in a name? A lot.

Maybe nothing is more boring to patients and their families than squabbles among doctors about how to classify diseases.  But here goes.

You may have read that PSP is one of the “frontotemporal dementias.”  The FTDs are an umbrella category of diseases with deficits involving degeneration of the frontal and temporal lobes.  The results are trouble planning, forming new ideas, multi-tasking, obeying rules and adapting to circumstances.  Some types of FTD also (or mostly) have problems with speech and language.  Yes, PSP includes some of those things to some degree, but unfortunately, that’s only one of many parts of PSP. 

The protein aggregating in the brain cells in the various FTDs can be tau, as in PSP, but only in a minority.  Even in those few with tau, the distribution of the aggregates is different from that of PSP.  The majority of FTDs don’t even have tau – instead, they have the proteins TDP-43, FUS or ubiquitin.  So, it has always irked me to hear PSP classified as an FTD.

But now, I’ve got backup:  In August 2022, a group of leading neuropathologists published a revised set of criteria for making a diagnosis of PSP at autopsy. 

This replaces a set of criteria from 1996, antedating modern methods of tissue staining (necessary for viewing through the microscope) certain observations about the pathology of PSP.  Now, here’s the critical part: the new criteria don’t require, or even accept, abnormalities in the temporal lobes in support of the diagnosis of PSP. 

The new criteria, called the “Rainwater Charitable Foundation Criteria” for the philanthropy funding the project, are very simple.  They require both of these:

  1. Neurofibrillary tangles or pre-tangles, at least mild in frequency, in two or more of the following regions: globus pallidus, subthalamic nucleus and substantia nigra
  2. Tufted astrocytes, at least mild in frequency, in either peri-Rolandic cortices or putamen

In English:

  • Neurofibrillary tangles: mature aggregates of tau protein
  • Pretangles: aggregates of tau protein that aren’t (yet) sufficiently well-formed to be called tangles
  • Globus pallidus: part of the basal ganglia, an important area for control of movement
  • Subthalamic nucleus: another movement-control area, a cluster of brain cells so-called because it’s just under the thalamus
  • Substantia nigra: yet another movement-control area, the one where dopamine is made; It’s also a critical one for Parkinson’s.
  • Tufted: containing a type of tau aggregate with a sort of fluffy appearance
  • Astrocytes: the main type of glia, which are non-electrical brain cells
  • Peri-Rolandic cortices: the folds of the cerebrum running down each side of the brain in front of and behind a long in-folding called the Rolandic fissure.  The pre-Rolandic cortex is part of the frontal lobe and serves motor control.  The post-Rolandic cortex is part of the parietal lobe and serves the sense of touch.
  • Putamen:  another movement control area of the basal ganglia

The fact that involvement of the temporal lobe is so mild and inconsistent in PSP as not to merit a place in the new diagnostic criteria should finally put an end to the notion that PSP should be classified as one of the fronto-temporal dementias. 

I was gratified to discover recently that the Memory and Ageing Center at UCSF, possibly the leading such institution in the world, now specifically states on its website’s home page that PSP, while sharing some symptoms with the FTDs, is not one of them.

So, why does this matter?  Because PSP is sufficiently different from the FTDs that it deserves to be researched and treated on its own.  Its sufferers and their families need a type of support not generally relevant to the FTDs.  Similarly, those serving the urgent and important needs of the FTD community should not be distracted by efforts aimed at PSP. 

Lecanemab: now for the (not that) bad news

A bombshell hit the news yesterday (11/20/22) about a breakthrough treatment for Alzheimer’s disease.  But the drug company announced the same news two months ago in the form of a press release.  Today’s story was merely about a formal presentation of the results at an Alzheimer’s conference that added some important safety data.  Here’s my blog post from September.

The drug is called lecanemab, and as its last three letters indicate, it’s a monoclonal antibody – in this case directed against the beta-amyloid protein.  That’s present in an abnormal, aggregated form in brain cells in Alzheimer’s but not in PSP.  In the trial, the antibody solution was infused intravenously every two weeks for 18 months and compared with a group of participants receiving placebo infusions.  The news was that lecanemab slowed the rate of worsening of Alzheimer’s by 27%.  This is great news from the PSP standpoint because it’s the first time that a monoclonal antibody was shown to slow progression of any neurodegenerative condition, even if it’s a different one.  We call that a “proof of principle.”

Today’s new information on the drug’s safety was most notable for a potentially serious issue called hemorrhagic encephalitis.  That’s where areas of the brain tissue undergo swelling and/or bleeding.  That combination is evidence of inflammation, the equivalent of a very sore arm after a Covid shot.  Among the 898 participants with AD who received active lecanemab over the 18 months of the trial, 13% had swelling, but for the 897 receiving placebo, the figure was 2% – a major difference.   For bleeding, the proportions were 17% for lecanemab and 9% for placebo – a minor difference.  Fortunately, none of those participants suffered important or permanent symptoms from the swelling or bleeding, which in most cases would not even have been suspected without the trial’s routine brain MRIs, and in all cases resolved in a few weeks.  However, one wonders how serious the problem could hypothetically be in a tiny percentage of people — too small a fraction to be detected in the 897 on lecanemab in this study.

The group on active lecanemab was a bit more likely than the placebo group to report a variety of serious side effects unrelated to brain swelling or bleeding: 14% vs 11%; and the lecanemab patients were more likely to drop out of the study because of other, assorted side effects: 7% vs 3%.

Now the FDA and Medicare/Medicaid have to decide if they’ll approve this treatment or if the cost (whatever that might turn out to be) and side effects outweigh the benefit. Or, they may require another large trial first.

So, the takeaway for those with PSP is that it’s possible to modestly slow the rate progression of a neurodegenerative disease with a monoclonal antibody treatment with probably only mild risk. The numbers about the hemorrhagic encephalitis are not to be ignored.  But I think that if a hypothetical treatment for PSP gave similar risk and benefit, and the out-of-pocket cost is affordable, I think the majority of people with PSP would ask where to sign up.