Monthly Archives: December 2024

Three action items

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Time for my occasional, highly selective roundup of recent research. But this time, it’s not about molecules or images. Instead, it’s three clinical things of possible immediate importance in our understanding or everyday management of PSP.

“Neuropathy” means problems with nerves outside the brain and spinal cord, sometimes causing numbness, tingling, imbalance, pain or weakness. Dr. Yumkham Devi and colleagues at the All India Institute of Medical Sciences in Rishikesh have performed one of the few studies to date of neuropathy in PSP. Using both subjective symptoms and nerve conduction testing, they found some degree of damage to the nerves in the limbs in 65% of their patients with PSP and 51% of those with Parkinson’s. The nerves were affected symmetrically, as typically occurs with the neuropathy of diabetes or malnutrition. In contrast, problems with individual nerves are more typical of compressive causes like carpal tunnel syndrome or sciatica. The authors hypothesize that the abnormal tau of PSP could be damaging the Schwann cells, which provide the insulating coat around most nerve fibers. Other research has suggested that Parkinson’s can cause neuropathy through nutritional disturbances such as poor absorption of vitamins by the intestine.

    Editorial comment: With only 15 people in this trial with PSP and neuropathy, clear conclusions about the relationship with levodopa use were impossible. However, the high frequency (65%) of neuropathy in PSP and the previous results on nutrition as a likely cause of neuropathy in Parkinson’s are instructive. They provide an important reason for those with PSP to maintain nutrition carefully despite their swallowing problems and to avoid the constipation that PSP often causes. Both issues are very manageable causes of nutritional disturbance that could cause neuropathy.

    Dr. Éadaoin Flynn and colleagues of Trinity College, Dublin have reviewed the literature of the dysphagia – the swallowing difficulty – of PSP. Only 20 of 932 published studies of the topic met their rigorous criteria. The most common issues occurred in the mouth, with difficulty coordinating the tongue. The single most common problem was transferring the food from the front of the mouth to the back, with incomplete swallows in 98%. Less common problems occurred in the pharynx and esophagus. Penetration of food into the airway above the vocal cords occurred in 40% and actual aspiration, penetration past the vocal cords, in 24%.

      Editorial comment: All PSP experts I know advise an evaluation by a speech/swallowing professional early in the course of the disease. Some even feel it should be done immediately upon diagnosis even if there is no subjective difficulty swallowing. All agree that it should be repeated at least annually or if the symptoms worsen significantly. The most common cause of death in PSP is pneumonia caused by aspiration, where chewed food irritates the lung tissue, making it hospitable to the growth of any bacteria subsequently inhaled from the air. This is low-hanging fruit for those with PSP, as the various modification to diet and eating methods really can make a difference in life expectancy.

      Dr. Michał Markiewicz and colleagues at the Medical University of Warsaw, Poland, have reviewed the literature on what we know about the quality of life in PSP and how it should influence everyday management. They discuss the strengths and weaknesses of the PSP-QoL Scale and cite data showing that items on depression and daytime sleepiness correlate best with overall reported quality of life.

      Editorial comment: Depression and daytime sleepiness are actually caused by the PSP process itself at work in the areas of the brain controlling emotion and sleep; they’re not just indirect results of other PSP-related symptoms. Therefore, direct treatment of these two symptoms with medication, exercise, or psychological intervention may usefully improve one’s quality of life.


      A report from the ASO front

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      The Comments section just received a trial participant’s personal report and some good questions about the anti-sense oligonucleotide (AS0) trial sponsored by Novartis.  As explained in my last post, all the patients in that trial have completed their participation and the data are being analyzed.  First, here’s the comment unedited (except for correcting the location of the PSP conference and my bracketed clarification in the fourth line), followed by my response.

      IT WORKS! My husband was in the trial. No cure but a great year – his condition was improved in so many ways. I have been waiting for someone at Cure PSP to put out the word. I assumed they were going to present at the Toronto conference but they did not.

      We are so sad they [Novartis] refuse to continue to give it to us. Novartis has a published policy to keep giving people in a trial drugs that provide help but denied us with the excuse it was phase 1. Even if it is too expensive when administered through the spine it provides evidence that this horrible disease can be managed and greatly improves life. We would love to go to Novartis and show them how it works. Hopefully they are not just proceeding on using it for Alzheimers. We have been watching and waiting to see if they release results. They need to publish them. HOPE MATTERS! Kathy and Steve from San Diego, California.

      Kathy and Steve:

      I’m so glad that you, Steve, had symptomatic benefit from NIO752.  You raise several good points deserving separate responses:

      • The known molecular mechanism of the drug would merely slow down, or hopefully halt, the future worsening of the disease, not improve it in absolute terms.  People entering clinical trials may start paying new attention to their health and changing their habits regarding diet, hydration, exercise, physical and other types of therapy, compliance with concomitant medication, and discontinuation of unnecessary concomitant medication that might have been producing side effects.  There’s also the possibility of a placebo effect.  All this, of course, could make someone entering the trial feel better and is why establishing true drug efficacy requires a control group. 
      • The reason not to provide the drug post-trial to Phase 1 trial completers is that the purpose of Phase 1 is to establish safety, and until that trial is over and the data analyzed, the drug’s safety remains unknown in people with PSP.  Even if the trial is over and the drug found to be safe, that applies only to the duration of the trial.  So, allowing a trial completer to continue to receive the drug for longer would be taking a safety risk, and there would no longer be a placebo group to use in assessing the magnitude of that risk.
      • That said, there’s a slight theoretical possibility that the reduction in tau production caused by NIO752 could actually allow recovery of normal function by some brain cells that were malfunctioning but still salvageable, producing an immediate symptomatic improvement.  But that might have no relationship to any long-term neuroprotective benefit.
      • I do have some good news in response to your hope that Novartis is still pursuing PSP rather than just Alzheimer’s.  I’ve heard that the company has been seeking information useful for the design of an efficacy PSP trial.  That suggests that such a trial is being at least provisionally planned. 
      • The results of Phase 1 trials are not always be published in journals, but they are often presented as posters at conferences and are announced by the company in the form of press releases.
      • Yes, HOPE DEFINITELY MATTERS!

      NIO752 update

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      Today reader RW posted a comment asking about the status of the NIO752 trial. I thought my answer was so, SO well-crafted and informative that I just had to promote it from a comment response to a full blog post, and here it is:


      RW:

      First, for the benefit of your fellow readers, NIO752 is the anti-sense oligonucleotide from Novartis. An ASO is a short span of RNA injected into the spinal fluid space. In this case, the injections are given four times: every three months for a year. The drug reduces production of tau at its source — where its gene is transcribed into protein. In my opinion, it’s more likely to work against PSP than any other past or current experimental drug. However, the need for the spinal injections could limit its appeal, especially if one or more of the oral (i.e., more convenient) drugs currently in more advanced stages of clinical testing reach the market first.
      The Phase 1 NIO752 trial ended a month or so ago and Novartis, apparently, is still crunching the numbers. It’s typical for that to take 2 or 3 months, so I wouldn’t infer anything from it. Keep in mind that this was only a Phase 1 trial, powered to assess safety, not efficacy. I haven’t heard anything through the grapevine about major safety problems during the trial, but you never know what the actual data might show or how the company might react in terms of continuing to advance the drug into a Phase 2 trial.
      LG

      Switching sides

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      I want to tell you about one small study that, although it needs expansion and confirmation, is exciting because it could allow a future PSP neuroprotective treatment to be prescribed before having to wait for symptoms to appear.

      You’ve probably heard of the protein “alpha-synuclein”  (pronounced “suh-NOO-klee-in”). It has a long list of normal functions in our brain cells, but in its various misfolded forms, is the major component of abnormal protein aggregates of Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy.  Now, a blood test for alpha-synuclein might actually provide a way to diagnose PSP despite the fact that tau, not alpha-synuclein, is PSP’s abnormally aggregating protein. 

      The new paper in the journal Biomedicines by researchers at the University of Catanzaro in Italy, have found the concentration of alpha-synuclein to be slightly greater in the red blood cells of people with PSP than in healthy people or those with PD.  The graph below from the journal article (with my explanatory notes and arrows) compares results from the eight people with PSP to 19 with PD and 18 healthy control participants.  The vertical axis is alpha-synuclein concentration expressed in nanograms of alpha-synuclein per milligram of red blood cells. 

      One paragraph of technical background on alpha-synuclein: While alpha-synuclein does most of its work in brain cells, helping in neurotransmitter release and protect against mis-application of the cell’s “suicide” program (called “apoptosis”), it’s also abundant in red blood cells.  In fact, it’s the second-most-abundant protein in red cells after, of course, hemoglobin.  The job of alpha-synuclein there is to help to stabilize their red cells’ outer membranes and to help in the process of removing the nucleus from the red cells’ precursor cells in the bone marrow.  Nucleus removal makes more room for hemoglobin and more important, allows the cells to deform more easily as they pass through capillaries.  That deformation provides a signal to the hemoglobin to release their oxygen to the tissue.

      Back to business: The graph shows clear overlaps between PSP and the other groups, but the medians do differ to a statistically significant degree.  The short arrow by the vertical axis points to a value of 85.06 ng/mg, which the researchers chose in retrospect as the best cutoff between normal and abnormal.  Using that definition, the sensitivity of the measure was 100%, meaning that all eight participants with PSP had an abnormal result (that is, a value higher than 85.06).  The same cutoff yielded a specificity of 70.6%, which is the fraction of the PD and HC participants with a normal result; in other words, the fraction that would be diagnosed correctly as “non-PSP.”  

      But if only 70.6% of the participants with “non-PSP” have a normal test result, that means that the other 29.4% have an “abnormal” result and would be falsely diagnosed with PSP.  PD is about 20 times as common in neurological practice populations as PSP, so for every 1,000 patients who might have PSP or PD and see a neurologist, about 50 have PSP and 950 have PD.  If you do the red cell test in all 1,000, that means that 29.4% of 950, or 279, will have an abnormal result.  If all 50 with PSP also have an abnormal result, that totals 339 people with abnormal results, of whom 279 (a whopping 82%) don’t actually have PSP.

      So, a neurologist seeing a result below that 85.06 cutoff would be able to reassure patient that they do not have PSP, with, of course, the usual precaution that outliers and lab errors do exist.  A result above the 85.06 cutoff would prompt other diagnostic tests with greater specificity, although probably with greater expense, inconvenience and/or discomfort.  I hasten to add that like any new research finding, this needs confirmation by other researchers using other, larger patient populations in all stages of illness. 

      You may recognize this result as the definition of a “screening test.”  That’s a relatively inexpensive, convenient, safe and sensitive test suitable for use in large populations of asymptomatic or at-risk people.  If a screening test is positive, further testing, or at least close observation, is advised.  A good example is a routine mammogram, where a negative reading is great news and a positive reading prompts further testing.  In this example, that testing usually results in a diagnosis of a benign cyst or scar or something else other than breast cancer, and the few women whose mammogram abnormalities turn out to be breast cancer and whose lives are saved by the ensuing treatment will be very glad to have had that screening test.  A similar situation could develop for PSP once we have an effective way to slow or halt progression of the disease.  That’s what the PSP neuroprotection trials currently under way hope to accomplish.

      It seems unlikely from the new data that red cell alpha-synuclein concentration would ever offer enough specificity to diagnose PSP to the exclusion of non-PSP.  But people with a positive test could then have, perhaps, an MRI, where certain arcane measures of the midbrain and basal ganglia could provide diagnostic information with the specificity for PSP that’s missing from the red cell alpha-synuclein test.  In this way, the red cell alpha-synuclein is similar to neurofilament light, a protein elevated in the blood and spinal fluid in PSP but also in several other neurodegenerative diseases.

      The senior author of the new paper is Dr. Andrea Quattrone, whom I know well and can vouch for.  He is an internationally recognized leader in discovering diagnostic markers for PSP.  The first-named author is Dr. Costanza Maria Cristiani.

      More technical stuff in italics: Why should alpha-synuclein occur in elevated amounts in a tau-based disorder like PSP?  Cristiani et al hypothesize that the red cells absorb most of their alpha-synuclein from the plasma (the liquid component of the blood) rather than being “born” with it in the bone marrow.  They cite previous findings that excessive tau protein impairs the blood brain barrier, which could allow alpha-synuclein, an abundant protein in the brain, to leak into the blood, where it’s “scavenged” by the red cells. An obvious next step is to check other tauopathies such as Alzheimer’s disease for elevated red cell alpha-synuclein.

      And now, on a personal note:  My career as a researcher started in Parkinson’s disease and for a decade starting in 1986, I led the clinical component of the project that discovered that alpha-synuclein was related to PD.  It began when I found and painstakingly worked up a large family with a rare, strongly inherited form of PD .  That work, which included many collaborators I recruited in multiple institutions and countries, showed that family’s illness to be caused by a mutation in the gene encoding alpha-synuclein, which had not previously been suspected of any relationship to PD.  Soon thereafter, others found alpha-synuclein as the major constituent of Lewy bodies (the protein aggregates of PD) in individuals with ordinary, non-familial PD without the mutation.  Now, alpha-synuclein treatments and diagnostic tests are being developed for PD.  So, if a critical diagnostic test for PSP, the disease to which I’ve devoted most of the more recent decades, should turn out to be based on alpha-synuclein, that would nicely satisfy the scientific narcissist in me.