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Diagnostic baby steps

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Back to my reports on the new PSP research presented at the International Parkinsonism and Movement Disorder Society conference in Copenhagen last month.  Last week I started with the treatment-related things.  Today it’s five presentations on diagnostic tests other than imaging.  As before, my editorial comments appear in italics.

Machine learning classifies Parkinson’s disease and progressive supranuclear palsy on saccade, pupil, and blink measures during a naturalistic free-viewing task

D. Brien, H. Riek, R. Yep, J. Huang, B. Coe, B. White, M. Habibi, D. Grimes, M. Jog, A. Lang, C. Marras, M. Masellis, P. Mclaughlin, A. Peltsch, A. Roberts, B. Tan, D. Beaton, W. Lou, E. Finger, A. Frank, D. Tang-Wai, C. Tartaglia, S. Black, R. Swartz, W. Oertel, D. Munoz (Kingston, Canada)

The researchers tracked eye movements using artificial intelligence software in 120 people with Parkinson’s disease, 8 with PSP, and 97 controls viewing a 10-minute movie.  They told the software the diagnosis and allowed it to create a profile of what sorts of eye movements correlated with which disease.  The result was 87% accuracy in distinguishing PD from PSP in a separate group of patients.  (The percentage refers to the area under the receiver operating curve – see my post on that statistical technique if you like). 

This technique is no more accurate than an exam by a skilled movement disorders specialist, but is potentially much easier to obtain and pay for.  Plus, it’s non-invasive.

Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson disease

K. Kang, A. Nunes, M. Sharma, A. Hall, R. Mishra, J. Casado, R. Cole, G. Barchard, A. Vaziri, A. Wills, A. Pantelyat (Baltimore, USA)

This is similar to the previous presentation in that it uses computerized analysis of patients’ fine movements to differentiate PSP from PD.  In this case, researchers analyzed multiple features of speech during passage reading, counting and a sustained “aah” sound.  They found multiple clear differences between PSP and PD in the average measurements of many features of speech but did not report areas under the receiver operating curve, so we don’t know how useful the measurements are at the individual level.  The researchers conclude that automated analysis is a feasible and non-invasive way to differentiate PSP from PD.  

We’ve long known that the speech of PSP differs from that of PD, and an experienced neurologist can easily distinguish the two over the phone. But this may be the first time the differences have been quantified so precisely.  This small study (only 11 patients with PSP, 10 with PD) should be replicated and its value at the individual level measured.  It all goes well, this could become a smartphone app.

Cognitive interference in postural control as a diagnostic and prognostic biomarker in Parkinsonian disorders.

R. Lloyd, C. Fearon, R. Reilly (Dublin, Ireland)

It’s well known that in PSP and PD, the balance problem is worse when the person has to concentrate on a cognitive task at the same time.  These researchers presented their plans for using that phenomenon to distinguish between the two diseases.  They will use an automated platform for balance assessment and the popular Stroop color-word test for cognition, with the patients attached to an electroencephalogram (EEG; brain wave recording) machine.  They expect that the cognitive task will aggravate forward/backward sway in PD and side-to-side sway in PSP, and that corresponding EEG changes will occur.  There’s no description of the results as of the conference’s submission date, nor on my PubMed search today. 

While this elaborate testing set-up would not be practical for real world use, it may be relatively easy to have patients walk down a clinical corridor, with appropriate safety measures, with and without simultaneous performance of a cognitive task.  The neurologist could eyeball the result.  Of course, that simplified version would require its own validation procedure before being recommended.

Remote monitoring of physical activity in progressive supranuclear palsy (PSP) using wearable sensors

A.-M. Wills, R. Mishra, M. Sharma, AJ. Hall, J. Casado, R. Cole, A. Vaziri, A. Pantelyat (Boston, USA)

This project tested a wearable motion sensor that has been proven in PD for its value in PSP.  Eleven patients with PSP wore the “PAMSys” device to measure overall activity, gait, and posture.  The results were compared to a version of the PSP Rating Scale modified for tele-neurology use.  The device was able to document disease progression over the 12-month period of observation.

Although little actual analysis of the data was presented in the abstract available.  But this result does show that objective measurements of the ability of patients with PSP to move around may not have to rely on snapshots in time every 3 months for clinical trials or less often for regular clinical care.  This avoids the technical difficulties in performing evaluations by video and the subjectivity of reports from patients or caregivers.  I’d expect such measurements to start appearing as secondary outcome measures in clinical trials very soon.

Posturography as an objective measure of disease progression and prognostication in progressive supranuclear palsy

G. Nuebling, S. Katzdobler, J. Levin, G. Höglinger, S. Lorenzl (Munich, Germany)

As an add-on to a 12-month drug trial for PSP from a decade ago, these researchers used an automated platform to measure the degree of sway of 44 patients with PSP with eyes open and then with eyes closed.  The delay since the data were gathered isn’t a result of procrastination.  It was to be able to assess the sway data as a predictor of long-term survival.  The result was that the data correlated very well with survival.  But the precision of the test for sole use as an outcome measure in 12-month neuroprotection trials was insufficient.  The result with eyes open was a better predictor than with eyes closed (hazard ratios 1.098 vs 1.001), but the sizes of that effect were small and the difference between them is not statistically significant. 

We know a lot about factors that affect long-term disability and survival in PSP, but not in an easily applied, quantitative way that could be used in clinical care.  This test could provide that if the apparatus can be modified to require less space in a clinic. 

A true public servant

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U.S. Congresswoman Jennifer Wexton of Virginia has just announced that she has been diagnosed with PSP at age 55. 

Here’s the story in this morning’s Washington Post.

Here’s Rep. Wexton’s own press release.

Rep. Wexton announced a diagnosis of Parkinson’s disease five months ago, but after noticing that her medication was not helping her as it did others in her PD support group, she sought additional professional opinions.  This is a very common route to a PSP diagnosis, as this blog’s readership well knows. Even the experts may not be able to distinguish the two disorders in the first year of symptoms.

Rep. Wexton’s staff has contacted CurePSP to coordinate efforts to help raise public awareness of PSP. 

We all wish Rep. Wexton well in her journey and congratulate her on her decision to publicize her diagnosis as a way to help others.

New advances in PSP treatment

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As promised, here’s the first installment of summaries of new, still-unpublished research from at the International Parkinson’s and Movement Disorders Society conference held in Copenhagen in August 2023. I’m starting with the presentations on treatment, the topic of most interest to this audience. As usual, I’ll be generous in sharing my own opinions on these developments, shown in italics.

A retrospective review of amantadine in progressive supranuclear palsy

N. McFarland, R. Farrukh, S. Mahn (Gainesville, Florida)

Amantadine is an old anti-Parkinson drug with modest symptomatic benefit but with some important side effects, including confusion and hallucinations in patients with existing cognitive symptoms, along with dry mouth, constipation, ankle swelling and other issues.  A few small, non-controlled series have shown benefit in some people with PSP.  Dr. McFarland and colleagues reviewed their own records, finding 44 patients with PSP who had been treated with amantadine and whose responses were adequately recorded.  Six claimed improvement and 31 claimed to be worse, but the change in the PSP Rating Scale over the 8 months of treatment was similar in the two groups.  It’s possible that the 14% improved in a way not measured by the PSP Rating Scale, or that much of the benefit was lost by the time of the follow-up exam, or that it was just placebo effect.  These unfavorable numbers do not change my own opinion that despite the possibility of side effects, a short trial of amantadine in non-demented patients who have reached maximal benefit on levodopa is worth trying until something better comes along.

Effects of exergaming-based tai chi and eye movement training on balance and gait in progressive supranuclear palsy: a case report

Y. Levitan-Marcus (Tel Aviv, Israel)

This is a case report of a 66-year old man with mid-stage PSP who underwent a 3-month course of 3 physical therapy sessions per week, 50 minutes each, over 12 weeks.  The therapy comprised “exergaming-based Tai Chi and eye movement training software.”  His frequency of falls and other measures of gait and balance improved noticeably, though quantification is not provided in the abstract.  This confirms previous case reports and small case series showing that eye-movement-based balance therapy can help the symptoms of PSP.  A randomized trial is now fully justifiable.

A tau-directed monoclonal antibody could alter the tau pathology of progressive supranuclear palsy

G. Beck, R. Yamashita, Y. Yonenobu, K. Ikenaka, S. Murayama, H. Mochizuki (Suita City, Japan)

You’ll recall that in 2019, the drug company AbbVie announced that its multi-center, controlled trial of tilavonemab, a monoclonal antibody directed against tau, had failed to slow the progression of PSP.  At about the same time, Biogen announced similar results for its own anti-tau antibody, gosuranemab.  Now, researchers in Japan have compared a brain autopsy from one of the patients randomized to active drug in the tilavonemab study to brains of three people with PSP who did not participate in the study.  They found that the brain’s immune system had been activated in the patient on tilavonemab, at least in the substantia nigra, one of the most important areas of damage in PSP.  The response comprised macrophages and microglia engulfing abnormal tau.  This is the sort of response hoped for, though clearly it was too little to help the patients.  Although this report includes only one patient to receive the treatment, it suggests that monoclonal antibodies against tau have potential against PSP.  Other drug companies are now testing antibodies directed against different parts of the tau molecule in hopes of improving upon tilavonemab’s results.

TEP-PSP: preliminary results of a therapeutic education program in progressive supranuclear palsy

A. Camara, C. Painous, M. Baixauli, J. Herrero, S. Pelaez, I. Martin, I. Quiñoa, C. Torregrosa, M. Carrasco, JC. Lopez Reyes, L. Maragall, Y. Compta (Barcelona, Spain)

This report describes what might be called “PSP 101” for patients and caregivers.  Researchers in Spain have organized a registry for PSP in Catalonia, the region of the country that includes Barcelona, with 5.5 million inhabitants.  So far, they have enrolled 15 patients, each with a caregiver.  They have administered a course of instruction comprising 5 sessions covering general knowledge of the disease, nursing care, speech and physical therapy, and occupational, psychological, and social support.  Patients’ and caregivers’ satisfaction with the sessions was very high, as measured by a standard scale.  Enrollment is continuing and the researchers plan a follow-up to assess long-term benefits of the program.  This sort of program can fill a need for patients and caregivers who may not be inclined to read (or remember) printed or on-line material, and its interactive nature may prove an advantage over those more passive methods of instruction.  If further observations continue to demonstrate success in Catalonia, and if a comparison with more traditional means of lay education proves favorable, PSP organizations elsewhere may want to adapt such a course to other languages, cultures, and systems of medical care and to scale it up to larger patient groups.

Sniffing the air outside my burrow

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Sorry for the long absence – 25 days.  But I have two good reasons.  One is that the day after my last post, my wife and I flew to Norway and Denmark for a vacation.  I wasn’t going to blog from vacation and an enforcer was constantly at my side.  Reason Two is that  I was planning to stay for the Movement Disorders Society conference in Copenhagen, but we both came down with Covid five days into the trip, isolated in our hotel room for the next five days and skedaddled home before the MDS.  We’re both just about over the symptoms now, thanks, but it sure took long enough.  At age 70, you just don’t bounce back like you used to.

But I haven’t forgotten about you all.  I’ve categorized, counted, and reviewed the on-line abstracts of all 52 PSP-related poster presentations at the MDS:

  • Clinical phenomenology: 11
  • Physiology, chemistry and molecular biology: 7
  • Epidemiology, cohort studies, and care delivery: 8
  • Treatment: 4
  • Diagnosis (non-imaging): 5
  • Non-PET imaging: 8
  • PET imaging: 9

Over the next few days, I’ll crank out some summaries, opinions, and reasons for us all to hope.

The mighty-chondria

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When someone with PSP reports a feeling of “weak muscles” to their neurologist, the answer is typically, “yes, you’re weak, but the problem isn’t in your muscles – it’s in the messages to your muscles from your brain.”  But it turns out that in PSP, muscles can be a problem, too, and that opens up some treatment potential.

We’ve known for decades that the mitochondria aren’t working right in PSP and other neurodegenerative diseases.  You’ll recall that those are the tiny factories in almost all our cells devoted to the biochemical process of respiration – that where oxygen and sugar combine to produce energy for the cell’s many functions.  Besides that very important job, mitochondria are also involved in processes such as neural plasticity (the ability of brain cells to react to external influences), calcium regulation, electrical properties of the cell and synaptic transmission.

Here’s a electron microscope photo of a single mitochondrion (from this source).

What brain cells and muscle cells have in common is the need to maintain very different concentrations of potassium between themselves and the surrounding fluid (called a “gradient”), and that takes lots of energy.  So, any defect in mitochondria will tend to hurt brain cells and muscle cells first and worst.  In fact, childhood neurological dysfunction and muscle weakness are the two main features of a whole category of diseases caused by single-gene mutations affecting proteins used only by mitochondria.

In PSP, the mitochondrial problem is more subtle, but we don’t know exactly what it is or what causes it.  Here are some strands of evidence:

  • Brain cells growing in a dish that have had their own mitochondria destroyed and replaced by mitochondria isolated from blood cells of people with PSP don’t recover from various kinds of stress as well the same brain cells with replacement mitochondria from healthy people. 
  • Toxins damaging an important series of chemical reactions in the mitochondria called Complex I can cause a PSP-like condition in lab animals. 
  • Complex I and other components of mitochondria are also damaged by tau molecules with an abnormal number or location of attached phosphate molecules (“phospho-tau”), which we know occur in PSP.  The net effect is excessive levels of “free radicals,” which are toxic by-products of normal respiration.
  • While the most important gene mutation contributing to PSP risk is in MAPT, which encodes tau, the next-most important is PERK (protein kinase RNA-like endoplasmic reticulum kinase), which regulates the responses to stress in mitochondria.
  • Coenzyme Q-10, a nutritional supplement that assists Complex I, may help some of the immediate symptoms of PSP, as shown by at least one double-blind trial.

All the above is simply background justification to suspect that muscles and not just brain should be involved in PSP.  But there’s more direct evidence, too:

  • Muscle weakness and fatigue are more common in PSP than in others of the same age.
  • Weight loss is common in PSP and occurs early in the disease course.  The same is true for both in Parkinson’s, but not as markedly.
  • Grip strength is impaired in PSP.  That could be a result of changes in the brain, but the duration of the muscle fiber contractions is prolonged in PSP, a sign of muscle dysfunction.
  • Men (but, oddly, not women) with PSP have a reduced overall muscle mass relative to others of the same age. 
  • Muscle biopsy in people with PSP shows modest evidence of the same severe change in mitochondria (called “ragged red fibers”) that occur in the genetic mitochondrial diseases of childhood.

So, what’s the take-home for people with PSP? 

  • First, EXERCISE – including low-intensity muscle-building exercises.  Discuss the details first with your neurologist or physical therapist, and probably also with your primary care physician to make sure your heart and lungs are up to the task. 
  • Second, HAVE HOPE that insights into the mitochondrial role in PSP will bring new treatment or neuroprotection targeted at those cellular processes in the brain.  In fact, one such medication, called AMX-0035 (a combination of taurursodiol and sodium phenylbutyrate) will be entering a Phase 3 trial for PSP in the next few months.  The combination under the brand name “Relyvrio” was approved last year by the FDA for Lou Gehrig disease, where there’s a similar mitochondrial problem, so I have very high hopes that the same will happen for PSP.

How to diagnose atypical Parkinsonisms

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I’ve been neglecting psp-blog.org for the past two weeks in favor of a project to help general neurologists diagnose PSP and other atypical Parkinsonian disorders (APDs) without having to refer to a movement disorders specialist.  I can hear you saying, “Great idea, but why now?”  Here’s how this started:

I’ve told you about CurePSP’s Centers of Care network.  That’s a group of (now) 32 medical school-based movement disorder centers with a special interest and expertise in PSP, CBD and in many cases, MSA as well.  The network’s mission is to improve the quality and availability of care for these disorders.  One of the problems standing in our way is the long wait for an initial appointment with a movement disorders specialist.  A survey among our own 32 centers showed an average wait of about 4 months.  For rapidly progressive disorders, that’s too long.

One partial solution we discussed is to educate general neurologists to make a confident diagnosis themselves and to institute appropriate management.  Then, the referral to a movement disorders specialist could be simply confirmatory.  Of course, making a diagnosis of any disease means looking for evidence against the competing diagnostic possibilities.  In the case of PSP, the main alternatives (a list called the “differential diagnosis”) are Parkinson’s disease, corticobasal degeneration, multiple system atrophy, and dementia with Lewy bodies. 

Then there’s a long list of less likely disorders that can resemble PSP, at least in some ways, at least in some cases, at least in the early stages.  They can be degenerative like PSP and the other four, but also genetic, infectious, autoimmune, nutritional, vascular, toxic, endocrine, psychiatric, neoplastic (directly related to tumors), and paraneoplastic (indirectly related to tumors).  The list includes 24 disorders that, like PSP, are treatable only at a symptomatic level but also, crucially, 31 with specific treatment to slow, halt or reverse progression of the disease.  All of those 55 are pretty rare as causes of a PSP-like picture, but the 31 with specific treatment must not be overlooked. 

We devised a decision algorithm to help the general neurologist navigate this daunting menu of options.  I can’t “publish” the list here just yet, as we want to submit it, along with an explanatory text, to a good, selective journal, and journals don’t like to accept previously published material.  Besides, we should show it to a few experts from outside of our 13-member writing committee, and of course, the peer review process at the journal could result in major changes.  Plus, the raw list of 55 disorders wouldn’t be that useful without the decision algorithm and the sub-lists of diagnostic features and recommended tests.  I’ll pass it along to you when I can in the next couple of months, but in the meantime, my blog post from March of this year on “PSP mimics” covers 30 of the 55 in a useful degree of detail.

Current treatment trials

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My last post was a nerdy list of pathogenetic mechanisms in PSP along with the statement that treatments to address most of those mechanisms are in the clinical pipeline. One of you wrote in to kick me out of my lofty, scientific detachment, asking just what those treatment candidates are. So here’s a list.

The first four panels are active trials and the last is future trials.

The first two and last panels show neuroprotection trials (i.e., to slow disease progression).

The third and fourth show symptomatic trials (i.e., to help the symptoms without affecting the underlying disease process).

For current information on how to enroll, visit clinicaltrials.gov and search on the drug and/or sponsor and/or “progressive supranuclear palsy.”

Six horsemen of the Apocalypse

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I watched a scientific presentation today in which the speaker started off by summarizing the leading theories of PSP’s pathogenesis.  That means not the external influences such as the genes received from one’s parents or whatever toxins or other stresses might help cause PSP in susceptible people.  Rather, it means the abnormal processes set in motion and operating inside in the brain cells leading to their dysfunction and eventually, their death. 

Here’s a quick rundown for you:

  • Tau splicing.  The tau protein is encoded by the MAPT gene, which has 14 sections called exons encoding separate fragments of the final protein.  These protein fragments are then stitched together, but sometimes one or more of them is omitted by design.  In healthy people, the product of exon 10 is included in about half of the final tau molecules, but in the tau tangles of PSP, that fragment is nearly always included.  This makes the tau more likely to aggregate.
  • Tau post-translational modifications. Many or most proteins have very small molecules attached to them at specific points to regulate their function and direct their folding pattern.  The abnormal tau of PSP has phosphate and other molecules in inappropriate places.  This could help explain the abnormal folding, which in turn produces toxic aggregates.
  • Tau degradation. The normal “garbage disposal” systems of brain cells gets rid of proteins or organelles (the tiny structures in cells that perform specific functions) that are either overproduced, defective or just worn out.  There are two basic kinds of such systems, the ubiquitin-proteasome system and the autophagy-lysosomal system.  Neither works as well as it should in PSP.  This allows abnormal tau and other toxic molecules to accumulate.
  • Intracellular tau spread. In many neurodegenerative diseases, the abnormally folded tau can travel from one brain cell to another, causing normal copies of those molecules to misfold in a similar fashion.  This creates a kind of chain reaction spreading the damage widely. The misfolding pattern of the tau is specific to each of the tauopathies.
  • Mitochondrial dysfunction. The mitochondria are the organelles in the cells that harvest energy from sugars with the help of oxygen.  In PSP, they function abnormally, possibly because of their own genetic mutations, possibly because their biochemistry is particularly sensitive to certain toxins in our environment.  Mitochondrial dysfunction doesn’t just deprive the cell of energy – it also produces toxic compounds such as free radicals that damage other cell components.
  • Gene expression errors. The most recently discovered pathomechanism has to do with abnormal regulation of access of the cell’s protein-making machinery to the DNA “blueprint.” That process is normally regulated by proteins collectively called “chromatin,” which coat and intertwine with the DNA in the nucleus.   One way the abnormality might work is that abnormal chromatin permits inappropriate access to certain genes that stimulate the immune system, producing a harmful inflammatory reaction in the brain.

All of these pathogenetic mechanisms except the first are currently being addressed by drugs in advanced stages of the development pipeline.  I really don’t know which horse to put my money on.

Don’t try this at home

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CurePSP recently received an inquiry from a PSP caregiver who had evaluated the individual with PSP twice over a 6-month period using the PSP Rating Scale and needed some guidance in interpreting the results.  We had to tell them that the PSPRS is designed for use only by neurologists experienced in evaluating people with movement disorders and eye movement disorders, so the scores they generated cannot be relied on.  Besides, the second score was about 30 points (on the 100-point scale) worse than the first, and no one with PSP progresses that quickly.  So, they must have administered the PSPRS incorrectly.

People with PSP and their caregivers who ask about the PSPRS are advised to pass it along to their neurologists, who can decide if they want to use it.  The PSPRS is still the world-wide standard “outcome measure” for PSP treatment trials and the rating standard for observational research.  But it has reached only limited acceptance in ordinary neurological practice outside of academic settings because it takes 10-15 minutes to apply, and most neurologists don’t have that kind of time in a visit to devote to it.

But don’t despair, you neurological do-it-yourself-ers.  There’s a newer scale called the Cortico-Basal Functional Scale (CBFS), which is designed to be completed by the patient and caregiver and works just as well for PSP as for CBS.  It’s not quite as precise as the PSPRS because it relies only on subjective symptoms and experiences, but it’s still quite reliable in assessing the severity of PSP and tracking its progression.  It has more potential to be adopted by neurologists for routine care because it can be completed at home the day before the visit or even in the office waiting room. You can download it via the link above, complete the 31 multiple-choice questions and bring the completed form to your next neurology visit.

I’m gonna dis the DaT

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My last post, on current imaging techniques for PSP, was kind of technical and its last paragraph promised that the next one would be something softer. But someone just sent a comment asking why I didn’t mention dopamine transporter (DaT) imaging. So I’ll defer the low-tech post and in this one I’ll explain why I omitted DaT scan from my previous post. Here’s why: It’s not useful in distinguishing PSP from its likeliest diagnostic alternatives.

The dopamine transporters are molecules in the caudate and putamen (which together are called the striatum). See the highlighted structures in the image just below:

The brain cells bearing the DaT molecules have their cell bodies down in the substantia nigra of midbrain and send their axons up to the basal ganglia to synapse in the caudate and putamen, where they use dopamine as their neurotransmitter. In PSP, MSA, CBD, dementia with Lewy bodies and some others, those neurons are among the first to die and in Parkinson’s they’re not the first, but they’re the most important. So any imaging technique that reveals those neurons will be abnormal in all those diseases.

In the images below, the red and yellow areas represent the greatest presence of DaT molecules. The “head” of the comma-shaped thing is the caudate and the “tail” is the putamen. They’re nice and chunky in the leftmost image, labeled HC for healthy control. People with PSP, MSA-Parkinson type and Parkinson’s disease have lesser DaT signals, and the differences among those are just related to the severity of illness in those three individuals. They all have the same basic abnormality.

So, the DaT scan can quantify the severity of disease but cannot distinguish among the various neurodegenerative causes of Parkinsonism. Of course, for purposes of patient care, one can quantify PSP severity more easily, cheaply and usefully with just a history and exam.

What DaT can do, and this is its only official, FDA-approved use, is to distinguish essential tremor, where the dopamine-producing neurons are normal, from degenerative causes of tremor, where of course they’re not. Uses of the DaT scan that have not been approved by the FDA because of insufficient data are to distinguish degenerative Parkinsonism from normal-pressure hydrocephalus, drug-induced Parkinsonism, hypothyroidism and a bunch of other things that cause muscle rigidity and slow movement for reasons other than loss of the dopamine-producing neurons. But all of those things can be diagnosed in other ways.

Another difficulty with the technique is that many commonly-used neurological drugs such as antidepressants can cause false-positive DaT scans by blocking the dopamine transporter.

Bottom line: Other than to distinguish unusual cases of essential tremor from degenerative Parkinsonism, most movement disorders specialists rarely or never order DaT scans for routine patient care because they add nothing to a properly performed history, neurological exam and MRI.