Tag Archives: PSP subtypes

Good old MRI comes through

Posted on by

We still don’t have a great diagnostic test for PSP.  The best we can do is about 80%-90% sensitivity, specificity and positive predictive value.  In English:

  • Sensitivity is the fraction of people with PSP who give a positive result on the test.
  • Specificity is the fraction of people without PSP who give a negative result on the test.
  • Positive predictive value is the fraction of people with a positive test who actually have PSP.
  • A single number combining these into something useful in evaluating a single individual — rather than in comparing groups — is the “area under the receiver operating curve” (AUC; see this post for an explanation).  The AUC ranges from 0.50, which is no better than a coin toss, to 1.00, which is perfect accuracy.  An acceptable diagnostic test typically has an AUC of at least 0.85.

Most of the studies of PSP diagnostic markers have important weaknesses such as:

  • The studies frequently set up artificial situations such as distinguishing PSP only from PD or normal aging rather than from the long list of other possibilities that must be considered in the real world.  
  • The patients’ “true diagnoses” are usually defined by history and examination alone rather than by autopsy.
  • The patients included in the study were already known to have PSP by history and exam (or sometimes by autopsy), while the purpose of the marker would be to identify PSP in its much earlier, equivocal stages or in borderline or atypical cases.
  • The patients with PSP in most such studies are only those with PSP-Richardson’s syndrome, who account for only about half of all PSP in the real world.

The best type of marker so far is ordinary MRI.  Recently, a group of neurologists in Athens, Greece led by first author Dr. Vasilios C. Constantinides and senior author Dr. Leonidas Stefanis evaluated the specificity of various MRI-based measurements of brain atrophy.  One strength of their study was that their 441 subjects included people not only with PSP and Parkinson’s disease, but also with a long list of other conditions with which PSP is sometimes confused as well as a group of healthy age-matched controls. 

The single best MRI marker per this study was the area of the midbrain, the fat, V-shaped structure indicated below:

They found that MRI markers provided:

  • High diagnostic value (AUC >0.950 and/or sensitivity and specificity ∼90 %) to distinguish PSP from multiple system atrophy, Parkinson’s disease, and control groups.
  • Intermediate diagnostic value (AUC 0.900 to 0.950 and/or sensitivity and specificity 80 % to 90 %) to distinguish PSP from Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, and mild cognitive impairment (an early stage usually of AD).  
  • Insufficient diagnostic value (AUC < 0.900 or sensitivity/specificity ∼80 %) to distinguish PSP from corticobasal degeneration, normal-pressure hydrocephalus, and primary progressive aphasia (a language abnormality that can be caused by multiple specific diseases).
  • Insufficient value to distinguish the non-Richardson PSP subtypes from corticobasal degeneration and primary progressive aphasia, but good performance in the other comparators.

The researchers also concluded that:

  • One MRI measurement isn’t best for all the possible PSP comparators. 
  • Sometimes a combination of two or three measurements performed better than any single measurement.

One weakness of their method was the use of subjects diagnosed by standard history/exam (i.e., “clinical”) criteria, rather than by autopsy. Another is that their patients with PSP had had symptoms for an average of three years, so these were not subtle or early-stage cases. A letter to the journal’s editor from Dr. Bing Chen of Qingdao City, China further pointed out that the study of Constantinides and colleagues failed to account for the subtle effects of neurological medications on brain atrophy.  As PSP and the comparator disorders may be treated with different sets of drugs, taking this factor into account might enhance or reduce the apparent diagnostic value of MRI atrophy measurements.  

So, bottom line?  Drs. Constantinides and colleagues have given us the first study of MRI markers in PSP to include meaningful numbers of subjects with non-Richardson subtypes.  It’s also one of the few studies of any kind of PSP marker to include comparison of PSP a wide range of diagnostic “competitors” beyond just Parkinson’s and healthy aged persons.  Another plus is that the test, routine MRI, is nearly universally available, relatively inexpensive, and non-invasive.

The hope is that Pharma companies or others with candidate drugs will now have fewer or lower hurdles in the way of initiating clinical trials.

Orphans, this could be your chance

Posted on by

Back in 2023, I posted an explanation of the ten PSP subtypes.  The archetypal subtype, PSP-Richardson syndrome accounts for about half of all PSP and, in contrast to most of the other subtypes, has a rapid progression rate, a validated rating scale, and highly accurate diagnostic criteria.  All of these features have led clinical trial sponsors to maximize their trials’ sensitivity and minimize their costs by restricting admission to people with PSP-Richardson.  But developing better outcome measures for non-Richardson forms of PSP could change that practice.

A big step toward realizing this goal was published last week in the journal Neurology by a group at the Mayo Clinic in Rochester, MN.  Led by first author Dr. Mahesh Kumar and senior authors Drs. Jennifer Whitwell and Keith Josephs, the study found that a good outcome measure for clinical neuroprotection trials in all PSP subtypes was to combine a measure of atrophy by MRI with a measure of clinical disability.  This is a major advance.

The researchers performed brain MRIs at the start and end of a one-year period in 88 people with PSP and 32 age-matched controls.  Of those with PSP, 50 had PSP-Richardson, 18 had “PSP-cortical” (three of the other nine subtypes) and 20 had “PSP-subcortical” (the other 6 of the subtypes).  They had to lump the non-Richardson subjects using their subtypes’ general anatomical predilections because most of the subtypes were too rare to analyze on their own.

Calculating how much each of ten important PSP-involved brain regions had atrophied over the one-year interval allowed the researchers to identify which region(s) might best serve as markers of progression for each of the three groups when coupled with standard clinical measures.  Those measures include such familiar instruments as the PSP Rating Scale and the Unified Parkinson’s Disability Rating Scale’s motor section as well as less familiar scales specific for cognition, gait, eye movement and speech.  All the scales were administered concurrently with each of the two MRIs. 

They expressed the sensitivity to one-year progression not by some abstract statistic, but by the number of patients needed in a double-blind trial to demonstrate with at least 80% certainty that patients on active drug enjoyed a 20% slowing of progression relative to the placebo group. (These specifications are typical for PSP clinical trials.)  The better the measure’s performance, the fewer patients are needed.

And the award for Best Performance by an Outcome Measure in a PSP Neuroprotection Trial goes to . . . a combination of the rate of atrophy of whatever brain region shrinks fastest in the patient’s specific subtype and the PSP Rating Scale score.

The real significance of this study’s result is that using an outcome measure customized to each participant’s PSP subtype could allow trials to enroll not just people with PSP-Richardson, but also those with any of the other subtypes.  That’s because the trial’s measure of success could be to compare each patient’s rate of progression during the trial to that of patients in the placebo group with the same PSP subtype. 

This could double the number of people eligible to enroll in PSP trials, which means cutting the enrollment period in half, with commensurate reduction in costs for the sponsor.  The hybrid measure is more sensitive to progression than the PSP Rating Scale alone, thereby reducing the number of patients required even more. 

Both factors could lower the financial barrier confronting a company hoping to mount a trial for a promising PSP drug.  That may be the most important bottleneck right now in the development of a treatment to prevent or slow the progression of PSP.s

That’s why this news is huge for PSP in general and for the “orphans” in particular.