Markers: the longitudinal approach

We got plenty of candidate PSP treatments.

We got drug companies willing to risk their resources on trials for a rare disease.

We got clinical trial sites with proven records of efficiency. 

We got patients willing to make the sacrifices demanded by clinical trials. 

What ain’t we got? 

We ain’t got markers. 

(Deepest apologies to Rodgers and Hammerstein.)

Markers in this context are simply diagnostic tests, and there are two kinds – trait markers and state markers.  Trait markers allow us to distinguish people with from those without the disease, preferably in a very early stage, where treatments designed to prevent further decline would be most likely to occur and most useful to the patient.  Trait markers also allow us to exclude from a PSP trial any people who don’t actually have PSP.  State markers, on the other hand, quantify the amount of damage that’s already occurred and the degree of benefit of the experimental treatment. 

The best trait marker for PSP to date is purely clinical, meaning that it does not require any sort of imaging, automated measurements of movement, gene testing or chemical testing of body fluids.  That’s the MDS-PSP Criteria, published in 2017. Other types of tests can help exclude from consideration other conditions such as Alzheimer’s, Parkinson’s, MSA, normal-pressure hydrocephalus and vascular parkinsonism, but they are only helpful in those cases where a specific alternative diagnosis is plausible.  They don’t positively diagnose PSP; they only rule out other things.

Two up-and-coming trait markers for PSP are spinal fluid levels of tau with a phosphate group on amino acid 181 (Ptau181) and neurofilament light chain (NfL).  Ptau181 levels are below normal, on average, in all forms of PSP except for the gait-freezing type (PSP-PGF).  This contrasts with Alzheimer’s disease, where that marker is elevated, on average.  The average level of neurofilament light chain (NfL) in the spinal fluid is much higher in PSP and CBS than in controls or Alzheimer’s but is also elevated in many other neurodegenerative disorders.  So the ratio of NfL divided by Ptau181 in the spinal fluid is an good marker for PSP, but cannot distinguish it from CBD, and for PSP-Richardson, it may not be as accurate as the bedside clinical criteria. For ordinary clinical use, a blood test would be easier than a spinal tap, and the utility of these levels as a state marker has not been adequately studied, even for CSF.  That requires a longitudinal study over a period of at least a year.  So the NfL/Ptau181 ratio isn’t ready for prime time as a PSP trait marker, much less as a state marker.

The most widely used state marker for PSP is still the PSP Rating Scale, which is also purely clinical. (Disclaimer: I developed the PSPRS starting in 1995 and published it in 2005 along with my statistician colleague Pam Ohman-Strickland.)   It takes 15 minutes to administer and requires no equipment other than an armless chair, a cup of water to test swallowing — and the apparatus between the neurologist’s ears.  In recent years, modifications of the PSPRS have been shorter, easier to administer by laypersons, or more directly reflective of the patient’s daily activities.  Although all of these revisions are valid and have been shown to correlate well with the full, original PSPRS, none has been widely tested in the field, and the PSPRS remains the standard for now.  But it’s not good enough.  Its score is affected by common non-PSP conditions such as injuries, arthritis or strokes, or by PSP-related conditions; for example, orientation testing can be affected by apathy, gait testing by muscle rigidity, blepharospasm by Botox and everything by dehydration or malnutrition.  So there’s a lot of variance in the PSPRS as measured from one visit to the next.  This dictates that trials be large enough and long enough to cancel out the “statistical noise,” and that costs money.

A longitudinal study is observational – it includes no treatment.  It enrolls patients with the disease of interest, or sometimes also healthy people with histories suggesting a high risk of developing that disease.  Many longitudinal trials also enroll control subjects with no apparent risk for the disease — typically spouses, relatives or friends of those in the first two groups.  All of the subjects undergo tests at entry using whatever diagnostic procedures are being evaluated as markers, some of which are repeated periodically.  The study follows the patients through their course, at least with interim histories and physical exams.  If feasible and appropriate, autopsies are obtained to verify the diagnosis and to correlate specific autopsy features with diagnostic test results during life.  The goal is to identify which, if any, of the diagnostic tests prove able to accurately identify people with the disease in the earliest stages and which can track their subsequent course with precision.

There are presently at least 8 PSP longitudinal studies in progress: 2 in Germany and 1 each in India, Italy, Japan, Luxembourg, the US/Canada and the UK.

At the PSP Study Group meeting on October 4, James Rowe of Cambridge updated the group on the longitudinal PROSPECT-M-UK study, which is headed by Huw Morris of University College London. (“M” is for MSA, a late addition.) It now includes 21 academic clinic sites in the UK and about 700 patients, of whom about 100 have made more than the initial visit.  They have found that using MRI measures of atrophy of certain regions of the cerebrum is more precise than the PSPRS, reducing the number of patients needed for a treatment trial by nearly half.  The measures were atrophy of frontal and temporal lobes and enlargement of the lateral ventricles, an indirect sign of diffuse cerebral atrophy.  This confirms and extends the findings in the two trials of monoclonal antibodies that failed to help PSP, where MRI at the start and end of the studies provided a sharper picture of the patients’ progression than the PSPRS.  The reduction of the sample size was even more marked for CBD, but in fairness, the PSPRS was not designed for that disease.  One of the PROSPECT-M-UK study’s specimen collections is skin biopsies.  These can be used to look for tau aggregation in nerve endings, a potential early-stage, only slightly invasive trait marker.  Skin biopsies can also be used to create stem cells, which are then converted into neuronal cultures in which experimental treatments can be tested.  In this case, each such “brain in a dish” will come with a detailed, standardized clinical record.  Even more important, that lab model is not a mouse with a PSP-like condition, but a human being with real PSP.

LK Prashanth of Vikram Hospital in Bangalore described the longitudinal PSP study being conducted by the Parkinson Research Alliance of India. The Pan-India Registry for PSP (PAIR-PSP) includes 15 centers with 68 patients, with a goal of 1,000 over the next 2 years.  They are performing whole genome sequencing along with more conventional measures.  They have found that PSP-Richardson syndrome, the classic form, exists in only 25% of their group.  Next is PSP-parkinsonism with 22% and PSP-CBS with 18%.

Martin Klietz of Hannover Medical School updated the group on the two German studies, DESCRIBE and ProPSP.  The first has enrolled 400 patients, the second, 276.  Each study covers the entire country, although one is based in the north, at Hannover and the other in the south, at Munich.

Rejko Krüger of the University of Luxembourg mentioned that his institution’s longitudinal Parkinsonism study, which recruits from that small country as well as nearby areas of France, Germany and Belgium, has recruited 80 patients to date, and is collecting skin biopsies and spinal fluid in addition to the usual imaging and clinical markers.

Takeshi Ikeuchi of Niigata University, Japan, described the Japanese Longitudinal Biomarker Study in PSP and CBD (JALPAC).  It has accumulated 337 patients with at least one visit, of whom 257 have had at least two.  They found PSP-Richardson in a slightly higher percentage, 35%, than did the study in India.  They found a good correlation of the PSPRS with disease duration but, as expected, wide range of velocities of progression across patients. 

No one at the meeting provided an update on the US/Canada study, which focuses not specifically on PSP or CBD, but on a much more inclusive disease category called frontotemporal dementia (FTD).  PSP and CBD are often classified within the category of the FTD’s because they usually feature dementia of frontal lobe origin.  The protein aggregating in the brain cells is different in the various FTD diseases – tau, TDP-43 and FUS are the most common.  The study, called “ALL-FTD,” is headed by Brad Boeve at the Mayo Clinic Rochester and Adam Boxer and Howard Rosen at UCSF.  It presently includes 21 sites in the US and 2 in Canada. The longitudinal arm has a goal of 1,100 patients and the biofluid-focused arm, with just one visit apiece, aims for 1,000 patients.  I’ll let you know about current PSP enrollment once I can squeeze that out of someone, but for more info, try their website.

Gabor Kovacs of the University of Toronto described a project based in Japan to study “incidental PSP.”  This is early brain changes of PSP that had not yet started to cause symptoms by the time of death.  It is found in specimens donated by families whose loved one died without known neurological illness.  One such collection, at Banner Health in Arizona, found very mild PSP pathology in 5% of their autopsied brains.  This means that 5% of the elderly population may be incubating PSP.  Of course “may” is the critical word, but analyzing the medical, genetic, and toxin exposure backgrounds of such a large group of people, even in retrospect, could provide valuable clues to the cause of PSP.

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