It’s not easy to diagnose the rare tauopathy progressive supranuclear palsy (PSP), but things might be looking up now that the old diagnostic guidelines have received a reboot. Armed with recent research findings and autopsy-confirmed cases, scientists led by Guenter Höglinger, German Center for Neurodegenerative Diseases (DZNE), Munich, and Irene Litvan, University of California, San Diego, have devised a new set of guidelines that not only help diagnose the disease earlier, but account for more of its different clinical presentations. Constructed by 47 clinician-researchers in this small field, the guidelines appear in the June issue of the journal Movement Disorders.
“We hope to identify patients with more subtle clinical symptoms in a much milder clinical state, as those patients would benefit more from a disease-modifying therapy,” said Höglinger. “Hopefully we will also be able to incorporate patients with other manifestations of the disease into clinical trials.”
“Professor Höglinger and his colleagues of the MDS-PSP study group are to be congratulated on setting new criteria,” John Steele wrote to Alzforum. Steele, who at the time worked with Jerzy Olszewski and J.C. Richardson at the University of Toronto, first described the disease in the 1960s (Steele et al., 1964). Indeed, PSP used to be called Steele-Richardson-Olszewski or Richardson syndrome.
The current diagnostic guidelines for PSP appeared almost two decades ago. They require both ocular-motor and postural problems to be present for a person to be diagnosed with PSP (Litvan et al., 1996). Over the years, these criteria proved specific for people with the typical presentation of the disease. However, a person needed to be relatively advanced in their course to be diagnosed. What’s more, the guidelines fail to pick up on cases that aren’t typical. For example, an atypical patient may have underlying PSP pathology, marked by aggregates of the four-repeat splice form of the microtubule-associated protein tau, but their first symptoms may look more like frontotemporal dementia, or Parkinson’s disease.
To design new criteria that capture a broader range of disease and catch it earlier, Hoeglinger and colleagues reviewed 462 articles about PSP, published after the previous guidelines, from the PubMed, Cochrane, Medline, and PSYCInfo databases. They also examined banked brain tissue that was accompanied by antemortem clinical data from 206 patients with PSP, as well as 231 disease controls who had had other proteinopathies.
Based on these data, the scientists built a system that addressed four categories of symptoms, up from the previous two. They kept ocular-motor dysfunction and postural instability. They added akinesia, in which voluntary movement is lost or impaired, and cognitive deficits. Depending on the severity of each clinical symptom, patients were assigned a level of certainty of one through three, with one being the most indicative of PSP (see image below).
Clinical Grid: The new PSP criteria incorporate four categories of clinical features. Lower-number levels imply more diagnostic certainty. [Courtesy of Hoeglinger et al., 2017, Mov Disord.]
The authors then devised a plan for how to translate those assessments into a diagnosis. To qualify for “probable” PSP, a person had to present with an ocular-motor problem plus one other category of deficit. For instance, restricted vertical gaze coupled with apathy or slowed thinking would be deemed probable PSP with a predominant frontal presentation. “Possible” PSP requires some sort of ocular-motor deficit either on its own or together with a different set of symptoms, for example, loss of grammar or limb rigidity. The one exception to the rule of requiring symptoms from two categories is akinesia, which is usually an symptom of advanced PD. Akinesia by itself is sufficient for a PSP diagnosis, because such an advanced PD symptom occurring early in disease raises suspicion of PSP rather than PD, Hoeglinger said.
The authors also introduced a new category called “suggestive of PSP.” These patients might have an ocular motor dysfunction, or not. They do not pass the threshold for possible or probable PSP, but may develop qualifying symptoms down the line. They may only have postural problems, or be unable to open their eyelids after closing them, for instance.
Since the new system for diagnosis is complicated, the researchers are developing an app that will help neurologists. The idea is that the clinician enters the symptom levels spelled out in the table, and the app will spit back out the diagnosis and certainty level.
Why make the system complex? Each of the clinical categories is useful for a different purpose, wrote the authors. In therapeutic and biological studies, only people with probable PSP should be included, since people with other diseases can dilute the outcome signals. This applies particularly to clinical trials currently underway for anti-tau antibodies and compounds that counter tau aggregation (Apr 2017 news). Possible PSP, on the other hand, might be well-suited for epidemiologic studies and clinical care, where researchers don’t want to miss cases of true PSP. People with “suggestive” symptoms could be included in longitudinal observational studies that map the progression of PSP. They could also help with development of biomarkers that herald early disease, and stand to benefit most from future disease modifying therapies.
The next step will be to validate the new criteria, said Hoeglinger. Two studies are underway—a retrospective study that applies the criteria to an independent set of autopsy-confirmed cases, and an international prospective study in the U.S., U.K., Europe, and Japan that will follow PSP patients as their disease progresses.—Gwyneth Dickey Zakaib
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