A novel diagnostic assay for parkinsonian tauopathies

Summary
The diagnosis of atypical parkinsonian disorders is difficult due to symptom overlap, especially at early stages.
As a result, these diseases often are misdiagnosed first as Parkinson’s disease or as another parkinsonian
disorder. Misdiagnosis not only causes high stress and anxiety to patients, families, and caregivers, but also is
a major impediment to developing effective therapy for these diseases. Some of the most challenging diagnoses
are those of the 4R-tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).
Although the original definitions of these diseases were relatively easy to distinguish, later pathological studies
showed that each has many subtypes with a large overlap, both with each other and with other movement
disorders and dementias. Though PSP and CBD (corticobasal degeneration, the pathological counterpart of
CBS) are distinct pathologically, biomarker studies have generally been unsuccessful in distinguishing between
them. However, a recent study (Horie et al., Nat. Med., 2022) has shown that mass-spectrometry detection of
two peptides derived from the second repeat in the microtubule-binding region (MTBR) of tau, called MTBR-
tau275 and MTBR-tau282, separated PSP from CBD with high sensitivity and specificity. These are exciting results
that could support future studies, including our ongoing biomarker studies of parkinsonian disorders, yet mass-
spectrometry is not ideal for routine biomarker analysis. Therefore, we propose to develop new assays using
aptamers specific for the two peptides, that will allow their detection in an ELISA-like assay format. To that end,
the Co-PI, Dr. Murakami, who is an aptamer expert will produce the needed aptamers and modify them to allow
sensitive detection of the minute amounts expected to be found in patient brain and CSF. We will then test the
assay using matching brain and CSF samples from patients diagnosed pathologically with PSP or CBD and
compare them with controls without a neurological disease. If successful, the new assay will provide the first
streamlined biomarker measurement for PSP and CBD/CBS, facilitating future diagnosis and clinical trials for
these diseases.

Grant Number: 1R21NS137072-01A1
NIH Institute/Center: NIH
Principal Investigator: GAL BITAN