2024 American Academy of Neurology Abstract Website

Negin Badihian¹, Farwa Ali¹, Hugo Botha¹, Rodolfo Savica¹, Mary Machulda², Heather Clark¹, Julie Stierwalt¹, Nha Trang Thu Pham³, Matthew Baker⁴, Rosa Rademakers⁵, Val Lowe³, Jennifer Whitwell³, Keith Josephs¹
¹Department of Neurology, Mayo Clinic, Rochester, MN, USA., ²Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA., ³Department of Radiology, Mayo Clinic, Rochester, MN, USA., ⁴Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA., ⁵VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.

Objective:

To report clinical and neuroimaging characteristics of two patients with progressive supranuclear palsy-Richardson’s syndrome (PSP-RS) who were found to harbor novel mutations in the microtubule associated protein, tau (MAPT) gene and compare their characteristics to PSP-RS patients without mutation.

Background:

PSP is a 4R tauopathy that has rarely been associated with mutations in the MAPT gene. We identified two patients with PSP-RS who harbored novel MAPT mutations. It is unknown whether these two novel mutations are associated with any unique clinical or neuroimaging characteristics.

Design/Methods:

Among 190 patients with PSP who were recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic during 2009 to 2023, we identified two patients who fulfilled diagnostic criteria for PSP-RS and harbor novel MAPT mutations. To investigate the potential effects of these mutations, we compared the clinical, and neuroimaging characteristics of these two patients to 20 randomly selected patients with PSP-RS without a MAPT mutation.

Results:

MAPT c.1024G>A, p.Glu342Lys, and MAPT c.1217 G>A, p.Arg406Gln mutations were found in 2 men who developed symptoms consistent with PSP at 60 and 62 years, respectively. Both patients with mutations had poorer performance on tests of verbal and visual episodic memory and showed subtle medial temporal lobe hypometabolism on [18f] fluorodeoxyglucose PET scans. Both patients with mutations also had elevated flortaucipir-PET uptake in bilateral medial temporal lobe regions (amygdala, entorhinal cortices, hippocampi, parahippocampal gyri) compared to non-mutation cases, without differences observed in PSP-related regions (globus pallidum, midbrain, superior frontal cortex and dentate nucleus of the cerebellum).

Conclusions:

Glu342Lys and Arg406Gln mutations are associated with PSP but appear to modify the PSP-RS phenotype by targeting the medial temporal lobe regions. This medial temporal targeting may lead to a higher burden of underlying tau which results in greater episodic memory loss and neurodegeneration as measured with fluorodeoxyglucose PET.