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.

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).

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.