Q351R MAPT mutation is associated with a mixed 3R/4R tauopathy and a slowly progressive cognitive, behavioural and parkinsonian syndrome

Abstract

Copyright © Author(s) (or their employer(s)) 2022. Introduction: We have previously reported the initial clinical and imaging findings of a woman with a novel MAPT Q351R mutation.1 2 We continued to assess her following these case reports until she died and have now analysed her brain at postmortem. Her case was of unique interest due to the novelty of the mutation and its clinical features1 as well as the strong binding seen on flortaucipir positron emission tomography (PET) imaging,2 which was suggestive of a very specific pathological finding, that of a mixed 3R/4R tauopathy, similar to that seen in other MAPT mutations (V337M and R406W),3 4 and consistent with the same type of paired helical filament tau pathology seen in Alzheimer’s disease (AD). She is the first patient with this mutation to come to autopsy and we report the findings in this study.

Methods: A patient with a Q351R mutation was seen over a 20-year period, during which time she was assessed clinically, and with repeated MR brain imaging (11 scans in total) as well as flortaucipir PET imaging. In this report, her MR imaging is compared against a cohort of 43 healthy individuals (all women; mean age 61.5 years old, range 49.7–68.5 years old). All participants gave their consent to take part. At the time of death, her brain was donated to the Queen Square Brain Bank for Neurological Disorders and underwent postmortem analysis.

Results: Clinical history She presented to a specialist cognitive neurology clinic in her late 40s with a 4-year history of amnestic symptoms and mild behavioural change, mainly in the form of apathy. Neurological examination was normal, but her initial neuropsychological assessment showed the presence of episodic and semantic memory impairment with other cognitive domains intact.1 Following this, there was a slow progression of cognitive and behavioural symptoms over the next 20 years, with increasing forgetfulness and apathy, as well as prominent disinhibition, change in appetite and musicophilia. In addition, 13 years into her illness, she developed parkinsonism with bradykinesia, rigidity and both resting and postural tremor. She was still living at home and was able to attend research appointments until her mid 60s. She died in her late 60s, 24 years into her illness.

Brain imaging: MR imaging throughout the course of her illness showed slowly progressive atrophy with a whole brain atrophy rate over the whole course of the illness of 0.7% per year (figure 1A). The pattern of involvement was initially dominated by focal medial temporal atrophy affecting the amygdala and anterior more than posterior hippocampus. Over time, there was progressive cortical involvement also, affecting the temporal and insular cortices and later the frontal and anterior cingulate cortices. Striatal atrophy, particularly ventrally, was seen later in the condition as well (figure 1B,C). In contrast, posterior cortical regions were relatively spared. Flortaucipir PET imaging showed strong binding of the tracer2 similar to that seen in both AD and a small subgroup of MAPT mutations (R406W and V337M) (figure 1D).