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Journal Articles Acta Neuropathologica Year : 2021

Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers

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David Wallon
  • Function : Author
Susana Boluda
  • Function : Author
Anne Rovelet-Lecrux
  • Function : Author
Manon Thierry
  • Function : Author
Julien Lagarde
  • Function : Author
  • PersonId : 755946
  • IdRef : 130610062
Laetitia Miguel
Magalie Lecourtois
  • Function : Author
Antoine Bonnevalle
  • Function : Author
Marie Sarazin
  • Function : Author
Michel Bottlaender
  • Function : Author
Mathieu Mula
  • Function : Author
Serge Marty
  • Function : Author
Natsuko Nakamura
  • Function : Author
Catherine Schramm
François Sellal
  • Function : Author
Thérèse Jonveaux
  • Function : Author
Camille Heitz
  • Function : Author
Isabelle Le Ber
  • Function : Author
Stéphane Epelbaum
  • Function : Author
Eloi Magnin
Aline Zarea
  • Function : Author
Stéphane Rousseau
Olivier Quenez
  • Function : Author
Didier Hannequin
  • Function : Author
Florence Clavaguera
  • Function : Author
Dominique Campion
  • Function : Author
Charles Duyckaerts
  • Function : Author
Gaël Nicolas

Abstract

Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.
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Dates and versions

hal-03630053 , version 1 (04-04-2022)

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David Wallon, Susana Boluda, Anne Rovelet-Lecrux, Manon Thierry, Julien Lagarde, et al.. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers. Acta Neuropathologica, 2021, 142 (2), pp.259-278. ⟨10.1007/s00401-021-02320-4⟩. ⟨hal-03630053⟩

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