title: The clinical, neuroanatomical, and neuropathologic phenotype ofTBK1-associated frontotemporal dementia: A longitudinal case report.
abstract: BACKGROUND
  Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD). However, the phenotype ofTBK1-associated FTD is currently unclear.
  
  
  METHODS
  We performed a single case longitudinal study of a patient who was subsequently found to have a novel A705fs mutation in theTBK1gene. He was assessed annually over a 7-year period with a series of clinical, cognitive, and magnetic resonance imaging assessments. His brain underwent pathological examination at postmortem.
  
  
  RESULTS
  The patient presented at the age of 64 years with an 18-month history of personality change including increased rigidity and obsessiveness, apathy, loss of empathy, and development of a sweet tooth. His mother had developed progressive behavioral and cognitive impairment from the age of 57 years. Neuropsychometry revealed intact cognition at first assessment. Magnetic resonance imaging showed focal right temporal lobe atrophy. Over the next few years his behavioral problems progressed and he developed cognitive impairment, initially with anomia and prosopagnosia. Neurological examination remained normal throughout without any features of motor neurone disease. He died at the age of 72 years and postmortem showed TDP-43 type A pathology but with an unusual novel feature of numerous TAR DNA-binding protein 43 (TDP-43)-positive neuritic structures at the cerebral cortex/subcortical white matter junction. There was also associated argyrophilic grain disease not previously reported in otherTBK1mutation cases.
  
  
  CONCLUSIONS
  TBK1-associated FTD can be associated with right temporal variant FTD with progressive behavioral change and relatively intact cognition initially. The case further highlights the benefits of next-generation sequencing technologies in the diagnosis of neurodegenerative disorders and the importance of detailed neuropathologic analysis.
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Carolin A M
authors.initials: CA
authors.lastname: Koriath
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Bocchetta
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Emilie
authors.initials: E
authors.lastname: Brotherhood
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Ione O C
authors.initials: IO
authors.lastname: Woollacott
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Penny
authors.initials: P
authors.lastname: Norsworthy
authors.affiliation: Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.affiliation: Applied Genomics for Neurodegenerative Diseases, German Centre for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Blauwendraat
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Dick
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gordon
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Harding
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Crutch
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Warren
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.affiliation: Department of Neurodegenerative Disease, MRC Prion Unit, UCL Institute of Neurology, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rohrer
keywords: Frontotemporal dementia; Neurogenetics; Neuropathology; TBK1