title: Effect of TMEM106B polymorphism on functional network connectivity in asymptomatic GRN mutation carriers.
abstract: OBJECTIVE
  Granulin (GRN) mutations represent one of the most frequent genetic causes of inherited frontotemporal dementia. The study of asymptomatic carriers of GRN Thr272fs mutation (aGRN+) provides a unique opportunity to study the natural history of the disease and the role of modulating factors on disease onset. It has been demonstrated that the TMEM106B polymorphism is associated with GRN-related frontotemporal dementia and affects age at onset in GRN mutation carriers.
  
  
  OBJECTIVE
  To ascertain whether TMEM106B genetic status modulates GRN disease by evaluating resting-state functional connectivity in aGRN+ individuals according to TMEM106 genetic variation.
  
  
  METHODS
  Academic tertiary referral center for neurodegenerative disorders in 17 asymptomatic carriers of aGRN+ and 14 healthy controls.
  
  
  METHODS
  Changes in resting-state functional connectivity, focusing on the default mode network, ventral and dorsal salience networks, executive network, frontoparietal networks, and attentive network and the effect of TMEM106B genotypes in aGRN+ participants and healthy controls (statistical nonparametric mapping).
  
  
  RESULTS
  aGRN+ participants showed decreased brain connectivity within the left frontoparietal network and increased connectivity in the executive network compared with healthy controls. The TMEM106B at-risk polymorphism (T/T) was associated with decreased connectivity within the ventral salience network (ie, middle frontal gyrus) and the left frontoparietal network (ie, left precuneus).
  
  
  CONCLUSIONS
  This study suggests that the TMEM106B polymorphism modulates brain connectivity in aGRN+ individuals, with additional damage of the ventral salience network and left frontoparietal network observed. Genotyping TMEM106B is of importance in aGRN+ individuals for prognostic purposes and to assess early brain damage.
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Premi
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Formenti
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gazzina
authors.affiliation: III Laboratory of Analyses, Brescia Hospital, Brescia, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.affiliation: Neuroradiology Unit, University of Brescia, Brescia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gasparotti
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
mesh_terms: D000328:Adult; D058070:Asymptomatic Diseases; D001921:Brain / Q000473:pathology; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009415:Nerve Net / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D000077153:Progranulins; D055815:Young Adult
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; C556915:TMEM106B protein, human