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Original Investigation |

Effect of TMEM106B Polymorphism on Functional Network Connectivity in Asymptomatic GRN Mutation Carriers

Enrico Premi, MD1; Anna Formenti, MD1; Stefano Gazzina, MD1; Silvana Archetti, MD2; Roberto Gasparotti, MD3; Alessandro Padovani, MD1; Barbara Borroni, MD1
[+] Author Affiliations
1Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy
2III Laboratory of Analyses, Brescia Hospital, Brescia, Italy
3Neuroradiology Unit, University of Brescia, Brescia, Italy
JAMA Neurol. 2014;71(2):216-221. doi:10.1001/jamaneurol.2013.4835.
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Importance  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.

Design, Setting, and Participants  Academic tertiary referral center for neurodegenerative disorders in 17 asymptomatic carriers of aGRN+ and 14 healthy controls.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Altered Resting-State Functional Connectivity in an aGRN+ Participant vs a Healthy Control

A, Reduced brain connectivity within the left frontoparietal network, mainly involving the superior parietal lobule. B, Increased connectivity within the executive network in the right precentral gyrus. P < .001 uncorrected. Threshold value is 30 voxels. Reference coordinates for each slice are shown. Results are superimposed on a 3-dimensional brain template. aGRN+ indicates granulin Thr272fs mutation; R, right.

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Figure 2.
Decreased Brain Connectivity in an aGRN+ Participant According to the TMEM106B rs1990622 Polymorphism

A, Decreased connectivity associated with the at-risk TMEM106B T/T genotype in the left frontoparietal network. B, Scatterplot of a 2-sample t test analysis considering TMEM106B T/T vs *C (T/C or C/C) genotypes at significant coordinates of reduced left frontoparietal network connectivity. C, Decreased connectivity associated with the at-risk TMEM106B T/T genotype in the ventral salience network. D, Scatterplot of a 2-sample t test analysis considering TMEM106B T/T vs*C (T/C or C/C) genotypes at significant coordinates of reduced right ventral salience network connectivity. All analyses are superimposed on a 3-dimensional brain template. P = .001 uncorrected. Threshold value is 30 voxels. Reference coordinates for each slice are shown. aGRN+ indicates granulin Thr272fs mutation; R, right.

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