Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers
Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carrier...
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Elsevier
2019-01-01
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Series: | NeuroImage: Clinical |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2213158219301019 |
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doaj-a3f8ca98fd184e7a904654d3aa928156 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Suzee E. Lee Ana C. Sias Eena L. Kosik Taru M. Flagan Jersey Deng Stephanie A. Chu Jesse A. Brown Anna A. Vidovszky Eliana Marisa Ramos Maria Luisa Gorno-Tempini Anna M. Karydas Giovanni Coppola Daniel H. Geschwind Rosa Rademakers Bradley F. Boeve Adam L. Boxer Howard J. Rosen Bruce L. Miller William W. Seeley |
spellingShingle |
Suzee E. Lee Ana C. Sias Eena L. Kosik Taru M. Flagan Jersey Deng Stephanie A. Chu Jesse A. Brown Anna A. Vidovszky Eliana Marisa Ramos Maria Luisa Gorno-Tempini Anna M. Karydas Giovanni Coppola Daniel H. Geschwind Rosa Rademakers Bradley F. Boeve Adam L. Boxer Howard J. Rosen Bruce L. Miller William W. Seeley Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers NeuroImage: Clinical |
author_facet |
Suzee E. Lee Ana C. Sias Eena L. Kosik Taru M. Flagan Jersey Deng Stephanie A. Chu Jesse A. Brown Anna A. Vidovszky Eliana Marisa Ramos Maria Luisa Gorno-Tempini Anna M. Karydas Giovanni Coppola Daniel H. Geschwind Rosa Rademakers Bradley F. Boeve Adam L. Boxer Howard J. Rosen Bruce L. Miller William W. Seeley |
author_sort |
Suzee E. Lee |
title |
Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers |
title_short |
Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers |
title_full |
Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers |
title_fullStr |
Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers |
title_full_unstemmed |
Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers |
title_sort |
thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers |
publisher |
Elsevier |
series |
NeuroImage: Clinical |
issn |
2213-1582 |
publishDate |
2019-01-01 |
description |
Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 “presymptomatic” clinically normal and three “prodromal” with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency. Keywords: Frontotemporal dementia, Progranulin, GRN, MRI, Thalamus |
url |
http://www.sciencedirect.com/science/article/pii/S2213158219301019 |
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doaj-a3f8ca98fd184e7a904654d3aa9281562020-11-24T21:49:18ZengElsevierNeuroImage: Clinical2213-15822019-01-0122Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriersSuzee E. Lee0Ana C. Sias1Eena L. Kosik2Taru M. Flagan3Jersey Deng4Stephanie A. Chu5Jesse A. Brown6Anna A. Vidovszky7Eliana Marisa Ramos8Maria Luisa Gorno-Tempini9Anna M. Karydas10Giovanni Coppola11Daniel H. Geschwind12Rosa Rademakers13Bradley F. Boeve14Adam L. Boxer15Howard J. Rosen16Bruce L. Miller17William W. Seeley18University of California, Memory and Aging Center, Department of Neurology, San Francisco, United States; Corresponding author at: UCSF Memory and Aging Center, MC: 1207, 675 Nelson Rising Lane, San Francisco, CA 94109, United States.University of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Neurobehavior Division, Department of Neurology, Los Angeles, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Neurobehavior Division, Department of Neurology, Los Angeles, United StatesUniversity of California, Neurobehavior Division, Department of Neurology, Los Angeles, United StatesMayo Clinic Jacksonville, Department of Neuroscience, Jacksonville, United StatesMayo Clinic, Department of Neurology, Rochester, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United StatesUniversity of California, Memory and Aging Center, Department of Neurology, San Francisco, United States; University of California, Department of Pathology, San Francisco, United StatesMutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 “presymptomatic” clinically normal and three “prodromal” with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency. Keywords: Frontotemporal dementia, Progranulin, GRN, MRI, Thalamushttp://www.sciencedirect.com/science/article/pii/S2213158219301019 |