Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia

Maria Luisa Mandelli, Eduard Vilaplana, Jesse A. Brown, H. Isabel Hubbard, Richard J. Binney, Suneth Attygalle, Miguel A. Santos-Santos, Zachary A. Miller, Mikhail Pakvasa, Maya L. Henry, Howard J. Rosen, Roland G. Henry, Gil D. Rabinovici, Bruce L. Miller, William W. Seeley, Maria Luisa Gorno-Tempini

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non-fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre-determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures.

Original languageEnglish
Pages (from-to)2778-2791
Number of pages14
Issue number10
StatePublished - Oct 1 2016

Bibliographical note

Funding Information:
The study was supported by grants from the National Institutes of Health (NINDS R01 NS050915, NIA P50 AG03006, NIA P50 AG023501, NIA P01 AG019724); State of California (DHS04-35516); Alzheimer's Disease Research Centre of California (03-75271 DHS/ADP/ ARCC); Larry L. Hillblom Foundation; John Douglas French Alzheimer's Foundation; Koret Family Foundation; Consortium for Frontotemporal Dementia Research; and McBean Family Foundation and a Career Scientist Award (NFD) from the US Department of Veterans Affairs Clinical Sciences R&D Program. These supporting sources had no involvement in the study design, collection, analysis or interpretation of data, nor were they involved in writing the paper or the decision to submit this report for publication.

Publisher Copyright:
© 2016 The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


  • connectivity
  • functional connectivity
  • longitudinal atrophy
  • primary progressive aphasia
  • tractography

ASJC Scopus subject areas

  • Medicine (all)


Dive into the research topics of 'Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia'. Together they form a unique fingerprint.

Cite this