BRAIN
A JOURNAL OF NEUROLOGY
Language networks in semantic dementia
Federica Agosta,
1,2
Roland G. Henry,
3
Raffaella Migliaccio,
1,4
John Neuhaus,
5
Bruce L. Miller,
1
Nina F. Dronkers,
6,7
Simona M. Brambati,
1,8
Massimo Filippi,
2
Jennifer M. Ogar,
1
Stephen
M. Wilson
1
and Maria Luisa Gorno-Tempini
1,9
1 Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA
2 Neuroimaging Research Unit, Institute of Experimental Neurology, Scientific Institute and University Hospital San Raffaele, Milan, Italy
3 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
4 Department of Neurological Sciences, II University of Naples, Naples, Italy
5 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
6 Center for Aphasia and Related Disorders, VA Northern California Health Care System, Martinez, CA, USA
7 Department of Neurology, University of California, Davis, CA, USA
8 Centre de recherche, Institut Universitaire de Ge´ riatrie de Montre´ al, Montre´ al, Que´bec, Canada
9 Center for Mind/Brain Sciences (CIMeC), University of Trento, Trento, Italy
Correspondence to: Maria Luisa Gorno-Tempini,
Memory and Aging Center,
Department of Neurology,
University of California,
San Francisco, 350 Parnassus Avenue,
Suite 905, San Francisco,
CA 94143-1207, USA
E-mail: marilu@memory.ucsf.edu
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key
aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal
lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion
tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance
imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-
parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate
fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each
tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging
results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic
resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel
and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean
diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus
was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus
callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The
left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional
magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study
shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter
connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal
superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during
sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and
may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology
and fluency in semantic dementia.
doi:10.1093/brain/awp233 Brain 2010: 133; 286–299 | 286
Received July 20, 2009. Accepted July 26, 2009. Advance Access publication September 16, 2009
 The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org

Keywords: semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based
morphometry
Abbreviations: ATL = anterior temporal lobe; BA = Brodmann area; DTI = diffusion tensor imaging; FA = fractional anisotropy;
FACT = fibre-assignment-by-continuous-tracking; fMRI = functional magnetic resonance imaging; ILF = inferior longitudinal fasci-
culus; 
//
= parallel diffusivity; 
?
= transverse diffusivity; MD = mean diffusivity; ROI = region of interest; SLF = superior longitudinal
fasciculus
Introduction
Semantic dementia is a clinical variant of primary progressive
aphasia and it is associated with progressive deterioration of seman-
tic knowledge, atrophy of the anterior temporal lobe (ATL) and most
often TAR DNA binding protein-43 related pathology (Hodges et al.,
1992; Snowden et al., 1992; Mummery et al., 2000; Rosen et al.,
2002; Davies et al., 2005). The pattern of impairment in semantic
dementia is characterized by a clear dissociation between marked
single-word comprehension, object knowledge and irregular word
reading deficits, and sparing of fluency, phonology, syntax and
working memory (Patterson and Hodges, 1992; Hodges and
Patterson, 1996; Gorno-Tempini et al., 2004).
Semantic deficits in semantic dementia have been attributed to
grey matter damage to the ATL (Mummery et al., 2000; Galton
et al., 2001; Rosen et al., 2002; Gorno-Tempini et al., 2004), but
the language network is a highly interactive system and the role of
altered anatomical and functional connectivity must be considered.
Results from several functional neuroimaging studies conducted in
semantic dementia suggest that certain aspects of the syndrome
could be due to a disconnection between the ATL and other
spared language areas (Mummery et al., 1999; Sonty et al.,
2007; Wilson et al., 2009). For instance, the ATL disconnection
could cause a dysfunction in the activity of posterior temporal
regions, i.e. ‘functional diaschisis’ (Mummery et al., 1999), altered
functional connectivity between Wernicke’s and Broca’s areas
(Sonty et al., 2007) or even compensatory hyperactivation in
the inferior parietal area (Sonty et al., 2007; Wilson et al.,
2009). Structural connectivity also needs to be investigated, but
evidence regarding the integrity of language white matter tracts in
semantic dementia and related disorders is still lacking.
Anatomical, network-level structural connectivity can be
investigated with diffusion tensor imaging (DTI)-based tracto-
graphy that allows in vivo segmentation of axonal trajectories, by
measuring the diffusivity of water along different directions on a
voxel-by-voxel basis (Conturo et al., 1999; Basser et al., 2000;
Wakana et al., 2004; Catani and Thiebaut de Schotten, 2008).
Once the tract is identified, values of fibre integrity can be obtained
including fractional anisotropy (FA), a measure of the degree to
which water diffusion has a common orientation, and mean diffu-
sivity (MD), a measure of the magnitude of water diffusion (Basser
et al., 1994). Furthermore, analysis of directional diffusivities—par-
allel (
//
) and transverse (
?
)—may provide additional information
on the underlying mechanisms of white matter integrity loss (Basser
et al., 1994). Myelin breakdown is consistently associated with
increased diffusivity perpendicular to the white matter tract (
?
),
while axonal damage is reflected in diffusivity changes parallel
(
//
) to the primary fibre orientation (Beaulieu, 2002; Song et al.,
2002; Sullivan et al., 2008; Vernooij et al., 2008). DTI metrics are
sensitive to the pathology of a number of neurological conditions
that result in axonal loss and/or disruption of myelin sheath, such as
stroke, multiple sclerosis, brain tumours and dementia (Rovaris et al.,
2005; Ciccarelli et al., 2008). To our knowledge, the only previous
DTI-based tractography study that included semantic dementia
patients in a group analysis identified DTI changes in the corpus
callosum and principal association fibres [i.e. uncinate fasciculus,
inferior longitudinal fasciculus (ILF) and arcuate fasciculus]
(Matsuo et al., 2008), however, the few semantic dementia patients
were not the focus of the study but were incorporated into a larger
cohort of behavioural frontotemporal dementia subjects, and the
contribution of semantic dementia patients to the overall finding is
uncertain (Matsuo et al., 2008).
The main white matter tracts that have been involved in lan-
guage processing are the ILF, the superior longitudinal fasciculus
(SLF), and the arcuate (Lu et al., 2002; Mandonnet et al., 2007;
Catani and Mesulam, 2008; Duffau, 2008; Glasser and Rilling,
2008). The ILF is a ventral associative bundle which connects
the temporal and occipital lobes, running along the lateral walls
of the inferior and posterior horns of the lateral ventricle (Catani
et al., 2003; Catani and Thiebaut de Schotten, 2008). The SLF is a
long associative bundle connecting the frontal regions with par-
ieto-temporal areas. It can be subdivided into different
components (Petrides and Pandya, 1984; Makris et al., 2005;
Schmahmann et al., 2007). Of interest to our study, subcom-
ponent II (SLF II) links the inferior parietal lobule with the posterior
and caudal prefrontal cortex, whereas SLF III connects the rostral
inferior parietal lobule with the ventral part of premotor and
prefrontal cortex (Petrides and Pandya, 1984; Makris et al.,
2005; Schmahmann et al., 2007). Another fibre tract within the
SLF, the arcuate fasciculus, connects the caudal part of the super-
ior and middle temporal gyri to the lateral prefrontal cortex
(Petrides and Pandya, 1984; Makris et al., 2005; Schmahmann
et al., 2007). To our knowledge, the integrity of these white
matter tracts in the semantic dementia and its relation to structural
and functional status of the cortex have never been investigated.
In this study, we used a multimodal imaging approach to study
the integrity of the left-hemisphere language network in semantic
dementia patients and healthy controls. In particular, we investi-
gated DTI-based macro- and micro-anatomical changes in the left
ILF, arcuate fasciculus and fronto-parietal SLF. The left uncinate
fasciculus and the genu and splenium of the corpus callosum were
also obtained for comparison with previous studies in frontotem-
poral dementia (Matsuo et al., 2008; Zhang et al., 2009). Patients
and controls underwent grey matter structural and functional
magnetic resonance imaging (fMRI) studies, allowing us to inves-
tigate the relationship between white matter findings and grey
matter integrity and functionality. We hypothesized that semantic
dementia would be associated with: (i) anatomical damage to a
Networks in semantic dementia Brain 2010: 133; 286–299 | 287