Behavioral/Systems/Cognitive
Neural Correlates of Syntactic Processing in the Nonfluent
Variant of Primary Progressive Aphasia
StephenM.Wilson,1,2 Nina F. Dronkers,3,4 Jennifer M. Ogar,1 Jung Jang,1 Matthew E. Growdon,1 Federica Agosta,1,5
Maya L. Henry,1 Bruce L. Miller,1 andMaria Luisa Gorno-Tempini1,6
1Memory and Aging Center, Department of Neurology, University of California, San Francisco, California 94143, 2Department of Speech, Language, and
Hearing Sciences, University of Arizona, Tucson, Arizona 85721, 3Center for Aphasia and Related Disorders, Veterans Administration Northern California
Health Care System, Martinez, California 94553, 4Department of Neurology, University of California, Davis, California 95817, 5Neuroimaging Research Unit,
Institute of Experimental Neurology, Division of Neuroscience, Scientific Institute and University Hospital San Raffaele, 20132 Milan, Italy, and 6Center for
Mind/Brain Sciences, University of Trento, 38068 Rovereto, Italy
The left posterior inferior frontal cortex (IFC) is important for syntactic processing, and has been shown in many functional imaging
studies to be differentially recruited for the processing of syntactically complex sentences relative to simpler ones. In the nonfluent
variant of primary progressive aphasia (PPA), degeneration of the posterior IFC is associated with expressive and receptive agramma-
tism; however, the functional status of this region in nonfluent PPA is not well understood. Our objective was to determine whether the
atrophic posterior IFC is differentially recruited for the processing of syntactically complex sentences in nonfluent PPA. Using structural
and functionalmagnetic resonance imaging,we quantified tissue volumes and functional responses to a syntactic comprehension task in
eight patients with nonfluent PPA, compared to healthy age-matched controls. In controls, the posterior IFC showed more activity for
syntactically complex sentences than simpler ones, as expected. In nonfluent PPA patients, the posterior IFC was atrophic and, unlike
controls, showed an equivalent level of functional activity for syntactically complex and simpler sentences. This abnormal pattern of
functional activitywas specific to the posterior IFC: themid-superior temporal sulcus, another regionmodulatedby syntactic complexity
in controls, showed normal modulation by complexity in patients. Amore anterior inferior frontal region was recruited by patients, but
did not support successful syntactic processing. We conclude that in nonfluent PPA, the posterior IFC is not only structurally damaged,
but also functionally abnormal, suggesting a critical role for this region in the breakdown of syntactic processing in this syndrome.
Introduction
Syntactic processing is a complex cognitive function whereby
speakers and listeners implicitly construct and manipulate ab-
stract hierarchical structures that specify the relationships
between thewords andmorphemes thatmake up sentences (Gib-
son, 1998). Neuropsychological and functional neuroimaging
studies have shown that brain regions throughout dominant
perisylvian cortex are involved in syntactic processing (Bates et
al., 1987a,b; Caplan andHildebrandt, 1998; Dronkers et al., 2004;
Tyler and Marslen-Wilson, 2008; Friederici et al., 2009). One
region thought to be particularly important is the posterior infe-
rior frontal cortex (IFC), which we define as including the pars
opercularis and triangularis of the inferior frontal gyrus, and the
adjacent inferior frontal sulcus. Patients with damage encom-
passing this area often present with Broca’s aphasia, which is
characterizedby expressive and receptive agrammatism(Caramazza
and Zurif, 1976; Goodglass, 1993), and numerous functional im-
aging studies have revealed increased inferior frontal activation
for syntactically complex sentences relative to simpler ones
(Stromswold et al., 1996; Caplan et al., 1999).
Primary progressive aphasia (PPA) is a clinical syndrome in
which progressive speech and/or language deficits are associated
with degeneration of dominant hemisphere language regions
(Mesulam, 2001). In particular, degeneration of inferior frontal cor-
tex has been associated with the nonfluent/agrammatic variant of
PPA, in which syntactic deficits are prominent (Gorno-Tempini et
al., 2004). Nonfluent PPA patients produce agrammatic speech
(Hodges and Patterson, 1996; Thompson et al., 1997; Weintraub et
al., 2009), are impaired in comprehending syntactically complex
sentences (Hodges and Patterson, 1996; Grossman and Moore,
2005), and are relatively insensitive to grammatical violations
(Grossman et al., 2005; Cotelli et al., 2007). Structural imaging stud-
ies using voxel-basedmorphometryhavedemonstrated associations
between left inferior frontal volume lossandbothreceptive (Amici et
al., 2007; Peelle et al., 2008) and expressive (Wilson et al., 2010)
syntactic deficits.
Received May 17, 2010; revised Sept. 24, 2010; accepted Oct. 18, 2010.
This work was supported by the National Institutes of Health [National Institute on Deafness and Other Commu-
nication Disorders Grant R03 DC010878 to S.M.W., National Institute of Neurological Disorders and Stroke Grant R01
NS050915 toM.L.G.-T., and National Institute on Aging Grants P50 AG03006 and P01 AG019724 to B.L.M.]; State of
California (DHS 04-35516); Alzheimer’s Disease Research Center of California (03-75271 DHS/ADP/ARCC); Larry L.
Hillblom Foundation; John Douglas French Alzheimer’s Foundation; Koret Family Foundation; and McBean Family
Foundation. We thank Laura Calverley for drawing the stimulus pictures, Max Besbris, Victor Laluz, Paul Keselman,
Lara Stables, and Adam Gazzaley for assistance with functional imaging, Kate Rankin and Judy Pa for helpful
discussions, twoanonymous reviewers for their constructive comments, all of themembers of theUCSFMemory and
Aging Center who contributed to patient evaluation and care, and all of the patients, caregivers, and volunteers for
their participation in our research.
Correspondence should be addressed to Stephen M. Wilson, Department of Speech, Language, and Hearing
Sciences, University of Arizona, P.O. Box 210071, Tucson, AZ 85721-0071. E-mail: smwilson@u.arizona.edu.
DOI:10.1523/JNEUROSCI.2547-10.2010
Copyright © 2010 the authors 0270-6474/10/3016845-10$15.00/0
The Journal of Neuroscience, December 15, 2010 • 30(50):16845–16854 • 16845

Unlike in stroke-induced Broca’s aphasia, in which the poste-
rior IFC and surrounding regions are typically completely de-
stroyed, atrophy is gradual and progressive in PPA. Since
functional and structural changes in neurodegenerative disease
do not necessarily correspond directly (Dickerson and Sperling,
2009), this raises the question of to what extent surviving neural
tissue in this region is functional. Metabolic studies have shown
hypometabolism of inferior frontal regions in nonfluent PPA
(Nestor et al., 2003, Rabinovici et al., 2008), but little is known
regarding task-related modulation of functional activity by syn-
tactic processing. One study of three nonfluent PPA patients
scanned during a sentence comprehension task showed reduced
left inferior frontal activity, but the small sample size did not
permit a direct comparison between patients and controls
(Cooke et al., 2003).
In this study, our primary aim was to determine whether the
atrophic left posterior IFC is differentially recruited for the pro-
cessing of syntactically complex sentences in nonfluent PPA, as it
is in normal subjects. We approached this question by using
structural and functional magnetic resonance imaging to quan-
tify regional changes in tissue volume and functional responses to
a syntactic comprehension task in patients with nonfluent PPA,
in comparison to healthy age-matched controls. More generally,
we compared the spatial distribution throughout the brain of
structural and functional changes, including potentially compen-
satory functional activity.
Materials andMethods
Participants. We successfully scanned eight patients with nonfluent PPA
and 24 normal controls over an 18 month period. Patients and normal
control subjects were recruited through theMemory andAgingCenter at
the University of California, San Francisco (UCSF). All participants gave
written informed consent, and the studywas approved by theCommittee
on Human Research at UCSF. Patients and controls received a compre-
hensive multidisciplinary evaluation including neurological history and
examination, neuropsychological testing, and neuroimaging.
A diagnosis of PPA required progressive deterioration of speech
and/or language functions, and that deficits be largely restricted to speech
and/or language for at least 2 years (Mesulam, 2001). Patients were diag-
nosed with the nonfluent variant of PPA based on new consensus guide-
lines (Gorno-Tempini et al., 2011). The nonfluent variant criteria require
the presence of one or both of two core features: agrammatism and/or
effortful speech. Additionally, at least two of three supporting features
must be present: comprehension deficits for syntactically complex sen-
tences, spared single-word comprehension, and/or spared object knowl-
edge. Neuroimaging results were not used for diagnostic purposes, but
only to rule out other causes of focal brain damage.
Additional inclusion criteria were fluency in English and a Mini-Mental
State Examination score of at least 15. Nine patients met these criteria and
were scanned, but one was excluded because she performed at chance on all
conditions, including those that required lexical knowledge alone (see be-
low), so all analyses were based on the remaining eight patients.
Two of the eight patients were severely agrammatic in their speech
production (e.g., “and uh a blanket . . . and . . . a thongs off the man . . .
and um . . . uh . . . teenagers um . . . in the kite”), two weremoderately so
(e.g., “the family is have a picnic, and um, the young son is flying their
kei- k- kite”), one was near-mute with severely agrammatic written lan-
guage (e.g., “man read book girl the coffee in cup”), one was near-mute
withmoderately agrammatic written language (e.g., “the couple having a
picnic, they are sitting a blanket under a tree”), and two had primarily
speech motor deficits, with intact syntax in production (e.g., “the fellow
is reading a book, the woman is pouring some l- liquids”), and mild
syntactic deficits evident only in comprehension of complex sentences.
All patients were clinically diagnosed with apraxia of speech, with severity
ranging from2to7onaseven-point scale (Wertz et al., 1984), and fourof the
eight were dysarthric (including the two who were near-mute).
Demographic, clinical, and neuropsychological characteristics for
all participants are provided in Table 1. There were no significant
differences between patients and controls in age, sex, handedness, or
education.
In addition to the 24 normal controls who took part in functional
imaging, structural images from another group of 50 healthy age-
matched controls were used to create a template for intersubject normal-
ization and voxel-based morphometry.
Experimental design. Participants were scanned with functional
MRI as they listened to sentences and selected the matching picture
from two choices: a target and a foil. Seven conditions that varied in
terms of the syntactic processing required (see below) were presented
in a block design. All conditions required sentence comprehension;
we did not use any low-level control conditions such as backwards
sentences or signal-correlated noise, since in pilot studies we had
found these to be confusing for some patients. There were three
blocks per condition, for a total of 21 blocks, presented in random
order. Each block was 28 s in length and contained four equally spaced
trials, and there were 16 s rest periods between blocks and at the
beginning and end of the experiment. The total duration of the func-
tional sequence was 940 s.
Table 1. Demographic, clinical, and neuropsychological characteristics of patients
and controls
Variable Controls Nonfluent PPA
Demographic
Age 66.8
4.2 69.3
7.3
Sex (M/F) 7/17 2/6
Handedness (R/L) 22/2 8/0
Education (years) 17.2
2.0 16.3
2.9
Clinical
Mini Mental Status Examination (30) 29.3
0.8 25.7
3.1*
Clinical Dementia Rating N/A 0.4
0.4 ††
Clinical Dementia Rating (sum of boxes) N/A 2.3
2.4
Age at disease onset N/A 63.8
6.7
Years from first symptom N/A 5.5
2.8
Language production
Confrontation naming (BNT, 15) 14.5
0.7 11.6
3.7*
Phonemic fluency (D words in 1 min) 17.6
4.1 6.7
3.6*†
Semantic fluency (Animals in 1 min) 23.8
4.3 11.2
5.5*†
Speech fluency (WAB, 10) 10.0
0.0 ‡ 4.9
3.5*
Apraxia of speech rating (MSE, 7) N/A 3.8
2.1*
Dysarthria rating (MSE, 7) N/A 2.5
3.1*
Repetition (WAB, 100) 99.5
0.9 ‡ 81.3
10.5*†
Language comprehension
Auditory word recognition (PPVT, 16) 15.7
0.7 13.6
2.7*
Sequential commands (WAB, 80) 80.0
0.0 ‡ 71.6
8.4*
Semantic knowledge (PPT-P, 52) 51.8
0.4 ‡ 49.0
2.9
Visuospatial function
Modified Rey–Osterrieth copy (17) 15.0
1.1 14.6
2.4
Visual memory
Modified Rey–Osterrieth delay (17) 11.7
2.3 9.4
3.4
Verbal memory
CVLT-MS trials 1– 4 (40) 28.7
3.1 ‡ 21.4
7.9*
CVLT-MS 30 s free recall (10) 7.9
1.6 ‡ 6.4
2.4
CVLT-MS 10 min free recall (10) 7.3
1.6 ‡ 0.1
0.4*
Executive function
Digit span backwards 5.6
1.2 3.4
1.3*
Modified trails (lines per minute) 37.8
12.6 19.3
11.8
Calculation (5) 4.8
0.4 4.9
0.4
Values aremeans
SD. Variableswere compared between patients and controls using t testwith unequal variance
where appropriate, the Wilcoxon signed-rank test for measures with floor or ceiling effects, and Fisher’s exact test
for discrete variables. *Significantly impaired relative to controls, p 0.05. †Excluding two patients who were
nearly mute. ‡Data from Gorno-Tempini et al. (2004) since present control groupwas not tested on these variables.
‡‡The Clinical Dementia Ratingwas 0 for 3 patients, 0.5 for 3 patients, and 1 for 2 patients. BNT, BostonNaming Test;
WAB, Western Aphasia Battery; MSE, Motor Speech Evaluation; PPVT, Peabody Picture Vocabulary Test; PPT-P,
Pyramids and Palm Trees—Pictures; CVLT-MS, California Verbal Learning Test—Mental Status. See Kramer et al.
(2003) for detailed description of neuropsychological testing procedures and Gorno-Tempini et al. (2004) for de-
tailed description of language testing procedures.
16846 • J. Neurosci., December 15, 2010 • 30(50):16845–16854 Wilson et al. • Syntactic Processing in Nonfluent PPA