Dement Geriatr Cogn Disord 2014;38:147–152

DOI: 10.1159/000358233 © 2014 S. Karger AG, Basel

Accepted: December 25, 2013 1420–8008/14/0384–0147$39.50/0
Published online: April 8, 2014 www.karger.com/dem

Original Research Article

Evaluation of the New Consensus Criteria for

the Diagnosis of Primary Progressive Aphasia
Using Fluorodeoxyglucose Positron Emission
Tomography
Jordi A. Matias-Guiu a Maria Nieves Cabrera-Martín b
Rocío García-Ramos a Teresa Moreno-Ramos a Maria Valles-Salgado a
José Luis Carreras b Jorge Matias-Guiu a
Departments of a Neurology and b Nuclear Medicine, Hospital Clinico San Carlos,
Health Research Institute ‘San Carlos’ (IdISCC), Universidad Complutense de Madrid,
Madrid, Spain

Key Words
Dementia · Aphasia · Alzheimer’s disease · Frontotemporal dementia ·
Positron emission tomography · Primary progressive aphasia

Abstract
Background: New consensus criteria have been proposed to classify primary progressive
aphasia (PPA) into three variants: agrammatic, semantic, and logopenic. Some studies have
subsequently addressed the usefulness of these criteria, with controversial results. We aimed
to determine the correlation between the clinical diagnosis according to the new criteria and
brain topography in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Meth-
ods: Patients meeting the PPA criteria were prospectively recruited in a single center during
a period of 18 months. They were clinically classified according to the new criteria and under-
went FDG-PET. The cerebral metabolism of each patient was compared to a healthy control
group using statistical parametric mapping. The expected variant according to the analysis of
PET imaging was compared with the clinical diagnosis using the consensus criteria. Results:
32 patients were included. 90% of them fulfilled the consensus criteria and could be classified
into one of the three clinical variants. The correlation with the cerebral metabolism was high:
the kappa index was 0.91 in the agrammatic variant, 0.71 in the semantic variant, and 0.74 in
the logopenic variant. Conclusions: A high correlation with the diagnosis obtained using
FDG-PET was found. However, an overdiagnosis of the logopenic variant was observed. These
results support the use of the new criteria, but some modifications or complementary studies
may still be necessary. © 2014 S. Karger AG, Basel

Jordi A. Matias-Guiu
Department of Neurology, Hospital Clinico San Carlos
Profesor Martin Lagos St.
ES–28040 Madrid (Spain)
E-Mail jordimatiasguiu @ hotmail.com
 Dement Geriatr Cogn Disord 2014;38:147–152 148
DOI: 10.1159/000358233 © 2014 S. Karger AG, Basel
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Matias-Guiu et al.: Evaluation of the New Consensus Criteria for the Diagnosis of
Primary Progressive Aphasia Using FDG-PET

Background

Primary progressive aphasia (PPA) is a clinical syndrome characterized by a progressive

impairment of language and relative sparing of the other cognitive domains [1, 2]. New
consensus criteria have recently been proposed for its diagnosis [3]. In this consensus, three
variants of PPA have been recognized: agrammatic, semantic, and logopenic. Each variant has
been linked to different brain topographies in functional or anatomic neuroimaging [4].
Specifically, the agrammatic variant has been associated with left frontal impairment, the
semantic variant with anterior temporal damage, and the logopenic variant with left tempo-
roparietal atrophy and hypometabolism. This consensus may imply an important innovation
in the investigation of PPA, since it allows the use of a common terminology between different
research groups.
However, some studies have been published concerning the usefulness of the classifi-
cation and these criteria, with controversial results [5–7]. Positron emission tomography
imaging with 18F-fluorodeoxyglucose (FDG-PET) aids in the topographic diagnosis, where
hypometabolism is associated with neurodegeneration [8]. Topography in PPA has been eval-
uated by means of magnetic resonance imaging or PET [4, 9], but correlation between the
clinical variants and topography has not been studied on an individual basis. Our objective
was to evaluate the correlation of the clinical variants using the new criteria and the topog-
raphy of impairment in functional neuroimaging with FDG-PET in order to assess whether
the pattern of hypometabolism of each patient was the expected one according to the clinical
variant.

Methods

A total of 32 consecutive patients with the diagnosis of PPA were prospectively recruited in the Cognitive
and Behavioral Neurology Unit of our center between November 2011 and April 2013. This unit, although
subspecialized, may be easily accessed from the primary care setting. The patients were clinically evaluated
and classified according to the new criteria. Addenbrooke’s Cognitive Examination was used to evaluate
general cognition [10, 11]. Speech and language functions were assessed according to suggested recommen-
dations in the consensus document. The Progressive Aphasia Symptom Severity (PASS) scale was used to
graduate the severity of language impairment. The PASS scale was scored according to data obtained from
the interview with patients and their caregivers as well as the language assessment [12]. Statistical analysis
was performed using SPSS (version 16, SPSS Inc.). Results are given as frequencies and percentages or as
means and ranges. The Kruskal-Wallis test was used to compare the scores obtained in the PASS domains
between the three variants of PPA.
FDG-PET was performed in a Siemens Biograph TruePoint PET-CT that integrates a 6-detector CT
with a high-resolution lutetium oxyorthosilicate PET scanner. Clinical classification and PET imaging were
obtained with an interval of less than 15 days. Studies were performed after a 4- to 6-hour fasting and at
rest. 18F-FDG (5 mCi) was administered intravenously. The CT scan parameters were the following: kVp/
effective mAs/rotation 130/40/1; slice thickness 3 mm; reconstruction interval 1.5 mm, and pitch 0.75.
Statistical parametric mapping (SPM8) software (The Wellcome Trust Centre for Neuroimaging, Institute
of Neurology, University College of London, UK) was used for imaging preprocessing and statistical
analyses. The images of all subjects were spatially normalized to the reference space of the Montreal
Neurological Institute. They were smoothed using an isotropic gaussian kernel with a 12-mm full width at
half maximum. Each patient’s images were then compared with a group of 9 healthy controls using the
two-sample t test with age as a covariate (table 1). An uncorrected p value of <0.001 was used as a statis-
tical threshold. The pattern of hypometabolic clusters was classified into agrammatic, semantic, and logo-
penic according to the recognized topography of each variant [3]. In cases in which two or more topogra-
phies overlapped, the variant with the greater statistical significance and cluster size was considered.
Analyses of each patient’s images were blinded to clinical data, and the expected variant according to the
results of PET imaging was finally compared with the clinical diagnosis following the consensus criteria.
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DOI: 10.1159/000358233 © 2014 S. Karger AG, Basel
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Matias-Guiu et al.: Evaluation of the New Consensus Criteria for the Diagnosis of
Primary Progressive Aphasia Using FDG-PET

Table 1. Sample characteristics

PPA group Healthy control
group

Number of patients 32 9
Gender (male) 13 (40.9) 4 (44.4)
Age, years 75.9 (53–89) 72.5 (52–88)
Age of onset, years 72.5 (49–87) –
Education, years 9.5 (0–20) 7.2 (2–12)
Hypertension 17 (53.1) 2 (22.2)
Diabetes mellitus 2 (6.3) 1 (11.1)
Dyslipidemia 15 (46.9) 3 (33.3)
Stroke 0 0
MMSE score 18.8 (4–30) 27.5 (21–30)
ACE score 46.7 (13–89) 82.5 (68–98)

Values represent numbers with percentages in parentheses or

means with ranges in parentheses. MMSE = Mini-Mental State Exami-
nation; ACE = Addenbrooke’s Cognitive Examination.

Table 2. Main clinical characteristics of the patients

Agrammatic PPA Semantic PPA Logopenic PPA Undetermined PPA

Number of patients 12 3 14 3
Age, years 75.5 (53–87) 69.3 (66–74) 77.1 (68–89) 78.0 (68–86)
Symptom duration, years 2.7 (0.8–6.0) 5.6 (3.5–8.0) 3.7 (0.8–9.0) 2.8 (1.0–5.0)
Education, years 10.3 (0–20) 11.6 (7–16) 9.0 (0–18) 11.6 (8–16)
MMSE score 23.0 (14–30) 21.6 (12–28) 14.5 (4–26) 23.6 (15–29)
ACE score 57.5 (29–79) 43.3 (23–59) 36.0 (13–77) 68.0 (36–89)
FAQ score 12.2 (0–32) 16.6 (5–29) 15.0 (0–34) 2.6 (0–8)
IDDD score 1.6 (1.0–2.7) 1.6 (1.3–2.0) 1.5 (1.0–2.2) 1.1 (1.0–1.3)

Values represent numbers or means with ranges in parentheses. ACE = Addenbrooke’s Cognitive Exami-
nation; MMSE = Mini-Mental State Examination; FAQ = Functional Activities Questionnaire; IDDD = Interview
for Deterioration in Daily Living Activities in Dementia.

In this way, sensitivity, specificity, and predictive values of the clinical diagnosis were calculated and
compared to the expected topography; this would allow the prediction of the topography of the clinical
variants following the new criteria. Cohen’s kappa index was also calculated to estimate the correlation
between the clinical diagnoses according to the new criteria and FDG-PET topography. The Hospital Ethics
Committee approved the research protocol, and informed consent was obtained from the subjects or their
caregivers.

Results

Twenty-nine patients were classified into one of three variants according to clinical
criteria [3]. Twelve patients fulfilled the criteria for the agrammatic, 3 for the semantic and
14 for the logopenic variant. Three patients did not meet the criteria for any of the clinical
categories. The mean age of the patients was 75.9 ± 7.9 years, and the median time from the
onset of symptoms was 3.2 years (range 2.0–4.8). Other clinical characteristics are summa-
rized in table 2.
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DOI: 10.1159/000358233 © 2014 S. Karger AG, Basel
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Matias-Guiu et al.: Evaluation of the New Consensus Criteria for the Diagnosis of
Primary Progressive Aphasia Using FDG-PET

Table 3. PASS rating

Agrammatic PPA Semantic PPA Logopenic PPA χ2 (p value)a

Total (sum of boxes) 13.1 (3.5–26) 7.3 (5.5–9) 8.8 (2–15) 1.2 (0.522)
Articulation 0.8 (0–3) 0 (0–0) 0 (0–0) 14.6 (0.001)
Fluency 1.8 (1–3) 0.5 (0–1) 0.9 (0–2) 8.3 (0.015)
Syntax and grammar 1.6 (0.5–3) 0 (0–0) 0.1 (0–0.5) 20.5 (<0.0001)
Word retrieval and expression 1.8 (0.5–3) 1.3 (1–2) 1.8 (0.5–3) 0.9 (0.631)
Repetition 1.2 (0–3) 0.8 (0–2) 0.9 (0.5–2) 0.7 (0.687)
Auditory comprehension 0.8 (0–2) 1.1 (0.5–2) 0.6 (0–2) 1.1 (0.552)
Single-word comprehension 0.4 (0–2) 1.1 (0.5–2) 0.2 (0–1) 6.0 (0.048)
Reading 1 (0–3) 0.8 (0.5–1) 1.3 (0–3) 0.4 (0.787)
Writing 1.7 (0–3) 0.6 (0.5–1) 1.7 (0–3) 1.5 (0.451)
Functional communication 1.6 (0.5–3) 0.8 (0.5–1) 1.2 (0.5–2) 2.5 (0.273)

Values represent means with ranges in parentheses in the different domains of the PASS scale. Each
language domain was rated as 0 (normal), 0.5 (very mild impairment), 1 (mild), 2 (moderate) and 3 (severe)
according to defined criteria. a Kruskall-Wallis test.

Table 4. Correlation between the clinical diagnosis and neuroimaging findings

Clinical classificationa FDG-PETb Sensitivity, Specificity, Positive Negative

% % predictive predictive
positive negative
value, % value, %

Agrammatic PPA 91.6 100 100 95.2

Positive 11 1
Negative 0 20
Semantic PPA 60 100 100 93.1
Positive 3 0
Negative 2 27
Logopenic PPA 91.6 94.4 78.5 94.4
Positive 11 3
Negative 1 17
All variants 96.1 33.3 86.2 66.6
Positive 25 4
Negative 1 2
a ‘Positive’ refers to the number of patients with the clinical diagnosis of the specific variant according to

the consensus criteria. b ‘Positive’ indicates a pattern of hypometabolism compatible with the specific clinical
variant. For example, a clinical diagnosis of agrammatic PPA was obtained in 12 cases, but the expected
pattern of FDG-PET (left frontal hypometabolism) was observed in 11 cases.
There were no cases with a compatible pattern of FDG-PET in which the clinical diagnosis of the agrammatic
variant was not considered using the consensus criteria.

Regarding language assessment, scoring in the PASS domains was different between the
three variants in articulation (p < 0.0001), and syntax and grammar (p < 0.0001). A trend
towards differences in single-word comprehension (p = 0.063) was also observed. No statis-
tically significant differences were observed in the other language features (table 3). Cohen’s
kappa index between the PPA variants according to the new clinical criteria and FDG-PET was
0.93 (95% CI 0.8–1) in the agrammatic variant, 0.71 (95% CI 0.33–1) in the semantic variant
 Dement Geriatr Cogn Disord 2014;38:147–152 151
DOI: 10.1159/000358233 © 2014 S. Karger AG, Basel
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Matias-Guiu et al.: Evaluation of the New Consensus Criteria for the Diagnosis of
Primary Progressive Aphasia Using FDG-PET

and 0.74 (95% CI 0.5–0.97) in the logopenic variant. Table 4 shows the sensitivity, specificity,
and positive and negative predictive values of the clinical criteria in relation to the topog-
raphy in FDG-PET that would be expected.

Discussion

In this study, we evaluated the correlation between the clinical classification of PPA using
the new consensus criteria and the topographic diagnosis using FDG-PET imaging. An
important result was that 90% of the patients fulfilled the consensus criteria and could be
classified into one of the three clinical variants. Furthermore, of the 3 patients who could not
be categorized into one of these three subtypes, only 1 had findings in FDG-PET compatible
with a variant of PPA. This fact contrasts with a previous study in which 19 patients from a
case series of 46 (41.3%) could not be classified into a single variant, and only 2 cases fulfilled
the diagnostic criteria for the logopenic subtype [5]. This previous study included a compre-
hensive neuropsychological and linguistic assessment, but the impairment of the different
aspects of language was defined by comparing the results obtained in tests with a healthy
control group. Comparison of aphasic patients and healthy controls may be difficult due to
the fact that test scores usually follow a dichotomic distribution, rather than a normal one.
This methodological difference may be an explanation for the discrepancies in the results
reported, as well as the limited sample size in both studies.
Our study also found sensitivity, specificity and predictive values of each variant of PPA
generally above 90%. The correlation between clinical variants and topography was high,
especially in the agrammatic variant. However, a lower correlation was found in the other two
variants, with a remarkably modest sensitivity (60%) and positive predictive value (78.5%)
for the diagnosis of semantic and logopenic variants, respectively. This may somehow reflect
a certain overdiagnosis of the logopenic variant and suggest the need for an improvement in
the differential diagnosis between logopenic and semantic variants.
We did not observe statistically significant differences in repetition between the agram-
matic and logopenic groups. The consideration of repetition impairment as a core criterion
in the logopenic variant may possibly explain why a certain overdiagnosis of the logopenic
variant was observed. Deficiency in semantic memory in both semantic and logopenic
variants, although to a different extent, could be another confounding factor, especially in
early stages. Reference data for each type of PPA in most used tests in language assessment
would probably improve the clinical diagnosis [6, 13].
Age of onset in our sample was 72.5 ± 8.4 years, which is relatively older than what has
been reported in other studies of PPA. It contrasts with earlier publications, in which the
onset of PPA was characteristically observed in the presenium, that is, before the age of 65
[14]. Our health catchment area is known for its considerable number of aging patients,
which, together with the fact that our unit is easily and directly accessed from the primary
care setting, may explain why a later age of onset was observed in our study. Considering this,
it could be hypothesized that PPA may in fact be more frequent in older people than expected.
However, community-based studies would be necessary to draw definitive conclusions
regarding the epidemiology of PPA.
In conclusion, our study showed that the consensus criteria allow the classification of
patients with PPA into one of the three variants in most cases, and that there is a high correlation
with the diagnosis obtained by means of FDG-PET imaging. This confirms the usefulness of the
consensus criteria in the assessment of patients with PPA. However, there was a group of patients
in whom there was no correlation with functional neuroimaging. More studies seem to be
necessary to evaluate whether the modification of some of these criteria may increase the corre-
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DOI: 10.1159/000358233 © 2014 S. Karger AG, Basel
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Matias-Guiu et al.: Evaluation of the New Consensus Criteria for the Diagnosis of
Primary Progressive Aphasia Using FDG-PET

lation of clinical diagnosis and brain topography, or whether imaging studies such as FDG-PET
or magnetic resonance imaging are necessary to support the diagnosis [15]. This correlation
could be important to achieve an accurate diagnosis, especially if we consider the predisposition
of certain pathological and molecular subtypes by certain brain topographies [16–18].

Disclosure Statement

The authors report no conflicts of interest.

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