doi:10.

1093/brain/aws080 Brain 2012: 135; 1537–1553 | 1537

BRAIN
A JOURNAL OF NEUROLOGY

Quantitative classification of primary progressive

aphasia at early and mild impairment stages

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M.-Marsel Mesulam,1 Christina Wieneke,1 Cynthia Thompson,1,2 Emily Rogalski1 and
Sandra Weintraub1

1 Cognitive Neurology and Alzheimer’s Disease Centre, Northwestern University, Feinberg School of Medicine, 320 East Superior Street, Chicago,
IL 60611, USA
2 Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL 60208, USA

Correspondence to: M.-Marsel Mesulam,

Cognitive Neurology and Alzheimer’s Disease Centre,
Northwestern University,
Feinberg School of Medicine,
320 East Superior Street,
Chicago, IL 60611, USA
E-mail: [email protected]

The characteristics of early and mild disease in primary progressive aphasia are poorly understood. This report is based on 25
patients with aphasia quotients 485%, 13 of whom were within 2 years of symptom onset. Word-finding and spelling deficits
were the most frequent initial signs. Diagnostic imaging was frequently negative and initial consultations seldom reached a
correct diagnosis. Functionality was preserved, so that the patients fit current criteria for single-domain mild cognitive impair-
ment. One goal was to determine whether recently published classification guidelines could be implemented at these early and
mild disease stages. The quantitative testing of the recommended core and ancillary criteria led to the classification of 80% of
the sample into agrammatic, logopenic and semantic variants. Biological validity of the resultant classification at these mild
impairment stages was demonstrated by clinically concordant cortical atrophy patterns. A two-dimensional template based on
orthogonal mapping of word comprehension and grammaticality provided comparable accuracy and led to a flexible road map
that can guide the classification process quantitatively or qualitatively. Longitudinal evaluations of initially unclassifiable
patients showed that the semantic variant can be preceded by a prodromal stage of focal left anterior temporal atrophy
during which prominent anomia exists without word comprehension or object recognition impairments. Patterns of quantitative
tests justified the distinction of grammar from speech abnormalities and the desirability of using the ‘agrammatic’ designation
exclusively for loss of grammaticality, regardless of fluency or speech status. Two patients with simultaneous impairments of
grammatical sentence production and word comprehension displayed focal atrophy of the inferior frontal gyrus and the anterior
temporal lobe. These patients represent a fourth variant of ‘mixed’ primary progressive aphasia. Quantitative criteria were least
effective in the distinction of the agrammatic from the logopenic variant and left considerable latitude to clinical judgement. The
widely followed recommendation to wait for 2 years of relatively isolated and progressive language impairment before making a
definitive diagnosis of primary progressive aphasia has promoted diagnostic specificity, but has also diverted attention away
from early and mild disease. This study shows that this recommendation is unnecessarily restrictive and that quantitative
guidelines can be implemented for the valid root diagnosis and subtyping of mildly impaired patients within 2 years of symptom
onset. An emphasis on early diagnosis will promote a better characterization of the disease stages where therapeutic interven-
tions are the most likely to succeed.

Keywords: aphasia; logopenic; semantic; agrammatic; anomic

Received December 5, 2011. Revised January 15, 2012. Accepted February 5, 2012. Advance Access publication April 23, 2012
ß The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: [email protected]
1538 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

Abbreviations: BNT = Boston Naming Test; NAT = Northwestern Anagram Test; NAVS = Northwestern Assessment of Verbs and
Sentences; PPA = primary progressive aphasia; PPA-G = agrammatic variant of PPA; PPA-L = logopenic variant of PPA;
PPA-M = mixed PPA variant; PPA-S = semantic variant of PPA; PPVT = Peabody Picture Vocabulary Test; SPPT = Sentence
Production Priming Test; WAB-R = Western Aphasia Battery-Revised

Introduction based on the identification of known carriers of disease-causing

mutations prior to the onset of clinical manifestations. This strat-
The diagnosis of primary progressive aphasia (PPA) requires the egy has been fruitful in a number of conditions with autosomal
fulfilment of three core criteria. First, the patient should have an dominant transmission, such as Alzheimer’s disease, Huntington’s

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aphasic disorder of recent onset as manifested by distortions of disease and frontotemporal degenerations (Geschwind et al.,
word usage or comprehension that cannot be attributed to more 2001; Ringman et al., 2004; Marshall et al., 2007; Borroni
elementary motor or perceptual deficits. Second, this language et al., 2008). With the exception of isolated case reports
impairment should constitute the most salient neurobehavioural (Cruchaga et al., 2009), this approach is not applicable to PPA
deficit and the chief impediment to the pursuit of customary since families where genetic mutations lead to a consistent PPA
daily living activities during the initial stages of the illness. Third, phenotype in affected members are rarely encountered (Mesulam
the underlying disease should be neurodegenerative and, there- et al., 2007; Beck et al., 2008; Borroni et al., 2008).
fore, progressive (Mesulam, 2001, 2003; Mesulam and This study followed a more indirect approach for identifying
Weintraub, 2008). early and mild disease stages. It is based on 25 patients, whose
As the PPA syndrome was being delineated, the heuristic rec- aphasia quotient on the Western Aphasia Battery-Revised
ommendation was made to delay definitive diagnosis until 2 years (WAB-R; Kertesz, 2006) was 485%, 13 of whom were enrolled
of a relatively isolated and functionally salient aphasia had elapsed. within 1–2 years since symptom onset. Although there is no test
This ‘2-year rule’ was introduced to exclude patients with the battery that can capture the complexity of a language disorder
rapidly progressive aphasias of Jacob–Creutzfeldt disease, as well with a single number, we assumed that an aphasia quotient
as patients in whom word-finding difficulties could have appeared 485% denoted a mild impairment stage of the disease. This
to lead the clinical picture until further evaluation showed equally cohort was also used to test whether the recently published clas-
prominent amnestic, comportmental or visuospatial deficits char- sification guidelines for subtyping PPA into agrammatic, semantic
acteristic of other dementia phenotypes (Mesulam and Weintraub, and logopenic subtypes (Gorno-Tempini et al., 2011) could be
1992; Mesulam, 2001). applied in a rigorous and quantitative fashion to patients with
The 2-year rule promoted specificity and nosological uniformity mild impairment.
by ensuring that only patients with an extended period of pre-
dominantly (if not exclusively) aphasic impairments would receive
the root diagnosis of PPA. However, this emphasis on established Subjects and methods
disease also tended to divert attention away from the early and
prodromal stages. In fact, a rich literature on the established and
Participants
advanced phases of PPA has emerged while information on the
early stages is rather sparse and anecdotal (Weintraub et al., The subjects were selected from a set of 100 patients consecutively
1990; LeRhun et al., 2005; Knopman et al., 2009; Sapolsky referred to the Northwestern University Cognitive Neurology and
Alzheimer’s Disease Centre for the evaluation of progressive language
et al., 2010, 2011; Rogalski et al., 2011).
impairments between 2007 and 2011. Nineteen of the patients did not
In contrast to PPA, a great deal of attention has been paid to
receive a PPA diagnosis because the aphasia was accompanied by
early and mild impairment stages in typical amnestic dementias of
equally prominent impairments of memory, executive function or com-
the Alzheimer-type. Such investigations have led to the delineation portment, seven did not agree to participate and five were excluded
of preclinical and prodromal disease mechanisms in ways that have because of left-handedness. The remaining 69 patients fulfilled the
promoted diagnostic sensitivity and insights into pathophysiology criteria for a PPA diagnosis and were recruited into a longitudinal
(Petersen et al., 1999; Jack et al., 2003). Progress along this line research programme. The aphasia quotients on the WAB-R (Kertesz,
of research can be attributed to the high prevalence of Alzheimer’s 2006) ranged from 35% to 97%. Two of the patients lacked crucial
disease and the importance of age as a major risk factor. These test results. Of the remaining 67 patients, 25 with aphasia quotients
two features enabled large-scale longitudinal studies of high-risk 485% yielded the clinical, neuropsychological and imaging data for
this study. For the purpose of this longitudinal investigation, the 2-year
(i.e. elderly) individuals so that prodromal features of Alzheimer’s
rule was ignored and a reliable history of an insidiously progressive
disease and their neurodiagnostic correlates could be delineated
language impairment was deemed sufficient for inclusion. The 13 pa-
prospectively. This approach is not practical in PPA where preva-
tients who did not have symptom duration of 42 years at the time of
lence is low and where no major risk factor has yet been enrolment received a more definitive PPA diagnosis by the 2-year rule
established. on subsequent clinical contacts in person or by telephone interview.
A second successful approach for capturing preclinical and very All participants were Caucasian, native English speakers and
early manifestations of neurodegenerative syndromes has been right-handed. The study was approved by the Institutional Review
Early and mild progressive aphasia types Brain 2012: 135; 1537–1553 | 1539

Table 1 Criteria for the diagnosis of PPA and its subtypes

A. Criteria for the root diagnosis of PPA

Diagnostic criteria for PPA (Mesulam, 2001, 2003)
The following three conditions must all be present.
1. A new and progressive language disorder (aphasia) as documented by neuropsychologically determined abnormalities in one or more of the
following domains: grammaticality of sentence production, word retrieval in speech, object naming, word and sentence comprehension,
spelling, reading, repetition. Isolated impairments of articulation do not qualify.
2. Relative preservation of episodic memory, executive functions, visuospatial skills and comportment as documented by history, medical records
and/or neuropsychological testing.
3. Imaging and other pertinent neurodiagnostic test results that rule out causes other than neurodegeneration.

B. Criteria for PPA subtypes

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Non-fluent/agrammatic variant (PPA-G) (Gorno-Tempini et al., 2011)
A. One of the following core features must be present.
1. Agrammatism in language production.
2. Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech).
B. Two of the following three ancillary features must be present.
1. Impaired comprehension of syntactically complex (non-canonical) sentences.
2. Spared single-word comprehension.
3. Spared object knowledge.

Semantic variant (PPA-S) (Gorno-Tempini et al., 2011)

A. Both of the following core features must be present.
1. Impaired object naming.
2. Impaired single-word comprehension.
B. Three of the following ancillary features must be present.
1. Impaired object knowledge, particularly for low-frequency or low-familiarity items.
2. Surface dyslexia or dysgraphia.
3. Spared repetition.
4. Spared grammaticality and motor aspects of speech.

Logopenic variant (PPA-L) (Gorno-Tempini et al., 2011)

A. Both of the following core features must be present.
1. Impaired single-word retrieval in spontaneous speech and naming.
2. Impaired repetition of phrases and sentences.
B. Three of the following ancillary features must be present.
1. Phonological errors (phonemic paraphasias) in spontaneous speech or naming.
2. Spared single-word comprehension and object knowledge.
3. Spared motor speech.
4. Absence of frank agrammatism.

Mixed variant (PPA-M) (Mesulam et al., 2009)

A. Both of the following features must be present.
1. Agrammatism in language production.
2. Word comprehension impairments.

Board at Northwestern University and informed consent was obtained WAB-R, a comprehensive tool for testing multiple aspects of language
from all participants. Thirty-seven normal control subjects were re- function, including speech fluency, communicative content, word and
cruited and deemed cognitively unimpaired following evaluation with sentence comprehension, repetition, naming, reading and writing. A
the Uniform Data Set of the National Alzheimer’s Disease Coordinating subset of these tests (speech fluency, content, comprehension, repeti-
Centre (Morris et al., 2006; Weintraub et al., 2009). The initial clinical tion and naming) is used to derive the aphasia quotient, which has a
diagnosis of PPA was made by the same clinician (M.M.) in all cases. maximum score of 100. The WAB has been validated against other
Review of records, history from a reliable informant, administration of language measures and has good interrater and test–retest reliability
standardized neuropsychological measures and clinical neuroimaging (Kertesz, 2006).
were used to confirm that the patient fulfilled all three criteria for The classification of PPA subtypes revolves around the core lan-
the root diagnosis of PPA listed in Table 1. guage domains of grammatical ability, word comprehension, object
naming, repetition and motor aspects of speech (Table 1). Ancillary
features include syntactic comprehension, object knowledge, phonolo-
Assessment of aphasia severity gic integrity of speech and surface dyslexia. None of the currently
The Western Aphasia Battery-Aphasia Quotient was used as a global existing test batteries capture all of these domains. The WAB was
measure of aphasia severity. The aphasia quotient is derived from the therefore supplemented by more specialized tests as well as
1540 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

a systematic analysis of recorded narrative speech. The recording was This set had previously been used to construct a quantitative template
obtained by instructing participants to view a wordless picture book of for subtyping PPA (Mesulam et al., 2009). Each item requires the pa-
the story of Cinderella and tell the story to the examiner. The narrative tient to match a word representing an object, action or attribute to one
was recorded using Praat software (version 5.0, http://www.praat of four picture choices. Performance in the PPVT-IV correlates with
.org) and ‘start’ and ‘end’ times of each narration were automatically word–word association tasks but not with tests of fluency (Mesulam
recorded, transcribed and coded by experienced personnel in the et al., 2009). Object knowledge was assessed with the three picture
Aphasia and Neurolinguistics Research Laboratory at Northwestern version of the Pyramids and Palm Trees test (Howard and Patterson,
University (Thompson et al., 1995, 1997). All coded transcripts were 1992) where the patient is asked to decide which of two pictures is
entered into the Systematic Analysis of Language Transcripts (SALT; conceptually more closely associated with a target object.
Miller and Chapman, 2000). We did not find an alternative validated test of repetition that was as
Grammaticality of sentence production was assessed on the basis of comprehensive as the one included in the WAB-R. The WAB-R Repetition
three factors: (i) qualitative assessment of morphosyntactic errors Subtest contains 15 items of ascending difficulty ranging from the repe-
(of noun morphology, verb morphology, argument structure and tition of single words to word strings, phrases and sentences. The first nine

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word order) in the recorded Cinderella narrative; (ii) scores on items were too easy and were not failed by any of the subjects. We
Northwestern Anagram Test (NAT; Weintraub et al., 2009); and therefore selected the six most difficult items where perfect performance
(iii) scores on the Sentence Production Priming Test (SPPT) of the yields a score of 66. Performance on this subset (REP6) was used to quan-
Northwestern Assessment of Verbs and Sentences (NAVS), an titate repetition abilities. Surface dyslexia and dysgraphia were examined
experimental battery in its final stages of standardization (Thompson, with selected examples of exceptional words from the Psycholinguistic
2011). In the NAVS-SPPT, the patient is shown pairs of reversible Assessment of Language Processing in Aphasia (Kay, 1992). Surface dys-
action pictures and asked to produce sentences of varying complexity lexia was assessed by asking the patient to read the following words:
according to primes provided by the examiner. In the case of ‘island’, ‘blood’, ‘routine’, ‘ceiling’, ‘mortgage’, ‘debt’, ‘gauge’, ‘tomb’,
object-extracted ‘Wh’ questions, the examiner would first point to ‘cough’ and ‘bouquet’. Surface dysgraphia was assessed by asking the
one of the pictures, such as a girl kissing a boy, and prime the patient patient to write the following words: ‘elephant’, ‘sword’, ‘soldier’,
with a question in the form of ‘who is the girl kissing?’ The patient ‘knock’, ‘ghost’, ‘shoe’, ‘queen’, ‘sledge’, ‘watch’ and ‘castle’. A compos-
would then be shown a picture of the reverse action and asked to ite score was obtained by averaging performance in the reading and
generate a question with the same object-extracted ‘Wh’ structure. A writing of the words.
subset of 15 non-canonical sentences (passive voice, object-extracted To control for differently scaled variables, quantitative performance
‘Wh’ questions and object relatives) were used to derive a score of scores were transformed into a percentage of the total possible score.
grammatical production in the NAVS-SPPT. Performance in this test In view of the mild aphasia, we assumed that a performance that fell
can potentially be influenced by impairments of working memory or 590% indicated impairment. In all quantitated domains, this cut-off
fluency. We therefore also used the NAT (Weintraub et al., 2009). represented a performance of at least two standard deviations below
During administration of the NAT, the patient is asked to order single control values (Table 2). The words per minute counts were not trans-
words, each printed on a separate card, to be syntactically consistent formed into percentages.
with an action depicted in a target picture. This test correlates with The Clinical Dementia Rating Scale (Morris, 1993) and the
other tests of grammatical sentence production but not with tests of Mini-Mental State Examination (Folstein et al., 1975) were used to
naming, single word comprehension or motor speech production. A assess global aspects of functionality and cognition, respectively. The
subset of 15 items from the NAT, representing the same non-canonical Clinical Dementia Rating places the heaviest emphasis on episodic
sentence types as those we chose for the NAVS-SPPT, were used to memory dysfunction and its consequences in daily life. The
derive an additional score of grammaticality. Performance on these Mini-Mental State Examination is also most focused on memory and
two sets of 15 non-canonical sentences was averaged to derive a orientation. The loss of points on the Mini-Mental State Examination,
composite score of grammatical sentence production (NAT and especially in its memory subtest, can potentially be attributed to the
NAVS-SPPT). aphasia (Osher et al., 2007). However, a high score is a reliable
The determination of whether the patient had ‘effortful, halting marker of preserved global cognition.
speech with inconsistent speech sound errors and distortions’ as
stated in the list of criteria in Table 1 was based on listening to the Magnetic resonance imaging
recorded narrative of the Cinderella story. The presence of
word-finding hesitations and phonemic speech errors was also deter- Structural magnetic resonance imaging (MRI) scans were acquired and
mined by listening to the narrative sample. Transcription and coding of reconstructed with the FreeSurfer image analysis suite (version 4.5.0)
this sample generated a fluency score expressed in words per minute. as previously described (Mesulam et al., 2009; Rogalski et al., 2011).
The ability to understand syntactic structure was assessed with the Cortical thickness maps of the PPA group were statistically contrasted
Sentence Comprehension Test of the NAVS, based on a subset of 15 against 27 right-handed age- and education-matched healthy volun-
non-canonical sentences of the same type as those chosen for the teers. Differences in cortical thickness between groups were calculated
NAVS-SPPT and NAT. In the NAVS-Sentence Comprehension Test, by conducting a general linear model on every vertex along the cor-
the patient is shown two scenes depicting reversible actions and tical surface. False Discovery Rate (FDR) was applied at 0.05 to adjust
needs to choose the one corresponding to the stimulus sentence for multiple comparisons and to detect areas of peak cortical thinning
spoken by the examiner. (i.e. atrophy) in PPA compared to controls (Genovese et al., 2002).
The Boston Naming Test (BNT) was used to assess the naming of
objects (Kaplan et al., 1983). It is a 60-item standardized and challen-
ging test in which items are administered in order of decreasing fre-
quency of occurrence in the language. Word comprehension was tested
Results
with a subset of 36 moderately difficult items (157–192) of the The age and education levels of the overall PPA group were not
Peabody Picture Vocabulary Test (PPVT-IV; Dunn and Dunn, 2006). significantly different from that of the 37 control subjects
Early and mild progressive aphasia types Brain 2012: 135; 1537–1553 | 1541

Table 2 Age, education and language scores

Subjects (n) Age Education WAB-AQ NAT and PPVT BNT REP6 NAVS-SCTnc PPT PALPA Words
NAVS-SPPT(nc) pictures (exceptional) per
minute
NC (37) 62 (6.7) 16 (2.4) 99 (1) 98 (2) 98 (3) 97 (3) 99 (3) 99 (3) 98 (2) 98 (4) 132  20
PPA (25) 65 (7.9) 16 (2.1) 92 (4) 88 (19) 87 (21) 72 (29) 86 (12) 93 (10) 94 (6) 84 (17) 103  33
2 SD5NC 97 94 92 91 96 93 94 90 92

Percentage of accuracy (and standard deviation) on the WAB-AQ, NAT and NAVS-SPPT(nc), PPVT, BNT, REP6, NAVS-SCTnc, PPT Pictures and PALPA (exceptional) tests.
Thirty-five to 37 normal control (NC) subjects participated in establishing normative values for all tests except for the words per minute, where the control value was derived
from 12 subjects.
AQ = aphasia quotient; SCT = Sentence Comprehension Test; NAVS-SCTnc = Sentence Comprehension Test for non-canonical sentences; PALPA (exceptional) = score
derived from reading and spelling of exceptional words in the Psycholinguistic Assessment of Language Processing in Aphasia battery; PPT pictures = the picture form of the

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Pyramids and Palm Trees Test; REP6 = a subset of the six most difficult items in the repetition subtest of the WAB.

(Table 2). There were 13 males and 12 females in the PPA group agrammatic’ subtype of Table 1 based on abnormal grammatical-
(Table 3). Age of onset, as approximated by information derived ity in language production as well as the ancillary conditions of
from the patient, reliable informants and medical records, was in preserved word comprehension and object knowledge (Table 4).
the 50s for 9 patients, in the 60s for 10 patients and in the 70s for Two of the patients (Patients 1 and 2) showed abnormal compre-
6 patients. All six of the oldest onset patients were female hension of non-canonical sentences, another ancillary criterion for
(Patients 6, 7, 18, 19, 22 and 25). Impaired word finding was this subtype. Patient 9 was included in this group, despite a
an initial symptom in all but two of the patients. The next most Pyramids and Palm Trees Test score that fell under the 90%
common initial sign was abnormal spelling, as reported by nine cut-off, because of the distinct agrammaticality (70% score), pre-
patients. Additional early changes included speech abnormalities served word comprehension, low words per minute and failure to
(slurring or mispronunciation), word comprehension errors, fulfil the criteria for another subtype. Although Patient 10 did not
misuse of words (semantic paraphasias) and difficulty with arith- fulfil the criteria for agrammaticality, he also fit the ‘non-fluent/
metic (Table 3). Abnormality of syntax (word order) was reported agrammatic’ designation according to the criteria in Table 1, be-
as an initial symptom in only one patient (Patient 8). cause of distinctly effortful and distorted speech on the recorded
The selectivity of the language impairment was also reflected in narrative as well as spared word and object knowledge. In order to
the Clinical Dementia Rating Sum of Boxes, which provides a promote uniformity in classification, Patients 1–9 were given a
global score of functionality ranging from 0 (unimpaired) to 18 suffix of ‘G’ to denote impaired grammaticality and a clinical pic-
(severely impaired). In the PPA group, median Clinical Dementia ture consistent with the PPA-G designation, whereas Patient 10
Rating Sum of Boxes was 1. The Mini-Mental Status Examination was given the suffix of ‘Sp’ to indicate that speech, rather than
was also high, with a mean of 27.5  2.1, where 30 is the highest grammatical ability, would have determined his inclusion into the
possible score. In keeping with these low Clinical Dementia Rating
‘non-fluent/agrammatic’ subgroup of Table 1.
scores, information obtained from patients and informants con-
Four patients (Patients 11–14) showed abnormal performance in
firmed preserved functionality. Many patients continued to work,
both object naming and word comprehension tests. The additional
some devoted more time to social and recreational activities, and a
sparing of repetition and grammaticality and the abnormal scores
few became engaged in new complex hobbies.
in tests of object knowledge or surface dyslexia/dysgraphia ful-
Brain CT or MRI obtained at the time that the patient sought
filled the criteria for the semantic variant (PPA-S). This is the
initial medical consultation was negative or reported non-focal at-
only group where initial clinical and quantitative scans invariably
rophy in 19 of the 25 cases and was therefore not helpful in
showed left anterior temporal atrophy and where word compre-
reaching a diagnostic formulation in 76% of the sample. PET
hension impairments were reported as salient initial symptoms
had been obtained in 8 of the 19 cases where structural scans
(Table 3).
were uninformative, and revealed the characteristic asymmetric
Six patients (Patients 15–20) fulfilled the core criteria for the
hypometabolism of PPA in 5 cases.
logopenic variant (PPA-L) because of abnormalities in repetition
and word-finding hesitations, with or without additional object
Empirical validation of classification naming impairments. Ancillary criteria included absence of
guidelines and the overlapping criteria abnormalities in speech, of word/object knowledge and of major
for agrammatic and logopenic subtypes impairments of grammaticality. Phonemic paraphasia, another an-
cillary feature for this variant, was seen in three (Patients 15, 16
of primary progressive aphasia and 17) of the six patients in this group. The two core features for
One goal was to determine whether the guidelines listed in PPA-L, word-finding hesitations and poor repetition were also
Table 1 could be applied strictly and quantitatively to the subtyp- prominent in PPA-G. The possibility that PPA-L and PPA-G have
ing of patients at early and mild stages of impairment. Eight different types of repetition impairment based on sentence or
patients (Patients 1–8) fulfilled the criteria for the ‘non-fluent/ word length was not tested.
Table 3 Onset, duration, functionality and clinical imaging
1542

Case Gender/age Years since Initial symptoms as reported by Functionality in daily living activities in Global function Diagnostics prior to entry into this study
number at onset onset/WAB-AQ patient/informant areas other than language (CDR/MMSE)
WF SP SY CO MI NU OR MRI/CT PET
P1-G M/53 5/90 + + + Unimpaired, out of work for unrelated 1/24 Negative NA
reasons, active in complex hobby.
P2-G M/61 1–2/93 + + + Unimpaired, but retired due to the 0/28 Negative Left hemisphere
aphasia.
P3-G M/50 1–2/93 + + + + Unimpaired, working. 0.5/27 Left parietal NA
P4-G M/60 1–2/95 + + Unimpaired, working. 1/29 Negative NA
P5-G F/55 1–2/88 + + Part-time work as health care 0.5/26 Negative Left temporoparietal
professional.
| Brain 2012: 135; 1537–1553

P6-G F/79 1–2/94 + + + Unimpaired, holds major board 0.5/30 Negative NA

membership.
P7-G F/71 4/89 + Unimpaired, civic, social activities 0.5/30 Negative NA
maintained.
P8-G F/60 1–2/94 + + + Unimpaired, but retired due to the 0.5/26 Negative NA
aphasia.
P9-G M/66 1–2/94 + + Unimpaired, working. 1.5/26 Non-focal atrophy NA
P10-Sp M/66 3/97 + + + Unimpaired, but retired due to the 2.5/30 Negative Negative
aphasia.
P11-S F/51 3/95 + + Unimpaired, but less invested in custom- 2.5/29 Left hemisphere NA
ary activities.
P12-S M/59 4/88 + + Stopped work, mild disinhibition, drives, 4/27 CT-left anterotemporal NA
independent in daily living.
P13-S F/60 1–2/85 + + Continues part-time work, pursues 1.5/24 Left temporal NA
complex hobby.
P14-S M/64 1–2/87 + Stopped work for unrelated reasons, 1/28 Left anterotemporal NA
travels widely, has complex hobby.
P15-L M/66 3/92 + Unimpaired, retired for unrelated reasons, 0/30 Negative Minimally abnormal
performs complex chores.
P16-L M/58 5/97 + Unimpaired, but retired due to the 0.5/27 Negative NA
aphasia, volunteers in high-level
activity.
P17-L M/56 1–2/87 + + Had to retire, performs complex chores at 1/23 Non-focal atrophy Left temporoparietal
home, less confident in driving.
P18-L F/72 1–2/97 + Unimpaired, successful in competitive 0/28 Negative Left hemisphere
hobby.
P19-L F/74 4/89 + + + Unimpaired. 0/24 Non-focal atrophy NA
P20-L F/53 4/95 + Unimpaired, working 1/30 Negative Left hemisphere
P21-M F/55 8/88 + + + Quit job due to the aphasia, 2/26 CT-negative NA
otherwise independent.
P22-M F/76 1–2/88 + + Unimpaired. 0.5/28 Negative NA
P23 M/63 1–2/90 + + + Unimpaired, working. 1/29 Left hemisphere Left hemisphere
P24 M/60 3/96 + Unimpaired, working. 0/29 Negative Negative
P25 F/75 3/92 + Unimpaired. 2/29 Negative NA

CDR = Clinical Dementia Rating Scale, Sum of Boxes (range 0–18, 18 is most impaired); CO = word comprehension impairment; F = female, M = male; MI = misuse of words (as in semantic paraphasias); MMSE = Mini-Mental State
Examination (range 0–30, 30 is most preserved); NA = data not available; NU = impaired handling of numbers (arithmetic); OR = errors in orthography (spelling); SP = speech impairment; SY = abnormal syntax (word order);
M.-M. Mesulam et al.

WAB-AQ = Aphasia quotient of the Western Aphasia Battery; WF = word-finding impairment.

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Table 4 Performance in language tasks

Case Grammaticality of sentence construction Effortful, Word Word Object Repetition Syntax Object Surface Phonemic Words
apraxic finding comprehension naming comprehension knowledge dyslexia, speech per
speech hesitation dysgraphia errors minute
NAT and NAVS-SPPT Morphosyntax (recorded (recorded PPVT BNT Rep6 NAVS- PPT Pictures PALPA (recorded (recorded
(nc) (%) errors narrative) narrative) (%) (%) (%) SCTnc (%) (%) Exceptional narrative) narrative)
(%)
Early and mild progressive aphasia types

P1-G 46 Yes Yes Yes 97 87 65 80 100 60 Yes 86

P2-G 74 No No Yes 100 98 83 60 96 100 No 59
P3-G 86 No No Yes 92 95 98 93 92 95 No 96
P4-G 80 No Yes Yes 100 97 97 100 94 65 No 55
P5-G 70 Yes No Yes 92 82 76 93 100 50 Yes 96
P6-G 54 Yes No Yes 94 90 80 93 96 95 No 80
P7-G 54 Yes Yes Yes 97 98 85 93 96 100 Yes 48
P8-G 60 Yes No Yes 97 97 71 93 98 90 Yes 99
P9-G 70 No No Yes 97 83 89 93 83 100 Yes 110
P10-Sp 100 No Yes No 97 68 95 100 98 90 Yes 106
P11-S 96 No No Yes 50 62 97 100 79 90 No NA
P12-S 100 No No No 47 23 95 93 81 65 No 164
P13-S 100 No No No 28 7 94 100 81 45 No NA
P14-S 100 No No No 86 10 95 93 96 70 No 152
P15-L 84 No No Yes 97 98 85 87 98 75 Yes 104
P16-L 100 No No Yes 100 97 86 100 96 90 Yes 141
P17-L 84 No No Yes 97 90 85 73 100 80 Yes 119
P18-L 90 No No Yes 97 88 88 100 94 100 No 158
P19-L 96 No No Yes 97 83 61 100 98 100 No 94
P20-L 87 No No Yes 100 90 82 93 98 100 No 99
P21-M 67 Yes No Yes 50 50 61 87 88 75 Yes 83
P22-M 70 Yes No Yes 72 93 68 100 96 85 No 71
P23 100 No No No 97 35 85 100 92 100 No 83
P24 100 No No Yes 97 40 100 100 98 70 No 106
P25 96 No No Yes 97 47 94 100 94 100 No 154

Performance with 590% accuracy falls below 2 SDs from normative values and was considered impaired. Shaded cells indicate domains included in the core or ancillary criteria for that subtype. Values in bold indicate presence of the
core criteria for that subtype.
BNT = Boston Naming Test; NA = data not available; NAT and NAVS-SPPT(nc) = mean of the scores (for non-canonical sentences) on the Northwestern Anagram Test and on the Sentence Production Priming Test of the
Northwestern Assessment of Verbs and Sentences; NAVS-SCTnc = Sentence Comprehension Test for non-canonical sentences in the Northwestern Assessment of Verbs and Sentences; PALPA (Exceptional) = Score derived from
Brain 2012: 135; 1537–1553

reading and spelling of exceptional words in the Psycholinguistic Assessment of Language Processing in Aphasia battery; PPT pictures = the picture form of the Pyramids and Palm Trees Test; REP6 = a subset of the six most difficult
items in the repetition subtest of the Western Aphasia Battery.
| 1543

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1544 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

The classification guidelines of Table 1 lead to some ambiguity patient sample, which led to the development of this template,
in differentiating PPA-G from PPA-L. For example, a patient with had a wide range of aphasia severity and provided subtyping in-
agrammatism, impaired repetition, impaired single-word retrieval formation based on a cut-off level of 60%. For the current sample
and phonemic paraphasias would fulfil the criteria for both vari- of less impaired patients, we chose a stringent cut-off at the 90%
ants as long as motor speech, single word comprehension and level of accuracy, and also assumed that each axis would have a
object knowledge are spared. Thus, Patients 5, 8, 15, 17 and 20 ‘grey zone’ of 10 percentage points, so that performance of better
fulfilled criteria for PPA-G as well as PPA-L. We chose to include than 90% would indicate a definitely preserved domain whereas
the former two in the PPA-G group because of the prominent performance of worse than 80% would indicate definite impair-
agrammatism and the remaining three in the PPA-L group because ment. In this template, the upper left quadrant beyond the grey
we interpreted the exclusionary criterion number 4 for PPA-L in zone contains PPA-G, the lower right quadrant beyond the grey
Table 1 (‘absence of “frank” agrammatism’) specifically to desig- zone PPA-S and the lower left quadrant beyond the grey zone
nate ‘prominent’ abnormalities of grammaticality, such as those

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PPA-M. The upper right quadrant beyond the grey zone is the
that should lead to overt morphosyntax errors in speech. most complex. Patients in this quadrant who have repetition im-
Conceivably, patients with PPA-G and PPA-L may score poorly pairments are classified as PPA-L, those who do not are unclassi-
in tests of grammaticality for different reasons: PPA-G because fiable by the criteria in Table 1. The grey zone was introduced to
of a fundamental syntax processing impairment and PPA-L due indicate that the boundaries between subtypes have a certain
to poor verbal working-memory. Longitudinal studies will be amount of blurring and also to allow clinical judgement greater
needed to show whether the PPA-L patients who also marginally latitude in classifying borderline cases, including those that simul-
fulfil PPA-G criteria will develop more pronounced grammar taneously fulfil the PPA-G and PPA-L criteria in Table 1.
impairments in time. The usefulness of the template was tested on the 21 patients
Two patients (Patients 21 and 22) had significant impairments in with definite PPA-G, PPA-L and PPA-S classifications according to
both grammaticality and word comprehension. This could not be the core and ancillary criteria listed in Table 4. The three unclas-
attributed to severity since the WAB aphasia quotient was 88 in sifiable patients (Patients 23–25) and the one patient with impair-
both (Tables 3 and 4). These patients can be classified as having a ment of speech but not grammar (Patient 10) were excluded. As
mixed subtype and correspond to the previously proposed PPA-M shown in Fig. 1, this template placed seven of the patients
designation (Mesulam et al., 2009). Three patients (Patients (Patients 1, 2, 5 and 6–9) in the PPA-G quadrant, three in the
23–25) were not classifiable by the criteria of Table 1. All three PPA-S quadrant (Patients 11–13), two in the PPA-M quadrant
stood out because of pronounced abnormalities in object naming. (Patients 21 and 22) and two in the PPA-L quadrant (Patients
They came close to fulfilling the criteria for PPA-S except that 16 and 19). Seven patients fell in the grey zone. Two of these,
word comprehension was preserved. Patients 3 and 4, were classified as PPA-G because of speech and
Although fluency, defined as the rate of word production, is no grammar abnormalities without repetition impairments. Four pa-
longer a defining variable in the classification of PPA, words per tients (Patients 15, 17, 18 and 20) were classified as PPA-L be-
minute measures were computed for 23 of the patients (Table 4). cause of abnormal repetition and mildly impaired or preserved
The PPA-G and PPA-M groups had the lowest words per minute grammaticality, and Patient 14 was classified as PPA-S because
scores. However, there was considerable overlap at the level of the PPVT score was lower than the 90% cut-off while grammat-
individual patients. For example, three patients with PPA-L icality and repetition were preserved. All patients who were clas-
(Patients 15, 19 and 20) and two of the initially unclassifiable
sified into the agrammatic, logopenic, semantic and mixed
patients (Patients 23 and 24) had words per minute scores that
subtypes based on the 10 domains of Table 4 were thus also
fell within the range of those in the PPA-G group. Fluency scores
classified by the relatively simpler rules of this template.
of 560 words per minute were only seen in PPA-G, but such low
scores were not necessarily present in all members of this group.
The words per minute scores were slightly above normal in the Return of the unclassifiables
two PPA-S patients for whom the measurements were available,
and reflected their tendency for logorrhoea and circumlocution. It The three unclassified subjects were recalled for return assess-
remains to be seen whether low fluency in PPA-L predicts future ments after 2-year (Patients 23 and 24) and 1-year (Patient
evolution to PPA-G. 25) intervals (Fig. 2). According to the template in Fig. 1,
Patients 23 and 24 would be classified as PPA-S at the retesting
stage because of the drop in PPVT performance to 590% ac-
Template approach to classification curacy. However, by the strict criteria of Table 1 and our cut-off
Table 4 lists performance in all 10 domains required by the recent at 90% accuracy, Patient 24 would have remained unclassifiable
classification criteria for PPA (Gorno-Tempini et al., 2011). We because of the PPT performance of 92% accuracy, indicative of
wanted to see whether a more condensed template approach, preserved object recognition and the accuracy in the repetition
previously tested on 16 patients (Mesulam et al., 2009), could task, which fell just under 90%. One subject, Patient 25, re-
yield similar results. This template consists of two orthogonal mained unclassifiable by either the template or strict criteria, des-
axes, one representing word comprehension, as measured by the pite the severe naming impairment that had progressed by the
PPVT, and the other grammaticality, as measured by the com- second visit, and can best be characterized as representing an
bined scores on the NAT and NAVS-SPPT (Fig. 1). The previous anomic form of PPA. If comprehension or repetition impairments
Early and mild progressive aphasia types Brain 2012: 135; 1537–1553 | 1545

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Figure 1 Quantitative template. Filled circles indicate impaired performance (590% accuracy) in repetition tasks. Open circles indicate
preserved repetition. The interval between 80% and 90% accuracy represents a grey zone where boundaries between subtypes are
blurred. Numbers correspond to subject numbers in Tables 3 and 4. nc = non-canonical sentences.

were to arise in the future, the patient could then fulfil the temporoparietal junction, temporooccipital cortex and Brodmann
criteria for PPA-S or PPA-L. area 37 in the inferolateral temporal lobe were also atrophied. The
atrophy was mostly in the left hemisphere but there was also
prominent atrophy in the temporoparietal junction and temporo-
Anatomy of atrophy occipital cortex of the right hemisphere. The two patients with
Seven of the nine patients with PPA-G had quantitative MRI PPA-M (Patients 21 and 22) had peak atrophy only in the left
(Patients 2 and 4–9). Atrophy in this group was only detected in hemisphere, involving the inferior frontal gyrus, superior temporal
the left hemisphere and involved the inferior frontal gyrus, the gyrus and the anterior parts of the temporal lobe, including tem-
temporoparietal junction, anterior part of the superior temporal poropolar cortex (Fig. 4B). These atrophy maps reflect the pooled
gyrus and the posterior part of the middle frontal gyrus, extending data for each group. With the exception of the patients with
into the precentral gyrus (Fig. 3A). Peak atrophy in the four pa- PPA-S, cortical thinning was generally too mild to be detected
tients with PPA-S was predominantly, though not exclusively, in at the level of individual scans so that a more fine-grained linkage
the left hemisphere and covered nearly the entire temporal lobe between atrophy patterns and individual performance levels could
with extension into the adjacent temporoparietal junction and pos- not be explored.
terior orbitofrontal cortex. A much smaller region of the right The three unclassified patients were scanned at baseline and
temporal lobe, mostly at the anterior tip, also showed significant return visits. At baseline, Patient 23 had only a clinical scan. It
atrophy (Fig. 3B). Peak atrophy in the six patients with PPA-L showed asymmetric atrophy of the left anterior temporal lobe
extended into most of the left temporal lobe with the exception (Fig. 5A). The baseline scan for Patient 24 showed atrophy con-
of its medial and temporopolar aspects (Fig. 4A). The fined to the anterior tip of the left temporal lobe, extending into
1546 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

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Figure 2 Baseline (blue) and follow-up (red) performance of initially unclassifiable subjects. The vertical axis represents accuracy in
percentages. AQ = aphasia quotient; nc = non-canonical sentences; SCT = Sentence Comprehension Test; PALPAex = score derived from
reading and spelling of exceptional words in the Psycholinguistic Assessment of Language Processing in Aphasia battery; PPTpics = the
picture form of the Pyramids and Palm Trees Test; REP6 = a subset of the six most difficult items in the repetition subtest of the WAB-R.
Early and mild progressive aphasia types Brain 2012: 135; 1537–1553 | 1547

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Figure 3 Atrophy patterns in PPA-G and PPA-S. Red and yellow areas designate peak atrophy sites at False Discovery Rate = 0.05,
full-width at half-maximum = 20 when patient groups were compared to a normal control group of 27 subjects. FG = fusiform gyrus;
IFG = inferior frontal gyrus; ITG = inferior temporal gyrus; MFG = middle frontal gyrus; MTG = middle temporal gyrus;
OFC = orbitofrontal cortex; PHG = parahippocampal gyrus; STG = superior temporal gyrus; TPC = temporopolar cortex;
TPJ = temporoparietal junction.

the pole (Fig. 5C). Two years later, Patient 23 showed pronounced 485% in each of the 25 patients. Functionality and global cog-
anterior temporal and lesser inferior frontal gyrus atrophy, both nitive abilities were largely preserved. While depression and frus-
confined to the left hemisphere (Fig. 5B). The 2-year repeat scan tration were common, as has been shown in prior work (Medina
of Patient 24 showed a slight increase in the areas of anterior and Weintraub, 2007), they were not paralysing. According to
temporal atrophy with no detectable spread to the right hemi- current nomenclature, each of these 25 patients would fit the
sphere (Fig. 5D). Patient 25 had no detectable atrophy at baseline diagnosis of single-domain (language) mild cognitive impairment
or return visit. (Petersen et al., 2009). In keeping with the mild severity of the
disease, structural and metabolic imaging during the initial medical
work-up was frequently uninformative. The clinician must there-

Discussion fore be prepared to consider a diagnosis of PPA in patients

who are fully functional, come with the single chief complaint of
This investigation focused on the diagnosis, classification and intermittent word-finding hesitations, have no other detectable
clinicoanatomical features of early and mild impairment stages in impairment in routine assessments of cognition, and whose ima-
a group of 25 consecutively enrolled patients with PPA. For the ging may be negative. In fact, accurate diagnosis was rarely ren-
purpose of the current investigation, we disregarded the widely dered at the initial medical encounter and the emerging aphasia
adopted recommendation to delay a definitive root diagnosis of was occasionally attributed to stress, depression or dysfunctional
PPA until at least 2 years of an isolated aphasia had elapsed vocal cords.
(Mesulam and Weintraub, 1992) and included 13 patients with The classification of language abnormalities in neurodegenera-
progressive symptoms of lesser duration. The language disorder tive disease is at least as challenging as it has been in patients with
was relatively mild as reflected by a WAB aphasia quotient cerebrovascular accidents. Initial characterizations of the PPA
1548 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

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Figure 4 Atrophy patterns in PPA-L and PPA-M. Red and yellow areas designate peak atrophy sites at False Discovery Rate = 0.05,
full-width at half-maximum = 20 when patient groups were compared to a normal control group of 27 subjects. BA37 = Brodmann area
37; IFG = inferior frontal gyrus; ITG = inferior temporal gyrus; MTG = middle temporal gyrus; OFC = orbitofrontal cortex;
PHG = parahippocampal gyrus; STG = superior temporal gyrus; TPC = temporopolar cortex; TOC = temporooccipital cortex;
TPJ = temporoparietal junction.

syndrome recognized the heterogeneity of the associated lan- practicability of the guidelines by showing differences at the
guage impairments and their differences from the subtypes iden- ‘group’ rather than ‘individual patient’ level (Gorno-Tempini
tified by classic aphasiology (Mesulam, 1982, 2001; Mesulam and et al., 2004; Leyton et al., 2011). This is a potentially important
Weintraub, 1992). Some of the aphasic features seen in PPA were distinction since a classification method may succeed in reaching a
incorporated into diagnostic criteria that were being compiled for certain inclusionary or exclusionary criterion at the group level
the clinical classification of frontotemporal lobar degenerations without necessarily ensuring that this is also the case at the level
(Neary et al., 1998). However, the resultant syndromes did not of each member of the group. One goal for the current investi-
fully capture the clinical spectrum of PPA and left gaps that had to gation was to address some of these procedural questions by
be filled-in by new sets of guidelines (Gorno-Tempini et al., 2004). determining whether a rigorous application of the published
The resultant Gorno-Tempini et al. (2011) classification of PPA has criteria could be achieved through the use of specific tests and
introduced a more comprehensive platform for research and clin- explicit cut-off scores in successively enrolled individual patients at
ical practice (Gorno-Tempini et al., 2004, 2011). Algorithms and the mild and early stages of PPA.
templates have been published to implement this classification but
numerous details remain to be worked out before the guidelines
can be transformed from principles into specific procedures Mild impairment stage of the
(Mesulam et al., 2009; Leyton et al., 2011). First, the 2011 guide- agrammatic variant of primary
lines do not specify the individual tests to be administered or
cut-off scores to be used. Secondly, they do not specify whether
progressive aphasia
the resultant subtyping is detectable early in the disease or The PPA-G subgroup had the highest proportion of patients seen
whether it can still be discerned beyond a certain stage of severity. within 2 years of symptom onset, probably because the relatively
Moreover, investigations in this area have illustrated the frequent speech distortions, such as mispronunciations of
Early and mild progressive aphasia types Brain 2012: 135; 1537–1553 | 1549

comprehensive classification system of Table 1, was seen in only

two of the patients and was also detected in the PPA-L group.
Even at these early stages of the disease, cortical maps showed
significant atrophy sites in the inferior frontal gyrus, temporopar-
ietal junction, superior temporal gyrus, posterior middle frontal
gyrus and the precentral gyrus (Fig. 3A). A previous study on a
group of patients with PPA with a much broader range of severity
had demonstrated correlations of atrophy with grammatical com-
petence in the inferior frontal gyrus, with fluency in the middle
frontal gyrus and with repetition in the posterior superior temporal
gyrus (Amici et al., 2007; Rogalski et al., 2011). The presence of

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atrophy in these three regions, and the impairments of grammat-
icality, repetition and fluency in the patients, suggests that similar
clinicoanatomical correlations are likely to exist at the early stages
of PPA-G as well. Atrophy was confined to the left hemisphere.
The degree of asymmetry was greater than what had been shown
in a group of patients with PPA-G with more advanced disease
(Mesulam et al., 2009).

The assessment of grammaticality

and fluency
In clinical practice, grammaticality is usually determined qualita-
tively by detecting morphosyntactic errors in spoken or written
sentences. Five of the patients with PPA-G displayed this feature
but three did not, despite their abnormal NAT and NAVS-SPPT
score, indicating that the quantitative tests may provide greater
sensitivity for detecting impairments of grammaticality, especially
in mildly impaired patients. Fluency in neurodegenerative aphasia
is not necessarily correlated with grammaticality and these features
of language may have different, albeit partially overlapping,
Figure 5 Atrophy at baseline and return visit. Red and yellow neuroanatomical substrates (Weintraub et al., 2009; Rogalski
areas designate peak atrophy sites at False Discovery et al., 2011; Thompson et al., 2012). The complex relationship
Rate = 0.05, full-width at half-maximum = 20 when the patient between grammaticality and fluency is illustrated in Table 4. In
was compared to a normal control group of 27 subjects. (A) general, the patients with PPA-G had the lowest words per
Only a clinical scan was available at baseline for Patient 23 minute scores. However, there was also overlap between the
(P23). It shows asymmetrical atrophy of anterior temporal cortex range of scores seen in PPA-G and those noted in members of
and enlargement of the temporal horn (TH) on the left. (B–D)
all other groups except for PPA-S.
Quantitative scans of cortical thinning. ATC = anterior temporal
Although the newer classification system of Table 1 no longer
cortex; IFG = inferior frontal gyrus; STG = superior temporal
gyrus; TPC = temporopolar cortex. lists fluency as a criterion, it uses the ‘non-fluent/agrammatic’
designation for one of the variants. The new classification
system also allows patients with effortful or apraxic speech to
receive this designation even if they have no significant impair-
ment of grammaticality, as illustrated by Patient 10 (Table 4). Our
multi-syllable words, led to early detection and referral. The shared approach has been to sharpen the scope of this variant by empha-
core feature was the impaired grammaticality of sentence con- sizing impaired grammaticality as the single core feature
struction as revealed by the combined NAT and NAVS-SPPT and shortening the designation to ‘agrammatic variant’. Aphasic
scores. Only patients with PPA-G and PPA-M had 580% accur- patients with speech apraxia but preserved grammatical ability
acy in this domain. This feature and the preservation of single may need to be placed in a separate category, as was done
word comprehension allowed the 2D template of Fig. 1 to cor- in the case of Patient 10, in order to maintain uniformity of the
rectly classify these patients, even without taking the other ancil- resultant symptom clusters. In fact, the quantitative brain scan
lary criteria into consideration. Although not listed as an ancillary of Patient 10 showed atrophy confined to the left anterior
feature for PPA-G, the next most frequent abnormality was in temporal lobe, more in keeping with his anomia (68% accuracy
phrase and sentence repetition. Impaired comprehension of in the BNT) than with the pattern characteristic of the
syntactically complex sentences, an ancillary criterion in the ‘non-fluent/agrammatic’ PPA variant.
1550 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

Prodromal and mild impairment stage Mild impairment stage of the logopenic
of the semantic variant of primary variant of primary progressive aphasia
progressive aphasia The most conspicuous clinical feature of PPA-L is an intermittent
The longitudinal course of the two initially unclassifiable patients, word-finding (or retrieval) impairment. There is currently no
Patients 23 and 24, shows that PPA-S has a prodromal stage method for the meaningful quantitation of word-finding hesita-
during which severe naming impairments emerge in isolation tions in PPA-L. The average words per minute score may be
and in the absence of detectable abnormality of single word com- uninformative since patients may produce voluminous circumlocu-
prehension or object knowledge. During this prodromal period, tions in response to some word finding obstacles and silent gaps in
peak cortical atrophy can be confined to the anterior tip of the response to others. The BNT is not adequate either since some
temporal lobe, exclusively within the left hemisphere (Fig. 5A and patients who have word-finding hesitations during the verbaliza-

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C). As the word comprehension and lesser object knowledge im- tion of ideas may have little difficulty naming externally presented
pairments in PPA-S become established (e.g. in Patients 11–14), objects. Impaired retrieval in speech is currently assessed qualita-
the atrophy expands posteriorly into the left temporal lobe, an- tively by evaluating narrative output. It is a core feature of PPA-L
teriorly into the adjacent orbitofrontal cortex and contralaterally but also commonly seen in the other subtypes (Table 4). The
into the anterior tip of the right temporal lobe (Fig. 3B). second core feature of PPA-L is impaired repetition, reflecting dys-
The emergence of lesser but significant object knowledge impair- function of the phonological loop within the language network
ments at this stage may reflect the spread of the temporopolar (Gorno-Tempini et al., 2008). This feature is also non-specific
atrophy to the homologous parts of the right hemisphere, while since it is frequently present in PPA-G, although the mechanisms
the extension into orbitofrontal cortex may explain the high inci- for repetition impairments in these two variants may be different.
dence of comportmental abnormalities in PPA-S as the dis- Phonemic paraphasias, listed as an ancillary feature, are also nei-
ease progresses. PPA-S was the only group where initial ther specific to nor particularly frequent in PPA-L, at least at the
diagnostic brain scans frequently revealed asymmetric atrophy of mild disease stages (Table 4).
the left anterior temporal cortex in individual patients (Table 3) Although the two core features may not be specific for PPA-L,
and where the initial symptoms could be reported as ‘forgetting they fit the distribution of the atrophy shown in Fig. 4A. The
the meaning of words’ rather than word finding hesitations. In atrophy of temporoparietal junction and adjacent parts of the su-
all patients with PPA-S, performance on tests of word comprehen- perior temporal gyrus in this group may account for the impair-
sion (PPVT) was distinctly inferior to performance on tests of ment of phonological loop function while the atrophy of lateral
object knowledge (Pyramids and Palm Trees Test), further illustrat- temporal cortex and BA37 may account for the word retrieval
ing the fact that aphasia rather than a more general impairment of impairments (Amici et al., 2007; DeLeon et al., 2007;
object knowledge is the core feature of this variant (Mesulam Gorno-Tempini et al., 2008; Rogalski et al., 2011). The absence
et al., 2009). Although anomia, as measured by BNT scores, of atrophy in the inferior frontal gyrus is in keeping with the pres-
was seen in all subtypes, BNT accuracy 550% was confined to ervation of grammaticality. In contrast to PPA-G and PPA-S,
PPA-S and its prodromal stages (Table 4). Surface dyslexia or dys- where the underlying pathology usually belongs to the family of
graphia, listed as an ancillary feature, was seen in three of the four frontotemporal lobar degenerations, the majority of autopsies in
patients with PPA-S but was also present in other PPA subtypes PPA-L have shown the pathology of Alzheimer’s disease, a path-
(Table 4). ology that typically causes the greatest atrophy in the medial tem-
Investigations on patients with semantic dementia (a syndrome poral lobe of both hemispheres (Knibb et al., 2006; Mesulam
that partially overlaps with PPA-S) had led to the suggestion that et al., 2008; Rohrer et al., 2012). It is therefore interesting to
the temporopolar regions contain ‘amodal’ object representations note that there was only very minimal medial temporal atrophy
(Adlam et al., 2006). If so, atrophy in the temporopolar areas in PPA-L at this early disease stage. If Alzheimer pathology is re-
should trigger comparable if not simultaneous impairments of sponsible for neuronal destruction in the majority of the PPA-L
naming an object, recognizing its name and understanding its patients in this study, it must represent a highly atypical form of
nature. This was not observed in Patients 23 and 24, both of the disease that preferentially attacks language rather than
whom had left anterior and polar temporal atrophy. The severe memory networks of the brain.
impairment of object naming in these two patients at a time when
object knowledge and word comprehension were both relatively The mixed and anomic variants of
preserved, is therefore inconsistent with the postulated presence
of amodal object representations in the anterior temporal lobe,
primary progressive aphasia phenotypes
at least in the left hemisphere. The severe anomia in Patients 23 The classification proposed by Gorno-Tempini et al. (2011) does
and 24, at a time when the atrophy was confined to the left not include a ‘mixed’ subtype. Such a subtype, PPA-M, character-
anterior temporal lobe, adds to the growing evidence that this ized by the combined presence of impaired grammaticality and
region mediates critical language functions related to lexical rep- word comprehension was previously described, but the possibility
resentations and their linkage to object representations (Gitelman that it merely designated end-stage disease could not be ruled out
et al., 2005; DeLeon et al., 2007; Schwartz et al., 2009; Lambon (Mesulam et al., 2009). In the current cohort, mildly impaired
Ralph et al., 2010). Patients 21 and 22, both with WAB aphasia quotients of 88%,
Early and mild progressive aphasia types Brain 2012: 135; 1537–1553 | 1551

Conclusions and comments on

classification guidelines
In clinical practice as in the research laboratory, the classification
of PPA occurs one patient at a time. It is therefore necessary to
have explicit and quantitative guidelines that can be validated at
the individual patient level. Since understanding disease evolution
and exploring therapeutic options both place a premium on early
diagnosis, such classification methods should also be practicable at
the stages of mild impairment. This study shows that the root
diagnosis of PPA can be made in patients with symptom duration

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of 52 years. It also shows that a strict application of the
Gorno-Tempini et al. (2011) core and ancillary guidelines, through
the uniform administration of standardized tests and explicit
cut-off scores, led to the classification of 80% of patients at
the mild and early disease stages. The inclusion of a ‘mixed’
phenotype (PPA-M) into the list of variants raises the success
rate to nearly 90%. Some patients fit criteria for both PPA-G
and PPA-L and required clinical judgement for disambiguation.
This overlap in the criteria for PPA-G and PPA-L may well
become less prominent in patients with more advanced disease.
Furthermore, the necessarily qualitative assessment of speech
characteristics (e.g. paraphasias, word-finding and apraxia) intro-
duced additional components of clinical judgement into the pro-
cess of subtyping. Nonetheless, the resultant classification
displayed considerable biological validity as demonstrated by the
Figure 6 Road map for subtyping PPA. The road map can be phenotypically concordant patterns of cortical atrophy.
used quantitatively, in which case ‘definite’ impairment can be
The choice of tests was necessarily arbitrary. Different tests that
defined through a z-score or deviation from normative values by
assess analogous domains will obviously need to be chosen for
a certain number of standard deviations. It can also be used
qualitatively, in which case, ‘definite’ and ‘insignificant’ can be patients who speak languages other than English. In patients
assessed on the basis of their prominence in the clinical assess- with more advanced disease or lower education levels, cut-offs
ment or impact on daily activities. The choice of tests can vary will also need to be lower (Mesulam et al., 2009). The core vari-
based on language, education and severity level. The branch ables of word comprehension and grammatical competence fre-
point that depends on the integrity of repetition is particularly quently showed pronounced quantitative deviation from control
challenging in mild disease stages since so few of the pa- values when abnormal, and led to relatively unambiguous identi-
tients, other than those in the PPA-G group, showed major fication of PPA-S, PPA-G and PPA-M even at the early disease
impairments in this domain. NAT and SPPT(nc) = mean of the stages, as shown by the template of Fig. 1. The one core feature
scores (for non-canonical sentences) on the NAT and on the
that did not show such profound abnormality was repetition in
Sentence Production Priming Test of the Northwestern
PPA-L. Either repetition impairment becomes prominent later in
Assessment of Verbs and Sentences; REP6 = a subset of the
the disease in PPA-L or the test we chose was not sufficiently
six most difficult items in the repetition subtest of the WAB;
? = unclassifiable. sensitive. The current investigation also suggests that mildly im-
paired patients with intact grammar and comprehension but
severe anomia should be suspected of being at a prodromal
stage of PPA-S, that some of these patients may remain at the
show that the mixed phenotype can emerge as a distinct clinical anomic stage and reflect an anomic form of PPA, that the
form in mild or early disease. In keeping with this phenotype, peak ‘non-fluent/agrammatic’ variant should be divided into an agram-
atrophy sites in these two patients were confined to the anterior matic subgroup (with or without abnormal speech) and a sub-
tip of the left temporal lobe and the left inferior frontal gyrus, the group with disturbance of speech but not grammar, and that
former accounting for the comprehension impairment and the the ancillary criteria of surface dyslexia, phonemic paraphasia
latter for the agrammaticality (Fig. 4B). The three patients who and syntactic comprehension are not particularly useful in the
could not be classified at the initial encounter, Patients 23–25, subtyping process. The resultant classification strategy can be out-
displayed a relatively isolated but severe anomia. Two of these lined in the form of a road map, modelled after the algorithm of
progressed to fulfil the PPA-S criteria. Conceivably, the third Leyton et al. (2011), which can be navigated quantitatively or
may also do so in time. However, the possibility exists that qualitatively (Fig. 6).
some patients will maintain such a profile, representing an The defining biological feature of PPA is a distinctly asymmetric
anomic variant of PPA (PPA-A). atrophy revolving around the left hemisphere language network of
1552 | Brain 2012: 135; 1537–1553 M.-M. Mesulam et al.

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