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BRAIN
A JOURNAL OF NEUROLOGY
1 Cognitive Neurology and Alzheimer’s Disease Centre, Northwestern University, Chicago, IL, USA
2 Department of Psychiatry and Behavioral Science, Northwestern University, Chicago, IL, USA
The semantic variant of primary progressive aphasia (PPA) is characterized by the combination of word comprehension deficits,
fluent aphasia and a particularly severe anomia. In this study, two novel tasks were used to explore the factors contributing to
the anomia. The single most common factor was a blurring of distinctions among members of a semantic category, leading to
errors of overgeneralization in word–object matching tasks as well as in word definitions and object descriptions. This factor
was more pronounced for natural kinds than artifacts. In patients with the more severe anomias, conceptual maps were more
extensively disrupted so that inter-category distinctions were as impaired as intra-category distinctions. Many objects that could
not be named aloud could be matched to the correct word in patients with mild but not severe anomia, reflecting a gradual
intensification of the semantic factor as the naming disorder becomes more severe. Accurate object descriptions were more
frequent than accurate word definitions and all patients experienced prominent word comprehension deficits that interfered with
everyday activities but no consequential impairment of object usage or face recognition. Magnetic resonance imaging revealed
three characteristics: greater atrophy of the left hemisphere; atrophy of anterior components of the perisylvian language network
in the superior and middle temporal gyri; and atrophy of anterior components of the face and object recognition network in the
inferior and medial temporal lobes. The left sided asymmetry and perisylvian extension of the atrophy explains the more
profound impairment of word than object usage and provides the anatomical basis for distinguishing the semantic variant of
primary progressive aphasia from the partially overlapping group of patients that fulfil the widely accepted diagnostic criteria
for semantic dementia.
Keywords: aphasia; frontotemporal lobar degeneration; language processing; progressive aphasia; semantic categorization
Abbreviations: PPA = primary progressive aphasia; PNFA = progressive non-fluent aphasia; SD = semantic dementia
Received March 13, 2009. Revised and Accepted April 17, 2009. . Advance Access publication June 8, 2009
ß The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournals.org
2554 | Brain 2009: 132; 2553–2565 M. Mesulam et al.
sented objects. Naming can fail because of impairments in object frequently seen in patients with cerebrovascular disease. One neu-
recognition (as in patients with associative agnosia), in word com- rodegenerative syndrome that has lent itself to particularly fruitful
prehension (as in the case of Wernicke’s aphasia), in lexical retrie- investigations of this type is primary progressive aphasia (PPA).
val (as in the case of the tip-of-the-tongue phenomenon) in PPA is diagnosed when history and clinical investigations deter-
phonological encoding (as manifested by phonemic paraphasias) mine that the cause is neurodegenerative, and that the language
or in linking the object to its lexical representations (as in the case impairment (defined by a dissolution of word-finding, word
of optic aphasia) (Goodglass et al., 1976; Beauvois, 1982; Farah comprehension or grammar) is initially the principal obstacle to
and Wallace, 1992; Goodglass, 1998; Levelt et al., 1999; Riddoch the customary conduct of daily living activities (Mesulam, 1982;
et al., 1999; Jefferies and Lambon Ralph, 2006). It is not possible Weintraub et al., 1990; Mesulam, 2003; Rogalski and Mesulam,
to name an object if is not recognized, if the word that represents 2007). Individual differences in the nature of the language impair-
its name is not comprehended, or if the linkage of object to word ment have led to the identification of several variants of PPA.
becomes ineffective. Conversely, neither comprehension of the According to a classification we use in clinical practice, the seman-
word nor recognition of the object is sufficient to support tic variant (PPA-S) is characterized by poor single word compre-
naming. Both must function optimally, simultaneously and inter- hension and fluent aphasia but relatively preserved syntax, the
actively for naming to succeed. agrammatic variant (PPA-G) by poor syntax and fluency but rela-
There is a rich and growing literature on anomia, including tively preserved word comprehension and the logopenic variant
articles that outline computational models of object classification, (PPA-L) by word-finding hesitations, poor repetition and variable
the category-specificity of naming disorders and the anatomical fluency on a background of preserved syntax and comprehension
remembered one instance when she had tried to ‘turn on’ a regular
Methods toothbrush as if it had been an electric toothbrush. To pursue this
incident further, one of us (E.R.) visited P1 at home and found no
Subjects evidence of object or appliance misuse. In fact, P1 had just baked a
cake and insisted that E.R. have a slice, serving it with no difficulty.
All patients were right handed as determined by the Edinburgh scale The relative preservation of visuospatial skills was shown by perfor-
(Oldfield, 1971), three were male and four female (Table 1). Age of mance on the Judgment of Line Orientation Test (Benton et al., 1978).
symptom onset was in their fifties. Duration of disease at the time of Only P7 performed in the mildly impaired range. Autobiographical
testing varied from 3 to 8 years. The diagnosis of PPA was made on memory, tested in the presence of an informant, revealed no major
the basis of a progressive language disturbance (i.e. aphasia) that was impairment of declarative memory for recent events. Reliable infor-
initially the most salient feature of the clinical picture (i.e. primary) and mants reported that the initial problems were confined to language
that was caused by neurodegeneration (i.e. progressive). The presence and that behavioural problems were not noticed for at least the first
of an aphasia was ascertained by an abnormal aphasia quotient (AQ) 2 years. Independence in activities of daily living was largely preserved,
on the Western Aphasia Battery (WAB) (Kertesz, 1982). The progres- especially in the initial 2–3 years and many patients were still driving,
sive nature of the problem was documented by history taken from the shopping and taking care of their finances at the time of testing.
patient, medical records and from at least one additional informant In addition to the seven PPA patients (P1–P7), five normal control
who lived in the same household. The diagnosis of semantic variant subjects (C1–C5) participated in Experiment 2. The control group did
was based on the presence of single word comprehension deficits as
not significantly differ from the patient group in age (62.8 6.7 versus
tested by a subset consisting of 36 of the difficult items (items 157–92)
59 5.2) or education (15 1.7 versus 16.6 2.5). Our patients did
P1 P2 P3 P4 P5 P6 P7
Age at testing/gender 57/F 65/M 56/F 63/M 53/F 65/M 54/F
Education 16 20 18 18 16 16 12
Handedness—Edinburgh R(+65) R(+80) R(+100) R(+100) R(+100) R(+100) R(+100)
Symptom duration (years) 3 7 7 5 3 8 3
Autobiographical memory failures NO NO NO NO NO NO NO
Object use/face recognition failures 1 NO NO NO NO NO NO
Judgment of line orientation (30) 21 20 30 – 28 25 17
PPT pictures (52) 40 38 42 42 28 29 42
PPVT (36) 16 NA 14 17 8 NA 10
Boston Naming Test 3/30 6/60 3/60 14/60 4/60 3/60 6/60
Western Aphasia Battery AQ (100) 77.5 81.2 75.5 88.2 65.9 73.2 83.2
WAB Subtests
Information content (10) 7 9 8 10 9 8 9
Fluency (10) 9 9 9 9 9 9 9
Yes/no questions (60) 57 51 51 60 51 54 60
Auditory word recognition (60) 45 49 46 59 42 56 54
Sequential commands (80) 75 80 64 71 28 70 80
Repetition (100) 98 95 84 97 74 85 91
Object naming (60) 20 19 21 33 6 12 31
Word fluency (animals) (20) 5 6 6 7 3 3 4
Sentence completion (10) 8 6 6 9 0 2 7
Responsive speech (10) 8 10 10 10 6 4 6
Handedness was evaluated with the Edinburgh scale. Autobiographical memory for recent events was assessed during the clinical visit in the presence of a reliable
witness to the events. Caregivers were questioned about evidence for failures in object usage or face recognition. Abnormal values in the PPT, PPVT-IV, BNT and the
Western Aphasia Battery Aphasia Quotient (WAB AQ) are shown in bold. Numbers in parentheses next to neuropsychological tests indicate maximum possible scores.
2556 | Brain 2009: 132; 2553–2565 M. Mesulam et al.
the areas of major atrophy. For two of the subjects (P2 and P6), only Each word and each picture was presented only once during the
outside scans were available and areas of atrophy were identified by word-to-picture and picture-to-word matching tasks. The set of stimuli
visual inspection of coronal and axial sections. For the other five in test forms A (drawings) and C (written words) were as follows:
patients, the scans were acquired with a Siemens Trio 3-Tesla scanner socks, belt, tie, vest, glove, brush, stapler, spatula, funnel, broom,
(Erlangen, Germany), using a 12-channel birdcage head coil, with a onion, corn, pepper, radish, celery, mouse, squirrel, frog, snake and
T1-weighted 3D MP-RAGE sequence (TR = 2300 ms, TE = 2.86 ms, flip cat. In forms B (drawings) and D (written words) the stimuli were:
angle = 9, FoV = 256 mm), recording 160 slices at a slice thickness of dress, coat, shirt, hat, shoe, hammer, pliers, saw, scissors, screwdriver,
1.2 mm according to the Alzheimer’s Disease Neuroimaging Initiative apple, grapes, strawberry, pear, pumpkin, elephant, hippopotamus,
(ADNI) protocol (http://www.loni.ucla.edu/ADNI/Research/Cores/ zebra, lion and camel. The stimuli were taken from the
documents/ADNI_Siemens_3.0T_Trio_VB12T.pdf). Cortical reconstruc- Northwestern Naming Battery (NNB), a comprehensive naming test
tion was performed on each subject with the FreeSurfer image analysis that is being standardized (Thompson and Weintraub). There were
suite version 4.1.0, which is available for download online (http:// no significant differences of word length, familiarity or frequency
surfer.nmr.mgh.harvard.edu/). Spherical maps for each subject when names of living objects (animals and fruits/vegetables) were
were morphed into a common spherical atlas using a non-linear sur- compared to names of non-living objects (clothing, tools)
face-registration procedure. This allows for high-registration, surface- (5.65 1.66 versus 5.60 2.19 for length; 3.27 0.87 versus
based averaging and comparison of cortical measurements across 3.73 0.55 for familiarity; 14.45 15.9 versus 26.17 30.7 for fre-
subjects (Fischl et al., 1999). The cortical thickness map of the PPA quency using the Celex database). Six of the seven subjects underwent
subject group was statistically contrasted to a map derived from a all phases of this experiment while subject P2 was only tested with the
separate control group of 11 right-handed subjects (five male, six word-to-picture forms. The testing in P6 included all phases but was
Statistical significance was indicated when P50.05. For cortical thick- The phenomenon of mispointing to semantically related items
ness data, statistical surface maps were generated using a general was not observed in P6 who had the longest disease duration at
linear model that displayed differences in cortical thickness between testing and whose incorrect choices targeted semantically related
groups for each vertex. False Discovery Rate (FDR), which controls for items as frequently as items that belonged to another category.
the expected proportion of false positives in a statistical test, was
applied to adjust for multiple comparisons (Genovese et al., 2002). Reciprocity of word–object matching impairments
A stringent threshold of P = 0.00001 was used to detect areas of and temporal consistency
peak cortical thinning (i.e. atrophy) in PPA compared to controls.
P1 was tested at her initial visit and 8 months later. Table 3 shows
her responses in the initial word-to-picture matching condition as
well as the responses in the word-to-picture and picture-to-word
Results conditions at retesting. Accuracy at the retesting session was iden-
tical (14 of 40 items) for both matching tasks. An item-by-item
Experiment 1 analysis of responses at the retesting session was conducted to
compute concordance, defined as the number of instances
Confrontation naming where a correct response in either matching task was associated
In agreement with the BNT scores, confrontation naming of the with a correct response in the other. This analysis showed a lack of
pictured objects used in this experiment was severely impaired concordance in 78% (95% CI 61–90%) of the 23 items that had
(Table 2). Failure rates ranged from a low of 55% in P4 to a been matched correctly in either the word-to-picture or picture-to-
Table 2 Errors and error types in naming the 40 object pictures and in the word-to-picture (W–P) and picture-to-word
(P–W) matching tasks (Experiment 1)
The last column on the right lists the percentage of unnamed objects that also failed to be matched correctly in the P–W task. This number indicates the proportion of
naming failures where the name was neither produced nor recognized.
2558 | Brain 2009: 132; 2553–2565 M. Mesulam et al.
Table 3 Matching performance of P1 during the initial Verbal definition of objects and their names
testing and at retest 8 months later (Experiment 1) Tables 4 and 5 show the distribution of the different kinds of
answers in the five patients for whom recordings were available.
Initial test Retest
The most common errors consisted of overgeneralizations, espe-
Stimulus W–P W–P P–W
cially at the sub-category level. In the group as a whole, the pat-
PUMPKIN pumpkin apple pumpkin tern of overgeneralization was nearly as prominent for words as it
HAT hat hat shirt was for objects. However, words elicited far fewer correct
ELEPHANT hippopotamus zebra hippopotamus responses than objects. In some cases, the generic descriptors
DRESS dress dress shirt
tended to be idiosyncratic or to reflect personal experience as in
PLIERS scissors pliers pliers
the case of P1 who called nearly all small animals ‘squirrels’, P3
SHOE shoe shoe shoe
who had been on safari and who defined the name and drawing
HAMMER hammer hammer scissors
ZEBRA hippopotamus elephant elephant of the larger animals as being ‘in Africa’, P5 who identified many
SHIRT coat shirt coat of the small animals as ‘bugs’ and P7 who defined many fruits as
STRAWBERRY grapes grapes pear ‘dessert’. There were also individual differences. Patient 5, for
APPLE grapes pumpkin grapes example, stood out with the high number of complete failures in
GRAPES grapes grapes grapes word definitions. There were instances where picture descriptions
SCREWDRIVER hammer scissors pliers were much more accurate than the definitions of the correspond-
PEAR apple hammer pear
Table 4 Distribution of various types of responses when patients were asked to verbally define the 40 words and
describe the 40 objects
Individual patients Wrong or ‘don’t know’ Too general at the category level Too general at the subcategory level Accurate
Word (%) Object (%) Word (%) Object (%) Word (%) Object (%) Word (%) Object (%)
P1 13 7.7 49 28 33 56 5.1 7.7
P3 5.1 5.1 23 20 54 39 18 42
P4 7.5 0 12 2.5 58 40 22 58
P5 42 10 40 45 12 32 5.0 12
P7 7.5 0 22 5.0 52 52 18 42
Percentages may not add up to exactly 100% because of rounding to two digits.
Group means Wrong or ‘don’t Too general at Too general at Accurate (%)
know’ (%) the category the subcategory
level (%) level (%)
Table 6 Samples from individual patients showing superiority of picture description in comparison to word definition
Table 7 Accuracy and response speed in computerized word-to-picture trials where the two choices on the screen were
semantically related or unrelated and where both were living or non-living objects (Experiment 2)
Figure 4 Distribution of cortical thinning in group of five PPA-S patients (P1, P3–P5 and P6) compared to a control group. f = fusiform
(occipitotemporal) gyrus; i = inferior temporal gyrus; m = middle temporal gyrus; p = temporal polar cortex; ph = parahippocampal gyrus;
s = superior temporal gyrus. Significance is displayed as a log(10) P-value.
Anomia in semantic variant of primary progressive aphasia Brain 2009: 132; 2553–2565 | 2561
decline with disease progression had been observed using a dif- These results suggest that the equivalent severity of impairments
ferent set of tasks in patients with the diagnosis of semantic in the two matching tasks does not necessarily reflect damage to
dementia, many of whom would have satisfied the diagnostic cri- convergent name-object representations for specific entities.
teria for PPA-S (Hodges et al., 1995; Rogers et al., 2004; Jefferies Rather, it appears as if some of the naming failures can also reflect
and Lambon Ralph, 2006; Rogers and Patterson, 2007). an impediment to the free flow of information between word and
The nature of the errors in the matching tasks of Experiment 1 object representations. Such a putative ‘traffic jam’ would cause a
led to the implication that the semantic map had been distorted bottleneck that compromises the efficiency and breadth of the
specifically through a blurring of distinctions among members of associations, without necessarily leading to an obliteration of spe-
the same category. This hypothesis was tested and confirmed by cific items in semantic knowledge stores. An alternative possibility
Experiment 2 where patients as a group were significantly slower is that semantic representations in PPA-S are underspecified so
in matching a word to one of two objects when both alternatives that the patient may randomly select correct or related items.
on the screen belonged to the same semantic category. Even in These observations on the lack of task and item consistency is
patients with 475% accuracy in this task (P1, P3, P4, P5 and P7), somewhat at odds with previous reports on semantic dementia
semantically related foils required a significantly longer time to (Jefferies and Lambon Ralph, 2006) and may reflect differences
reject. This slowing of responses indicated that members of the in the methods of testing, patient population or disease severity. It
same category were less easy to differentiate from one another does appear, however, that the obstruction to the flow of infor-
than from members of another category. Control subjects did not mation between an object and its name is more severe for the
display this semantic competition (or interference) effect. The only
The second caveat is more problematic. The picture of an object levels of identification that progress from the general to the
provides perceptual as well as associative clues about its nature increasingly more specific levels of representation (Gorno
whereas the name of an object provides clues that are strictly Tempini and Price, 2001; Damasio et al., 2004; Bright et al.,
symbolic. Surface clues, such as the shape of a garment or the 2005). The anterior components of this network, located in the
legs of an animal, could thus account for the apparently greater anterior fusiform, parahippocampal, inferotemporal and temporo-
preservation of object identification, complicating the interpreta- polar areas, were severely atrophied in our patients, but more so
tion of the results in Tables 4 and 5. However, it should be noted on the left side. The distribution of atrophy was remarkably uni-
that our subjects displayed frequent word comprehension lapses, form within the set of our seven patients and, with the possible
even for familiar words, whereas there was no evidence of con- exception of the consistent leftward asymmetry and clear involve-
sequential impairments of object usage. By such a practical criter- ment of perisylvian cortex, is in agreement with what has been
ion, our patients had relatively preserved non-verbal object reported in groups of semantic dementia patients (Price et al.,
knowledge at least for familiar items, a conclusion consistent 1996; Gorno-Tempini et al., 2004; Mummery et al., 1999;
with some but not all reports of patients with progressive semantic Bright et al., 2005).
aphasia (Bozeat et al., 2002; Negri et al., 2007). A cautious inter- The neurodegeneration in our patients triggered a reversion to a
pretation of the available information would lead to the conclusion shallower mode of associative encoding whereby words and
that neither word nor object concepts are intact in PPA-S and that objects elicited overly general, insufficiently differentiated con-
the distorted concepts lead to excessive generalizations reflecting a cepts. Only distinctions among major categories survived, each
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