Primary progressive aphasia and the language network: The 2013

H. Houston Merritt Lecture

M.-Marsel Mesulam
Neurology 2013;81;456-462
DOI 10.1212/WNL.0b013e31829d87df

This information is current as of July 29, 2013

The online version of this article, along with updated information and services, is
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SPECIAL ARTICLE

Primary progressive aphasia and the

language network
The 2013 H. Houston Merritt Lecture

M.-Marsel Mesulam, MD ABSTRACT

Objective: Review of clinical and biological features of primary progressive aphasia (PPA).
Correspondence to Results and conclusions: The PPA syndrome arises when language-dominant (usually left)
Dr. Mesulam: hemisphere becomes the principal target of neurodegeneration. Depending on the distribution
mmesulam@northwestern.edu
of neuronal loss within the language network, agrammatic (PPA-G), logopenic (PPA-L), and semantic
(PPA-S) subtypes are identified. The most common underlying neuropathology is frontotemporal
degeneration with tauopathy in PPA-G, frontotemporal degeneration with TDP-43 proteinopathy
in PPA-S, and Alzheimer pathology in PPA-L. When Alzheimer pathology is detected, the neurofibril-
lary tangles show lower entorhinal-to-neocortical ratios and greater leftward asymmetry in PPA than
in the typical amnestic dementia of Alzheimer disease. The e4 allele of APOE, a major risk factor for
Alzheimer pathology in amnestic dementias, is not a risk factor for Alzheimer pathology in PPA.
These observations indicate that Alzheimer disease has biological variants with distinct patterns of
lesion distribution and perhaps also molecular background. The selective vulnerability of the lan-
guage network in PPA is likely to reflect complex interactions between factors that determine the
type of histopathology, on one hand, and those that influence the resilience of the language network,
on the other. A history of learning disability, including dyslexia, is emerging as one of the potential
factors in this second group of determinants. Patient care in PPA should be individualized so that
speech therapy can address the specific type of language impairment while pharmacologic therapy
is directed to the underlying disease process. Neurologyâ 2013;81:456–462

GLOSSARY
AD 5 Alzheimer disease; ATL 5 anterior temporal lobe; bvFTD 5 behavioral variant of frontotemporal dementia; CBDp 5
corticobasal degeneration pathology; CVA 5 cerebrovascular accidents; FTLD-TAU 5 frontotemporal lobar degeneration
with tauopathy; FTLD-TDP 5 frontotemporal lobar degeneration characterized by abnormal precipitates of the transactive
response DNA binding protein TDP-43; IFG 5 inferior frontal gyrus; NFT 5 neurofibrillary tangles; PPA 5 primary progressive
aphasia; PPA-G 5 agrammatic subtype of primary progressive aphasia; PPA-L 5 logopenic subtype of primary progressive
aphasia; PPA-S 5 semantic subtype of primary progressive aphasia; PSPp 5 progressive supranuclear palsy pathology;
TPJ 5 temporoparietal junction.

Not long ago, the terms dementia and Alzheimer disease (AD) were used synonymously, and
memory loss was considered an inevitable feature of dementia. This is no longer the prevailing
opinion. We now know that there are multiple neurodegenerative entities that can cause demen-
tias without Alzheimer pathology or memory loss. Primary progressive aphasia (PPA) is one of
the syndromes that led to this broadening of concepts related to dementia specifically and cor-
tical neurodegeneration in general.1
The PPA syndrome is diagnosed when 3 criteria are met. First, the patient should have the
insidious onset and gradual progression of a language impairment (i.e., aphasia) manifested by
deficits in word finding, word usage, word comprehension, or sentence construction. Second,
the aphasia should initially arise as the most salient (i.e., primary) impairment and should con-
stitute the principal factor underlying the disruption of daily living activities. Third, diagnostic
testing should point to a neurodegenerative, and therefore progressive, process as the only under-
lying cause.2 Patients with salient initial impairments in other cognitive domains but who also
happen to have aphasic disturbances, or those who display speech impairments without aphasia,
do not qualify for the diagnosis of PPA.
From the Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the article.

456 © 2013 American Academy of Neurology

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 According to evidence gathered from multiple
autopsy series, approximately 30% of patients with
PPA are found to have the neuropathology of fronto-
temporal lobar degeneration with tauopathy (FTLD-
TAU), while an additional 30% have a different form
of FTLD characterized by abnormal precipitates of
the transactive response DNA binding protein
TDP-43 (FTLD-TDP). The remaining 40% of
patients display Alzheimer pathology with the charac-
teristic b-amyloid plaques and neurofibrillary tangles
(NFT). This heterogeneity shows that the clinical spec-
ificity of the PPA syndrome is not determined by the
histopathology of the neurodegeneration but, rather,
Figure 1 Quantitative map of peak atrophy sites in primary progressive aphasia
All maps were generated with the FreeSurfer software by comparing cortical thickness in
patients with primary progressive aphasia (PPA) to 27 controls. All patients and controls
were right-handed. Peak atrophy sites (significant at conservative false discovery rate
thresholds of 0.01–0.015) are displayed in red and yellow. (A) Quantitative map shows pro-
nounced asymmetry of atrophy in a combined group of 16 patients with PPA with all aphasia
subtypes consecutively enrolled in a longitudinal study.29 (B) Left hemisphere peak atrophy
sites in a group of 4 patients with the agrammatic subtype of PPA (PPA-G). (C) Left hemi-
sphere peak atrophy sites in 7 patients with the logopenic subtype of PPA (PPA-L). (D) Peak
atrophy site in a 61-year-old woman with the semantic subtype of PPA (PPA-S). At the time
of this scan, she had been symptomatic for 2 years and correctly answered only 7% of items
in a test of object naming and 28% of items in a test of word association. Neurologically
intact controls performed both tasks with virtually no errors. B and C are reproduced from
Mesulam et al.6 and D from Mesulam et al.,7 with permission. ATL 5 anterior temporal lobe;
IFG 5 inferior frontal gyrus; STG 5 superior temporal gyrus; TPJ 5 temporoparietal junction.
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by its anatomical predilection for the language network
of the brain.
The most characteristic anatomical hallmark of
PPA is the greater atrophy of the language-dominant
left hemisphere (figure 1A). The asymmetry can be
quite pronounced and the right side of the brain may
initially appear to be intact. Within the left hemisphere,
peak atrophy sites extend into all major components of
the language network, including the inferior frontal
gyrus (IFG), the superior temporal gyrus (STG), the
temporoparietal junction (TPJ), and anterolateral tem-
poral cortex (ATL). In patients whose structural scans
are normal at the time of symptom onset, SPECT or
PET scans may show decreased blood flow and metab-
olism in language-related areas of the left hemisphere.
However, MRI, CT, and even PET scans at such early
stages may be completely normal and may lead the
clinician to attribute the symptoms to anxiety or other
non-neurologic factors.3 In approximately 40% of
left-handers, language dominance is located in the right
hemisphere. In such individuals PPA arises on a back-
ground of asymmetrical atrophy of the right hemi-
sphere.4 Age at symptom onset in PPA is most
commonly in the 50s and early 60s, with a generally
even representation of men and women.
The patterns of language impairment in PPA vary
from patient to patient in a manner that reflects the
anatomical distribution of peak atrophy sites. In con-
trast to cerebrovascular accidents (CVA), where cortical
and white matter components of the core lesion site are
both abruptly and completely destroyed, many neuro-
degenerative diseases start by causing a gradual and par-
tial loss of neurons and leave the underlying white
matter relatively intact. The indolent pace of neuronal
attrition is also likely to allow substantial synaptic reor-
ganization within the affected neurocognitive network
even as the disease progresses. Using the metaphor of
a circuit board, cerebrovascular lesions can be said to
pull the plug on the network constituents at the core
lesion site whereas neurodegeneration can be said to
induce a short circuit that is slowly propagated through-
out the affected network. These are some of the reasons
why the aphasia patterns identified by CVA-based clas-
sic aphasiology do not quite fit the clinical patterns that
emerge in PPA.
According to current practice, the language impair-
ment in PPA is classified into one of 3 principal pat-
terns: agrammatic, logopenic, and semantic.3,5 The
core feature of the agrammatic subtype (PPA-G) is a
distortion of word and sentence construction as man-
ifested by abnormal word order (syntax), distorted use
of word endings, misuse of pronouns, and a paucity of
small grammatical words such as articles and preposi-
tions. In mild cases, these abnormalities may only
emerge in writing samples. Most agrammatic patients
will also have abnormal sentence repetition and low
Neurology 81 July 30, 2013 457
 fluency, as if every word required extra effort to be
retrieved and produced, even in the absence of any
dysarthria. Word comprehension is spared but gram-
matically complex sentences may fail to be deciphered.
The most distinctive anatomical feature of PPA-G is
the presence of peak atrophy sites within the left IFG,
where the Broca area is located (figure 1B).
The logopenic subtype (PPA-L) is characterized
by intermittent interruptions of fluency on a back-
ground of intact grammar and comprehension.
The patient may appear perfectly fluent if allowed
to engage in small talk and generalities but starts to
display frequent word-finding hesitations when
access to specific terms and infrequently used words
becomes necessary. Many patients will circumvent
these retrieval blocks through circumlocutions but a
careful listener will detect a pervasive simplification
and superficiality of output. Object naming impair-
ments (anomia), based on word retrieval failures,
are usually present and may elicit phonologic para-
phasias. Abnormal repetition has been included as a
necessary criterion for the research-based diagnosis
of this subtype.5 However, this feature can be so
mild that its inclusion as a core criterion may need
further evaluation.3,6 The distinctive anatomical
pattern in PPA-L is one where the atrophy is much
more pronounced in the posterior than anterior
parts of the language network. Peak atrophy sites
include the TPJ where the inferior parietal lobule
abuts the posterior parts of the superior and middle
temporal gyri (figure 1C).
The core features of the semantic subtype (PPA-S)
include profound impairments of object naming and
word comprehension on a background of preserved
fluency, repetition, and grammar. Initially, the rela-
tively preserved ability to understand conventional
sentences contrasts sharply with severe deficits in
understanding nouns that denote concrete entities,
especially animals, fruits, and vegetables. For example,
a patient who appropriately answers questions such as
“Why should virtuous people be rewarded?” will react
to words such as “lion,” “lemon,” or “pumpkin” as if
they belonged to an unknown language. Initial com-
prehension and naming impairments display the phe-
nomenon of taxonomic interference whereby words
are understood and objects named at a generic but
not specific level of meaning.7 An analogous impair-
ment at the stage of translating thoughts into words
leads to the semantic paraphasias and vagueness of
speech content. At the very early stages, PPA-S may
present as an isolated but severe anomia. As the disease
progresses, the comprehension impairment extends to
all word classes and sentences. The distinctive peak
atrophy sites in PPA-S are concentrated within the
anterior temporal lobe (ATL) of the left hemisphere
(figure 1D).
458 Neurology 81 July 30, 2013
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The anatomy of atrophy in PPA-S challenges cur-
rent concepts related to the neurology of language.
The standard model of language revolves around
the Broca area in the IFG, Wernicke area in the
TPJ, and their interconnections through the arcuate
fasciculus. This standard model does not even mention
the ATL. Considering the severe word comprehension
and naming impairments of patients with PPA-S with
peak atrophy sites confined to the left ATL (figure
1D), it is difficult to escape the conclusion that this
area plays a critical role in language function. The
clinicoanatomical correlations in PPA-S suggest that
the standard model is incomplete and that the left
ATL should be inserted into the language network as
a third major hub with a critical role in word compre-
hension and object naming. This relationship, although
implied by observations on patients with temporal lobe
epilepsy,8,9 seems to have eluded 150 years of aphasiol-
ogy, presumably because the ATL is relatively immune
to focal CVAs.
Accurate clinical classification of PPA increases the
precision with which the clinician can predict the
nature of the underlying pathology. The most consis-
tent relationship is seen in PPA-S, where at least
80% of patients will be found at autopsy to have
FTLD-TDP pathology of type C.10,11 The clinical
identification of PPA-S will therefore signal a very
low probability of Alzheimer pathology and, there-
fore, little justification for prescribing Alzheimer
drugs such as cholinesterase inhibitors or meman-
tine.12 The situation is more complex in the other
2 subtypes. In PPA-G, the majority of patients have
FTLD-TAU, as manifested by Pick bodies, cortico-
basal degeneration pathology (CBDp), or progressive
supranuclear palsy pathology (PSPp). The latter
2 terms are extremely confusing since they are being
used to denote the species of tauopathy rather than
the clinical syndrome of the same name. In fact, many
of the PPA-G patients with CBDp and PSPp at
autopsy will have had very few, if any, of the clinical
features associated with syndromic CBD or PSP.
According to the ongoing autopsy series of the North-
western ADC Brain Bank, approximately 60% of
patients with PPA-G have FTLD-TAU, with the
remaining having Alzheimer pathology or FTLD-TDP
of type A. The pattern is completely different in PPA-L,
where approximately 60% of patients have Alzheimer
pathology and the remainder FTLD-TAU or FTLD-
TDP of type A.
Within the same PPA subtype, patients with and
without Alzheimer pathology are clinically indistin-
guishable; they both have asymmetric atrophy, progress-
ive aphasia, and relative preservation of memory for
recent events. The questions of differential diagnosis
in these patients can be addressed with the help of bio-
markers such as amyloid imaging and determinations
 of phospho-tau and b-amyloid in the CSF. A positive a negative amyloid scan with normal CSF b-amyloid
amyloid scan with PET on a background of high and phospho-tau excludes Alzheimer pathology with a
phospho-tau and low b-amyloid in the CSF signals great deal of certainty. Patients will frequently ask
a very high likelihood of Alzheimer pathology, while whether the diagnosis is PPA or AD. The clinician
needs to state that it can be both, and then explain
that in this context the term PPA refers to the clinical
Figure 2 Quantitative analysis of neurofibrillary tangles in amnestic and features experienced by the patient while the term Alz-
aphasic forms of Alzheimer pathology
heimer refers to the nature of the microscopic changes
that damage the language-related parts of the brain.
The Alzheimer pathology in PPA has distinctive
features that set it apart from the Alzheimer pathology
seen in patients with the more typical amnestic phe-
notype that characterizes the vast majority of late-
onset dementias. In the amnestic manifestations of
Alzheimer pathology, the NFT do not display consis-
tent hemispheric asymmetry. They are also most
numerous within structures critical for episodic memory
such as the hippocampus and entorhinal cortex. The
pattern is quite different in patients with PPA with
autopsy-proven Alzheimer pathology.13 In such patients,
the NFT display higher neocortical-to-entorhinal ratios
and also significantly higher numbers in the language-
related cortices of the left hemisphere than in analogous
regions on the right (figure 2). Moreover, the e4
allele of APOE, the most important risk factor for
typical amnestic forms of AD, does not appear to
be a risk factor for Alzheimer pathology in PPA
(figure 3).13 These lines of evidence reinforce the
view that AD is not uniform and that it has biolog-
ically distinct variants, each with its own pattern of
NFT distribution and corresponding phenotype.
Other such variants have been associated with fron-
tal-type dementias, posterior cortical atrophy syn-
dromes, and corticobasal syndromes.14–17 Whether
these additional variants of Alzheimer pathology
will also display distinctive patterns of APOE allele
frequencies remains to be determined. From a prac-
tical point of view, the failure to recognize such
atypical clinical presentations promotes the unwar-
ranted categorical exclusion of patients with PPA
from clinical trials related to AD.
In contrast to the NFT, amyloid plaques did not
reveal differential distributions in amnestic vs aphasic
patients with Alzheimer pathology.13 This finding is
in keeping with results of PET imaging in PPA,
which show that amyloid positivity tends to be sym-
The counting was done with the methods of unbiased stereology. (A) Neurofibrillary tangles
(NFT) in a patient with symptom onset at age 54 years and a clinical picture characterized
metrically distributed despite the asymmetry of the
by salient memory loss typical of an amnestic dementia. The NFT count is much higher in en- neurodegeneration.18 While b-amyloid may well play
torhinal cortex, an area critical for memory, than in neocortical regions that are critical for lan- an important role in the evolution of Alzheimer
guage. (B) NFT in a patient with symptom onset at age 56 years and a clinical picture of the pathology, these observations reinforce the view that
logopenic subtype of primary progressive aphasia (PPA-L). The NFT pattern is completely dif-
ferent. There are more NFT in language-related areas such as the superior temporal gyrus and
the clinical impairments experienced by the patient
the temporoparietal junction than in entorhinal cortex. Not all cases show this neocortical pre- ultimately reflect the distribution of the NFT rather
dominance. As a group, however, PPA patients with Alzheimer pathology have higher neocor- than the distribution of the amyloid plaques.
tical-to-entorhinal ratios of NFT. There is also an asymmetrical distribution, with the language-
In the vast majority of cases, PPA arises sporadi-
dominant left hemisphere showing greater numbers. The data for these graphs come from a
study by Gefen et al.13 In this study, the TPJ counts were obtained in the inferior parietal lobule. cally. However, PPA has also been described in families
ENTO 5 entorhinal cortex; STG 5 superior temporal gyrus; TPJ 5 temporoparietal juncture. with mutations in genes for PS1, MAPT, C9orf72,

Neurology 81 July 30, 2013 459

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Figure 3 APOE e4 allele frequencies
The e4 allele frequency in patients with an amnestic dementia of the Alzheimer type
(ADAT) who also had autopsy-proven Alzheimer pathology (AP) was significantly higher
than in controls (14.4% vs 50%, p 5 0.009). However, the e4 allele frequency in patients
with primary progressive aphasia (PPA) who had AP at autopsy (21.4%) did not differ from
control values (p 5 0.44). The data come from a study by Gefen at al.13
and especially GRN.19–21 In 2 kindreds, PPA emerged
as the uniform phenotype for all siblings (3/4 in the
PPA1 family and 2/3 in the PPA2 family) who were
shown to have GRN mutations.22 Affected members
who came to autopsy had FTLD-TDP pathology of
type A. The initial expectation that such kindreds with
uniform genotype–phenotype relationships would help
to clarify the putative molecular mechanisms underly-
ing the selective vulnerability of the language network
in PPA had to be abandoned as it became clear that
practically identical GRN mutations can also lead to
the behavioral variant of frontotemporal dementia
(bvFTD), a syndrome where behavior and personality
rather than language undergo progressive dissolution.
This indeterminacy of the relationship between
genotype and phenotype supports the conclusion that
the patterns of selective vulnerability in neurodegen-
erations are likely to reflect complex interactions
between molecular factors that define the nature of
the histopathology and individual factors that influ-
ence its preferential distribution. The individual
factors participating in these interactions could be
rooted in genetic, developmental, or acquired phe-
nomena. For example, mild developmental anomalies
and early acquired lesions of the left hemisphere have
been reported in patients who had experienced no
language impairment during most of adulthood but
who then developed PPA in later life.19 Furthermore,
a history of learning disability, including develop-
mental dyslexia, was found to be significantly more
frequent in patients with PPA and their first-degree
relatives than in patients with the typical amnestic
dementia of AD or the bvFTD syndrome (figure 4).23
460 Neurology 81 July 30, 2013
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The concentration of developmental language disabil-
ities in some of the families reported in this study was
quite striking. One of the PPA probands, who had a
personal history of delayed reading skills, reported
that 3 of his children and both granddaughters were
dyslexic, although highly successful in their chosen
adult careers. Another PPA proband, who denied a
personal history of learning disability, reported that
all 5 of his siblings had difficulties with learning to
read or spell. These observations have collectively
generated the speculation that PPA may reflect the
tardive manifestation of a genetic or acquired vulner-
ability of the language network that stays compen-
sated during most of adulthood but that becomes a
locus of least resistance for the expression of an inde-
pendently arising neurodegenerative disease. In other
individuals with different vulnerabilities, the same
neurodegenerative process would be expected to lead
to different distributions of peak neuronal damage
and to their corresponding phenotypes. Such tardive
manifestations of remote vulnerabilities are not unknown
in neurology. For example, patients with a history of
poliomyelitis may experience the re-emergence of
weakness that had recovered from the remote attack
while others with recovered childhood hemiplegia may
later in life experience a progressive hemiparkinsonism
on the side of the recovered weakness.24,25
Gradual intensification of the impairments is the
hallmark of PPA.26–28 Each clinical subtype displays a
somewhat different progression trajectory. In PPA-S,
the extension of ATL atrophy into the anterior insula,
posterior orbitofrontal cortex, and contralateral ATL
may lead to the emergence of anomalous behaviors
characteristic of frontotemporal syndromes (figure 5).
In PPA-G, the spread of atrophy to motor areas and
basal ganglia may lead to the emergence of movement
disorders characteristic of CBD and PSP syndromes.
The trajectory of PPA-L is the most variable. In some
patients, additional IFG atrophy leads to the emergence
of features characteristic of PPA-G. In others, the
spread of atrophy into additional parts of the temporal
lobe leads to word comprehension and memory
impairments.
Patient care in PPA can be divided into sympto-
matic and etiologic components. The symptomatic
approach starts with an evaluation by a knowledge-
able speech therapist who can work with the patient
and family to maximize communicative effectiveness
and who can also assess the potential usefulness of
assistive software and hardware. The etiologic compo-
nent of patient care revolves around the judicious use
of clinical subtyping and biomarker information to
surmise the nature of the underlying disease process.
Based on this information, the clinician can decide
whether to use Alzheimer medications or to channel
the patient into clinical trials relevant to AD or FTLD.

Figure 4 Learning disability frequencies in primary progressive aphasia
The data for this graph come from Rogalski et al.,23 who found that the frequency of learning
disability (LD) was higher in patients with primary progressive aphasia (PPA) and their first-
degree relatives that in the other groups (p , 0.001). ADAT 5 amnestic dementia of the
Alzheimer type; bvFTD 5 behavioral variant of frontotemporal dementia; NC 5 normal
control.
Although it is being diagnosed with increasing fre-
quency, PPA is still a rare syndrome, so patients, fam-
ilies, and clinicians may find it difficult to access
appropriate resources. A dedicated Web site, the inter-
national PPA connection (ppaconnection.org), has
been established to serve as a registry for patients and
resources. Its goal is to link patients and clinicians to
relevant local resources around the world and, in the
future, help launch collaborative clinical trials when
promising therapeutic interventions become available.
The site also contains demonstrations of key diagnostic
features and a section on frequently asked questions.
Figure 5 Progression trajectories in primary progressive aphasia
PPA-G 5 agrammatic subtype of primary progressive aphasia; PPA-L 5 logopenic subtype of
primary progressive aphasia; PPA-S 5 semantic subtype of primary progressive aphasia.
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The field of PPA is clearly witnessing considerable
progress in diagnostic accuracy, clinical characterization,
differential diagnosis, and clinicopathologic correlation.
Much additional work, however, remains to be done
to identify more creative interventions aimed at the clin-
ical symptoms as well as more effective therapeutic
agents aimed at the underlying disease process. These
are challenges that PPA shares with nearly all other neu-
rodegenerative syndromes. While these challenges are
being addressed, PPA will continue to offer unique
opportunities for exploring the neurobiology of lan-
guage on one hand and the molecular basis of selective
vulnerability to neurodegeneration on the other.
ACKNOWLEDGMENT
Sandra Weintraub, PhD, Emily Rogalski, PhD, Cynthia Thompson, PhD,
Changiz Geula, PhD, Eileen Bigio, MD, Christina Wieneke, and Tamar Ge-
fen made major contributions to the work summarized in this lecture.
STUDY FUNDING
Supported by DC008552 from the National Institute on Deafness and
Communication Disorders and AG13854 (Alzheimer Disease Center)
from the National Institute on Aging.
DISCLOSURE
The author reports no disclosures relevant to the manuscript. Go to
Neurology.org for full disclosures.
Received April 18, 2013. Accepted in final form April 26, 2013.
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This Week’s Neurology® Podcast

Evidence-based guideline: Treatment of tardive syndromes:
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This podcast begins and closes with Dr. Robert Gross, Editor-in-
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focuses his interview with Dr. M.-Marsel Mesulam on the
H. Houston Merritt Lecture on selective cognitive impairments and distinct neuropathologic
entities of primary progressive aphasia. Disclosures can be found at www.neurology.org.
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462 Neurology 81 July 30, 2013

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Primary progressive aphasia and the language network: The 2013 H. Houston
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M.-Marsel Mesulam
Neurology 2013;81;456-462
DOI 10.1212/WNL.0b013e31829d87df

This information is current as of July 29, 2013

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