Primary progressive aphasias associated with C9orf72 expansions: Another side of the story.

C9orf72 repeat expansions are rarely associated with primary progressive aphasias (PPA). In-depth characterization of the linguistic deficits, and the underlying patterns of grey-matter atrophy in PPA associated with the C9orf72 expansions (PPA-C9orf72) are currently lacking. In this study, we comprehensively analyzed a unique series of 16 patients affected by PPA-C9orf72. Eleven patients were issued from two independent French and Finnish cohorts, and five were identified by means of literature review. Voxel-based morphometry (VBM) studies were performed on three of them. This study depicts the spectrum of C9orf72-related aphasic phenotypes, and illustrates their linguistic presentation. The non-fluent/agrammatic variant was the most frequent phenotype in our series (9/16 patients, 56%), with apraxia of speech being the main defining feature. Left frontal lobe atrophy was present in these subjects, peaking in inferior frontal gyrus. Three patients (19%) showed the semantic variant, with progression of atrophy in temporo-polar regions, later involving orbitofrontal cortex. Anterior temporal lobe dysfunction was also particularly relevant in two patients (12.5%) with mixed forms of PPA. Lastly, two patients (12.5%) had unclassifiable PPA with predominating word-finding difficulties. No PPA-C9orf72 patients in our series fulfilled the criteria of the logopenic variant. Importantly, this study underlines the role of C9orf72 mutation in the disruption of the most anterior parts of the language network, including prefrontal and temporo-polar areas. It provides guidelines for C9orf72 testing in PPA patients, with important clinical impact as gene-specific therapies are upcoming.

The role of semantic memory in prospective memory and episodic future thinking: new insights from a case of semantic dementia.

Prospective memory (PM), the ability to remember to execute planned actions, and episodic future thinking (EFT), the ability to imagine future personal events, are two core aspects of future-oriented cognition. The present study aimed for the first time at examining the role of semantic memory loss in PM and EFT in a single case patient (SL) at the early stage of semantic dementia.First, we investigated various types of PM as well as episodic memory of new events using a validated ecological assessment via virtual reality. Second, we examined EFT using a temporally extended version of the TEMPau task, which measures episodic aspects of remembering the past and imagining the future taking temporal distance into account.Patient SL was deficient in semantically linked event-based PM and was unable to provide any EFT for the most distant period but was preserved in other types of PM and near and intermediate EFT.These findings provide new evidence on the role of semantic memory in PM depending on the type of intention and in EFT depending on the temporal distance mirroring autobiographical memory. Finally, they point out a specific link between PM and near EFT in future-oriented cognition.

Primary Progressive Aphasia Associated With GRN Mutations: New Insights Into the Nonamyloid Logopenic Variant.

OBJECTIVE: To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with GRN (progranulin) mutations and to study their neuroanatomic correlates. METHODS: Patients with PPA carrying GRN mutations (PPA-GRN) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA. RESULTS: Among the 235 patients with PPA, 45 (19%) carried GRN mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%). CONCLUSIONS: This study shows that the most frequent PPA variant associated with GRN mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. GRN testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming GRN gene-specific therapies.

A Reliable and Rapid Language Tool for the Diagnosis, Classification, and Follow-Up of Primary Progressive Aphasia Variants.

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking. Methods: We developed and evaluated a rapid language test for PPA ("PARIS") assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia ("LAST", "ART"). Results: The application duration of the "PARIS" was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the "PARIS" reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the "LAST" and "ART," the "PARIS" also had the highest sensitivity for detecting language decline. Conclusions: The "PARIS" is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing.

Does surface dyslexia/dysgraphia relate to semantic deficits in the semantic variant of primary progressive aphasia?

The semantic variant of primary progressive aphasia (sv-PPA) is a degenerative condition which causes surface dyslexia/dysgraphia, resulting in reading/writing errors of irregular words with non-transparent grapheme-to-phoneme correspondences (e.g., 'plaid') as opposed to regular words (e.g., 'cat'). According to connectionist models, most authors have attributed this deficit to semantic impairments, but this assumption is at odds with symbolic models, such as the DRC account, stating that the reading/writing of irregulars relies on the mental lexicon. Our study investigated whether sv-PPA affects the lexicon in addition to the semantic system, and whether semantic or lexical deficits cause surface dyslexia/dysgraphia, while challenging the two major models of written language. We explored a cohort of 12 sv-PPA patients and 25 matched healthy controls using a reading and writing task, a semantic task (category decision: living vs. non-living), and a lexical task (lexical decision: word vs. no-neighbor non-word). Correlation analyses were conducted to assess the relationship between reading/writing scores of irregulars and semantic vs. lexical performance. Furthermore, item-by-item analyses explored the consistency of reading/writing errors with item-specific semantic and lexical errors. Results showed that sv-PPA patients are impaired at reading and writing irregular words, and that they have impaired performance in both the semantic and the lexical task. Reading/writing scores with irregulars correlated significantly with performance in the lexical but not the semantic task. Item-by-item analyses revealed that failure in the lexical task on a given irregular word is a good predictor of reading/writing errors with that item (positive predictive value: 77.5%), which was not the case for the semantic task (positive predictive value: 42.5%). Our findings show that sv-PPA is not restricted to semantic damage but that it also comprises damage to the mental lexicon, which appears to be the major factor for surface dyslexia/dysgraphia. Our data support symbolic models whereas they challenge connectionist accounts.

Color Categorization Independent of Color Naming.

Color is continuous, yet we group colors into discrete categories associated with color names (e.g., yellow, blue). Color categorization is a case in point in the debate on how language shapes human cognition. Evidence suggests that color categorization depends on top-down input from the language system to the visual cortex. We directly tested this hypothesis by assessing color categorization in a stroke patient, RDS, with a rare, selective deficit in naming visually presented chromatic colors, and relatively preserved achromatic color naming. Multimodal MRI revealed a left occipito-temporal lesion that directly damaged left color-biased regions, and functionally disconnected their right-hemisphere homologs from the language system. The lesion had a greater effect on RDS's chromatic color naming than on color categorization, which was relatively preserved on a nonverbal task. Color categorization and naming can thus be independent in the human brain, challenging the mandatory involvement of language in adult human cognition.

Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile.

Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

Lexical access in semantic variant PPA: Evidence for a post-semantic contribution to naming deficits.

The most salient clinical symptom of semantic variant primary progressive aphasia (PPA) is a profound and pervasive anomia. These patients' naming impairments have been shown to reflect in large part a domain-general deterioration of conceptual knowledge that impacts both linguistic and non-linguistic processing. However, it is possible that post-semantic stages of lexical access may also contribute to naming deficits. To clarify the stages at which lexical access breaks down in semantic variant PPA, eleven French-speaking patients were asked to name objects, and were then queried for semantic, lexical-syntactic, and word form information pertaining to the items they could not name. Specifically, our goal was to determine whether patients can access intermediate representations known as lemmas, which mediate the arbitrary mapping between semantic representations and word forms (phonological and orthographic forms). The French language was chosen for this study because nouns in French are marked for grammatical gender, a prototypical type of lexical-syntactic information, represented at the level of the lemma. Access to word form information is also dependent on lemma access under some theoretical views. We found that six of the eleven patients showed partial access to either lexical-syntactic properties of unnamed items (grammatical gender), word form information (initial letter), or both. Access to these types of information suggests that a lemma has been retrieved, implying a breakdown at the post-semantic stage of word form retrieval. Our results suggest that although degraded conceptual knowledge is the main cause of naming deficits in semantic variant PPA, in some patients, a post-semantic component also contributes to the impairment.

The Brain Network of Naming: A Lesson from Primary Progressive Aphasia.

OBJECTIVE: Word finding depends on the processing of semantic and lexical information, and it involves an intermediate level for mapping semantic-to-lexical information which also subserves lexical-to-semantic mapping during word comprehension. However, the brain regions implementing these components are still controversial and have not been clarified via a comprehensive lesion model encompassing the whole range of language-related cortices. Primary progressive aphasia (PPA), for which anomia is thought to be the most common sign, provides such a model, but the exploration of cortical areas impacting naming in its three main variants and the underlying processing mechanisms is still lacking. METHODS: We addressed this double issue, related to language structure and PPA, with thirty patients (11 semantic, 12 logopenic, 7 agrammatic variant) using a picture-naming task and voxel-based morphometry for anatomo-functional correlation. First, we analyzed correlations for each of the three variants to identify the regions impacting naming in PPA and to disentangle the core regions of word finding. We then combined the three variants and correlation analyses for naming (semantic-to-lexical mapping) and single-word comprehension (lexical-to-semantic mapping), predicting an overlap zone corresponding to a bidirectional lexical-semantic hub. RESULTS AND CONCLUSIONS: Our results showed that superior portions of the left temporal pole and left posterior temporal cortices impact semantic and lexical naming mechanisms in semantic and logopenic PPA, respectively. In agrammatic PPA naming deficits were rare, and did not correlate with any cortical region. Combined analyses revealed a cortical overlap zone in superior/middle mid-temporal cortices, distinct from the two former regions, impacting bidirectional binding of lexical and semantic information. Altogether, our findings indicate that lexical/semantic word processing depends on an anterior-posterior axis within lateral-temporal cortices, including an anatomically intermediate hub dedicated to lexical-semantic integration. Within this axis our data reveal the underpinnings of anomia in the PPA variants, which is of relevance for both diagnosis and future therapy strategies.

Damage to the medial motor system in stroke patients with motor neglect.

BACKGROUND AND OBJECTIVES: Motor neglect (MN) is a clinically important condition whereby patients with unilateral brain lesions fail to move their contralateral limbs, despite normal muscle strength, reflexes, and sensation. MN has been associated with various lesion sites, including the parietal and frontal cortex, the internal capsule, the lenticulostriate nuclei, and the thalamus. In the present study, we explored the hypothesis that MN depends on a dysfunction of the medial motor system by performing a detailed anatomical analysis in four patients with MN. METHODS: Ten patients participated in the study: four with MN, four with left visual neglect but without MN, and three patients with left hemiplegia without MN. We used specific scales for clinical and neuropsychological assessment. We drew the lesion borders directly onto the original brain images of each patient, and plotted the lesions on anatomical atlases for gray and white matter. RESULTS: Lesion locations were highly heterogeneous in our MN patients, and included frontal and parietal sites, basal ganglia, and white matter. The only consistently damaged structure across all MN patients was the cingulum bundle, a major pathway of the medial motor system important for motor initiative, and a key connection with limbic structures crucial for motivational aspects of actions. Three MN patients with additional damage to lateral fronto-parietal networks had also signs of contralesional visual neglect. The cingulum bundle was intact in all the control patients with visual neglect or hemiplegia. CONCLUSIONS: Cingulum damage may induce MN through unilateral dysfunction of the medial motor system. Additional lateral fronto-parietal dysfunction can result in the association with visual neglect.

Deciphering logopenic primary progressive aphasia: a clinical, imaging and biomarker investigation.

Within primary progressive aphasia the logopenic variant remains less understood than the two other main variants, namely semantic and non-fluent progressive aphasia. This may be because of the relatively small number of explored patients and because of the lack of investigations with a comprehensive three-level characterization of cognitive, brain localization and biological aspects. The aim of the present study was to decipher the logopenic variant through a multimodal approach with a large cohort of 19 patients (age 66.5 ± 8.7 years, symptom duration 3.2 ± 0.6 years) using detailed cognitive and linguistic assessments, magnetic resonance imaging and perfusion single-photon emission computed tomography as well as cerebrospinal fluid biomarkers screening for Alzheimer pathology. The linguistic assessment unveiled that language dysfunction is not limited to the typical feature of word finding and verbal working memory impairments but that it extends into the language system affecting to some degree syntactic production, phonological encoding and semantic representations. Perfusion tomography revealed damage of the temporal-parietal junction with a peak of significance in the superior temporal gyrus (Brodmann area 42), and of some less significant prefrontal areas (Brodmann areas 8, 9 and 46), whereas hippocampal cortices were unaffected. Magnetic resonance imaging, which was visually assessed in a larger group of 54 patients with logopenic, non-fluent, semantic variants as well as with posterior cortical atrophy, confirmed that the logopenic variant demonstrates predominant atrophy of left temporal-parietal junction, but that this atrophy pattern has a relatively poor sensitivity and specificity for clinical diagnosis. Finally, the biomarker study revealed that two-thirds of the logopenic patients demonstrated a profile indicative of Alzheimer pathology whereas one-third had a non-Alzheimer profile. Splitting the two groups showed that logopenic aphasia due to probable Alzheimer pathology is a more aggressive variant characterized by more extensive language/cognitive disorders affecting, in addition to lexical processes and verbal working memory, also phoneme sequencing, semantic processing and ideomotor praxis. Concordantly, logopenic aphasia due to probable Alzheimer pathology demonstrated more extensive brain hypoperfusion involving larger regions throughout the inferior parietal, the posterior-superior and the middle temporal cortex. These findings allow for unfolding logopenic aphasia into two subvariants differing by disease severity, lesion nature and lesion distribution, which has important implications for diagnosis, patient management and for potential future trials with anti-Alzheimer drugs. The present data therefore provide novel insight into the cognition and brain damage of logopenic patients while unveiling the existence of distinct diseases constituting a 'logopenic aphasia complex'.

Brain activations during letter-by-letter reading: a follow-up study.

Lesions affecting the ventral cortex of the left temporal lobe commonly yield a selective reading impairment known as pure alexia. It is thought to result from the disruption or deafferentation of the Visual Word Form Area (VWFA), a region in the left lateral occipitotemporal sulcus activated whenever normal subjects are viewing alphabetic strings. Most pure alexic patients retain the ability to identify single letters, and develop a strategy of letter-by-letter (LBL) reading. We recently studied fMRI activations in LBL readers and clarified the underlying mechanisms. However, LBL reading is a dynamic process which may improve over months or years of practice, although the cerebral bases of this continuing improvement are currently unknown. We had the opportunity to run the same behavioural testing and fMRI experiment a second time in an alexic patient, 8 months after collecting the data reported by Cohen et al. [Cohen, L., Henry, C., Dehaene, S., Molko, N., Lehéricy, S., Martinaud, O., Lemer, C., and Ferrieux, S. (2004). The pathophysiology of letter-by-letter reading. Neuropsychologia, 42, 1768-1780]. We analyze the changes that occurred over this period in the pattern of reading-related activations, while the patient's LBL reading improved. The activation level decreased in most of the overall network between the two sessions. This general trend contrasted with a focal increase restricted to specific left frontal and parietal areas. When studying the contrast between words and consonant strings, which may be taken as a correlate of LBL reading, we also found a general decrease, except for similar left frontal and parietal regions, which showed a significant increase. We suggest that the pattern of evolution fits with the minimal hypothesis of normal strategic abilities and skill learning, associated with perceptual tuning in right-hemispheric structures able to substitute the disrupted VWFA.

The pathophysiology of letter-by-letter reading.

Pure alexia is a frequent and incapacitating consequence of left occipitotemporal lesions. It is thought to result from the disruption or the disconnection of the visual word form area (VWFA), a region reproducibly located within the left occipito-temporal sulcus, and encoding the abstract identity of strings of visual letters. Alexic patients often retain effective single letter recognition abilities, and develop an effortful letter-by-letter reading strategy which is the basis of most rehabilitation techniques. We study a patient who developed letter-by-letter reading following the surgical removal of left occipito-temporal regions. Using anatomical and functional MRI in the patient and in normal controls, we show that alexia resulted from the deafferentation of left fusiform cortex, and we analyze the network of brain regions subtending letter-by-letter reading. We propose that during letter-by-letter reading (1) letters are identified in the intact right-hemispheric visual system, with a central role for the region symetrical to the VWFA; (2) letters are serially transferred to the left hemisphere through the intact segment of the corpus callosum; (3) word identity is eventually recovered in the left hemisphere through verbal working memory processes involving inferior frontal and supramarginal cortex.