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1.  Syntactic processing depends on dorsal language tracts 
Neuron  2011;72(2):397-403.
Frontal and temporal language areas involved in syntactic processing are connected by several dorsal and ventral tracts, but the functional roles of the different tracts are not well understood. To identify which white matter tract(s) are important for syntactic processing, we examined the relationship between white matter damage and syntactic deficits in patients with primary progressive aphasia, using multimodal neuroimaging and neurolinguistic assessment. Diffusion tensor imaging showed that microstructural damage to left hemisphere dorsal tracts—the superior longitudinal fasciculus including its arcuate component—was strongly associated with deficits in comprehension and production of syntax. Damage to these dorsal tracts predicted syntactic deficits after gray matter atrophy was taken into account, and fMRI confirmed that these tracts connect regions modulated by syntactic processing. In contrast, damage to ventral tracts—the extreme capsule fiber system or the uncinate fasciculus—was not associated with syntactic deficits. Our findings show that syntactic processing depends primarily on dorsal language tracts.
doi:10.1016/j.neuron.2011.09.014
PMCID: PMC3201770  PMID: 22017996
2.  White matter damage in primary progressive aphasias: a diffusion tensor tractography study 
Brain  2011;134(10):3011-3029.
Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts’ mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia.
doi:10.1093/brain/awr099
PMCID: PMC3187537  PMID: 21666264
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; diffusion tensor imaging
3.  Multimodal Cuing of Autobiographical Memory in Semantic Dementia 
Neuropsychology  2011;25(1):98-104.
Objective
Individuals with semantic dementia (SD) have impaired autobiographical memory (AM), but the extent of the impairment has been controversial. According to one report (Westmacott et al., 2001), patient performance was better when visual cues were used instead of verbal cues; however, the visual cues used in that study (family photographs) provided more retrieval support than do the word cues that are typically used in AM studies. In the present study, we sought to disentangle the effects of retrieval support and cue modality.
Method
We cued AMs of 5 SD patients and 5 controls with words, simple pictures, and odors. Memories were elicited from childhood, early adulthood, and recent adulthood; they were scored for level of detail and episodic specificity.
Results
The patients were impaired across all time periods and stimulus modalities. Within the patient group, words and pictures were equally effective as cues (Friedman test; χ2 = 0.25, p = 0.61), whereas odors were less effective than both words and pictures (for words vs. odors, χ2 = 7.83, p = 0.005; for pictures vs. odors, χ2 = 6.18, p = 0.01). There was no evidence of a temporal gradient in either group (for SD patients, χ2 = 0.24, p = 0.89; for controls, χ2 < 2.07, p = 0.35).
Conclusions
Once the effect of retrieval support is equated across stimulus modalities, there is no evidence for an advantage of visual cues over verbal cues. The greater impairment for olfactory cues presumably reflects degeneration of anterior temporal regions that support olfactory memory.
doi:10.1037/a0021005
PMCID: PMC3058931  PMID: 21090900
AUTOBIOGRAPHICAL MEMORY; ODORS; SEMANTIC DEMENTIA
4.  Connected speech production in three variants of primary progressive aphasia 
Brain  2010;133(7):2069-2088.
Primary progressive aphasia is a clinical syndrome defined by progressive deficits isolated to speech and/or language, and can be classified into non-fluent, semantic and logopenic variants based on motor speech, linguistic and cognitive features. The connected speech of patients with primary progressive aphasia has often been dichotomized simply as ‘fluent’ or ‘non-fluent’, however fluency is a multidimensional construct that encompasses features such as speech rate, phrase length, articulatory agility and syntactic structure, which are not always impacted in parallel. In this study, our first objective was to improve the characterization of connected speech production in each variant of primary progressive aphasia, by quantifying speech output along a number of motor speech and linguistic dimensions simultaneously. Secondly, we aimed to determine the neuroanatomical correlates of changes along these different dimensions. We recorded, transcribed and analysed speech samples for 50 patients with primary progressive aphasia, along with neurodegenerative and normal control groups. Patients were scanned with magnetic resonance imaging, and voxel-based morphometry was used to identify regions where atrophy correlated significantly with motor speech and linguistic features. Speech samples in patients with the non-fluent variant were characterized by slow rate, distortions, syntactic errors and reduced complexity. In contrast, patients with the semantic variant exhibited normal rate and very few speech or syntactic errors, but showed increased proportions of closed class words, pronouns and verbs, and higher frequency nouns, reflecting lexical retrieval deficits. In patients with the logopenic variant, speech rate (a common proxy for fluency) was intermediate between the other two variants, but distortions and syntactic errors were less common than in the non-fluent variant, while lexical access was less impaired than in the semantic variant. Reduced speech rate was linked with atrophy to a wide range of both anterior and posterior language regions, but specific deficits had more circumscribed anatomical correlates. Frontal regions were associated with motor speech and syntactic processes, anterior and inferior temporal regions with lexical retrieval, and posterior temporal regions with phonological errors and several other types of disruptions to fluency. These findings demonstrate that a multidimensional quantification of connected speech production is necessary to characterize the differences between the speech patterns of each primary progressive aphasic variant adequately, and to reveal associations between particular aspects of connected speech and specific components of the neural network for speech production.
doi:10.1093/brain/awq129
PMCID: PMC2892940  PMID: 20542982
primary progressive aphasia; progressive non-fluent aphasia; semantic dementia; logopenic progressive aphasia; speech production
5.  Neural correlates of syntactic processing in the non-fluent variant of primary progressive aphasia 
The left posterior inferior frontal cortex (IFC) is important for syntactic processing, and has been shown in many functional imaging studies to be differentially recruited for the processing of syntactically complex sentences relative to simpler ones. In the non-fluent variant of primary progressive aphasia (PPA), degeneration of the posterior IFC is associated with expressive and receptive agrammatism, however the functional status of this region in non-fluent PPA is not well understood. Our objective was to determine whether the atrophic posterior IFC is differentially recruited for the processing of syntactically complex sentences in non-fluent PPA. Using structural and functional magnetic resonance imaging, we quantified tissue volumes and functional responses to a syntactic comprehension task in eight patients with non-fluent PPA, compared to healthy age-matched controls. In controls, the posterior IFC showed more activity for syntactically complex sentences than simpler ones, as expected. In non-fluent PPA patients, the posterior IFC was atrophic and, unlike controls, showed an equivalent level of functional activity for syntactically complex and simpler sentences. This abnormal pattern of functional activity was specific to the posterior IFC: the mid superior temporal sulcus, another region modulated by syntactic complexity in controls, showed normal modulation by complexity in patients. A more anterior inferior frontal region was recruited by patients, but did not support successful syntactic processing. We conclude that in non-fluent PPA, the posterior IFC is not only structurally damaged, but is also functionally abnormal, suggesting a critical role for this region in the breakdown of syntactic processing in this syndrome.
doi:10.1523/JNEUROSCI.2547-10.2010
PMCID: PMC3024013  PMID: 21159955
syntactic processing; primary progressive aphasia; progressive non-fluent aphasia; inferior frontal gyrus; superior temporal sulcus; functional magnetic resonance imaging
6.  Language networks in semantic dementia 
Brain  2009;133(1):286-299.
Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.
doi:10.1093/brain/awp233
PMCID: PMC2801321  PMID: 19759202
semantic dementia; semantic knowledge; diffusion tensor-based tractography; functional MRI; voxel-based morphometry
7.  Automated MRI-based classification of primary progressive aphasia variants 
NeuroImage  2009;47(4):1558-1567.
Degeneration of language regions in the dominant hemisphere can result in primary progressive aphasia (PPA), a clinical syndrome characterized by progressive deficits in speech and/or language function. Recent studies have identified three variants of PPA: progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA). Each variant is associated with characteristic linguistic features, distinct patterns of brain atrophy, and different likelihoods of particular underlying pathogenic processes, which makes correct differential diagnosis highly clinically relevant. Evaluation of linguistic behavior can be challenging for non-specialists, and neuroimaging findings in single subjects are often difficult to evaluate by eye. We investigated the utility of automated structural MR image analysis to discriminate PPA variants (N=86) from each other and from normal controls (N=115). T1 images were preprocessed to obtain modulated grey matter (GM) images. Feature selection was performed with principal components analysis (PCA) on GM images as well as images of lateralized atrophy. PC coefficients were classified with linear support vector machines, and a cross-validation scheme was used to obtain accuracy rates for generalization to novel cases. The overall mean accuracy in discriminating between pairs of groups was 92.2%. For one pair of groups, PNFA and SD, we also investigated the utility of including several linguistic variables as features. Models with both imaging and linguistic features performed better than models with only imaging or only linguistic features. These results suggest that automated methods could assist in the differential diagnosis of PPA variants, enabling therapies to be targeted to likely underlying etiologies.
doi:10.1016/j.neuroimage.2009.05.085
PMCID: PMC2719687  PMID: 19501654
8.  The neural basis of surface dyslexia in semantic dementia 
Brain  2008;132(1):71-86.
Semantic dementia (SD) is a neurodegenerative disease characterized by atrophy of anterior temporal regions and progressive loss of semantic memory. SD patients often present with surface dyslexia, a relatively selective impairment in reading low-frequency words with exceptional or atypical spelling-to-sound correspondences. Exception words are typically ‘over-regularized’ in SD and pronounced as they are spelled (e.g. ‘sew’ is pronounced as ‘sue’). This suggests that in the absence of sufficient item-specific knowledge, exception words are read by relying mainly on subword processes for regular mapping of orthography to phonology. In this study, we investigated the functional anatomy of surface dyslexia in SD using functional magnetic resonance imaging (fMRI) and studied its relationship to structural damage with voxel-based morphometry (VBM). Five SD patients and nine healthy age-matched controls were scanned while they read regular words, exception words and pseudowords in an event-related design. Vocal responses were recorded and revealed that all patients were impaired in reading low-frequency exception words, and made frequent over-regularization errors. Consistent with prior studies, fMRI data revealed that both groups activated a similar basic network of bilateral occipital, motor and premotor regions for reading single words. VBM showed that these regions were not significantly atrophied in SD. In control subjects, a region in the left intraparietal sulcus was activated for reading pseudowords and low-frequency regular words but not exception words, suggesting a role for this area in subword mapping from orthographic to phonological representations. In SD patients only, this inferior parietal region, which was not atrophied, was also activated by reading low-frequency exception words, especially on trials where over-regularization errors occurred. These results suggest that the left intraparietal sulcus is involved in subword reading processes that are differentially recruited in SD when word-specific information is lost. This loss is likely related to degeneration of the anterior temporal lobe, which was severely atrophied in SD. Consistent with this, left mid-fusiform and superior temporal regions that showed reading-related activations in controls were not activated in SD. Taken together, these results suggest that the left inferior parietal region subserves subword orthographic-to-phonological processes that are recruited for exception word reading when retrieval of exceptional, item-specific word forms is impaired by degeneration of the anterior temporal lobe.
doi:10.1093/brain/awn300
PMCID: PMC2638692  PMID: 19022856
semantic dementia; dyslexia; parietal lobe; voxel-based morphometry; functional MRI
9.  Cognition and Anatomy in Three Variants of Primary Progressive Aphasia 
Annals of neurology  2004;55(3):335-346.
We performed a comprehensive cognitive, neuroimaging, and genetic study of 31 patients with primary progressive aphasia (PPA), a decline in language functions that remains isolated for at least 2 years. Detailed speech and language evaluation was used to identify three different clinical variants: nonfluent progressive aphasia (NFPA; n = 11), semantic dementia (SD; n = 10), and a third variant termed logopenic progressive aphasia (LPA; n = 10). Voxel-based morphometry (VBM) on MRIs showed that, when all 31 PPA patients were analyzed together, the left perisylvian region and the anterior temporal lobes were atrophied. However, when each clinical variant was considered separately, distinctive patterns emerged: (1) NFPA, characterized by apraxia of speech and deficits in processing complex syntax, was associated with left inferior frontal and insular atrophy; (2) SD, characterized by fluent speech and semantic memory deficits, was associated with anterior temporal damage; and (3) LPA, characterized by slow speech and impaired syntactic comprehension and naming, showed atrophy in the left posterior temporal cortex and inferior parietal lobule. Apolipoprotein E ε4 haplotype frequency was 20% in NFPA, 0% in SD, and 67% in LPA. Cognitive, genetic, and anatomical features indicate that different PPA clinical variants may correspond to different underlying pathological processes.
doi:10.1002/ana.10825
PMCID: PMC2362399  PMID: 14991811

Results 1-9 (9)