Dataset Information

Grammatical comprehension deficits in non-fluent/agrammatic primary progressive aphasia.

ABSTRACT: Grammatical comprehension difficulty is an essential supporting feature of the non-fluent/agrammatic variant of primary progressive aphasia (naPPA), but well-controlled clinical measures of grammatical comprehension are unavailable.To develop a measure of grammatical comprehension and examine this comparatively in PPA variants and behavioural-variant frontotemporal degeneration (bvFTD) and to assess the neuroanatomic basis for these deficits with volumetric grey matter atrophy and whole-brain fractional anisotropy (FA) in white matter tracts.Case-control study.Academic medical centre.39 patients with variants of PPA (naPPA=12, lvPPA=15 and svPPA=12), 27 bvFTD patients without aphasia and 12 healthy controls.Grammatical comprehension accuracy.Patients with naPPA had selective difficulty understanding cleft sentence structures, while all PPA variants and patients with bvFTD were impaired with sentences containing a centre-embedded subordinate clause. Patients with bvFTD were also impaired understanding sentences involving short-term memory. Linear regressions related grammatical comprehension difficulty in naPPA to left anterior-superior temporal atrophy and reduced FA in corpus callosum and inferior frontal-occipital fasciculus. Difficulty with centre-embedded sentences in other PPA variants was related to other brain regions.These findings emphasise a distinct grammatical comprehension deficit in naPPA and associate this with interruption of a frontal-temporal neural network.

SUBMITTER: Charles D

PROVIDER: S-EPMC3925677 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Grammatical comprehension deficits in non-fluent/agrammatic primary progressive aphasia.

Charles Dorothy D Olm Christopher C Powers John J Ash Sharon S Irwin David J DJ McMillan Corey T CT Rascovsky Katya K Grossman Murray M

Journal of neurology, neurosurgery, and psychiatry 20130913 3

<h4>Importance</h4>Grammatical comprehension difficulty is an essential supporting feature of the non-fluent/agrammatic variant of primary progressive aphasia (naPPA), but well-controlled clinical measures of grammatical comprehension are unavailable.<h4>Objective</h4>To develop a measure of grammatical comprehension and examine this comparatively in PPA variants and behavioural-variant frontotemporal degeneration (bvFTD) and to assess the neuroanatomic basis for these deficits with volumetric g ...[more]

PMID: 24039027

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Project description:The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) presents with a gradual decline in grammar and motor speech resulting from selective degeneration of speech-language regions in the brain. There has been considerable progress in identifying treatment approaches to remediate language deficits in other primary progressive aphasia variants; however, interventions for the core deficits in nfvPPA have yet to be systematically investigated. Further, the neural mechanisms that support behavioural restitution in the context of neurodegeneration are not well understood. We examined the immediate and long-term benefits of video implemented script training for aphasia (VISTA) in 10 individuals with nfvPPA. The treatment approach involved repeated rehearsal of individualized scripts via structured treatment with a clinician as well as intensive home practice with an audiovisual model using 'speech entrainment'. We evaluated accuracy of script production as well as overall intelligibility and grammaticality for trained and untrained scripts. These measures and standardized test scores were collected at post-treatment and 3-, 6-, and 12-month follow-up visits. Treatment resulted in significant improvement in production of correct, intelligible scripted words for trained topics, a reduction in grammatical errors for trained topics, and an overall increase in intelligibility for trained as well as untrained topics at post-treatment. Follow-up testing revealed maintenance of gains for trained scripts up to 1 year post-treatment on the primary outcome measure. Performance on untrained scripts and standardized tests remained relatively stable during the follow-up period, indicating that treatment helped to stabilize speech and language despite disease progression. To identify neural predictors of responsiveness to intervention, we examined treatment effect sizes relative to grey matter volumes in regions of interest derived from a previously identified speech production network. Regions of significant atrophy within this network included bilateral inferior frontal cortices and supplementary motor area as well as left striatum. Volumes in a left middle/inferior temporal region of interest were significantly correlated with the magnitude of treatment effects. This region, which was relatively spared anatomically in nfvPPA patients, has been implicated in syntactic production as well as visuo-motor facilitation of speech. This is the first group study to document the benefits of behavioural intervention that targets both linguistic and motoric deficits in nfvPPA. Findings indicate that behavioural intervention may result in lasting and generalized improvement of communicative function in individuals with neurodegenerative disease and that the integrity of spared regions within the speech-language network may be an important predictor of treatment response.

Project description:It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating Sum of Boxes (CDR-SB). We investigated the data's clustering tendency and cluster stability to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.

Project description:BackgroundA subset of patients with the nonfluent variant of primary progressive aphasia (PPA) exhibit concomitant single-word comprehension problems, constituting a 'mixed variant' phenotype. This phenotype is rare and currently not fully characterized. The aim of this study was twofold: to assess the prevalence and nature of single-word comprehension problems in the nonfluent variant and to study multimodal imaging characteristics of atrophy, tau, and amyloid burden associated with this mixed phenotype.MethodsA consecutive memory-clinic recruited series of 20 PPA patients (12 nonfluent, five semantic, and three logopenic variants) were studied on neurolinguistic and neuropsychological domains relative to 64 cognitively intact healthy older control subjects. The neuroimaging battery included high-resolution volumetric magnetic resonance imaging processed with voxel-based morphometry, and positron emission tomography with the tau-tracer [18F]-THK5351 and amyloid-tracer [11C]-Pittsburgh Compound B.ResultsSeven out of 12 subjects who had been classified a priori with nonfluent variant PPA showed deficits on conventional single-word comprehension tasks along with speech apraxia and agrammatism, corresponding to a mixed variant phenotype. These mixed variant cases included three females and four males, with a mean age at onset of 65 years (range 44-77 years). Object knowledge and object recognition were additionally affected, although less severely compared with the semantic variant. The mixed variant was characterized by a distributed atrophy pattern in frontal and temporoparietal regions. A more focal pattern of elevated [18F]-THK5351 binding was present in the supplementary motor area, the left premotor cortex, midbrain, and basal ganglia. This pattern was closely similar to that seen in pure nonfluent variant PPA. At the individual patient level, elevated [18F]-THK5351 binding in the supplementary motor area and premotor cortex was present in six out of seven mixed variant cases and in five and four of these cases, respectively, in the thalamus and midbrain. Amyloid biomarker positivity was present in two out of seven mixed variant cases, compared with none of the five pure nonfluent cases.ConclusionsA substantial proportion of PPA patients with speech apraxia and agrammatism also have single-word comprehension deficits. At the neurobiological level, the mixed variant shows a high degree of similarity with the pure nonfluent variant of PPA.Trial registrationEudraCT, 2014-002976-10 . Registered on 13-01-2015.

Project description:The agrammatic variant of primary progressive aphasia affects normal grammatical language production, often occurs with apraxia of speech, and is associated with left frontal abnormalities on cross-sectional neuroimaging studies. We aimed to perform a detailed assessment of longitudinal change on structural and molecular neuroimaging to provide a complete picture of neurodegeneration in these patients, and to determine how patterns of progression compare to patients with isolated apraxia of speech (primary progressive apraxia of speech). We assessed longitudinal structural MRI, diffusion tensor imaging and 18F-fluorodeoxyglucose PET in 11 agrammatic aphasia subjects, 20 primary progressive apraxia of speech subjects, and 62 age and gender-matched controls with two serial assessments. Rates of change in grey matter volume and hypometabolism, and white matter fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were assessed at the voxel-level and for numerous regions of interest. The greatest rates of grey matter atrophy in agrammatic aphasia were observed in inferior, middle, and superior frontal gyri, premotor and motor cortices, as well as medial temporal lobe, insula, basal ganglia, and brainstem compared to controls. Longitudinal decline in metabolism was observed in the same regions, with additional findings in medial and lateral parietal lobe. Diffusion tensor imaging changes were prominent bilaterally in inferior and middle frontal white matter and superior longitudinal fasciculus, as well as right inferior fronto-occipital fasciculus, superior frontal and precentral white matter. More focal patterns of degeneration of motor and premotor cortex were observed in primary progressive apraxia of speech. Agrammatic aphasia showed greater rates of grey matter atrophy, decline in metabolism, and white matter degeneration compared to primary progressive apraxia of speech in the left frontal lobe, predominantly inferior and middle frontal grey and white matter. Correlations were also assessed between rates of change on neuroimaging and rates of clinical decline. Progression of aphasia correlated with rates of degeneration in frontal and temporal regions within the language network, while progression of parkinsonism and limb apraxia correlated with degeneration of motor cortex and brainstem. These findings demonstrate that disease progression in agrammatic aphasia is associated with widespread neurodegeneration throughout regions of the language network, as well as connecting white matter tracts, but also with progression to regions outside of the language network that are responsible for the development of motor symptoms. The fact that patterns of progression differed from primary progressive apraxia of speech supports the clinical distinction of these syndromes.

Project description:Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non-fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre-determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures.

Dataset Information

Grammatical comprehension deficits in non-fluent/agrammatic primary progressive aphasia.

Publications

Grammatical comprehension deficits in non-fluent/agrammatic primary progressive aphasia.

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