Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease.
ABSTRACT: Quantifiers such as many and some are thought to depend in part on the conceptual representation of number knowledge, while object nouns such as cookie and boy appear to depend in part on visual feature knowledge associated with object concepts. Further, number knowledge is associated with a frontal-parietal network while object knowledge is related in part to anterior and ventral portions of the temporal lobe. We examined the cognitive and anatomic basis for the spontaneous speech production of quantifiers and object nouns in non-aphasic patients with focal neurodegenerative disease associated with corticobasal syndrome (CBS, n=33), behavioral variant frontotemporal degeneration (bvFTD, n=54), and semantic variant primary progressive aphasia (svPPA, n=19). We recorded a semi-structured speech sample elicited from patients and healthy seniors (n=27) during description of the Cookie Theft scene. We observed a dissociation: CBS and bvFTD were significantly impaired in the production of quantifiers but not object nouns, while svPPA were significantly impaired in the production of object nouns but not quantifiers. MRI analysis revealed that quantifier production deficits in CBS and bvFTD were associated with disease in a frontal-parietal network important for number knowledge, while impaired production of object nouns in all patient groups was related to disease in inferior temporal regions important for representations of visual feature knowledge of objects. These findings imply that partially dissociable representations in semantic memory may underlie different segments of the lexicon.
Project description:Loss of warmth is well-documented in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) at a group level, and has been linked to salience (SN) and semantic-appraisal (SAN) network atrophy. However, clinical observations of individual patients show much greater heterogeneity, thus measuring this clinical variability and identifying the underlying neurologic mechanisms is a critical step for understanding the symptom profile of any one patient. We used reliable change indexes with premorbid and current informant-based evaluations to characterize patterns of change on the warmth subscale of the Interpersonal Adjective Scale (IAS) questionnaire in 132 patients (21 bvFTD, 19 svPPA, 22 nonfluent variant primary progressive aphasia [nfvPPA], 37 Alzheimer's disease [AD]) and 33 healthy older adults. We investigated whether individual differences in warmth change were reflected in SN or SAN functional connectivity, or structural volume of individual brain regions in these two networks. Though one subset of patients showed significant drop in warmth to abnormally low levels (bvFTD: 38%; svPPA: 21%; nfvPPA: 5%; AD: 11%), a second subset significantly dropped but remained within the clinically normal range (bvFTD: 33%; svPPA: 21%; nfvPPA: 9%; AD: 5%), and a third subset did not drop and stayed in the clinically normal range (bvFTD: 29%; svPPA: 58%; nfvPPA: 86%; AD: 84%). Furthermore, interpersonal warmth score was strongly predicted by SN functional connectivity (p?<?.01), but not by SAN functional connectivity or by structural volume in these networks. Our results extend earlier group-level findings by showing wide individual variability in degree of disease-related reduction of interpersonal warmth and SN functional connectivity in bvFTD and svPPA, and highlight new approaches to revealing how brain connectivity predicts behavior on an individual patient level. Our findings suggest that measures of interpersonal warmth can provide important clinical information about changes in underlying brain networks, and help clinicians and clinical researchers better identify which bvFTD and svPPA patients are at greater risk for interpersonal disruption.
Project description:To contrast the relationships of hormonal eating peptides and hypothalamic volumes to eating behavior and metabolic changes (body mass index [BMI]) in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA).Seventy-five patients with dementia (19 bvFTD, 26 svPPA, and 30 Alzheimer disease dementia) and 23 controls underwent fasting blood analyses of leptin, ghrelin, cholecystokinin, peptide tyrosine tyrosine (PYY), and agouti-related peptide (AgRP) levels. On brain MRI anterior, posterior, and total hypothalamic volumes were measured. Relationships between endocrine measures, hypothalamic volumes, eating behaviors, and BMI were investigated.Levels of AgRP were higher in patients with bvFTD (69 ± 89 pg/mL) and svPPA (62 ± 81 pg/mL) compared with controls (23 ± 19 pg/mL, p < 0.01). No differences were found for leptin, oxytocin, cholecystokinin, ghrelin, and PYY levels. Patients with bvFTD and svPPA had higher scores on questionnaires measuring eating behaviors. Atrophy of the posterior and total hypothalamus was observed in the bvFTD group only. Linear regression modeling revealed that leptin and AgRP levels predicted BMI.Eating abnormalities are multifactorial in FTD. In bvFTD, they are in part related to hypothalamic degeneration, with potential disintegration of the network connections between the hypothalamus and orbitofrontal cortex/reward pathways. In svPPA, although hypothalamic volumes are preserved, this group experiences elevated AgRP levels similar to bvFTD, which predicts BMI in both groups. This finding highlights the potential key role of AgRP in eating and metabolic changes and provides a potential target for treatment to modify disease progression.
Project description:BACKGROUND:The tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain. METHODS:We performed 18F-flortaucipir imaging in patients with the FTD syndromes (n?=?45): nonfluent variant primary progressive aphasia (nfvPPA) (n?=?11), corticobasal syndrome (CBS) (n?=?10), behavioral variant frontotemporal dementia (bvFTD) (n?=?10), semantic variant primary progressive aphasia (svPPA) (n?=?2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n?=?6), chromosome 9 open reading frame 72 (C9ORF72) (n?=?5), and progranulin (GRN) (n?=?1). All patients underwent MRI and ?-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 ?-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches. RESULTS:On qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of ?-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology. CONCLUSIONS:18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.
Project description:BACKGROUND:The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. OBJECTIVE:We aimed to quantify the extent of language deficits in this patient group. METHODS:We assessed a cohort of patients with bvFTD (n?=?24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n?=?14), nonfluent variant primary progressive aphasia (nfvPPA; n?=?18), and healthy age-matched individuals (n?=?24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images. RESULTS:Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. CONCLUSIONS:bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker.
Project description:Frontotemporal dementia (FTD), a neurodegenerative disease broadly characterized by socioemotional impairments, includes three clinical subtypes: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant primary progressive aphasia (nfvPPA). Emerging evidence has shown emotional reactivity impairments in bvFTD and svPPA, whereas emotional reactivity in nfvPPA is far less studied. In 105 patients with FTD (49 bvFTD, 31 svPPA and 25 nfvPPA) and 27 healthy controls, we examined three aspects of emotional reactivity (physiology, facial behavior and subjective experience) in response to a sad film. In a subset of the sample, we also examined the neural correlates of diminished aspects of reactivity using voxel-based morphometry. Results indicated that all three subtypes of FTD showed diminished physiological responding in respiration rate and diastolic blood pressure; patients with bvFTD and svPPA also showed diminished subjective experience, and no subtypes showed diminished facial behavior. Moreover, there were differences among the clinical subtypes in brain regions where smaller volumes were associated with diminished sadness reactivity. These results show that emotion impairments extend to sadness reactivity in FTD and underscore the importance of considering different aspects of sadness reactivity in multiple clinical subtypes for characterizing emotional deficits and associated neurodegeneration in FTD.
Project description:The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and semantic variant (svPPA) of frontotemporal dementia (FTD) are neurodegenerative diseases. Previous works have shown alterations of fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor images (DTIs). This manuscript is aimed at using DTI images to build a global tractography and to identify atrophy patterns of white matter in each variant. Twenty patients with svPPA, 20 patients with nfvPPA, 26 patients with behavioral variant of FTD (bvFTD) and, 33 controls were included. An analysis based on the connectivity of structural networks showed changes in FA and MD in svPPA and nfvPPA with respect to bvFTD. Much damage in the internal networks of the left temporal lobe was found in svPPA patients; in contrast, patients with nfvPPA showed atrophy in networks from the basal ganglia to motor and premotor areas. Those findings support the dual stream model of speech and language.
Project description:This study evaluated the efficacy of phonological and orthographic treatments for anomia in the semantic and logopenic variants of primary progressive aphasia (svPPA and lvPPA, respectively). Both treatments were administered for 6 months. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (remediation items). Oral naming accuracy was measured for trained and untrained picture exemplars, as well as matched items from an untrained condition (UC). Written naming and scene description tasks were also conducted. For all tasks, the change in naming accuracy from baseline to 1 month post-treatment was compared between the UC and each treatment condition. These comparisons indicated that both treatments were effective in the remediation and prophylaxis of anomia in both variants. Furthermore, generalisation to untrained exemplars occurred in both subtypes, whereas item generalisation occurred in lvPPA, and task generalisation was present in svPPA.
Project description:Language comprehension engages a distributed network of frontotemporal, parietal, and sensorimotor regions, but it is still unclear how meaning of words and their semantic relationships are represented and processed within these regions and to which degrees lexico-semantic representations differ between regions and semantic types. We used fMRI and representational similarity analysis to relate word-elicited multivoxel patterns to semantic similarity between action and object words. In left inferior frontal (BA 44-45-47), left posterior middle temporal and left precentral cortex, the similarity of brain response patterns reflected semantic similarity among action-related verbs, as well as across lexical classes-between action verbs and tool-related nouns and, to a degree, between action verbs and food nouns, but not between action verbs and animal nouns. Instead, posterior inferior temporal cortex exhibited a reverse response pattern, which reflected the semantic similarity among object-related nouns, but not action-related words. These results show that semantic similarity is encoded by a range of cortical areas, including multimodal association (e.g., anterior inferior frontal, posterior middle temporal) and modality-preferential (premotor) cortex and that the representational geometries in these regions are partly dependent on semantic type, with semantic similarity among action-related words crossing lexical-semantic category boundaries.
Project description:BACKGROUND:We performed an observational study of laughter during seminaturalistic conversations between patients with dementia and familial caregivers. Patients were diagnosed with (1) behavioural variant frontotemporal dementia (bvFTD), (2) right temporal variant frontotemporal dementia (rtFTD), (3) semantic variant of primary progressive aphasia (svPPA), (4) non-fluent variant primary progressive aphasia (nfvPPA) or (5) early onset Alzheimer's disease (eoAD). We hypothesised that those with bvFTD would laugh less in response to their own speech than other dementia groups or controls, while those with rtFTD would laugh less regardless of who was speaking. METHODS:Patients with bvFTD (n=39), svPPA (n=19), rtFTD (n=14), nfvPPA (n=16), eoAD (n=17) and healthy controls (n=156) were recorded (video and audio) while discussing a problem in their relationship with a healthy control companion. Using the audio track only, laughs were identified by trained coders and then further classed by an automated algorithm as occurring during or shortly after the participant's own vocalisation ('self' context) or during or shortly after the partner's vocalisation ('partner' context). RESULTS:Individuals with bvFTD, eoAD or rtFTD laughed less across both contexts of self and partner than the other groups. Those with bvFTD laughed less relative to their own speech comparedwith healthy controls. Those with nfvPPA laughed more in the partner context compared with healthy controls. CONCLUSIONS:Laughter in response to one's own vocalisations or those of a conversational partner may be a clinically useful measure in dementia diagnosis.
Project description:<h4>Introduction</h4>The Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring.<h4>Methods</h4>Linear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data.<h4>Results</h4>Among PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change.<h4>Discussion</h4>The FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.