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.
Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration.However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined.Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia (bvFTD; n = 29) and semantic variant primary progressive aphasia (svPPA; n = 15), relative to healthy older individuals (n = 37) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification.Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry.The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere.The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification).DTI associations of impaired social cognition were more consistent than corresponding grey matter associations.These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes.The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.
Behavioural variant frontotemporal dementia (bvFTD) is clinically and pathologically heterogeneous. In contrast to the syndromes of primary progressive aphasia (PPA), language dysfunction is not a defining feature of bvFTD and is generally not emphasised clinically. However, very little information is available concerning neurolinguistic processing in bvFTD. Key language functions were analysed in a large, comprehensively characterised cohort of patients with bvFTD (n=25) in relation both to healthy older controls (n=24) and a cohort of patients representing core PPA syndromes (progressive nonfluent aphasia and semantic dementia; n=35). Relative to healthy controls, patients with bvFTD showed a profile of neurolinguistic deficits that were less severe than PPA but still extensive, affecting naming, semantic and sentence processing and literacy skills but sparing word repetition. Voxel-based morphometry in the bvFTD cohort revealed a correlated profile of widespread grey matter loss affecting dominant prefrontal, peri-Sylvian and anterior temporal cortices comprising the canonical language network. Language decline may be a significant if under-recognised issue in bvFTD, with implications both for clinical diagnosis and management of these patients and emerging models of language network disintegration in neurodegenerative disease.
HTLV-1–associated myelopathy (HAM; HTLV-1 is human T-lymphotropic virus type 1) is a chronic debilitating neuroinflammatory disease with a predilection for the thoracic cord. Tissue damage is attributed to the cellular immune response to HTLV-1–infected lymphocytes. The brains of HTLV-1–infected patients, with and without HAM but no clinical evidence of brain involvement, were examined using a specific 18-kDa translocator protein ligand, 11C-PBR28, and T1-weighted and diffusion-weighted MRI. Methods: Five subjects with HAM and 2 HTLV-1 asymptomatic carriers were studied. All underwent clinical neurologic assessment including cognitive function and objective measures of gait, quantification of HTLV-1 proviral load in peripheral blood mononuclear cells, and human leukocyte antigen–antigen D related expression on circulating CD8+ lymphocytes. 11C-PBR28 PET and MRI were performed on the same day. 11C-PBR28 PET total volume of distribution and distribution volume ratio (DVR) were estimated using 2-tissue-compartment modeling. MRI data were processed using tools from the FMRIB Software Library to estimate mean diffusivity (MD) and gray matter (GM) fraction changes. The results were compared with data from age-matched healthy volunteers. Results: Across the whole brain, the total volume of distribution for the subjects with HAM (5.44 ± 0.84) was significantly greater than that of asymptomatic carriers (3.44 ± 0.80). The DVR of the thalamus in patients with severe and moderate HAM was higher than that in the healthy volunteers, suggesting increased translocator protein binding (z > 4.72). Subjects with more severe myelopathy and with high DR expression on CD8+ lymphocytes had increased DVR and MD (near-significant correlation found for the right thalamus MD: P = 0.06). On the T1-weighted MRI scans, the GM fraction of the brain stem was reduced in all HTLV-1–infected patients compared with controls (P < 0.001), whereas the thalamus GM fraction was decreased in patients with HAM and correlated with the disease severity. There was no correlation between neurocognitive function and these markers of central nervous system inflammation. Conclusion: This pilot study suggests that some patients with HAM have asymptomatic inflammation in the brain, which can be detected and monitored by 11C-PBR28 PET together with structural and diffusion-weighted MRI.
The Primary Progressive Aphasias (PPA) are a group of language-led dementias presenting canonically as Semantic Dementia (SemD), Progressive Non-Fluent Aphasia (PNFA) or Logopenic Aphasia (LPA). A further subtype of progressive aphasia associated with progranulin mutations (GAA) has been described. The PPA spectrum is neurobiologically heterogeneous and may be underpinned by Alzheimer or non-Alzheimer pathologies; in particular, LPA is closely associated with Alzheimer's disease. There is a need both for improved understanding of syndrome pathophysiology and accurate diagnostic biomarkers in PPA. Here we assessed changes in white matter pathways in relation to clinical syndrome and grey matter loss in a cohort of patients with PPA. 26 consecutive patients with a clinical diagnosis of PPA (8 SemD; 8 PNFA; 7 LPA; 3GAA) and 20 healthy age-matched individuals had volumetric brain MRI and DTI. Tractographic and VBM changes in PPA syndromes compared with healthy controls and between syndromes were assessed using Tract Based Spatial Statistics and SPM8 software. PPA syndromic groups showed well-defined fractional anisotropy (FA), axial (DA) and radial diffusivity (DR) changes affecting white matter pathways implicated in language processing (Figure 1). Compared with healthy individuals, all PPA groups showed reduced FA and increased DR and DA in the anterior superior longitudinal fasciculus (SLF), and additional tracts were involved in particular syndromes (in SemD, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and commissural pathways; in PNFA, more posterior SLF; in LPA and GAA, ILF). Inter-group comparisons showed significantly (Threshold free cluster enhancement corrected p < 0.05) greater involvement of ILF and UF in SD than in PNFA or GAA; and greater involvement of left ILF in GAA than PNFA. Tract alterations were largely restricted to the left hemisphere in GAA but bi-hemispheric in other syndromes. There was evidence of correlation between white matter changes and regional grey matter loss. DTI delineates specific profiles of language network breakdown in PPA and may generate useful biomarkers for distinguishing PPA syndromes and pathologies. Patterns of reduced Fractional Anisotropy (TFC corrected p < 0.05) in each disease group versus controls with intensity scores (left) and 3D tract reconstructions (right) rendered onto a temple ICBM152 Brain.
The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.
The Primary Progressive Aphasias (PPA) are a group of language-led dementias presenting canonically as Semantic Dementia (SemD), Progressive Non-Fluent Aphasia (PNFA) or Logopenic Aphasia (LPA). A further subtype of progressive aphasia associated with progranulin mutations (GAA) has been described. The PPA spectrum is neurobiologically heterogeneous and may be underpinned by Alzheimer or non-Alzheimer pathologies; in particular, LPA is closely associated with Alzheimer's disease. There is a need both for improved understanding of syndrome pathophysiology and accurate diagnostic biomarkers in PPA. Here we assessed changes in white matter pathways in relation to clinical syndrome and grey matter loss in a cohort of patients with PPA. 26 consecutive patients with a clinical diagnosis of PPA (8 SemD; 8 PNFA; 7 LPA; 3GAA) and 20 healthy age-matched individuals had volumetric brain MRI and DTI. Tractographic and VBM changes in PPA syndromes compared with healthy controls and between syndromes were assessed using Tract Based Spatial Statistics and SPM8 software. PPA syndromic groups showed well-defined fractional anisotropy (FA), axial (DA) and radial diffusivity (DR) changes affecting white matter pathways implicated in language processing (Figure 1). Compared with healthy individuals, all PPA groups showed reduced FA and increased DR and DA in the anterior superior longitudinal fasciculus (SLF), and additional tracts were involved in particular syndromes (in SemD, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and commissural pathways; in PNFA, more posterior SLF; in LPA and GAA, ILF). Inter-group comparisons showed significantly (Threshold free cluster enhancement corrected p <0.05) greater involvement of ILF and UF in SD than in PNFA or GAA; and greater involvement of left ILF in GAA than PNFA. Tract alterations were largely restricted to the left hemisphere in GAA but bi-hemispheric in other syndromes. There was evidence of correlation between white matter changes and regional grey matter loss. DTI delineates specific profiles of language network breakdown in PPA and may generate useful biomarkers for distinguishing PPA syndromes and pathologies. Patterns of reduced Fractional Anisotropy (TFCE corrected p <0.05) in each disease group versus controls with intensity scores (left) and 3D tract reconstructions (right) rendered onto a template ICBM152 Brain.
The current study examined motor timing in frontotemporal dementia (FTD), which manifests as progressive deterioration in social, behavioural and cognitive functions. Twenty-patients fulfilling consensus clinical criteria for behavioural variant FTD (bvFTD), 11 patients fulfilling consensus clinical criteria for semantic-variant primary progressive aphasia (svPPA), four patients fulfilling criteria for nonfluent/agrammatic primary progressive aphasia (naPPA), eight patients fulfilling criteria for Alzheimer׳s disease (AD), and 31 controls were assessed on both an externally- and self-paced finger-tapping task requiring maintenance of a regular, 1500 ms beat over 50 taps. Grey and white matter correlates of deficits in motor timing were examined using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). bvFTD patients exhibited significant deficits in aspects of both externally- and self-paced tapping. Increased mean inter-response interval (faster than target tap time) in the self-paced task was associated with reduced grey matter volume in the cerebellum bilaterally, right middle temporal gyrus, and with increased axial diffusivity in the right superior longitudinal fasciculus, regions and tracts which have been suggested to be involved in a subcortical-cortical network of structures underlying timing abilities. This suggests that such structures can be affected in bvFTD, and that impaired motor timing may underlie some characteristics of the bvFTD phenotype.
Voice processing in neurodegenerative disease is poorly understood. Here we undertook a systematic investigation of voice processing in a cohort of patients with clinical diagnoses representing two canonical dementia syndromes: temporal variant frontotemporal lobar degeneration (n = 14) and Alzheimer's disease (n = 22). Patient performance was compared with a healthy matched control group (n = 35). All subjects had a comprehensive neuropsychological assessment including measures of voice perception (vocal size, gender, speaker discrimination) and voice recognition (familiarity, identification, naming and cross-modal matching) and equivalent measures of face and name processing. Neuroanatomical associations of voice processing performance were assessed using voxel-based morphometry. Both disease groups showed deficits on all aspects of voice recognition and impairment was more severe in the temporal variant frontotemporal lobar degeneration group than the Alzheimer's disease group. Face and name recognition were also impaired in both disease groups and name recognition was significantly more impaired than other modalities in the temporal variant frontotemporal lobar degeneration group. The Alzheimer's disease group showed additional deficits of vocal gender perception and voice discrimination. The neuroanatomical analysis across both disease groups revealed common grey matter associations of familiarity, identification and cross-modal recognition in all modalities in the right temporal pole and anterior fusiform gyrus; while in the Alzheimer's disease group, voice discrimination was associated with grey matter in the right inferior parietal lobe. The findings suggest that impairments of voice recognition are significant in both these canonical dementia syndromes but particularly severe in temporal variant frontotemporal lobar degeneration, whereas impairments of voice perception may show relative specificity for Alzheimer's disease. The right anterior temporal lobe is likely to have a critical role in the recognition of voices and other modalities of person knowledge.
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