Aisling H. Buckley

White matter tract signatures of the progressive aphasias.

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 Alzheimers 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.

Flavour identification in frontotemporal lobar degeneration

Background Deficits of flavour processing may be clinically important in frontotemporal lobar degeneration (FTLD). Objective To examine flavour processing in FTLD. Methods We studied flavour identification prospectively in 25 patients with FTLD (12 with behavioural variant frontotemporal dementia (bvFTD), eight with semantic variant primary progressive aphasia (svPPA), five with non-fluent variant primary progressive aphasia (nfvPPA)) and 17 healthy control subjects, using a new test based on cross-modal matching of flavours to words and pictures. All subjects completed a general neuropsychological assessment, and odour identification was also assessed using a modified University of Pennsylvania Smell Identification Test. Brain MRI volumes from the patient cohort were analysed using voxel-based morphometry to identify regional grey matter associations of flavour identification. Results Relative to the healthy control group, the bvFTD and svPPA subgroups showed significant (p<0.05) deficits of flavour identification and all three FTLD subgroups showed deficits of odour identification. Flavour identification performance did not differ significantly between the FTLD syndromic subgroups. Flavour identification performance in the combined FTLD cohort was significantly (p<0.05 after multiple comparisons correction) associated with grey matter volume in the left entorhinal cortex, hippocampus, parahippocampal gyrus and temporal pole. Conclusions Certain FTLD syndromes are associated with impaired flavour identification and this is underpinned by grey matter atrophy in an anteromedial temporal lobe network. These findings may have implications for our understanding of abnormal eating behaviour in these diseases.

Voice processing in dementia: a neuropsychological and neuroanatomical analysis

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.

Auditory object cognition in dementia.

Highlights ► A study of nonverbal auditory object processing in four dementia syndromes. ► Subjects were assessed using a novel, customised neuropsychological battery. ► Different dementia syndromes lead to distinct auditory processing impairments. ► Evidence is provided for separable stages of nonverbal auditory processing.

Impairments of auditory scene analysis in Alzheimer's disease.

Parsing of sound sources in the auditory environment or ‘auditory scene analysis’ is a computationally demanding cognitive operation that is likely to be vulnerable to the neurodegenerative process in Alzheimer’s disease. However, little information is available concerning auditory scene analysis in Alzheimers disease. Here we undertook a detailed neuropsychological and neuroanatomical characterization of auditory scene analysis in a cohort of 21 patients with clinically typical Alzheimers disease versus age-matched healthy control subjects. We designed a novel auditory dual stream paradigm based on synthetic sound sequences to assess two key generic operations in auditory scene analysis (object segregation and grouping) in relation to simpler auditory perceptual, task and general neuropsychological factors. In order to assess neuroanatomical associations of performance on auditory scene analysis tasks, structural brain magnetic resonance imaging data from the patient cohort were analysed using voxel-based morphometry. Compared with healthy controls, patients with Alzheimers disease had impairments of auditory scene analysis, and segregation and grouping operations were comparably affected. Auditory scene analysis impairments in Alzheimers disease were not wholly attributable to simple auditory perceptual or task factors; however, the between-group difference relative to healthy controls was attenuated after accounting for non-verbal (visuospatial) working memory capacity. These findings demonstrate that clinically typical Alzheimers disease is associated with a generic deficit of auditory scene analysis. Neuroanatomical associations of auditory scene analysis performance were identified in posterior cortical areas including the posterior superior temporal lobes and posterior cingulate. This work suggests a basis for understanding a class of clinical symptoms in Alzheimers disease and for delineating cognitive mechanisms that mediate auditory scene analysis both in health and in neurodegenerative disease.

White matter tract signatures of impaired social cognition in frontotemporal lobar degeneration

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.

The Language Profile of Behavioral Variant Frontotemporal Dementia

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 patents 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.

Degradation of cognitive timing mechanisms in behavioural variant frontotemporal dementia.

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.

05 White matter tract changes in the primary progressive aphasias

Introduction The primary progressive aphasias (PPA) are a group of neurodegenerative language-led dementias. Three major subtypes are recognised: progressive nonfluent aphasia (PNFA) characterised by speech apraxia and agrammatism; semantic dementia (SemD), characterised by loss of vocabulary due to primary semantic memory impairment; and logopenic aphasia (LPA), characterised by word-finding pauses, anomia, and impaired phonological memory. Other subtypes have been proposed including aphasia associated with progranulin mutations (GAA). Whereas considerable progress has been made in defining profiles of cortical atrophy in PPA, information about white matter tracts connecting cortical areas remains limited. Here we addressed this issue using diffusion tensor tractography in a cohort of patients with PPA. Methods 20 consecutive patients with a clinical diagnosis of PPA (7 SemD, 6 PNFA, 5 LPA, 2 GAA) and 12 age-matched healthy controls underwent volumetric brain MRI with diffusion tensor imaging (DTI). White matter tract changes in each group and inter-group differences were assessed using Tract Based Spatial Statistics (http://www.fmrib.ox.ac.uk/fsl/tbss). Results PPA syndromic groups showed well-defined fractional anisotropy, axial and radial diffusivity changes tracking white matter pathways implicated in language processing. Compared with healthy individuals, all PPA groups showed changes in the anterior superior longitudinal fasciculus (SLF), and additional tracts were involved in particular subgroups (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 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 restricted to the left hemisphere in GAA but bi-hemispheric in other syndromes. Discussion PPA syndromes are associated with distinctive profiles of altered white matter tract integrity and these tract changes provide substrates for the dysfunction of specific language networks in PPA.

The neurolinguistic profile of behavioral variant frontotemporal dementia

Background:Posterior cortical atrophy (PCA) is a syndrome characterized by progressive visual perceptual difficulties often associated with other neurological manifestations including apraxia, aphasia and cognitive symptoms. Because the underlying neuropathology is frequently that of Alzheimer’s Disease, it has become known as the “visual presentation” of this disorder. While patients with PCA have difficulties with extrinsic perception, we do not know whether “intrinsic perception”, including the ability to visualize imagery, is affected. This is an important question taking into account the cognitive value of visual imagery which forms the basis of imagination, which enables a number of cognitive tasks including behavior rehearsal, anxiety reduction, recreation, motor skill enhancement and others. Since visual imagery is a subjective experiential phenomenon, it is difficult to quantify or characterize in a person. The Vividness of Visual Imagery Questionnaire (VVIQ: Marks 1973) is a valid psychometric instrument used for measuring visual imagery differences in individuals (see Richardson, 1994; McKelvie, 1995 for reviews). The questionnaire consists of sixteen items that are each completed twice; once to determine the vividness of several images recalled by the participant when their eyes are open, and then once again for the same images obtained when their eyes are closed. The test uses a self-reported 5 point Likert scale to objectively measure the vividness of each mental image. Methods: The VVIQ was administered to 7 patients with PCA and 8 age matched controls. Results: Although the vividness of mental imagery values for an image obtained with participant’s eyes open did not differ significantly from the values obtained from the typical control group [F(13,14)1⁄42.1257, p1⁄4 0.1686] it was shown that when the individuals with PCA ranked the vividness of amental image obtained with their eyes closed the vividness ranking was statistically lower than those obtained by the control participants [F(13, 14)1⁄4 4.7045, p1⁄40.0492]. Conclusions:The results of this pilot study indicate that participants with PCA maintain their ability to vividly visualize images with eyes open, however they may demonstrate a decrease in their ability to vividly visualize images with eyes closed when compared to their typical peers.