[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick's disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant.
Cognitive and behavioral neurology: official journal of the Society for Behavioral and Cognitive Neurology 06/2015; 28(2):92-97. DOI:10.1097/WNN.0000000000000060 · 1.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Emotional behavioral disturbances are hallmarks of many dementias but their pathophysiology is poorly understood. Here we addressed this issue using the paradigm of emotionally salient sounds.
[Show abstract][Hide abstract] ABSTRACT: Abnormal responsiveness to salient sensory signals is often a prominent feature of dementia diseases, particularly the frontotemporal lobar degenerations, but has been little studied. Here we assessed processing of one important class of salient signals, looming sounds, in canonical dementia syndromes. We manipulated tones using intensity cues to create percepts of salient approaching ("looming") or less salient withdrawing sounds. Pupil dilatation responses and behavioral rating responses to these stimuli were compared in patients fulfilling consensus criteria for dementia syndromes (semantic dementia, n = 10; behavioral variant frontotemporal dementia, n = 16, progressive nonfluent aphasia, n = 12; amnestic Alzheimer's disease, n = 10) and a cohort of 26 healthy age-matched individuals. Approaching sounds were rated as more salient than withdrawing sounds by healthy older individuals but this behavioral response to salience did not differentiate healthy individuals from patients with dementia syndromes. Pupil responses to approaching sounds were greater than responses to withdrawing sounds in healthy older individuals and in patients with semantic dementia: this differential pupil response was reduced in patients with progressive nonfluent aphasia and Alzheimer's disease relative both to the healthy control and semantic dementia groups, and did not correlate with nonverbal auditory semantic function. Autonomic responses to auditory salience are differentially affected by dementias and may constitute a novel biomarker of these diseases.
[Show abstract][Hide abstract] ABSTRACT: Auditory scene analysis is a demanding computational process that is performed automatically and efficiently by the healthy brain but vulnerable to the neurodegenerative pathology of Alzheimer's disease. Here we assessed the functional neuroanatomy of auditory scene analysis in Alzheimer's disease using the well-known ‘cocktail party effect’ as a model paradigm whereby stored templates for auditory objects (e.g., hearing one's spoken name) are used to segregate auditory ‘foreground’ and ‘background’. Patients with typical amnestic Alzheimer's disease (n = 13) and age-matched healthy individuals (n = 17) underwent functional 3 T-MRI using a sparse acquisition protocol with passive listening to auditory stimulus conditions comprising the participant's own name interleaved with or superimposed on multi-talker babble, and spectrally rotated (unrecognisable) analogues of these conditions. Name identification (conditions containing the participant's own name contrasted with spectrally rotated analogues) produced extensive bilateral activation involving superior temporal cortex in both the AD and healthy control groups, with no significant differences between groups. Auditory object segregation (conditions with interleaved name sounds contrasted with superimposed name sounds) produced activation of right posterior superior temporal cortex in both groups, again with no differences between groups. However, the cocktail party effect (interaction of own name identification with auditory object segregation processing) produced activation of right supramarginal gyrus in the AD group that was significantly enhanced compared with the healthy control group. The findings delineate an altered functional neuroanatomical profile of auditory scene analysis in Alzheimer's disease that may constitute a novel computational signature of this neurodegenerative pathology.
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia.
The Lancet Neurology 02/2015; 14(3). DOI:10.1016/S1474-4422(14)70324-2 · 21.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Crowding is a breakdown in the ability to identify objects in clutter, and is a major constraint on object recognition. Crowding particularly impairs object perception in peripheral, amblyopic and possibly developing vision. Here we argue that crowding is also a critical factor limiting object perception in central vision of individuals with neurodegeneration of the occipital cortices. In the current study, individuals with posterior cortical atrophy (n = 26), typical Alzheimer's disease (n = 17) and healthy control subjects (n = 14) completed centrally-presented tests of letter identification under six different flanking conditions (unflanked, and with letter, shape, number, same polarity and reverse polarity flankers) with two different target-flanker spacings (condensed, spaced). Patients with posterior cortical atrophy were significantly less accurate and slower to identify targets in the condensed than spaced condition even when the target letters were surrounded by flankers of a different category. Importantly, this spacing effect was observed for same, but not reverse, polarity flankers. The difference in accuracy between spaced and condensed stimuli was significantly associated with lower grey matter volume in the right collateral sulcus, in a region lying between the fusiform and lingual gyri. Detailed error analysis also revealed that similarity between the error response and the averaged target and flanker stimuli (but not individual target or flanker stimuli) was a significant predictor of error rate, more consistent with averaging than substitution accounts of crowding. Our findings suggest that crowding in posterior cortical atrophy can be regarded as a pre-attentive process that uses averaging to regularize the pathologically noisy representation of letter feature position in central vision. These results also help to clarify the cortical localization of feature integration components of crowding. More broadly, we suggest that posterior cortical atrophy provides a neurodegenerative disease model for exploring the basis of crowding. These data have significant implications for patients with, or who will go on to develop, dementia-related visual impairment, in whom acquired excessive crowding likely contributes to deficits in word, object, face and scene perception.
[Show abstract][Hide abstract] ABSTRACT: The pathophysiology of nonfluent primary progressive aphasia (nfvPPA) remains poorly understood. Here, we compared quantitatively speech parameters in patients with nfvPPA versus healthy older individuals under altered auditory feedback, which has been shown to modulate normal speech output. Patients (n=15) and healthy volunteers (n=17) were recorded during reading aloud under delayed auditory feedback [DAF] with latency 0, 50 or 200 msec and under DAF at 200 msec plus 0.5 octave upward pitch shift. DAF in healthy older individuals was associated with reduced speech rate and emergence of speech sound errors, particularly at latency 200msec. Around a third of the healthy older group under DAF showed speech slowing and frequency of speech sound errors within the range of the nfvPPA cohort. Our findings suggest that (in addition to any anterior, primary language output disorder) these key features of nfvPPA may reflect distorted speech input signal processing, as simulated by DAF. DAF may constitute a novel candidate pathophysiological model of posterior dorsal cortical language pathway dysfunction in nfvPPA.
Journal of the Neurological Sciences 09/2014; 347(1-2). DOI:10.1016/j.jns.2014.09.039 · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia (TEA) and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy (TLE). Our patient's compulsive versifying after seizure cessation may have occurred through disinhibitory facilitation following normalisation of left temporal activity, or via enhanced connections between neocortical and limbic areas due to reorganisation of cerebral networks as a result of longstanding seizure activity. Our case complements previous observations of emergence of altered behaviour with reduced seizure frequency in patients with TLE. Such cases support the notion that reduced seizure frequency has the potential not only to stabilise or improve memory function, but also to initiate complex, specific behaviour patterns, in patients with TEA or TLE.
[Show abstract][Hide abstract] ABSTRACT: Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy. This case complements previous observations of emergence of altered behavior with reduced seizure frequency in patients with temporal lobe epilepsy. Such cases suggest that reduced seizure frequency has the potential not only to stabilize or improve memory function, but also to trigger complex, specific behavioral alterations.