The architecture of abnormal reward behaviour in dementia: multimodal hedonic phenotypes and brain substrate.

Abnormal reward processing is a hallmark of neurodegenerative diseases, most strikingly in frontotemporal dementia. However, the phenotypic repertoire and neuroanatomical substrates of abnormal reward behaviour in these diseases remain incompletely characterized and poorly understood. Here we addressed these issues in a large, intensively phenotyped patient cohort representing all major syndromes of sporadic frontotemporal dementia and Alzheimer's disease.

Remote versus face-to-face neuropsychological testing for dementia research: a comparative study in people with Alzheimer's disease, frontotemporal dementia and healthy older individuals.

Objectives: We explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research.

Design: We used a longitudinal design for healthy controls, who completed face-to-face assessments 3-4 years before remote assessments. For patients, we used a cross-sectional design, contrasting a prospective remote cohort with a retrospective face-to-face cohort matched for age/education/severity.

Decoding expectation and surprise in dementia: the paradigm of music.

Making predictions about the world and responding appropriately to unexpected events are essential functions of the healthy brain. In neurodegenerative disorders, such as frontotemporal dementia and Alzheimer's disease, impaired processing of 'surprise' may underpin a diverse array of symptoms, particularly abnormalities of social and emotional behaviour, but is challenging to characterize. Here, we addressed this issue using a novel paradigm: music.

Laughter as a paradigm of socio-emotional signal processing in dementia.

Laughter is a fundamental communicative signal in our relations with other people and is used to convey a diverse repertoire of social and emotional information. It is therefore potentially a useful probe of impaired socio-emotional signal processing in neurodegenerative diseases. Here we investigated the cognitive and affective processing of laughter in forty-seven patients representing all major syndromes of frontotemporal dementia, a disease spectrum characterised by severe socio-emotional dysfunction (twenty-two with behavioural variant frontotemporal dementia, twelve with semantic variant primary progressive aphasia, thirteen with nonfluent-agrammatic variant primary progressive aphasia), in relation to fifteen patients with typical amnestic Alzheimer's disease and twenty healthy age-matched individuals.

Automated profiling of spontaneous speech in primary progressive aphasia and behavioral-variant frontotemporal dementia: An approach based on usage-frequency.

Language production provides important markers of neurological health. One feature of impairments of language and cognition, such as those that occur in stroke aphasia or Alzheimer's disease, is an overuse of high frequency, "familiar" expressions. We used computerized analysis to profile narrative speech samples from speakers with variants of frontotemporal dementia (FTD), including subtypes of primary progressive aphasia (PPA).

The neurophysiological architecture of semantic dementia: spectral dynamic causal modelling of a neurodegenerative proteinopathy.

The selective destruction of large-scale brain networks by pathogenic protein spread is a ubiquitous theme in neurodegenerative disease. Characterising the circuit architecture of these diseases could illuminate both their pathophysiology and the computational architecture of the cognitive processes they target. However, this is challenging using standard neuroimaging techniques.

Altered phobic reactions in frontotemporal dementia: A behavioural and neuroanatomical analysis.

Introduction: Abnormal behavioural and physiological reactivity to emotional stimuli is a hallmark of frontotemporal dementia (FTD), particularly the behavioural variant (bvFTD). As part of this repertoire, altered phobic responses have been reported in some patients with FTD but are poorly characterised.

Methods: We collected data (based on caregiver reports) concerning the prevalence and nature of any behavioural changes related to specific phobias in a cohort of patients representing canonical syndromes of FTD and Alzheimer's disease (AD), relative to healthy older controls.

Impaired phonemic discrimination in logopenic variant primary progressive aphasia.

Logopenic variant primary progressive aphasia (lvPPA) is the least well defined of the major primary progressive aphasia (PPA) syndromes. We assessed phoneme discrimination in patients with PPA (semantic, nonfluent/agrammatic, and logopenic variants) and typical Alzheimer's disease, relative to healthy age-matched participants. The lvPPA group performed significantly worse than all other groups apart from tAD, after adjusting for auditory verbal working memory.

Altered Time Awareness in Dementia.

Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals.

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer's disease: A proof-of-principle behavioural study.

Sleep disruption is a key clinical issue in the dementias but the sleep phenotypes of these diseases remain poorly characterised. Here we addressed this issue in a proof-of-principle study of 67 patients representing major syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD), in relation to 25 healthy older individuals. We collected reports on clinically-relevant sleep characteristics - time spent overnight in bed, sleep quality, excessive daytime somnolence and disruptive sleep events.

The functional neuroanatomy of emotion processing in frontotemporal dementias.

Impaired processing of emotional signals is a core feature of frontotemporal dementia syndromes, but the underlying neural mechanisms have proved challenging to characterize and measure. Progress in this field may depend on detecting functional changes in the working brain, and disentangling components of emotion processing that include sensory decoding, emotion categorization and emotional contagion. We addressed this using functional MRI of naturalistic, dynamic facial emotion processing with concurrent indices of autonomic arousal, in a cohort of patients representing all major frontotemporal dementia syndromes relative to healthy age-matched individuals.

Altered learning under uncertainty in unmedicated mood and anxiety disorders.

Anxiety is characterized by altered responses under uncertain conditions, but the precise mechanism by which uncertainty changes the behaviour of anxious individuals is unclear. Here we probe the computational basis of learning under uncertainty in healthy individuals and individuals suffering from a mix of mood and anxiety disorders. Participants were asked to choose between four competing slot machines with fluctuating reward and punishment outcomes during safety and stress.

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins.

Findings of Impaired Hearing in Patients With Nonfluent/Agrammatic Variant Primary Progressive Aphasia.

Importance: Despite being characterized as a disorder of language production, nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) is frequently associated with auditory symptoms. However, to our knowledge, peripheral auditory function has not been defined in this condition.

Objective: To assess peripheral hearing function in individuals with nfvPPA compared with healthy older individuals and patients with Alzheimer disease (AD).

Melody Processing Characterizes Functional Neuroanatomy in the Aging Brain.

The functional neuroanatomical mechanisms underpinning cognition in the normal older brain remain poorly defined, but have important implications for understanding the neurobiology of aging and the impact of neurodegenerative diseases. Auditory processing is an attractive model system for addressing these issues. Here, we used fMRI of melody processing to investigate auditory pattern processing in normal older individuals.

Sensitivity of Speech Output to Delayed Auditory Feedback in Primary Progressive Aphasias.

Delayed auditory feedback (DAF) is a classical paradigm for probing sensori-motor interactions in speech output and has been studied in various disorders associated with speech dysfluency and aphasia. However, little information is available concerning the effects of DAF on degenerating language networks in primary progressive aphasia: the paradigmatic "language-led dementias." Here we studied two forms of speech output (reading aloud and propositional speech) under natural listening conditions (no feedback delay) and under DAF at 200 ms, in a cohort of 19 patients representing all major primary progressive aphasia syndromes vs.

Retained capacity for perceptual learning of degraded speech in primary progressive aphasia and Alzheimer's disease.

Background: Processing of degraded speech is a promising model for understanding communication under challenging listening conditions, core auditory deficits and residual capacity for perceptual learning and cerebral plasticity in major dementias.

Methods: We compared the processing of sine-wave-degraded speech in 26 patients with primary progressive aphasia (non-fluent, semantic, and logopenic variants), 10 patients with typical Alzheimer's disease and 17 healthy control subjects. Participants were required to identify sine-wave words that were more predictable (three-digit numbers) or less predictable (place names).

Cardiac responses to viewing facial emotion differentiate frontotemporal dementias.

Objective: To establish proof-of-principle for the use of heart rate responses as objective measures of degraded emotional reactivity across the frontotemporal dementia spectrum, and to demonstrate specific relationships between cardiac autonomic responses and anatomical patterns of neurodegeneration.

Methods: Thirty-two patients representing all major frontotemporal dementia syndromes and 19 healthy older controls performed an emotion recognition task, viewing dynamic, naturalistic videos of facial emotions while ECG was recorded. Cardiac reactivity was indexed as the increase in interbeat interval at the onset of facial emotions.

Agnosia for bird calls.

The cognitive organisation of nonverbal auditory knowledge remains poorly defined. Deficits of environmental sound as well as word and visual object knowledge are well-recognised in semantic dementia. However, it is unclear how auditory cognition breaks down in this disorder and how this relates to deficits in other knowledge modalities.

Primary progressive aphasia: a clinical approach.

The primary progressive aphasias are a heterogeneous group of focal 'language-led' dementias that pose substantial challenges for diagnosis and management. Here we present a clinical approach to the progressive aphasias, based on our experience of these disorders and directed at non-specialists. We first outline a framework for assessing language, tailored to the common presentations of progressive aphasia.

Motor signatures of emotional reactivity in frontotemporal dementia.

Automatic motor mimicry is essential to the normal processing of perceived emotion, and disrupted automatic imitation might underpin socio-emotional deficits in neurodegenerative diseases, particularly the frontotemporal dementias. However, the pathophysiology of emotional reactivity in these diseases has not been elucidated. We studied facial electromyographic responses during emotion identification on viewing videos of dynamic facial expressions in 37 patients representing canonical frontotemporal dementia syndromes versus 21 healthy older individuals.

Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia.

Background: Interoception (the perception of internal bodily sensations) is strongly linked to emotional experience and sensitivity to the emotions of others in healthy subjects. Interoceptive impairment may contribute to the profound socioemotional symptoms that characterize frontotemporal dementia (FTD) syndromes, but remains poorly defined.

Methods: Patients representing all major FTD syndromes and healthy age-matched controls performed a heartbeat counting task as a measure of interoceptive accuracy.

Donepezil enhances understanding of degraded speech in Alzheimer's disease.

Auditory dysfunction under complex, dynamic listening conditions is a clinical hallmark of Alzheimer's disease (AD) but challenging to measure and manage. Here, we assessed understanding of sinewave speech (a paradigm of degraded speech perception) and general cognitive abilities in 17 AD patients, before and following a 10 mg dose of donepezil. Relative to healthy older individuals, patients had impaired sinewave speech comprehension that was selectively ameliorated by donepezil.

Behavioural and neuroanatomical correlates of auditory speech analysis in primary progressive aphasias.

Background: Non-verbal auditory impairment is increasingly recognised in the primary progressive aphasias (PPAs) but its relationship to speech processing and brain substrates has not been defined. Here we addressed these issues in patients representing the non-fluent variant (nfvPPA) and semantic variant (svPPA) syndromes of PPA.

Methods: We studied 19 patients with PPA in relation to 19 healthy older individuals.

Functional neuroanatomy of speech signal decoding in primary progressive aphasias.

The pathophysiology of primary progressive aphasias remains poorly understood. Here, we addressed this issue using activation fMRI in a cohort of 27 patients with primary progressive aphasia (nonfluent, semantic, and logopenic variants) versus 15 healthy controls. Participants listened passively to sequences of spoken syllables in which we manipulated 3-key auditory speech signal characteristics: temporal regularity, phonemic spectral structure, and pitch sequence entropy.