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Previous research suggests that emotional prosody perception is impaired in neurodegenerative diseases like Alzheimer’s disease (AD) and primary progressive aphasia (PPA). However, no previous research has investigated emotional prosody perception in these diseases under non-ideal listening conditions. We recruited 18 patients with AD, and 31 with PPA (nine logopenic (lvPPA); 11 nonfluent/agrammatic (nfvPPA) and 11 semantic (svPPA)), together with 24 healthy age-matched individuals. Participants listened to speech stimuli conveying three emotions in clear and noise-vocoded forms and had to identify the emotion being conveyed. We then conducted correlation analyses between task performance and measures of socio-emotional functioning. All patient groups showed significant impairments in identifying clear emotional prosody compared to healthy individuals. These deficits were exacerbated under noise-vocoded conditions, with all patient groups performing significantly worse than healthy individuals and patients with lvPPA performing significantly worse than those with svPPA. Significant correlations with social cognition measures were observed more consistently for noise-vocoded than clear emotional prosody comprehension. These findings open a window on a dimension of real-world emotional communication that has often been overlooked in dementia, with particular relevance to social cognition, and begin to suggest a novel candidate paradigm for investigating and quantifying this systematically.

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. Here we addressed this issue using a novel technique—spectral dynamic causal modelling—that estimates the effective connectivity between brain regions from resting-state fMRI data. We studied patients with semantic dementia—the paradigmatic disorder of the brain system mediating world knowledge—relative to healthy older individuals. We assessed how the effective connectivity of the semantic appraisal network targeted by this disease was modulated by pathogenic protein deposition and by two key phenotypic factors, semantic impairment and behavioural disinhibition. The presence of pathogenic protein in SD weakened the normal inhibitory self-coupling of network hubs in both antero-mesial temporal lobes, with development of an abnormal excitatory fronto-temporal projection in the left cerebral hemisphere. Semantic impairment and social disinhibition were linked to a similar but more extensive profile of abnormally attenuated inhibitory self-coupling within temporal lobe regions and excitatory projections between temporal and inferior frontal regions. Our findings demonstrate that population-level dynamic causal modelling can disclose a core pathophysiological feature of proteinopathic network architecture—attenuation of inhibitory connectivity—and the key elements of distributed neuronal processing that underwrite semantic memory.

ObjectivesWe explored whether adapting neuropsychological tests for online administration during the COVID-19 pandemic was feasible for dementia research.DesignWe 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.SettingRemote assessments were conducted using video-conferencing/online testing platforms, with participants using a personal computer/tablet at home. Face-to-face assessments were conducted in testing rooms at our research centre.ParticipantsThe remote cohort comprised 25 patients (n=8 Alzheimer’s disease (AD); n=3 behavioural variant frontotemporal dementia (bvFTD); n=4 semantic dementia (SD); n=5 progressive non-fluent aphasia (PNFA); n=5 logopenic aphasia (LPA)). The face-to-face patient cohort comprised 64 patients (n=25 AD; n=12 bvFTD; n=9 SD; n=12 PNFA; n=6 LPA). Ten controls who previously participated in face-to-face research also took part remotely.Outcome measuresThe outcome measures comprised the strength of evidence under a Bayesian framework for differences in performances between testing environments on general neuropsychological and neurolinguistic measures.ResultsThere was substantial evidence suggesting no difference across environments in both the healthy control and combined patient cohorts (including measures of working memory, single-word comprehension, arithmetic and naming; Bayes Factors (BF)01 >3), in the healthy control group alone (including measures of letter/category fluency, semantic knowledge and bisyllabic word repetition; all BF01 >3), and in the combined patient cohort alone (including measures of working memory, episodic memory, short-term verbal memory, visual perception, non-word reading, sentence comprehension and bisyllabic/trisyllabic word repetition; all BF01 >3). In the control cohort alone, there was substantial evidence in support of a difference across environments for tests of visual perception (BF01=0.0404) and monosyllabic word repetition (BF01=0.0487).ConclusionsOur findings suggest that remote delivery of neuropsychological tests for dementia research is feasible.

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. We manipulated the temporal (rhythmic) structure and familiarity of melodies in a passive listening, 'sparse' fMRI protocol. A distributed cortico-subcortical network was activated by auditory stimulation compared with silence; and within this network, we identified separable signatures of anisochrony processing in bilateral posterior superior temporal lobes; melodic familiarity in bilateral anterior temporal and inferior frontal cortices; and melodic novelty in bilateral temporal and left parietal cortices. Left planum temporale emerged as a 'hub' region functionally partitioned for processing different melody dimensions. Activation of Heschl's gyrus by auditory stimulation correlated with the integrity of underlying cortical tissue architecture, measured using multi-parameter mapping. Our findings delineate neural substrates for analyzing perceptual and semantic properties of melodies in normal aging. Melody (auditory pattern) processing may be a useful candidate paradigm for assessing cerebral networks in the older brain and potentially, in neurodegenerative diseases of later life.

The speech we hear every day is typically “degraded” by competing sounds and the idiosyncratic vocal characteristics of individual speakers. While the comprehension of “degraded” speech is normally automatic, it depends on dynamic and adaptive processing across distributed neural networks. This presents the brain with an immense computational challenge, making degraded speech processing vulnerable to a range of brain disorders. Therefore, it is likely to be a sensitive marker of neural circuit dysfunction and an index of retained neural plasticity. Considering experimental methods for studying degraded speech and factors that affect its processing in healthy individuals, we review the evidence for altered degraded speech processing in major neurodegenerative diseases, traumatic brain injury and stroke. We develop a predictive coding framework for understanding deficits of degraded speech processing in these disorders, focussing on the “language-led dementias”—the primary progressive aphasias. We conclude by considering prospects for using degraded speech as a probe of language network pathophysiology, a diagnostic tool and a target for therapeutic intervention.

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. In the combined PPA cohort, voxel‐based morphometry correlated phonemic discrimination score with grey matter in left angular gyrus. Our findings suggest that impaired phonemic discrimination may help differentiate lvPPA from other PPA subtypes, with important diagnostic and management implications.

Background Patients with behavioural variant frontotemporal dementia (bvFTD) and right temporal variant frontotemporal dementia (rtvFTD) commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people. Method The QSTAC was administered to 12 patients with bvFTD, 7 patients with rtvFTD and 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also underwent pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment. Result After accounting for nonverbal executive and peripheral hearing performance, patients with bvFTD and rtvFTD showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with bvFTD showed a deficit in dichotic listening compared with the rtvFTD group. Conclusion bvFTD and rtvFTD have distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.

BackgroundHearing impairment has emerged as a potent association of cognitive decline in dementia and a promising treatment target. To realise this promise, we need to resolve fundamental questions concerning the roles of peripheral versus central auditory deficits in different dementias.MethodsUsing a novel psychoacoustic battery – the Queen Square Tests of Auditory Cognition (QSTAC)– we combined pre-existing and novel measures of peripheral and central hearing functions, to charac- terise discrete ‘auditory phenotypes’ across dementia syndromes. Customised auditory symptom ques- tionnaires (completed by patients’ caregivers) were used to capture daily-life hearing-related disability and care burden. Patient groups: Alzheimer’s disease, frontotemporal dementia, primary progressive aphasia (PPA) and control. Neuroanatomical associations of specific hearing deficits were assessed using voxel-based morphometry.ResultsSyndromic signatures of peripheral and central auditory dysfunction were identified. Alzheimer’s disease was associated with prominent impairments of auditory scene analysis and dichotic listening. PPA syndromes and behavioural variant FTD (BvFTD) were principally associated with deficits of sound pattern analysis, sound identity, emotion recognition and degraded speech perception, which stratified according to sub-syndrome (logopoenic, semantic, nonfluent).ConclusionsTaken together, our findings suggest that major dementias have characteristic and differenti- ated auditory phenotypes, reflecting a complex interplay of peripheral hearing and auditory cognitive dysfunction.jeremy.johnson@doctors.org.uk

BackgroundWhilst current diagnostic criteria for primary progressive aphasia syndromes (PPA) emphasise impaired language output and linguistic processing, deficits of auditory analysis are increasingly rec- ognised in PPA syndromes. We assessed phonemic discrimination and its neuroanatomical correlates in patients representing all major PPA variants, compared with typical Alzheimer’s disease (tAD) and healthy age-matched individuals.Methods81 patients with PPA or typical Alzheimer’s disease, and 73 controls performed a phonemic minimal pair discrimination task. Neuroanatomical associations of phonemic discrimination performance across the PPA cohort were assessed using voxel-based morphometry.ResultsPatients with logopoenic variant primary progressive aphasia (lvPPA) as a group performed sig- nificantly worse than both the healthy control group and other PPA variants, after adjusting for auditory verbal working memory. Patients with typical Alzheimer’s disease showed a similar pattern of performance to the lvPPA group. Voxel-based morphometry revealed a significant association of regional grey matter in left angular gyrus with phonemic discrimination performance.ConclusionsImpaired phonemic discrimination is a component of lvPPA and may help differentiate this syndrome from other forms of PPA. These findings speak to the emerging theme of auditory perceptual dysfunction in the progressive aphasias, with implications both for refining diagnostic criteria and developing new clinical biomarkers.jeremy.johnson@doctors.org.uk

The clinical complexity and pathological diversity of neurodegenerative diseases impose immense challenges for diagnosis and the design of rational interventions. To address these challenges, there is a need to identify new paradigms and biomarkers that capture shared pathophysiological processes and can be applied across a range of diseases. One core paradigm of brain function is predictive coding: the processes by which the brain establishes predictions and uses them to minimise prediction errors represented as the difference between predictions and actual sensory inputs. The processes involved in processing unexpected events and responding appropriately are vulnerable in common dementias but difficult to characterise. In my PhD work, I have exploited key properties of music - its universality, ecological relevance and structural regularity - to model and assess predictive cognition in patients representing major syndromes of frontotemporal dementia - non-fluent variant PPA (nfvPPA), semantic-variant PPA (svPPA) and behavioural-variant FTD (bvFTD) - and Alzheimer's disease relative to healthy older individuals. In my first experiment, I presented patients with well-known melodies containing no deviants or one of three types of deviant - acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). I assessed accuracy detecting melodic deviants and simultaneously-recorded pupillary responses to these deviants. I used voxel-based morphometry to define neuroanatomical substrates for the behavioural and autonomic processing of these different types of deviants, and identified a posterior temporo-parietal network for detection of basic acoustic deviants and a more anterior fronto-temporo-striatal network for detection of syntactic pitch deviants. In my second chapter, I investigated the ability of patients to track the statistical structure of the same musical stimuli, using a computational model of the information dynamics of music to calculate the information-content of deviants (unexpectedness) and entropy of melodies (uncertainty). I related these information-theoretic metrics to performance for detection of deviants and to 'evoked' and 'integrative' pupil reactivity to deviants and melodies respectively and found neuroanatomical correlates in bilateral dorsal and ventral striatum, hippocampus, superior temporal gyri, right temporal pole and left inferior frontal gyrus. Together, chapters 3 and 4 revealed new hypotheses about the way FTD and AD pathologies disrupt the integration of predictive errors with predictions: a retained ability of AD patients to detect deviants at all levels of the hierarchy with a preserved autonomic sensitivity to information-theoretic properties of musical stimuli; a generalized impairment of surprise detection and statistical tracking of musical information at both a cognitive and autonomic levels for svPPA patients underlying a diminished precision of predictions; the exact mirror profile of svPPA patients in nfvPPA patients with an abnormally high rate of false-alarms with up-regulated pupillary reactivity to deviants, interpreted as over-precise or inflexible predictions accompanied with normal cognitive and autonomic probabilistic tracking of information; an impaired behavioural and autonomic reactivity to unexpected events with a retained reactivity to environmental uncertainty in bvFTD patients. Chapters 5 and 6 assessed the status of reward prediction error processing and updating via actions in bvFTD. I created pleasant and aversive musical stimuli by manipulating chord progressions and used a classic reinforcement-learning paradigm which asked participants to choose the visual cue with the highest probability of obtaining a musical 'reward'. bvFTD patients showed reduced sensitivity to the consequence of an action and lower learning rate in response to aversive stimuli compared to reward. These results correlated with neuroanatomical substrates in ventral and dorsal attention networks, dorsal striatum, parahippocampal gyrus and temporo-parietal junction. Deficits were governed by the level of environmental uncertainty with normal learning dynamics in a structured and binarized environment but exacerbated deficits in noisier environments. Impaired choice accuracy in noisy environments correlated with measures of ritualistic and compulsive behavioural changes and abnormally reduced learning dynamics correlated with behavioural changes related to empathy and theory-of-mind. Together, these experiments represent the most comprehensive attempt to date to define the way neurodegenerative pathologies disrupts the perceptual, behavioural and physiological encoding of unexpected events in predictive coding terms.