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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. We studied 27 patients with behavioural variant frontotemporal dementia, 58 with primary progressive aphasia (22 semantic variant, 24 non-fluent/agrammatic variant and 12 logopenic) and 34 with typical amnestic Alzheimer's disease, in relation to 42 healthy older individuals. Changes in behavioural responsiveness were assessed for canonical primary rewards (appetite, sweet tooth, sexual activity) and non-primary rewards (music, religion, art, colours), using a semi-structured survey completed by patients' primary caregivers. Changes in more general socio-emotional behaviours were also recorded. We applied multiple correspondence analysis and k -means clustering to map relationships between hedonic domains and extract core factors defining aberrant hedonic phenotypes. Neuroanatomical associations were assessed using voxel-based morphometry of brain MRI images across the combined patient cohort. Altered (increased and/or decreased) reward responsiveness was exhibited by most patients in the behavioural and semantic variants of frontotemporal dementia and around two-thirds of patients in other dementia groups, significantly ( P < 0.05) more frequently than in healthy controls. While food-directed changes were most prevalent across the patient cohort, behavioural changes directed toward non-primary rewards occurred significantly more frequently ( P < 0.05) in the behavioural and semantic variants of frontotemporal dementia than in other patient groups. Hedonic behavioural changes across the patient cohort were underpinned by two principal factors: a 'gating' factor determining the emergence of altered reward behaviour and a 'modulatory' factor determining how that behaviour is directed. These factors were expressed jointly in a set of four core, trans-diagnostic and multimodal hedonic phenotypes: 'reward-seeking', 'reward-restricted', 'eating-predominant' and 'control-like'-variably represented across the cohort and associated with more pervasive socio-emotional behavioural abnormalities. The principal gating factor was associated ( P < 0.05 after correction for multiple voxel-wise comparisons over the whole brain) with a common profile of grey matter atrophy in anterior cingulate, bilateral temporal poles, right middle frontal and fusiform gyri: the cortical circuitry that mediates behavioural salience and semantic and affective appraisal of sensory stimuli. Our findings define a multi-domain phenotypic architecture for aberrant reward behaviours in major dementias, with novel implications for the neurobiological understanding and clinical management of these diseases., Competing Interests: The authors report no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., Setting: Remote 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., Participants: The 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 Measures: The outcome measures comprised the strength of evidence under a Bayesian framework for differences in performances between testing environments on general neuropsychological and neurolinguistic measures., Results: There 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 BF 01 >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 BF 01 >3). In the control cohort alone, there was substantial evidence in support of a difference across environments for tests of visual perception (BF 01 =0.0404) and monosyllabic word repetition (BF 01 =0.0487)., Conclusions: Our findings suggest that remote delivery of neuropsychological tests for dementia research is feasible., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Intramammary infections (IMI) are common in primigravid dairy heifers and can negatively affect future milk production. Bismuth subnitrate-based internal teat sealants (ITS) have been used to prevent prepartum IMI in dairy heifers by creating a physical barrier within the teat, preventing pathogens from entering the gland, though determination of when to administer ITS in heifers has yet to be investigated. The objectives of this study were to determine if administration of ITS in primigravid heifers reduced the odds of IMI at calving and if administration of ITS at different stages of gestation (75 vs. 35 d prepartum) affected the odds of IMI at calving. A total of 270 heifers were used at a single farm. One quarter of each heifer was randomly chosen to be aseptically sampled and administered ITS 75 d prepartum (ITS75), another quarter of each heifer was sampled and received ITS 35 d prepartum (ITS35), whereas the remaining 2 quarters of each heifer served as control quarters (CON) and were not sampled before calving. Within 12 h of calving, aseptic colostrum samples were collected from all quarters to determine quarter infection status. When an IMI was caused by mastitis pathogens other than non-aureus staphylococci (NAS), CON quarters were 3 times [95% confidence interval (CI): 1.4-6.3] and 2.5 times (95% CI: 1.2-4.9) more likely to be infected at calving than ITS75 and ITS35 quarters, respectively. For IMI with NAS, CON quarters were 5.8 (95% CI: 3.2-10.5) and 6.4 (95% CI: 3.4-12.0) times more likely to be infected than ITS75 and ITS35 quarters, respectively. Odds of IMI at calving was similar between ITS75 and ITS35 quarters for both NAS (odds ratio = 0.9) and other pathogens (odds ratio = 1.2). Results indicate that ITS administration at either 75 and 35 d prepartum reduced IMI prevalence at calving in primigravid dairy heifers. Farm specific factors may influence prevalence and timing of heifer IMI and earlier administration of ITS provides an extended period of protection for the developing gland., (Copyright © 2021 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

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. We assessed cognitive labelling (identification) and valence rating (affective evaluation) of samples of spontaneous (mirthful and hostile) and volitional (posed) laughter versus two auditory control conditions (a synthetic laughter-like stimulus and spoken numbers). Neuroanatomical associations of laughter processing were assessed using voxel-based morphometry of patients' brain MR images. While all dementia syndromes were associated with impaired identification of laughter subtypes relative to healthy controls, this was significantly more severe overall in frontotemporal dementia than in Alzheimer's disease and particularly in the behavioural and semantic variants, which also showed abnormal affective evaluation of laughter. Over the patient cohort, laughter identification accuracy was correlated with measures of daily-life socio-emotional functioning. Certain striking syndromic signatures emerged, including enhanced liking for hostile laughter in behavioural variant frontotemporal dementia, impaired processing of synthetic laughter in the nonfluent-agrammatic variant (consistent with a generic complex auditory perceptual deficit) and enhanced liking for numbers ('numerophilia') in the semantic variant. Across the patient cohort, overall laughter identification accuracy correlated with regional grey matter in a core network encompassing inferior frontal and cingulo-insular cortices; and more specific correlates of laughter identification accuracy were delineated in cortical regions mediating affective disambiguation (identification of hostile and posed laughter in orbitofrontal cortex) and authenticity (social intent) decoding (identification of mirthful and posed laughter in anteromedial prefrontal cortex) (all p < .05 after correction for multiple voxel-wise comparisons over the whole brain). These findings reveal a rich diversity of cognitive and affective laughter phenotypes in canonical dementia syndromes and suggest that laughter is an informative probe of neural mechanisms underpinning socio-emotional dysfunction in neurodegenerative disease., Competing Interests: Declaration of competing interest The authors report no competing interests. No part of the study procedures was pre-registered prior to the research being conducted. No part of the study analyses was pre-registered prior to the research being conducted., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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. We studied 62 patients (24 female; aged 53-88) representing major syndromes of frontotemporal dementia (behavioural variant, semantic variant primary progressive aphasia, non-fluent-agrammatic variant primary progressive aphasia) and typical amnestic Alzheimer's disease, in relation to 33 healthy controls (18 female; aged 54-78). Participants heard famous melodies containing no deviants or one of three types of deviant note-acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). Using a regression model that took elementary perceptual, executive and musical competence into account, we assessed accuracy detecting melodic deviants and simultaneously recorded pupillary responses and related these to deviant surprise value (information-content) and carrier melody predictability (entropy), calculated using an unsupervised machine learning model of music. Neuroanatomical associations of deviant detection accuracy and coupling of detection to deviant surprise value were assessed using voxel-based morphometry of patients' brain MRI. Whereas Alzheimer's disease was associated with normal deviant detection accuracy, behavioural and semantic variant frontotemporal dementia syndromes were associated with strikingly similar profiles of impaired syntactic and semantic deviant detection accuracy and impaired behavioural and autonomic sensitivity to deviant information-content (all P  < 0.05). On the other hand, non-fluent-agrammatic primary progressive aphasia was associated with generalized impairment of deviant discriminability ( P  < 0.05) due to excessive false-alarms, despite retained behavioural and autonomic sensitivity to deviant information-content and melody predictability. Across the patient cohort, grey matter correlates of acoustic deviant detection accuracy were identified in precuneus, mid and mesial temporal regions; correlates of syntactic deviant detection accuracy and information-content processing, in inferior frontal and anterior temporal cortices, putamen and nucleus accumbens; and a common correlate of musical salience coding in supplementary motor area (all P  < 0.05, corrected for multiple comparisons in pre-specified regions of interest). Our findings suggest that major dementias have distinct profiles of sensory 'surprise' processing, as instantiated in music. Music may be a useful and informative paradigm for probing the predictive decoding of complex sensory environments in neurodegenerative proteinopathies, with implications for understanding and measuring the core pathophysiology of these diseases., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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). Analysis was performed on language samples from 29 speakers with semantic variant PPA (svPPA), 25 speakers with logopenic variant PPA (lvPPA), 34 speakers with non-fluent variant PPA (nfvPPA), 14 speakers with behavioral variant FTD (bvFTD) and 20 older normal controls (NCs). We used frequency and collocation strength measures to determine use of familiar words and word combinations. We also computed word counts, content word ratio and a combination ratio, a measure of the degree to which the individual produces connected language. All dementia subtypes differed significantly from NCs. The most discriminating variables were word count, combination ratio, and content word ratio, each of which distinguished at least one dementia group from NCs. All participants with PPA, but not participants with bvFTD, produced significantly more frequent forms at the level of content words, word combinations, or both. Each dementia group differed from the others on at least one variable, and language production variables correlated with established behavioral measures of disease progression. A machine learning classifier, using narrative speech variables, achieved 90% accuracy when classifying samples as NC or dementia, and 59.4% accuracy when matching samples to their diagnostic group. Automated quantification of spontaneous speech in both language-led and non-language led dementias, is feasible. It allows extraction of syndromic profiles that complement those derived from standardized tests, warranting further evaluation as candidate biomarkers. Inclusion of frequency-based language variables benefits profiling and classification., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

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.

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. Neuroanatomical correlates of altered phobic reactivity were assessed using voxel-based morphometry., Results: 46 patients with bvFTD, 20 with semantic variant primary progressive aphasia, 25 with non-fluent variant primary progressive aphasia, 29 with AD and 55 healthy age-matched individuals participated. Changes in specific phobia were significantly more prevalent in the combined FTD cohort (15.4% of cases) and in the bvFTD group (17.4%) compared both to healthy controls (3.6%) and patients with AD (3.5%). Attenuation of phobic reactivity was reported for individuals in all participant groups, however new phobias developed only in the FTD cohort. Altered phobic reactivity was significantly associated with relative preservation of grey matter in left posterior middle temporal gyrus, right temporo-occipital junction and right anterior cingulate gyrus, brain regions previously implicated in contextual decoding, salience processing and reward valuation., Conclusion: Altered phobic reactivity is a relatively common issue in patients with FTD, particularly bvFTD. This novel paradigm of strong fear experience has broad implications: clinically, for diagnosis and patient well-being; and neurobiologically, for our understanding of the pathophysiology of aversive sensory signal processing in FTD and the neural mechanisms of fear more generally., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions., (Copyright © 2020 Requena-Komuro, Marshall, Bond, Russell, Greaves, Moore, Agustus, Benhamou, Sivasathiaseelan, Hardy, Rohrer and Warren.)

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. Difficulty falling or staying asleep at night and excessive daytime somnolence were significantly more frequently reported for patients with both FTD and AD than healthy controls. On average, patients with FTD and AD retired earlier and patients with AD spent significantly longer in bed overnight than did healthy controls. Excessive daytime somnolence was significantly more frequent in the FTD group than the AD group; AD syndromic subgroups showed similar sleep symptom profiles while FTD subgroups showed more variable profiles. Sleep disturbance is a significant clinical issue in major FTD and AD variant syndromes and may be even more salient in FTD than AD. These preliminary findings warrant further systematic investigation with electrophysiological and neuroanatomical correlation in major proteinopathies., (© 2019 The Authors.)

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. We predicted that anxious individuals under stress would learn faster about punishments and exhibit choices that were more affected by those punishments, thus formalizing our predictions as parameters in reinforcement learning accounts of behaviour. Overall, the data suggest that anxious individuals are quicker to update their behaviour in response to negative outcomes (increased punishment learning rates). When treating anxiety, it may therefore be more fruitful to encourage anxious individuals to integrate information over longer horizons when bad things happen, rather than try to blunt their responses to negative outcomes.

Transrectal palpation of the reproductive tract is the most common method for pregnancy determination in cattle and is considered a veterinary skill that new veterinary medicine (DVM) graduates should perform proficiently. However, using privately owned cattle to train students can be difficult because producers may believe that transrectal palpation by inexperienced students increases the risk of pregnancy wastage compared with examination by an experienced clinician. We used a randomized field trial of 1,216 healthy Holstein and Jersey cattle in 2 commercial dairy herds to estimate the effect of veterinary student transrectal palpation on early pregnancy loss. All cattle were determined to be pregnant using transrectal ultrasonography at approximately 37 d after artificial insemination. Cattle were then allocated into 2 groups based upon their ear tag number (study group = 598; control group = 618). Cattle in the study group were immediately palpated after ultrasonography by a fourth-year veterinary student, whereas control cattle were not subject to any additional pregnancy assessment. For analysis, the student palpators were divided into 2 groups: students who had previously had formal palpation training via an elective bovine palpation class (n = 30) and students who had not had palpation training (n = 134). All cattle were reevaluated using transrectal ultrasonography approximately 70 d after artificial insemination. A total of 53 (4.36%) animals lost their pregnancy between the first and second pregnancy assessments. Of the animals that lost their pregnancy, 26 (4.35%) were study group cows and 27 (4.37%) were control cows. Of the 26 cows documented to have had pregnancy loss within the study group, 20 out of 378 (5.3%) had been palpated by students who had not taken the palpation elective and 6 out of 220 (2.7%) had been palpated by students who had completed the elective. We found no difference in pregnancy loss between student-palpated and clinician-ultrasounded cattle, supporting the safety of using privately owned animals for student bovine palpation and pregnancy diagnosis training without affecting early pregnancy loss., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

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. Seventeen patients with behavioural variant frontotemporal dementia [four female; mean (standard deviation) age 64.8 (6.8) years], 12 with semantic variant primary progressive aphasia [four female; 66.9 (7.0) years], nine with non-fluent variant primary progressive aphasia [five female; 67.4 (8.1) years] and 22 healthy controls [12 female; 68.6 (6.8) years] passively viewed videos of universal facial expressions during functional MRI acquisition, with simultaneous heart rate and pupillometric recordings; emotion identification accuracy was assessed in a post-scan behavioural task. Relative to healthy controls, patient groups showed significant impairments (analysis of variance models, all P < 0.05) of facial emotion identification (all syndromes) and cardiac (all syndromes) and pupillary (non-fluent variant only) reactivity. Group-level functional neuroanatomical changes were assessed using statistical parametric mapping, thresholded at P < 0.05 after correction for multiple comparisons over the whole brain or within pre-specified regions of interest. In response to viewing facial expressions, all participant groups showed comparable activation of primary visual cortex while patient groups showed differential hypo-activation of fusiform and posterior temporo-occipital junctional cortices. Bi-hemispheric, syndrome-specific activations predicting facial emotion identification performance were identified (behavioural variant, anterior insula and caudate; semantic variant, anterior temporal cortex; non-fluent variant, frontal operculum). The semantic and non-fluent variant groups additionally showed complex profiles of central parasympathetic and sympathetic autonomic involvement that overlapped signatures of emotional visual and categorization processing and extended (in the non-fluent group) to brainstem effector pathways. These findings open a window on the functional cerebral mechanisms underpinning complex socio-emotional phenotypes of frontotemporal dementia, with implications for novel physiological biomarker development., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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)., Design, Setting, and Participants: This cross-sectional single-center study was conducted at the Dementia Research Centre of University College London between August 2015 and July 2018. A consecutive cohort of patients with nfvPPA and patients with AD were compared with healthy control participants. No participant had substantial otological or cerebrovascular disease; all eligible patients fulfilling diagnostic criteria and able to comply with audiometry were included., Main Outcomes and Measures: We measured mean threshold sound levels required to detect pure tones at frequencies of 500, 1000, 2000, 4000, and 6000 Hz in the left and right ears separately; these were used to generate better-ear mean and worse-ear mean composite hearing threshold scores and interaural difference scores for each participant. All analyses were adjusted for participant age., Results: We studied 19 patients with nfvPPA (9 female; mean [SD] age, 70.3 [9.0] years), 20 patients with AD (9 female; mean [SD] age, 69.4 [8.1] years) and 34 control participants (15 female; mean [SD] age, 66.7 [6.3] years). The patients with nfvPPA had significantly higher scores than control participants on better-ear mean scores (patients with nfvPPA: mean [SD], 36.3 [9.4] decibels [dB]; control participants: 28.9 [7.3] dB; age-adjusted difference, 5.7 [95% CI, 1.4-10.0] dB; P = .01) and worse-ear mean scores (patients with nfvPPA: 42.2 [11.5] dB; control participants: 31.7 [8.1] dB; age-adjusted difference, 8.5 [95% CI, 3.6-13.4] dB; P = .001). The patients with nfvPPA also had significantly higher better-ear mean scores than patients with AD (patients with AD: mean [SD] 31.1 [7.5] dB; age-adjusted difference, 4.8 [95% CI, 0.0-9.6] dB; P = .048) and worse-ear mean scores (patients with AD: mean [SD], 33.8 [8.2] dB; age-adjusted difference, 7.8 [95% CI, 2.4-13.2] dB; P = .005). The difference scores (worse-ear mean minus better-ear mean) were significantly higher in the patients with nfvPPA (mean [SD], 5.9 [5.2] dB) than control participants (mean [SD], 2.8 [2.2] dB; age-adjusted difference, 2.8 [95% CI, 0.9-4.7] dB; P = .004) and patients with AD (mean [SD], 2.8 [2.1] dB; age-adjusted difference, 3.0 [95% CI, 0.9-5.1] dB; P = .005)., Conclusions and Relevance: In this study, patients with nfvPPA performed worse on pure-tone audiometry than healthy older individuals or patients with AD, and the difference was not attributable to age or general disease factors. Cases of nfvPPA were additionally associated with increased functional interaural audiometric asymmetry. These findings suggest conjoint peripheral afferent and more central regulatory auditory dysfunction in individuals with nfvPPA.

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. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

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.

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. healthy older individuals and patients with other canonical dementia syndromes (typical Alzheimer's disease and behavioral variant frontotemporal dementia). Healthy controls and most syndromic groups showed a quantitatively or qualitatively similar profile of reduced speech output rate and increased speech error rate under DAF relative to natural auditory feedback. However, there was no group effect on propositional speech output rate under DAF in patients with nonfluent primary progressive aphasia and logopenic aphasia. Importantly, there was considerable individual variation in DAF sensitivity within syndromic groups and some patients in each group (though no healthy controls) apparently benefited from DAF, showing paradoxically increased speech output rate and/or reduced speech error rate under DAF. This work suggests that DAF may be an informative probe of pathophysiological mechanisms underpinning primary progressive aphasia: identification of "DAF responders" may open up an avenue to novel therapeutic applications.

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). The change in identification performance within each session indexed perceptual learning. Neuroanatomical associations of degraded speech processing were assessed using voxel-based morphometry., Results: Patients with non-fluent and logopenic progressive aphasia and typical Alzheimer's disease showed impaired identification of sine-wave numbers, whereas all syndromic groups showed impaired identification of sine-wave place names. A significant overall identification advantage for numbers over place names was shown by patients with typical Alzheimer's disease, patients with semantic progressive aphasia and healthy control participants. All syndromic groups showed spontaneous perceptual learning effects for sine-wave numbers. For the combined patient cohort, grey matter correlates were identified across a distributed left hemisphere network extending beyond classical speech-processing cortices., Conclusions: These findings demonstrate resilience of auditory perceptual learning capacity across dementia syndromes, despite variably impaired perceptual decoding of degraded speech and reduced predictive integration of semantic knowledge. This work has implications for the neurobiology of dynamic sensory processing and plasticity in neurodegenerative diseases and for development of novel biomarkers and therapeutic interventions.

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. We then consider the defining features of the canonical progressive nonfluent, semantic and logopenic aphasic syndromes, including 'clinical pearls' that we have found diagnostically useful and neuroanatomical and other key associations of each syndrome. We review potential diagnostic pitfalls and problematic presentations not well captured by conventional classifications and propose a diagnostic 'roadmap'. After outlining principles of management, we conclude with a prospect for future progress in these diseases, emphasising generic information processing deficits and novel pathophysiological biomarkers.

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. We had the opportunity to study a patient with a typical syndrome of semantic dementia who had extensive premorbid knowledge of birds, allowing us to assess the impact of the disease on the processing of auditory in relation to visual and verbal attributes of this specific knowledge category. We designed a novel neuropsychological test to probe knowledge of particular avian characteristics (size, behaviour [migratory or nonmigratory], habitat [whether or not primarily water-dwelling]) in the nonverbal auditory, visual and verbal modalities, based on a uniform two-alternative-forced-choice procedure. The patient's performance was compared to healthy older individuals of similar birding experience. We further compared his performance on this test of bird knowledge with his knowledge of familiar human voices and faces. Relative to healthy birder controls, the patient showed marked deficits of bird call and bird name knowledge but relatively preserved knowledge of avian visual attributes and retained knowledge of human voices and faces. In both the auditory and visual modalities, his knowledge of the avian characteristics of size and behaviour was intact whereas his knowledge of the associated characteristic of habitat was deficient. This case provides further evidence that nonverbal auditory knowledge has a fractionated organisation that can be differentially targeted in semantic dementia., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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. Gray matter associations of emotional reactivity were assessed using voxel-based morphometry of patients' brain MR images., Results: Relative to healthy controls, all patient groups had impaired emotion identification, whereas cardiac reactivity was attenuated in those groups with predominant fronto-insular atrophy (behavioral variant frontotemporal dementia and nonfluent primary progressive aphasia), but preserved in syndromes focused on the anterior temporal lobes (right temporal variant frontotemporal dementia and semantic variant primary progressive aphasia). Impaired cardiac reactivity correlated with gray matter atrophy in a fronto-cingulo-insular network that overlapped correlates of cognitive emotion processing., Interpretation: Autonomic indices of emotional reactivity dissociate from emotion categorization ability, stratifying frontotemporal dementia syndromes and showing promise as novel biomarkers. Attenuated cardiac responses to the emotions of others suggest a core pathophysiological mechanism for emotional blunting and degraded interpersonal reactivity in these diseases.

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. Neuroanatomical associations of emotional expression identification accuracy and facial muscle reactivity were assessed using voxel-based morphometry. Controls showed characteristic profiles of automatic imitation, and this response predicted correct emotion identification. Automatic imitation was reduced in the behavioural and right temporal variant groups, while the normal coupling between imitation and correct identification was lost in the right temporal and semantic variant groups. Grey matter correlates of emotion identification and imitation were delineated within a distributed network including primary visual and motor, prefrontal, insular, anterior temporal and temporo-occipital junctional areas, with common involvement of supplementary motor cortex across syndromes. Impaired emotional mimesis may be a core mechanism of disordered emotional signal understanding and reactivity in frontotemporal dementia, with implications for the development of novel physiological biomarkers of socio-emotional dysfunction in these diseases.

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. In addition, patients had volumetric MRI for voxel-based morphometric analysis, and their caregivers completed a questionnaire assessing patients' daily-life sensitivity to the emotions of others., Results: Interoceptive accuracy was impaired in patients with semantic variant primary progressive aphasia relative to healthy age-matched individuals, but not in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Impaired interoceptive accuracy correlated with reduced daily-life emotional sensitivity across the patient cohort, and with atrophy of right insula, cingulate, and amygdala on voxel-based morphometry in the impaired semantic variant group, delineating a network previously shown to support interoceptive processing in the healthy brain., Conclusion: Interoception is a promising novel paradigm for defining mechanisms of reduced emotional reactivity, empathy, and self-awareness in neurodegenerative syndromes and may yield objective measures for these complex symptoms.

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. Our findings demonstrate impaired perception of degraded speech in AD but retained perceptual learning capacity that can be harnessed by acetylcholinesterase inhibition, with implications for designing communication interventions and acoustic environments in dementia.

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. Relative to healthy controls, nonfluent variant patients showed reduced activation of medial Heschl's gyrus in response to any auditory stimulation and reduced activation of anterior cingulate to temporal irregularity. Semantic variant patients had relatively reduced activation of caudate and anterior cingulate in response to increased entropy. Logopenic variant patients showed reduced activation of posterior superior temporal cortex to phonemic spectral structure. Taken together, our findings suggest that impaired processing of core speech signal attributes may drive particular progressive aphasia syndromes and could index a generic physiological mechanism of reduced computational efficiency relevant to all these syndromes, with implications for development of new biomarkers and therapeutic interventions., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

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. We manipulated three key auditory parameters-temporal regularity, phonemic spectral structure and prosodic predictability (an index of fundamental information content, or entropy)-in sequences of spoken syllables. The ability of participants to process these parameters was assessed using two-alternative, forced-choice tasks and neuroanatomical associations of task performance were assessed using voxel-based morphometry of patients' brain magnetic resonance images., Results: Relative to healthy controls, both the nfvPPA and svPPA groups had impaired processing of phonemic spectral structure and signal predictability while the nfvPPA group additionally had impaired processing of temporal regularity in speech signals. Task performance correlated with standard disease severity and neurolinguistic measures. Across the patient cohort, performance on the temporal regularity task was associated with grey matter in the left supplementary motor area and right caudate, performance on the phoneme processing task was associated with grey matter in the left supramarginal gyrus, and performance on the prosodic predictability task was associated with grey matter in the right putamen., Conclusions: Our findings suggest that PPA syndromes may be underpinned by more generic deficits of auditory signal analysis, with a distributed cortico-subcortical neuraoanatomical substrate extending beyond the canonical language network. This has implications for syndrome classification and biomarker development.

Despite considerable evidence for abnormalities of self-awareness in Alzheimer's disease (AD), the cognitive mechanisms of altered self-processing in AD have not been fully defined. Here we addressed this issue in a detailed analysis of self/non-self-processing in three patients with AD. We designed a novel neuropsychological battery comprising tests of tactile body schema coding, attribution of tactile events to self versus external agents, and memory for self- versus non-self-generated vocal information, administered in conjunction with a daily life measure of self/non-self-processing (the Interpersonal Reactivity Index). Three male AD patients (aged 54-68 years; one with a pathogenic mutation in the Presenilin 1 gene, one with a pathogenic mutation in the Amyloid Precursor Protein gene, and one with a CSF protein profile supporting underlying AD pathology) were studied in relation to a group of eight healthy older male individuals (aged 58-74 years). Compared to healthy controls, all patients had relatively intact tactile body schema processing. In contrast, all patients showed impaired memory for words previously presented using the patient's own voice whereas memory for words presented in other voices was less consistently affected. Two patients showed increased levels of emotional contagion and reduced perspective taking on the Interpersonal Reactivity Index. Our findings suggest that AD may be associated with deficient self/non-self differentiation over time despite a relatively intact body image: this profile of altered self-processing contrasts with the deficit of tactile body schema previously described in frontotemporal dementia associated with C9orf72 mutations. We present these findings as a preliminary rationale to direct future systematic study in larger patient cohorts.

Anxiety and stress-related disorders constitute a large global health burden, but are still poorly understood. Prior work has demonstrated clear impacts of stress upon basic cognitive function: biasing attention toward unexpected and potentially threatening information and instantiating a negative affective bias. However, the impact that these changes have on higher-order, executive, decision-making processes is unclear. In this study, we examined the impact of a translational within-subjects stress induction (threat of unpredictable shock) on two well-established executive decision-making biases: the framing effect (N = 83), and temporal discounting (N = 36). In both studies, we demonstrate (a) clear subjective effects of stress, and (b) clear executive decision-making biases but (c) no impact of stress on these decision-making biases. Indeed, Bayes factor analyses confirmed substantial preference for decision-making models that did not include stress. We posit that while stress may induce subjective mood change and alter low-level perceptual and action processes (Robinson et al., 2013c), some higher-level executive processes remain unperturbed by these impacts. As such, although stress can induce a transient affective biases and altered mood, these need not result in poor financial decision-making.

Stress can precipitate the onset of mood and anxiety disorders. This may occur, at least in part, via a modulatory effect of stress on decision-making. Some individuals are, however, more resilient to the effects of stress than others. The mechanisms underlying such vulnerability differences are nevertheless unknown. In this study we attempted to begin quantifying individual differences in vulnerability by exploring the effect of experimentally induced stress on decision-making. The threat of unpredictable shock was used to induce stress in healthy volunteers (N = 47) using a within-subjects, within-session design, and its impact on a financial decision-making task (the Iowa Gambling Task) was assessed alongside anxious and depressive symptomatology. As expected, participants learned to select advantageous decks and avoid disadvantageous decks. Importantly, we found that stress provoked a pattern of harm-avoidant behaviour (decreased selection of disadvantageous decks) in individuals with low levels of trait anxiety. By contrast, individuals with high trait anxiety demonstrated the opposite pattern: stress-induced risk-seeking (increased selection of disadvantageous decks). These contrasting influences of stress depending on mood and anxiety symptoms might provide insight into vulnerability to common mental illness. In particular, we speculate that those who adopt a more harm-avoidant strategy may be better able to regulate their exposure to further environmental stress, reducing their susceptibility to mood and anxiety disorders.

Perimesencephalic subarachnoid hemorrhage (pSAH) has been described as a distinct form of subarachnoid hemorrhage (SAH) associated with good outcomes. We report a 48-year-old female who developed cerebral infarction due to severe diffuse vasospasm following pSAH. The patient presented with non-aneurysmal pSAH and was discharged home on day 5. However, one week later she developed an acute onset of right hemiparesis. A brain MRI showed acute infarctions on diffusion weighted imaging and her cerebral angiogram showed diffuse vasospasm. The patient received intra-arterial diltiazem and hypervolemic-hypertensive-hemodilution therapy with resulting resolution of the vasospasm and hemiparesis. While not as common as in SAH, there is a potential for the occurrence of cerebral infarction due to vasospasm after pSAH., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The principles of optical matched filtering are applied to the problem of screening specimens of mouse urinary bladders that may exhibit hyperplasia or contain carcinomas resulting from the ingestion of controlled amounts of 2-acetylaminofluorene. The construction of the matched filter and the experimental procedure are optimized for a small group of specimens to the extent that thirteen of twenty-two normal specimens are correctly classified, and all fifteen of the abnormal specimens are correctly classified.

An optical analog correlation technique was used to detect morphologic abnormalities in rat liver cells. The method employs an optical matched filter for correlating a test pathological specimen with a control specimen. Experimental results show appreciable promise that such an optical correlator can be employed as a tool for rapid mass screening of a variety of pathological specimens.