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. 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

Dependency of magnetocardiographically determined fetal cardiac time intervals on gestational age, gender and postnatal biometrics in healthy pregnancies

BACKGROUND: Magnetocardiography enables the precise determination of fetal cardiac time intervals (CTI) as early as the second trimester of pregnancy. It has been shown that fetal CTI change in course of gestation. The aim of this work was to investigate the dependency of fetal CTI on gestational age, gender and postnatal biometric data in a substantial sample of subjects during normal pregnancy. METHODS: A total of 230 fetal magnetocardiograms were obtained in 47 healthy fetuses between the 15(th )and 42(nd )week of gestation. In each recording, after subtraction of the maternal cardiac artifact and the identification of fetal beats, fetal PQRST courses were signal averaged. On the basis of therein detected wave onsets and ends, the following CTI were determined: P wave, PR interval, PQ interval, QRS complex, ST segment, T wave, QT and QTc interval. Using regression analysis, the dependency of the CTI were examined with respect to gestational age, gender and postnatal biometric data. RESULTS: Atrioventricular conduction and ventricular depolarization times could be determined dependably whereas the T wave was often difficult to detect. Linear and nonlinear regression analysis established strong dependency on age for the P wave and QRS complex (r(2 )= 0.67, p < 0.001 and r(2 )= 0.66, p < 0.001) as well as an identifiable trend for the PR and PQ intervals (r(2 )= 0.21, p < 0.001 and r(2 )= 0.13, p < 0.001). Gender differences were found only for the QRS complex from the 31(st )week onward (p < 0.05). The influence on the P wave or QRS complex of biometric data, collected in a subgroup in whom recordings were available within 1 week of birth, did not display statistical significance. CONCLUSION: We conclude that 1) from approximately the 18(th )week to term, fetal CTI which quantify depolarization times can be reliably determined using magnetocardiography, 2) the P wave and QRS complex duration show a high dependency on age which to a large part reflects fetal growth and 3) fetal gender plays a role in QRS complex duration in the third trimester. Fetal development is thus in part reflected in the CTI and may be useful in the identification of intrauterine growth retardation

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. 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<0.05 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

Gendered Representations of Male and Female Social Actors in Iranian Educational Materials

This research investigates the representations of gendered social actors within the subversionary discourse of equal educational opportunities for males and females in Iranian English as a Foreign Language (EFL) books. Using critical discourse analysis (CDA) as the theoretical framework, the authors blend van Leeuwen’s (Texts and practices: Readings in critical discourse analysis, Routledge, London, 2003) ‘Social Actor Network Model’ and Sunderland’s (Gendered discourses, Palgrave Macmillan, Hampshire, 2004) ‘Gendered Discourses Model’ in order to examine the depictions of male and female social actors within this gendered discourse. The gendered discourse of equal opportunities was buttressed by such representations within a tight perspective in proportion to gender ideologies prevailing in Iran. Resorting to CDA, we can claim that resistance against such gendered discourse in Iranian EFL textbooks militates against such gender norms. These representations of male and female social actors in school books are indicative of an all-encompassing education, reinforcing that the discourse of equal opportunities is yet to be realized in the education system of Iran

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. 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 functional neuroanatomy of emotion processing in frontotemporal dementias

This is a pre-copyedited, author-produced version of an article accepted for publication in Brain following peer review. The version of record: Charles R Marshall, Christopher J D Hardy, Lucy L Russell et al., The functional neuroanatomy of emotion processing in frontotemporal dementias, Brain, awz204, is available online at: https://doi.org/10.1093/brain/awz204Brain Research TrustAlzheimer’s SocietyLeonard Wolfson Experimental Neurology CentreMedical Research Council UKNIHR UCLH Biomedical Research Centr

Pitfalls in TCR gene clonality testing: teaching cases

Clonality testing in T-lymphoproliferations has technically become relatively easy to perform in routine laboratories using standardized multiplex polymerase chain reaction protocols for T-cell receptor (TCR) gene analysis as developed by the BIOMED-2 Concerted Action BMH4-CT98-3936. Expertise with clonality diagnostics and knowledge about the biology of TCR gene recombination are essential for correct interpretation of TCR clonality data. Several immunobiological and technical pitfalls that should be taken into account to avoid misinterpretation of data are addressed in this report. Furthermore, we discuss the need to integrate the molecular data with those from immunohistology, and preferably also flow cytometric immunophenotyping, for appropriate interpretation. Such an interactive, multidisciplinary diagnostic model guarantees integration of available data to reach the most reliable diagnosis

Distances and ages of globular clusters using Hipparcos parallaxes of local subdwarfs

We discuss the impact of Population II and Globular Cluster (GCs) stars on the derivation of the age of the Universe, and on the study of the formation and early evolution of galaxies, our own in particular. The long-standing problem of the actual distance scale to Population II stars and GCs is addressed, and a variety of different methods commonly used to derive distances to Population II stars are briefly reviewed. Emphasis is given to the discussion of distances and ages for GCs derived using Hipparcos parallaxes of local subdwarfs. Results obtained by different authors are slightly different, depending on different assumptions about metallicity scale, reddenings, and corrections for undetected binaries. These and other uncertainties present in the method are discussed. Finally, we outline progress expected in the near future.Comment: Invited review article to appear in: `Post-Hipparcos Cosmic Candles', A. Heck & F. Caputo (Eds), Kluwer Academic Publ., Dordrecht, in press. 22 pages including 3 tables and 2 postscript figures, uses Kluwer's crckapb.sty LaTeX style file, enclose

Genome-wide BAC-end sequencing of Cucumis melo using two BAC libraries

<p>Abstract</p> <p>Background</p> <p>Although melon (<it>Cucumis melo </it>L.) is an economically important fruit crop, no genome-wide sequence information is openly available at the current time. We therefore sequenced BAC-ends representing a total of 33,024 clones, half of them from a previously described melon BAC library generated with restriction endonucleases and the remainder from a new random-shear BAC library.</p> <p>Results</p> <p>We generated a total of 47,140 high-quality BAC-end sequences (BES), 91.7% of which were paired-BES. Both libraries were assembled independently and then cross-assembled to obtain a final set of 33,372 non-redundant, high-quality sequences. These were grouped into 6,411 contigs (4.5 Mb) and 26,961 non-assembled BES (14.4 Mb), representing ~4.2% of the melon genome. The sequences were used to screen genomic databases, identifying 7,198 simple sequence repeats (corresponding to one microsatellite every 2.6 kb) and 2,484 additional repeats of which 95.9% represented transposable elements. The sequences were also used to screen expressed sequence tag (EST) databases, revealing 11,372 BES that were homologous to ESTs. This suggests that ~30% of the melon genome consists of coding DNA. We observed regions of microsynteny between melon paired-BES and six other dicotyledonous plant genomes.</p> <p>Conclusion</p> <p>The analysis of nearly 50,000 BES from two complementary genomic libraries covered ~4.2% of the melon genome, providing insight into properties such as microsatellite and transposable element distribution, and the percentage of coding DNA. The observed synteny between melon paired-BES and six other plant genomes showed that useful comparative genomic data can be derived through large scale BAC-end sequencing by anchoring a small proportion of the melon genome to other sequenced genomes.</p

Connectivity of larval stages of sedentary marine communities between hard substrates and offshore structures in the North Sea

Man-made structures including rigs, pipelines, cables, renewable energy devices, and ship wrecks, offer hard substrate in the largely soft-sediment environment of the North Sea. These structures become colonised by sedentary organisms and non-migratory reef fish, and form local ecosystems that attract larger predators including seals, birds, and fish. It is possible that these structures form a system of interconnected reef environments through the planktonic dispersal of the pelagic stages of organisms by ocean currents. Changes to the overall arrangement of hard substrate areas through removal or addition of individual man-made structures will affect the interconnectivity and could impact on the ecosystem. Here, we assessed the connectivity of sectors with oil and gas structures, wind farms, wrecks, and natural hard substrate, using a model that simulates the drift of planktonic stages of seven organisms with sedentary adult stages associated with hard substrate, applied to the period 2001–2010. Connectivity was assessed using a classification system designed to address the function of sectors in the network. Results showed a relatively stable overall spatial distribution of sector function but with distinct variations between species and years. The results are discussed in the context of decommissioning of oil and gas infrastructure in the North Sea