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BackgroundBinary reversals (exemplified by ‘yes’/‘no’ confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined.MethodsWe conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression.ResultsData were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes.ConclusionsBinary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

BackgroundHearing loss has been proposed as a modifiable risk factor for dementia. However, the relationship between hearing, neurodegeneration, and cognitive change, and the extent to which pathological processes such as Alzheimer’s disease and cerebrovascular disease influence these relationships, is unclear.MethodsData from 287 adults born in the same week of 1946 who underwent baseline pure tone audiometry (mean age=70.6 years) and two time point cognitive assessment/multimodal brain imaging (mean interval 2.4 years) were analysed. Hearing impairment at baseline was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre-clinical Alzheimer’s Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of confounders including baseline β-amyloid deposition and white matter hyperintensity volume.Results111 out of 287 participants had hearing impairment. Compared with those with preserved hearing, hearing impaired individuals had faster rates of whole brain atrophy, and worse hearing (higher pure tone average) predicted faster rates of hippocampal atrophy. In participants with hearing impairment, faster rates of whole brain atrophy predicted greater cognitive change. All observed relationships were independent of β-amyloid deposition and white matter hyperintensity volume.ConclusionsHearing loss may influence dementia risk via pathways distinct from those typically implicated in Alzheimer’s and cerebrovascular disease in cognitively unimpaired older adults.

The Memory Policeis a disconcerting novel set on a mysterious island. Inhabitants of this island suffer objects being ‘disappeared’, and we follow our narrator’s journey as they try to navigate these disappearances. Henning in their compelling recent essay suggests that the novel can be more fully appreciated by engaging with a literature of forgetting and draws parallels between the events in the book and the course of the neurodegenerative process of Alzheimer’s disease. In this commentary, I suggest that the progressive deterioration of conceptual knowledge described in the novel most closely resembles that seen in the rare neurodegenerative disease, semantic dementia.

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.

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.

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.

There is a need for a reliable, noninvasive biomarker for Alzheimer's disease (AD). We assessed whether short-latency afferent inhibition (SAI), a transcranial magnetic stimulation paradigm that assesses cholinergic circuits of the brain, could become such a biomarker.

The poem "Beachcomber" by Jeanette Hattersley is presented. First Line: Geologists say shells; Last Line: was full.

The poem "The unlocked door" by Chris Hardy is presented. First Line: We were in a churchyard; Last Line: has anything to say.

UCLThe recently recognised association between hearing impairment and dementia has important clinical and public health implications but remains poorly understood. In daily life, the most important sound we hear is speech: making sense of spoken messages that are ‘degraded’ by noise is fundamental to suc- cessful communication and depends on neural computations in the auditory brain that are vulnerable to neurodegenerative pathologies. Measuring degraded speech perception might therefore index both real-world hearing function and the underlying disease process in dementia.We administered tests of degraded speech and pure tone audiometry, before correlating these measures with questionnaire data on real-world hearing ability in healthy control participants and patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD) and the primary progressive aphasias (PPA). Audiometric performance was modulated by auditory cognitive performance and correlated poorly with real-world hearing ability. Degraded speech tests were able to stratify syndromic groups and showed significantly better correlation with real-world hearing measures.Our findings suggest that auditory brain function is a critical determinant of daily life communication in people with dementia: tests of auditory cognition may constitute a ‘real-word audiogram’ for these diseases, adding value to standard audiometry and potentially detecting neurodegenerative patholo- gies earlier.

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

A 30-year-old patient was admitted with shortness of breath and cough. Previous electronic entries state a history of asthma and hay fever. Repeated clerking by junior doctor states admission for treatment of likely exacerbation of asthma. The patient failed to fully improve with repeated courses of oral corticosteroids, regular nebulisers and oral antibiotics. The patient failed to improve even after several repeated admissions for similar admissions. On each admission she was subjected to CT scan and steroid courses, and at one point even had the authenticity of her symptoms questioned. Eventually she was found to have a case of tracheomalacia. Unfortunately, despite the eventual diagnosis, the patient has suffered side effects due to the delayed diagnosis and repeated treatment courses.

The cDNAs for four rabbit cytokine genes [interleukin 2 (IL-2), IL-4, IL-6 and IL-10] have been cloned from primary lymphocytes by polymerase chain reaction (PCR) methods. IL-2 and IL-10 are both highly conserved between rabbit and other species. IL-4 and IL-6 are less strongly conserved, at both nucleotide and amino acid levels, and exhibit structural differences. An extension of the coding region of rabbit IL-6 relative to all other reported IL-6 genes results from a mutation in the usual stop codon which allows translation to continue for a further 27 amino acids. Analysis of IL-6 from four other lagomorph species suggests that this mutation is specific to the European rabbit. Sequence and structural differences of IL-4 and IL-6, while presumably not altering function, may render them highly species-specific. Several alternatively spliced variants of IL-2 and IL-4 are also reported.

The poem "London Fields" by Chris Hardy is presented. First Line: In Marsala a waiter said; Last Line: about the kitchen butterfly.

The poem "Tis Not Upon Earth" by Chris Hardy is presented. First Line: Why comest thou here, so pale and clear? Last Line: And the myrtle of love fadeth never there!

Objectives. We conducted an initial clinical trial of a newly developed cardiac magnetic resonance imaging (CMRI) system. We evaluated left ventricular (LV) function in 85 patients to compare the clinical utility of the CMRI system with echocardiography, the current noninvasive gold standard.

Fossil mtDNA of 10 ovicaprine bones from Neolithic, Bronze Age and Roman archaeological layers have been extracted in order to test their osteological determination as sheep or goat or to determine them when osteological criteria were absent. Only one sample could not be amplified. The five more reliable osteological determinations (humerus, radius, metacarpus) have been confirmed by fossil mtDNA. A sixth less reliable sheep bone (ulna) has been determined as goat. Three other undetermined bones (young metacarpus and vertebrae) have been determined as goat. Although anecdotal, these results illustrate the possibilities yielded by new molecular methods for special specific determinations with more important scientific implications.

Mammalian species presently living on Mediterranean islands have been brought in by man. The question of their geographical origin and of the time of their introduction is often a matter of debate. We studied this problem using a population of rabbits (European rabbit: Oryctolagus cuniculus) living in Zembra, an island off Tunisia. Archaeological surveys show that rabbit has been introduced to the island by Bronze Age or Roman people, between the IIIrd Millenium B.C. and the IIIrd century A.D. Part of the 16S-rRNA gene of mitochondrial DNAs from fossil bones of different ages (dated back to 130–390 A.D.) was characterized and compared to that of present day rabbits of differing geographical origin. The data suggest that animals present on Zembra in late Roman times belonged to the same maternal lineage as present populations from Northern Spain and Southern France.

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.

The poem "The Bridge" is presented by Chris Hardy. First Line: Metal slats rattle, Last Line: the way we came.

The poem "Naming Rain" by Chris Hardy is presented. First Line: We can walk, then climb that last bit. Last Line: in this world.

The poem "What We Came Looking For" Chris Hardy, is presented. First Line: She might remember to tell you, Last Line: what we came looking for this time.

The poem "Sickle" by Chris Hardy is presented. First Line: white sharp edge to blue; Last Line: knows.

•Sleep is a key concern in dementias but their sleep phenotypes are not well defined.•We addressed this issue in major FTD and AD syndromes versus healthy older controls.•We surveyed sleep duration, quality and disruptive events, and daytime somnolence.•Sleep symptoms were frequent in FTD and AD and distinguished these diseases.•Sleep disturbance is an important clinical issue across major FTD and AD syndromes.

Hearing 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, which hearing measures best capture cognitive symptoms and disability and whether hearing measures predict clinical course and brain atrophy.Using pre-existing and novel stimuli, created at the Dementia Research Centre, University College London, we have designed a unique test battery to assess central auditory function. This will be used to ‘phenotype’ central auditory dysfunction in Alzheimer’s disease (AD) and the primary progressive aphasias (PPA) and compare them with controls as well as across disease groups.This will provide new tools to determine how auditory measures relate to clinical symptoms and daily-life disability and care burden. Using voxel-based morphometry (VBM) we also aim to correlate test measures with regional brain degeneration and measure how hearing deficits predict longitudinal clinical course.Here we present the make-up of the battery, explaining the motivation behind component tests and how they probe different stations of the auditory hierarchy. We also make predictions of likely group-specific outcomes, based on neuroanatomical disease predilection.

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Discusses issues related to the U.S. Court of Appeals' opinion on June 23, 2006 to vacate the Securities and Exchange Commission's (SEC) rule requiring the majority of advisers to hedge funds to register, the Court determined that the SEC rule, which was based on its interpretation of client, was arbitrary. Implication of the decision on many of those that registered solely in response to the rule; Background on a subsequent Order issued by the Court directing the Court Clerk to withhold issuance of any mandate; Potential move of the SEC regarding the ruling.

The article reports on the good performance of car racer Malcolm Oastler during the round four of the 2015 New South Wales Hillclimb Championship at Fairbairn Park from April 11-12, 2015.

The poem "Life Line," by Chris Hardy is presented. First Line: When I was a boy; Last Line: beneath the tap.

The poem "Heaven and Earth" by Chris Hardy is presented. First Line: Every night an owl tries; Last Line: a world of light.

Presents a letter to the editor about power stations in the plain of central Arcadia.