Binary reversals: a diagnostic sign in primary progressive aphasia.

BACKGROUND: Binary 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. METHODS: We 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. RESULTS: Data 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. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.

Peripheral hearing loss at age 70 predicts brain atrophy and associated cognitive change.

BACKGROUND: Hearing 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. METHODS: Data 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 ß-amyloid deposition and white matter hyperintensity volume. RESULTS: 111 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 ß-amyloid deposition and white matter hyperintensity volume. CONCLUSIONS: Hearing loss may influence dementia risk via pathways distinct from those typically implicated in Alzheimer's and cerebrovascular disease in cognitively unimpaired older adults.

Symptom-based staging for logopenic variant primary progressive aphasia.

BACKGROUND AND PURPOSE: Logopenic variant primary progressive aphasia (lvPPA) is a major variant presentation of Alzheimer's disease (AD) that signals the importance of communication dysfunction across AD phenotypes. A clinical staging system is lacking for the evolution of AD-associated communication difficulties that could guide diagnosis and care planning. Our aim was to create a symptom-based staging scheme for lvPPA, identifying functional milestones relevant to the broader AD spectrum. METHODS: An international lvPPA caregiver cohort was surveyed on symptom development under an 'exploratory' survey (34 UK caregivers). Feedback from this survey informed the development of a 'consolidation' survey (27 UK, 10 Australian caregivers) in which caregivers were presented with six provisional clinical stages and feedback was analysed using a mixed-methods approach. RESULTS: Six clinical stages were endorsed. Early symptoms included word-finding difficulty, with loss of message comprehension and speech intelligibility signalling later-stage progression. Additionally, problems with hearing in noise, memory and route-finding were prominent early non-verbal symptoms. 'Milestone' symptoms were identified that anticipate daily-life functional transitions and care needs. CONCLUSIONS: This work introduces a new symptom-based staging scheme for lvPPA, and highlights milestone symptoms that could inform future clinical scales for anticipating and managing communication dysfunction across the AD spectrum.

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia.

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (non-fluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all P < 0.05). In a receiver operating characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in predefined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (P < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

INTRODUCTION: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design. RESULTS: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid ("PPA-Squared"). DISCUSSION: This work introduces a symptom-led staging scheme and functional scale for semantic and non-fluent/agrammatic variants of PPA. Our findings have implications for diagnostic and care pathway guidelines, trial design, and personalized prognosis and treatment for PPA. HIGHLIGHTS: We introduce new symptom-led perspectives on primary progressive aphasia (PPA). The focus is on non-fluent/agrammatic (nfvPPA) and semantic (svPPA) variants. Foregrounding of early and non-verbal features of PPA and clinical trajectories is featured. We introduce a symptom-led staging scheme for PPA. We propose a prototype for a functional impairment scale, the PPA Progression Planning Aid.

microRNA-based predictor for diagnosis of frontotemporal dementia.

AIMS: This study aimed to explore the non-linear relationships between cell-free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis. METHODS: We initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls). RESULTS: On the basis of cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non-linear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ~90% of cases. CONCLUSIONS: The fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.

'Like going into a chocolate shop, blindfolded': What do people with primary progressive aphasia want from speech and language therapy?

BACKGROUND: Primary progressive aphasia (PPA) describes a group of language-led dementias. PPAs are complex, diverse and difficult to diagnose, and therefore conventional models of aphasia and dementia treatment do not meet their needs. The research evidence on intervention for PPA is developing, but to date there are only a few case studies exploring the experiences of people with PPA (PwPPA) themselves. AIMS: To explore the experiences and opinions of PwPPA and their communication partners (CPs) to understand how speech and language therapy (SLT) services can better meet their needs. METHODS & PROCEDURES: A qualitative research approach was used whereby PwPPA and their friends or family members were recruited to participate in focus groups, via advertisements in the Rare Dementia Support PPA group newsletters. Consenting participants were allocated to attend one of four focus groups hosted on an online video conferencing platform. Participants were asked about their communication difficulties, and how SLT could address these needs. All meetings were transcribed, and data were examined using reflexive thematic analysis. OUTCOMES & RESULTS: Six PwPPA and 14 CPs representing all three PPA variants and mixed PPA participated in the focus groups. Four main themes were identified during the analysis of the focus group discussions: (1) CPs' burden, (2) adjusting to the diagnosis, (3) communication abilities and difficulties and (4) beyond language. A further 10 subthemes were identified. CONCLUSIONS & IMPLICATIONS: This study provides a greater understanding of the experiences and needs of PwPPA and their families in relation to SLT. This work underlines the importance of a person-centred approach that considers the broader needs of both the PwPPA and the people around them. This will enable service providers to deliver SLT that meets the needs of PwPPA and their families and will also inform future research in this field. WHAT THIS PAPER ADDS: What is already known on this subject We know that PwPPA can maintain or even make improvements in word retrieval and speech fluency with SLT exercises. There is also developing evidence of the benefits of interventions such as CP training, communication aid support and other functional interventions. What this paper adds to existing knowledge This study provides an understanding of the experiences and opinions of people living with PPA and their families in relation to SLT. Results demonstrate that PwPPA and their families have to navigate a complex journey, identifying strategies to support communication but also the influence of personality and other cognitive symptoms. SLT was useful, but not always available. What are the potential or actual clinical implications of this work? This study will enable service providers to better plan, justify funding for and delivery of SLT that will meet the needs of PwPPA and their families. Most importantly this work underlines the importance of a person-centred approach, incorporating the broader needs of the person with PPA and those around them.

Shouting from far away: three poems about living with speechlessness.

We present three poems written from personal experience of living with primary progressive non-fluent aphasia (primary progressive apraxia of speech). The poems provide a window on this illness 'from the inside', and vividly illustrate how intellect and inner life may survive strikingly intact, even after speech is lost.

Hearing and dementia: from ears to brain.

The association between hearing impairment and dementia has emerged as a major public health challenge, with significant opportunities for earlier diagnosis, treatment and prevention. However, the nature of this association has not been defined. We hear with our brains, particularly within the complex soundscapes of everyday life: neurodegenerative pathologies target the auditory brain, and are therefore predicted to damage hearing function early and profoundly. Here we present evidence for this proposition, based on structural and functional features of auditory brain organization that confer vulnerability to neurodegeneration, the extensive, reciprocal interplay between 'peripheral' and 'central' hearing dysfunction, and recently characterized auditory signatures of canonical neurodegenerative dementias (Alzheimer's disease, Lewy body disease and frontotemporal dementia). Moving beyond any simple dichotomy of ear and brain, we argue for a reappraisal of the role of auditory cognitive dysfunction and the critical coupling of brain to peripheral organs of hearing in the dementias. We call for a clinical assessment of real-world hearing in these diseases that moves beyond pure tone perception to the development of novel auditory 'cognitive stress tests' and proximity markers for the early diagnosis of dementia and management strategies that harness retained auditory plasticity.

Music appreciation phenotypes in patients with frontotemporal dementia: A pilot study.

OBJECTIVES: Frontotemporal dementia (FTD) can present with changes in music appreciation. Research has suggested a relationship of altered music appreciation phenotypes with typical socio-emotional changes. We aimed to determine the prevalence and severity of music appreciation phenotypes in FTD and study the relationship with emotion recognition capacities in order to examine whether they could serve as a proxy for changes in socio-emotional functioning. METHODS/DESIGN: Based on reported musical changes in the literature, we developed an informant-based questionnaire to assess musical changes and a music test to assess music emotion recognition. Social cognition was assessed with the Ekman 60 faces test in a subgroup of patients (n = 23). Relationships between measures were assessed with linear regressions. RESULTS: We included 47 patients (44.7% female, mean age 65.0 ± 8.4, 31 behavioral variant FTD (bvFTD), 10 semantic dementia (SD), and six progressive nonfluent aphasia (PNFA)). Thirty-six caregivers were included in the music emotion recognition test as controls. Altered music appreciation phenotypes were observed in 79% of the FTD patients. Musicophilia was present in a third of bvFTD patients, and only in up to 10% in language FTD variants. Changes in music appreciation were not associated with decreased music emotion recognition or visual emotion recognition. Compared to controls, bvFTD performed worse on the music emotion recognition task (p < 0.003), and no differences were found with SD (p = 0.06) and PNFA patients (p = 0.8). CONCLUSIONS: Music appreciation phenotypes are highly prevalent in FTD patients. Future studies should further investigate the potential diagnostic value of changes in music processing.

Primary progressive aphasia: ReADing the clinical GRANularity.

Primary progressive aphasia remains a diagnostic challenge despite (or even because of) the increasing availability of ancillary tests and biomarkers. We present a 67-year-old man with apparently sporadic logopenic aphasia and positive Alzheimer biomarkers who was subsequently found also to have a pathogenic mutation in the progranulin gene. This was signalled by early atypical features (mild expressive agrammatism and behavioural change, rapid clinical deterioration) around the core logopenic aphasia syndrome. Each of the canonical progressive aphasia syndromes has a 'halo' of less typical variants that may herald alternative or additional pathologies. The accurate diagnosis of primary progressive aphasia depends on careful clinical analysis to direct investigations appropriately.

Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation.

BACKGROUND: The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer's disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) METHODS: Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aß42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1ß), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. RESULTS: In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). CONCLUSION: Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.

A Clinicopathologic Study of Movement Disorders in Frontotemporal Lobar Degeneration.

BACKGROUND: Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking. OBJECTIVE: The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD. METHODS: In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018. At postmortem, neurodegenerative pathologies were systematically evaluated following consensus criteria. Degeneration of the substantia nigra was assessed as a marker of presynaptic dopaminergic parkinsonism using semiquantitative methods. RESULTS: A total of 55 patients (35 men [64%]) were included with median (interquartile range) age at diagnosis of 58.8 (52.6-63.9) years and a disease duration of 9.6 (6.2-12.9) years. Movement disorders were present in 19 (35%) patients without differences among disease subtypes. The most common syndromes were parkinsonism (9 patients [16%]), usually as an additional late feature, and corticobasal syndrome (CBS, 7 patients [13%]), commonly as a presenting feature. Substantia nigra degeneration was present in 37 (67%) patients although it did not show a good clinical correlation with movement disorders. Those with Pick's disease showed milder substantia nigra degeneration and better response to levodopa. CONCLUSIONS: Movement disorders can present in all FTLD subtypes, more commonly as a late additional feature (parkinsonism) or as a presenting symptom (CBS). The underlying pathophysiology is complex and likely to involve structures outside the presynaptic striatonigral system. © 2020 International Parkinson and Movement Disorder Society.

Primary Progressive Aphasia: Toward a Pathophysiological Synthesis.

PURPOSE OF REVIEW: The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers. RECENT FINDINGS: Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering 'fragmentary' syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies.

Impairments of auditory scene analysis in posterior cortical atrophy.

Although posterior cortical atrophy is often regarded as the canonical 'visual dementia', auditory symptoms may also be salient in this disorder. Patients often report particular difficulty hearing in busy environments; however, the core cognitive process-parsing of the auditory environment ('auditory scene analysis')-has been poorly characterized. In this cross-sectional study, we used customized perceptual tasks to assess two generic cognitive operations underpinning auditory scene analysis-sound source segregation and sound event grouping-in a cohort of 21 patients with posterior cortical atrophy, referenced to 15 healthy age-matched individuals and 21 patients with typical Alzheimer's disease. After adjusting for peripheral hearing function and performance on control tasks assessing perceptual and executive response demands, patients with posterior cortical atrophy performed significantly worse on both auditory scene analysis tasks relative to healthy controls and patients with typical Alzheimer's disease (all P < 0.05). Our findings provide further evidence of central auditory dysfunction in posterior cortical atrophy, with implications for our pathophysiological understanding of Alzheimer syndromes as well as clinical diagnosis and management.

Frontotemporal dementia, music perception and social cognition share neurobiological circuits: A meta-analysis.

Frontotemporal dementia (FTD) is a neurodegenerative disease that presents with profound changes in social cognition. Music might be a sensitive probe for social cognition abilities, but underlying neurobiological substrates are unclear. We performed a meta-analysis of voxel-based morphometry studies in FTD patients and functional MRI studies for music perception and social cognition tasks in cognitively normal controls to identify robust patterns of atrophy (FTD) or activation (music perception or social cognition). Conjunction analyses were performed to identify overlapping brain regions. In total 303 articles were included: 53 for FTD (n = 1153 patients, 42.5% female; 1337 controls, 53.8% female), 28 for music perception (n = 540, 51.8% female) and 222 for social cognition in controls (n = 5664, 50.2% female). We observed considerable overlap in atrophy patterns associated with FTD, and functional activation associated with music perception and social cognition, mostly encompassing the ventral language network. We further observed overlap across all three modalities in mesolimbic, basal forebrain and striatal regions. The results of our meta-analysis suggest that music perception and social cognition share neurobiological circuits that are affected in FTD. This supports the idea that music might be a sensitive probe for social cognition abilities with implications for diagnosis and monitoring.

Using the Medical Research Council framework and public involvement in the development of a communication partner training intervention for people with primary progressive aphasia (PPA): Better Conversations with PPA.

BACKGROUND: Primary progressive aphasia is a language-led dementia resulting in a gradual dissolution of language. Primary progressive aphasia has a significant psychosocial impact on both the person and their families. Speech and language therapy is one of the only available management options, and communication partner training interventions offer a practical approach to identify strategies to support conversation. The aim of this study was to define and refine a manual and an online training resource for speech and language therapists to deliver communication partner training to people with primary progressive aphasia and their communication partners called Better Conversations with primary progressive aphasia. METHODS: The Better Conversations with primary progressive aphasia manual and training program were developed using the Medical Research Council framework for developing complex interventions. The six-stage development process included 1. Exploratory review of existing literature including principles of applied Conversation Analysis, behaviour change theory and frameworks for chronic disease self-management, 2. Consultation and co-production over 12 meetings with the project steering group comprising representatives from key stakeholder groups, 3. Development of an initial draft, 4. Survey feedback followed by a consensus meeting using the Nominal Group Techniques with a group of speech and language therapists, 5. Two focus groups to gather opinions from people with PPA and their families were recorded, transcribed and Thematic Analysis used to examine the data, 6. Refinement. RESULTS: Co-production of the Better Conversations with primary progressive aphasia resulted in seven online training modules, and a manual describing four communication partner training intervention sessions with accompanying handouts. Eight important components of communication partner training were identified in the aggregation process of the Nominal Group Technique undertaken with 36 speech and language therapists, including use of video feedback to focus on strengths as well as areas of conversation breakdown. Analysis of the focus groups held with six people with primary progressive aphasia and seven family members identified three themes 1) Timing of intervention, 2) Speech and language therapists' understanding of types of dementia, and 3) Knowing what helps. These data informed refinements to the manual including additional practice activities and useful strategies for the future. CONCLUSIONS: Using the Medical Research Council framework to develop an intervention that is underpinned by a theoretical rationale of how communication partner training causes change allows for the key intervention components to be strengthened. Co-production of the manual and training materials ensures the intervention will meet the needs of people with primary progressive aphasia and their communication partners. Gathering further data from speech and language therapists and people living with primary progressive aphasia and their families to refine the manual and the training materials enhances the feasibility of delivering this in preparation for a phase II NHS-based randomised controlled pilot-feasibility study, currently underway.

Suspecting dementia: canaries, chameleons and zebras.

The early and accurate diagnosis of dementia is more important than ever before but remains challenging. Dementia is increasingly the business of neurologists and, with ageing populations worldwide, will become even more so in future. Here we outline a practical, symptom-led, bedside approach to suspecting dementia and its likely diagnosis, inspired by clinical experience and based on recognition of characteristic syndromic patterns. We show how clinical intuition reflects underlying signature profiles of brain involvement by the diseases that cause dementia and suggest next steps that can be taken to define the diagnosis. We propose 'canaries' that provide an early warning signal of emerging dementia and highlight the 'chameleons' that disguise or mimic this, as well as the 'zebras' that herald a rare (and sometimes curable) diagnostic opportunity.

Thalamic nuclei in frontotemporal dementia: Mediodorsal nucleus involvement is universal but pulvinar atrophy is unique to C9orf72.

Thalamic atrophy is a common feature across all forms of FTD but little is known about specific nuclei involvement. We aimed to investigate in vivo atrophy of the thalamic nuclei across the FTD spectrum. A cohort of 402 FTD patients (age: mean(SD) 64.3(8.2) years; disease duration: 4.8(2.8) years) was compared with 104 age-matched controls (age: 62.5(10.4) years), using an automated segmentation of T1-weighted MRIs to extract volumes of 14 thalamic nuclei. Stratification was performed by clinical diagnosis (180 behavioural variant FTD (bvFTD), 85 semantic variant primary progressive aphasia (svPPA), 114 nonfluent variant PPA (nfvPPA), 15 PPA not otherwise specified (PPA-NOS), and 8 with associated motor neurone disease (FTD-MND), genetic diagnosis (27 MAPT, 28 C9orf72, 18 GRN), and pathological confirmation (37 tauopathy, 38 TDP-43opathy, 4 FUSopathy). The mediodorsal nucleus (MD) was the only nucleus affected in all FTD subgroups (16-33% smaller than controls). The laterodorsal nucleus was also particularly affected in genetic cases (28-38%), TDP-43 type A (47%), tau-CBD (44%), and FTD-MND (53%). The pulvinar was affected only in the C9orf72 group (16%). Both the lateral and medial geniculate nuclei were also affected in the genetic cases (10-20%), particularly the LGN in C9orf72 expansion carriers. Use of individual thalamic nuclei volumes provided higher accuracy in discriminating between FTD groups than the whole thalamic volume. The MD is the only structure affected across all FTD groups. Differential involvement of the thalamic nuclei among FTD forms is seen, with a unique pattern of atrophy in the pulvinar in C9orf72 expansion carriers.

Pure tone audiometry and cerebral pathology in healthy older adults.

BACKGROUND: Hearing impairment may be a modifiable risk factor for dementia. However, it is unclear how hearing associates with pathologies relevant to dementia in preclinical populations. METHODS: Data from 368 cognitively healthy individuals born during 1 week in 1946 (age range 69.2-71.9 years), who underwent structural MRI, 18F-florbetapir positron emission tomography, pure tone audiometry and cognitive testing as part of a neuroscience substudy the MRC National Survey of Health and Development were analysed. The aim of the analysis was to investigate whether pure tone audiometry performance predicted a range of cognitive and imaging outcomes relevant to dementia in older adults. RESULTS: There was some evidence that poorer pure tone audiometry performance was associated with lower primary auditory cortex thickness, but no evidence that it predicted in vivo ß-amyloid deposition, white matter hyperintensity volume, hippocampal volume or Alzheimer's disease-pattern cortical thickness. A negative association between pure tone audiometry and mini-mental state examination score was observed, but this was no longer evident after excluding a test item assessing repetition of a single phrase. CONCLUSION: Pure tone audiometry performance did not predict concurrent ß-amyloid deposition, small vessel disease or Alzheimer's disease-pattern neurodegeneration, and had limited impact on cognitive function, in healthy adults aged approximately 70 years.