We investigated semantic cognition in the logopenic variant of primary progressive aphasia, including (i) the status of verbal and non-verbal semantic performance; and (ii) whether the semantic deficit reflects impaired semantic control. Our a priori hypothesis that individuals with logopenic variant of primary progressive aphasia would exhibit semantic control impairments was motivated by the anatomical overlap between the temporoparietal atrophy typically associated with logopenic variant of primary progressive aphasia and lesions associated with post-stroke semantic aphasia and Wernicke's aphasia, which cause heteromodal semantic control impairments. We addressed the presence, type (semantic representation and semantic control; verbal and non-verbal), and progression of semantic deficits in logopenic variant of primary progressive aphasia. Since most people with logopenic variant of primary progressive aphasia have Alzheimer's disease pathology and are part of a broader multi-dimensional phenotype space encompassing Alzheimer's disease sub-types, we compared semantic performance in logopenic variant of primary progressive aphasia and typical amnestic Alzheimer's disease. Given the differences in lesion and atrophy patterns in semantic aphasia and Wernicke's aphasia versus semantic-dementia/semantic-variant primary progressive aphasia patients, our second aim was to examine atrophy patterns in people with logopenic variant of primary progressive aphasia and typical Alzheimer's disease compared to age-matched controls. Twenty-seven patients participated in the study. People were grouped into those meeting consensus criteria for logopenic variant of primary progressive aphasia (N = 10) and others who may have previously satisfied definitions of logopenic variant of primary progressive aphasia but had progressed with multi-domain cognitive impairments (herein referred to as 'logopenic variant of primary progressive aphasia+'; N = 8). People with typical amnestic Alzheimer's disease (N = 9) were relatively preserved across verbal and non-verbal semantic assessments. Logopenic variant of primary progressive aphasia patients were impaired on both verbal and non-verbal semantic tasks and their impairments showed the hallmark characteristics of a semantic control deficit. Logopenic variant of primary progressive aphasia and logopenic variant of primary progressive aphasia + patients showed effects of varying semantic control demands, positive cueing effects, and correlated performance between semantic and executive tasks. Whole-brain voxel-based morphometry, comparing each of the patient groups to age-matched controls, revealed significantly reduced grey and white matter in the bilateral hippocampi and lateral temporal regions in typical Alzheimer's disease patients. The logopenic variant of primary progressive aphasia group exhibited an asymmetric pattern of reduced grey and white matter intensity in the language-dominant left hemisphere, including a significant portion of the lateral and medial temporal lobe. Logopenic variant of primary progressive aphasia + patients demonstrated reduced grey and white matter in the left temporal lobe extending sub-cortically, anteriorly and posteriorly, as well as right temporal involvement. Our findings could aid diagnostic sub-typing of primary progressive aphasia by adopting semantic control features and offer improved clinical characterization of logopenic variant of primary progressive aphasia in the trajectory of semantic decline. Investigating semantic cognition in the logopenic variant of primary progressive aphasia, Henderson et al. report two key findings: (i) patients' performance declines in line with increasing semantic control demands, and (ii) this pattern of decline is true for both verbal and non-verbal semantic tasks.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On this data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualisable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.

Impaired phonological short-term memory is a core feature of the logopenic variant of primary progressive aphasia (lvPPA), but it is not clear whether a core phonological processing deficit is also present. We asked three questions: (i) beyond short-term memory impairment, do lvPPA patients have an impairment within phonology itself?; (ii) is their performance in working memory and naming reflective of this phonological impairment?; and (iii) is their repetition performance related to structural and functional differences in key language-dominant regions? We compared non-word and word repetition and short-term memory performance in patients with typical Alzheimer’s disease (tAD), lvPPA per consensus criteria, and others who previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (lvPPA+). Bayesian analyses revealed no group differences in phonological tasks of word and non-word repetition. We found very strong evidence for an effect of self-reported hearing loss on word and non-word repetition, but not multi-syllabic word/phrase repetition. A comparison of phonological versus working memory and naming tasks produced either no evidence or evidence for no correlation. Beyond the expected grey matter reductions in patients relative to controls, there was anecdotal evidence for an association between non-word repetition and functional connectivity between dorsal premotor and posterior superior temporal gyrus regions in patients. Our results indicated that, in the absence of self-reported hearing loss, patients did not exhibit impairments in tasks tapping “pure” phonological processing. Our results suggest that instead of having a core phonological impairment, lvPPA patients have a working memory/buffering impairment.

Behavioural changes are a central feature of frontotemporal dementia (FTD); they occur in both behavioural-variant (bvFTD) and semantic dementia (SD)/semantic-variant primary progressive aphasia subtypes. In this study, we addressed two current clinical knowledge gaps: (i) are there qualitative or clear distinctions between behavioural profiles in bvFTD and SD; and (ii) what are the precise roles of the prefrontal cortex and anterior temporal lobes in supporting social behaviour? Resolving these conundrums is crucial for improving diagnostic accuracy and for the development of targeted interventions to treat challenging behaviours in FTD. Informant questionnaires to assess behavioural changes included the Cambridge Behavioural Inventory-Revised and two targeted measures of apathy and impulsivity. Participants completed a detailed neuropsychological battery to permit investigation of the relationship between cognitive status (including social-semantic knowledge, general semantic knowledge and executive function) with behaviour change in FTD. To explore changes in regional grey matter volume, a subset of patients had structural MRI. Diagnosis-based group comparisons were supplemented by a transdiagnostic approach that encompassed the spectrum of bvFTD, SD and 'mixed' or intermediate cases. Such an approach is sensitive to the systematic graded variation in FTD and allows the neurobiological underpinnings of behaviour change to be explored across an FTD spectrum. We found a wide range of behavioural changes across FTD. Although quantitatively more severe on average in bvFTD, as expected, the item-level analyses found no evidence for qualitative differences in behavioural profiles or 'behavioural double dissociations' between bvFTD and SD. Comparisons of self and informant ratings revealed strong discrepancies in the perspective of the caregiver versus the patient. Logistic regression revealed that neuropsychological measures had better discriminative accuracy for bvFTD versus SD than caregiver-reported behavioural measures. A principal component analysis of all informant questionnaire domains extracted three components, interpreted as reflecting: (i) apathy; (ii) challenging behaviours; and (iii) activities of daily living. More severe apathy in both FTD subtypes was associated with: (i) increased levels of impaired executive function; and (ii) anterior cingulate cortex atrophy. Questionnaire ratings of impaired behaviour were not correlated with either anterior temporal lobe atrophy or degraded social-semantic knowledge. Together, these findings highlight the presence of a wide range of behavioural changes in both bvFTD and SD, which vary by degree rather than quality. We recommend a transdiagnostic approach for future studies of the neuropsychological and neuroanatomical underpinnings of behavioural deficits in FTD.

In this two-part investigation, we examined whether Alzheimer’s disease (AD) phenotypes are distinct clinical entities or represent positions within a graded multidimensional space. First, using a large retrospective dataset of past research participants (n = 413) from memory clinics, we examined the comparative distributions of cognitive performance in people diagnosed with typical amnestic AD (tAD), logopenic variant of primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA), across a broad range of disease severities. Secondly, a prospective deep phenotyping study of lvPPA (n = 18) compared to typical AD (n = 9) addressed the following questions: (1) Does the multidimensional cognitive pattern of impairment only emerge in advanced lvPPA, and how does it compare to tAD? (2) Do memory deficits in lvPPA appear in a simple clinic-level cognitive assessment or require in-depth neuropsychological investigation? (3) To what extent is performance on verbal episodic memory attributable to language impairment? (4) Do the patterns of decline in lvPPA and tAD stay categorical or multidimensional over time? We explored the associations between scores derived from a principal component analysis of cognitive measures, and grey matter volumes in key memory- and language-related brain regions, at baseline and longitudinally. The clinic-level assessment revealed similar results in both the prospective and retrospective data: (i) patients showed graded distinctions (e.g., predominant visual versus language impairment in people with PCA versus lvPPA) and overlap (e.g., shared weakness in domains such as memory); and (ii) people with lvPPA and tAD were equally impaired on both verbal and non-verbal memory tests. Longitudinal assessment showed phenotypic dispersion: (i) people with tAD showed varied patterns of phenotypic differentiation; and (ii) people with lvPPA and lvPPA + exhibited a multidimensional pattern of decline with decreasing principal component scores and worsening multi-domain cognitive performance. The results of Bayesian linear regressions showed evidence for the association of grey matter volumes in language and memory networks with principal component analysis derived scores. The graded distinctions amongst typical amnestic and atypical (language and visual) phenotypes of AD support the proposal for a transdiagnostic, multidimensional phenotype geometry that spans all AD subtypes.

Semantic Dementia (SD) is a neurodegenerative disease characterised by progressive deterioration of semantic knowledge, resulting in diminished understanding of concepts, whether encountered in verbal or non-verbal form. Over the past three decades, a number of studies employing a range of treatment techniques and learning methods have examined whether patients with SD can relearn previously known concepts or learn and retain new information. In this article, we review this research, addressing two main questions: a) Can aspects of semantic knowledge that are 'lost' due to degeneration be re-acquired? b) How much do other memory systems (working and episodic memory) interact with and depend on semantic memory? Several studies demonstrate successful relearning of previously known words and concepts in SD, particularly after regular, prolonged practice; but this success tends to diminish once practice ceases, and furthermore often fails to generalise to other instances of the same object/concept. This pattern suggests that, with impaired semantic knowledge, learning relies to an abnormal extent on perceptual factors, making it difficult to abstract away from the specific visual or other perceptual format in which a given concept has been trained. Furthermore, the impact of semantic 'status' of a word or object on both working and episodic memory indicates pervasive interaction of these other memory systems with conceptual knowledge.

This chapter focusses on the cognitive and behavioral aspects of semantic dementia (SD). Extensive neuropsychological studies of SD have made considerable and defining contributions to our understanding of the cognitive and neural bases of semantic memory, as well as the nature of its gradual degradation in this neurodegenerative disorder. We discuss the neuropsychological findings alongside the epidemiology, pathology, and neuroanatomy of SD. In considering the implications of a cognitive disorder, conclusions rely on the aspects of performance that are spared as well as those that are impaired; accordingly, in addition to describing the striking impairments in SD, this chapter considers the cognitive functions that people with SD still do well. SD is a devastating disease, but the selectivity of its deficits provides unique and powerful theoretical insights about semantic memory.

Background: Amongst different subtypes of frontotemporal dementia (FTD), semantic dementia (SD, also known as the semantic variant of primary progressive aphasia, svPPA), is the least likely to have a genetic basis. Methods: Our study had two aims: (i) to describe two SD cases and detailed assessments of their unaffected monozygotic (MZ) twins, and (ii) to review cases with FTD-associated mutations or known family history classified as SD/svPPA either in the Genetic Frontotemporal dementia Initiative (GENFI) or in the published literature. Results: The two affected twins displayed characteristic features of SD, both in neuroimaging and cognition, whereas their MZ twins exhibited no abnormalities in either regard, even up to 15 years of follow-up for one affected twin. Only five cases out of more than 1300 people in GENFI were classified as svPPA, with a genetic mutation. The systematic review revealed 29 cases with sufficient clinical and language details regarding 'genetic' SD/svPPA. A comparison of these five GENFI and 29 literature cases to the patterns observed in a large number of sporadic cases revealed critical differences in presentation. Conclusions: Both parts of our study suggest that true SD/svPPA is unlikely to have an autosomal dominant genetic aetiology and that, while mutation carriers may resemble SD/svPPA in some respects, they may not meet current clinical diagnostic criteria for this condition. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work and the first author (SKH) were supported and funded by the Bill & Melinda Gates Foundation, Seattle, WA, and Gates Cambridge Trust (Grant Number: OPP1144). This study was supported by the Cambridge Centre for Parkinson-Plus; the Medical Research Council (MC\_UU\_00030/14; MR/P01271X/1; MR/T033371/1); the Wellcome Trust (220258); the National Institute for Health and Care Research Cambridge Clinical Research Facility and the National Institute for Health and Care Research Cambridge Biomedical Research Centre (BRC-1215-20014; NIHR203312); an MRC Programme grant to MALR (MR/R023883/1) and an intramural award (MC\_UU\_00005/18); and MRC Career Development Award (MR/V031481/1). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Twin data were acquired under the PrEPPAReD protocol, approved by the Cambridge 2 Research Ethics Committee (REC reference: 07/Q0102/3; Title: Prospective Evaluation of Parkinson Plus & Related Disorders, formerly entitled: Diagnosis and prognosis in Progressive Supranuclear Palsy (PSP), Corticobasal degeneration (CBD) and Dementia). The affected twins had provided consent to research before losing mental capacity and the decision to include them in research after the loss of mental capacity was affirmed by their personal consultee as set out in the Health and Social Care Framework law for England and Wales. All healthy participants provided written informed consent. For data acquisition of genetic participants, all GENFI sites had local ethical approval for the study from relevant institutional review board or research ethics committee and all participants provided written informed consent. Analyses of GENFI data were conducted under the Cambridge Genetic Frontotemporal Dementia Initiative protocol approved by the Cambridge 2 Research Ethics Committee (REC reference: 17/EE/0032; title: Cambridge Genetic Frontotemporal Dementia Initiative). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The authors confirm that the derived data supporting the findings of this study are available within the article and its supplementary material.

Degraded semantic memory is a prominent feature of frontotemporal dementia (FTD). It is classically associated with semantic dementia and anterior temporal lobe (ATL) atrophy, but semantic knowledge can also be compromised in behavioural variant FTD. Motivated by understanding behavioural change in FTD, recent research has focused selectively on social-semantic knowledge, with proposals that the right ATL is specialized for social concepts. Previous studies have assessed very different types of social concepts and have not compared performance with that of matched non-social concepts. Consequently, it remains unclear to what extent various social concepts are (i) concurrently impaired in FTD, (ii) distinct from general semantic memory and (iii) differentially supported by the left and right ATL. This study assessed multiple aspects of social-semantic knowledge and general conceptual knowledge across cohorts with ATL damage arising from either neurodegeneration or resection. We assembled a test battery measuring knowledge of multiple types of social concept. Performance was compared with non-social general conceptual knowledge, measured using the Cambridge Semantic Memory Test Battery and other matched non-social-semantic tests. Our trans-diagnostic approach included behavioural variant FTD, semantic dementia and 'mixed' intermediate cases to capture the FTD clinical spectrum, as well as age- matched healthy controls. People with unilateral left or right ATL resection for temporal lobe epilepsy were also recruited to assess how selective damage to the left or right ATL impacts social- and non-social-semantic knowledge. Social- and non-social-semantic deficits were severe and highly correlated in FTD. Much milder impairments were found after unilateral ATL resection, with no left versus right differences in social-semantic knowledge or general semantic processing and with only naming showing a greater deficit following left versus right damage. A principal component analysis of all behavioural measures in the FTD cohort extracted three components, interpreted as capturing (i) FTD severity, (ii) semantic memory and (iii) executive function. Social and non-social measures both loaded heavily on the same semantic memory component, and scores on this factor were uniquely associated with bilateral ATL grey matter volume but not with the degree of ATL asymmetry. Together, these findings demonstrate that both social- and non-socialsemantic knowledge degrade in FTD (semantic dementia and behavioural variant FTD) following bilateral ATL atrophy. We propose that social-semantic knowledge is part of a broader conceptual system underpinned by a bilaterally implemented, functionally unitary semantic hub in the ATLs. Our results also highlight the value of a trans-diagnostic approach for investigating the neuroanatomical underpinnings of cognitive deficits in FTD.

Despite the recognition that epilepsy can substantially disrupt memory, there are few published accounts of whether and how this disruption varies across different types of memory and/or different types of epilepsy. This review explores four main questions: (1) Are working, episodic and semantic memory differentially affected by epilepsy? (2) Do various types of epilepsy, and their treatment, have different, specifiable effects on memory? (3) Are the usual forms of neuropsychological assessments of memory – many or most designed for other conditions – appropriate for patients with epilepsy? (4) How can research on epilepsy contribute to our understanding of the neuroscience of memory?We conclude that widespread and multifactorial problems are seen in working memory in all patient groups, while patients with temporal lobe epilepsy seem particularly prone to episodic memory deficit, and those with frontal lobe epilepsy to executive function deficits that may in turn impair semantic control. Currently, it is difficult to make individual patient predictions about likely memory deficits based on seizure aetiology and type, but it is possible to guide and tailor neuropsychological assessments in an individualised way. We make recommendations for future directions in validating and optimising neuropsychological assessments, and consider how to approach effective shared decision making about the pros and cons of seizure treatment strategies, especially at crucial educational stages such as adolescence.

Impaired social cognition is a core deficit in frontotemporal dementia (FTD). It is most commonly associated with the behavioural-variant of FTD, with atrophy of the orbitofrontal and ventromedial prefrontal cortex. Social cognitive changes are also common in semantic dementia, with atrophy centred on the anterior temporal lobes. The impairment of social behaviour in FTD has typically been attributed to damage to the orbitofrontal cortex and/or temporal poles and/or the uncinate fasciculus that connects them. However, the relative contributions of each region are unresolved. In this Review, we present a unified neurocognitive model of controlled social behaviour that not only explains the observed impairment of social behaviours in FTD, but also assimilates both consistent and potentially contradictory findings from other patient groups, comparative neurology and normative cognitive neuroscience. We propose that impaired social behaviour results from damage to two cognitively- and anatomically-distinct components. The first component is social-semantic knowledge, a part of the general semantic-conceptual system supported by the anterior temporal lobes bilaterally. The second component is social control, supported by the orbitofrontal cortex, medial frontal cortex and ventrolateral frontal cortex, which interacts with social-semantic knowledge to guide and shape social behaviour.

The functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected literatures-(i) face recognition and (ii) semantic memory. To generate a unified account of the ATLs, we tested the predictions from each literature and examined the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge, and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left = 10, right = 7), and 14 controls completed tasks assessing perceptual face matching, person knowledge and general semantic memory. People with SD were impaired across all semantic tasks, including person knowledge. Despite commensurate total ATL damage, unilateral resection generated mild impairments, with minimal differences between left- and right-ATL resection. Face matching performance was largely preserved but slightly reduced in SD and right TLE. All groups displayed the familiarity effect in face matching; however, it was reduced in SD and right TLE and was aligned with the level of item-specific semantic knowledge in all participants. We propose a neurocognitive framework whereby the ATLs underpin a resilient bilateral representation system that supports semantic memory, person knowledge and face recognition.

Connected speech samples elicited by a picture description task are widely used in the assessment of aphasias, but it is not clear what their interpretation should focus on. Although such samples are easy to collect, analyses of them tend to be time-consuming, inconsistently conducted and impractical for non-specialist settings. Here, we analysed connected speech samples from patients with the three variants of primary progressive aphasia (semantic, svPPA N = 9; logopenic, lvPPA N = 9; and non-fluent, nfvPPA N = 9), progressive supranuclear palsy (PSP Richardson's syndrome N = 10), corticobasal syndrome (CBS N = 13) and age-matched healthy controls (N = 24). There were three principal aims: (i) to determine the differences in quantitative language output and psycholinguistic properties of words produced by patients and controls, (ii) to identify the neural correlates of connected speech measures and (iii) to develop a simple clinical measurement tool. Using data-driven methods, we optimized a 15-word checklist for use with the Boston Diagnostic Aphasia Examination 'cookie theft' and Mini Linguistic State Examination 'beach scene' pictures and tested the predictive validity of outputs from least absolute shrinkage and selection operator (LASSO) models using an independent clinical sample from a second site. The total language output was significantly reduced in patients with nfvPPA, PSP and CBS relative to those with svPPA and controls. The speech of patients with lvPPA and svPPA contained a disproportionately greater number of words of both high frequency and high semantic diversity. Results from our exploratory voxel-based morphometry analyses across the whole group revealed correlations between grey matter volume in (i) bilateral frontal lobes with overall language output, (ii) the left frontal and superior temporal regions with speech complexity, (iii) bilateral frontotemporal regions with phonology and (iv) bilateral cingulate and subcortical regions with age of acquisition. With the 15-word checklists, the LASSO models showed excellent accuracy for within-sample k-fold classification (over 93%) and out-of-sample validation (over 90%) between patients and controls. Between the motor disorders (nfvPPA, PSP and CBS) and lexico-semantic groups (svPPA and lvPPA), the LASSO models showed excellent accuracy for within-sample k-fold classification (88-92%) and moderately good (59-74%) differentiation for out-of-sample validation. In conclusion, we propose that a simple 15-word checklist provides a suitable screening test to identify people with progressive aphasia, while further specialist assessment is needed to differentiate accurately some groups (e.g. svPPA versus lvPPA and PSP versus nfvPPA). Henderson et al. analysed connected speech samples from patients with primary progressive aphasia, progressive supranuclear palsy and corticobasal syndrome and optimized simple, easy-to-use and practical word checklists for two widely used picture narratives.

Semantic dementia (SD) is characterized by progressive impairment in conceptual knowledge due to anterior temporal lobe (ATL) neurodegeneration. Extended neuropsychological assessments can quantitatively demonstrate the semantic impairment, but this graded loss of knowledge can also be readily observed in the qualitative observation of patients’ recall of single concepts. Here, we present the results of a simple task of object drawing-from-name, by patients with SD (N = 19), who have isolated atrophy of the ATL bilaterally. Both cross-sectionally and longitudinally, patient drawings demonstrated a pattern of degradation in which rare and distinctive features (such as the hump on a camel) were lost earliest in disease course, and there was an increase in the intrusion of prototypical features (such as the typical small ears of most mammals on an elephant) with more advanced disease. Crucially, patient drawings showed a continuum of conceptual knowledge loss rather than a binary ‘present’ or ‘absent’ state. Overall, we demonstrate that qualitative evaluation of line drawings of animals and objects provides fascinating insights into the transmodal semantic deficit in SD. Our results are consistent with a distributed-plus-hub model of semantic memory. The graded nature of the deficit in semantic performance observed in our subset of longitudinally observed patients suggests that the temporal lobe binds feature-based semantic attributes in its central convergence zone.

Clinical variants of primary progressive aphasia (PPA) are diagnosed on unique patterns of language dysfunction and corresponding brain changes. Mounting evidence indicates (i) within-/between-category clinical heterogeneity; (ii) overlapping language profiles between variants; and (iii) the presence of co-occurring non-linguistic cognitive deficits in some patients that may be independent of aphasia magnitude and disease severity. The neurobiological bases of such cognitive-linguistic heterogeneity further remain unclear. An understanding of the relationship between these variables is important for improved PPA characterisation. Here, we bridge these knowledge gaps using a data-driven transdiagnostic approach to capture language, cognitive changes and their associations with grey and white matter degeneration across PPA variants, irrespective of diagnostic labels. Forty-seven PPA patients (13 semantic, 15 non-fluent and 19 logopenic variant) underwent assessments of general cognition (Addenbrooke’s Cognitive Examination – III), errors on language performance (Mini Linguistic Status Examination), and structural and diffusion magnetic resonance imaging to capture whole-brain grey and white matter changes, respectively. Behavioural data for all patients were entered into varimax-rotated principal component analyses to derive statistically independent dimensions explaining the majority of performance variation. To uncover neural correlates of cognitive heterogeneity in PPA, emergent components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes). Four behavioural principal components emerged: general cognition, semantics, working memory, and motor-speech/phonology (Figure 1). Performance patterns on the latter three principal components were in keeping with each variant’s characteristic profile (Figure 2). General cognitive changes were most marked in logopenic PPA. Regardless of clinical diagnosis, general cognitive performance was associated with inferior/posterior parietal grey and white matter involvement, semantic dysfunction with bilateral temporal grey and white matter, working memory deficits with temporoparietal and frontostriatal involvement, and motor-speech/phonology impairment with inferior/middle frontal regions (Figure 3). Pervasive cognitive and linguistic heterogeneity in PPA closely relates to individual-level variations on multiple dimensions of behavioural changes and grey and white matter degeneration of regions within and beyond the language network. The employment of such transdiagnostic approaches may help expand clinical boundaries by showing symptom clusters shared across distinct variants.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant pri-mary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indi-cate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phono-logical information and weighted prediction error. In the presence of intact temporal cortex, frontal neurode-generation results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predic-tions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech.

The loss of semantic memory is a key feature of frontotemporal dementia (FTD), and is associated with atrophy of the anterior temporal lobes (ATLs). The role of the left and right ATLs in supporting social-semantic knowledge is unclear. To address this, we developed a social-semantic battery comprising exemplars of social concepts such as person-specific knowledge, abstract social concepts, and understanding of social norms. Performance on this battery was directly compared with non-social semantic knowledge, measured using the Cambridge Semantic Test Battery. 48 people with FTD (behavioural-variant FTD = 26, semantic dementia = 22), and 19 age-matched healthy controls were recruited. Participants completed both semantic batteries, alongside tests of general cognition and executive function. Participants also underwent a 3T T1-weighted structural MRI scan. All neuropsychological tasks were entered into a principal component analysis (with varimax rotation) to explore graded variations in cognitive performance in FTD. Voxel-based morphometry was conducted to explore grey matter correlates of social and non-social semantic knowledge. The relative contributions of the left and right ATL to social-semantic knowledge were tested by including ATL volume and asymmetry indices as predictors in a multiple regression analysis. People with SD and bvFTD were impaired in both social-and non-social knowledge tasks. The principal component analysis indicated separate components for semantic memory and executive function. Both social and non-social semantic tasks loaded onto the semantic memory component (Figure 1). People with SD scored significantly worse than bvFTD on the semantic memory component (t = 5.18, p<0.0001), while people with bvFTD scored worse than SD on the executive function component (t = 3.97, p<0.001) (Figure 2). Semantic memory factor scores were correlated with grey matter in the bilateral ATLs (Figure 3). There were no significant clusters associated with scores on the executive function component. Multiple regression revealed that performance on the semantic memory component was predicted by the magnitude but not the asymmetry of ATL atrophy. Both social and non-social forms of semantic knowledge are impaired by FTD, and this degradation is associated with bilateral ATL atrophy. These results suggest a shared representation for all types of semantic memory across the ATLs.