Progression to corticobasal syndrome: a longitudinal study of patients with nonfluent primary progressive aphasia and primary progressive apraxia of speech.

BACKGROUND AND OBJECTIVES: Nonfluent variant primary progressive aphasia (nfvPPA) and primary progressive apraxia of speech (PPAOS) can be precursors to corticobasal syndrome (CBS). Details on their progression remain unclear. We aimed to examine the clinical and neuroimaging evolution of nfvPPA and PPAOS into CBS. METHODS: We conducted a retrospective longitudinal study in 140 nfvPPA or PPAOS patients and applied the consensus criteria for possible and probable CBS for every visit, evaluating limb rigidity, akinesia, limb dystonia, myoclonus, ideomotor apraxia, alien limb phenomenon, and nonverbal oral apraxia (NVOA). Given the association of NVOA with AOS, we also modified the CBS criteria by excluding NVOA and assigned every patient to either a progressors or non-progressors group. We evaluated the frequency of every CBS feature by year from disease onset, and assessed gray and white matter volume loss using SPM12. RESULTS: Asymmetric akinesia, NVOA, and limb apraxia were the most common CBS features that developed; while limb dystonia, myoclonus, and alien limb were rare. Eighty-two patients progressed to possible CBS; only four to probable CBS. nfvPPA and PPAOS had a similar proportion of progressors, although nfvPPA progressed to CBS earlier (p-value = 0.046), driven by an early appearance of limb apraxia (p-value = 0.0041). The non-progressors and progressors both showed premotor/motor cortex involvement at baseline, with spread into prefrontal cortex over time. DISCUSSION: An important proportion of patients with nfvPPA and PPAOS progress to possible CBS, while they rarely develop features of probable CBS even after long follow-up.

Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes.

BACKGROUND: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. OBJECTIVE: Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA. METHODS: Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n = 87), naPPA (n = 25), and healthy controls (HC, n = 41). We related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes. RESULTS: Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA. CONCLUSION: Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels.

C9orf72 Repeat Expansion Does Not Affect the Phenotype in Primary Progressive Aphasia.

Primary progressive aphasia (PPA) forms the spectrum of language variants of frontotemporal lobar degeneration (FTLD), including three subtypes each consisting of distinctive speech and language features. Repeat expansion in C9orf72 gene is the most common genetic cause of FTLD. However, thus far only little is known about the effects of the C9orf72 repeat expansion on the phenotype of PPA. This retrospective study aimed at determining the differences between the PPA phenotypes of the C9orf72 expansion carriers and non-carriers. Our results demonstrated no significant differences between these groups, indicating that the C9orf72 repeat expansion does not substantially affect the phenotype of PPA.

A Meta-Analysis of Neuropsychological Functioning in the Logopenic Variant of Primary Progressive Aphasia: Comparison with the Semantic and Non-Fluent Variants.

OBJECTIVES: The logopenic variant of primary progressive aphasia (lvPPA) has disparate pathological and anatomical features when compared to the semantic (svPPA) and non-fluent (nfvPPA) variants of PPA. As such, there is increasing need for measures that improve diagnostic accuracy particularly when etiology-specific treatments become available. In the current study, we used meta-analytic methods to establish the neuropsychological profile of lvPPA and compare it to recent findings in svPPA and nfvPPA. METHODS: We extracted neuropsychological data from 51 publications representing 663 lvPPA patients and 1379 controls. We calculated Hedges' g effect sizes for nine domains of neuropsychological functioning in lvPPA and assessed the influence of demographic, disease, and task characteristics on effect size magnitude. Results obtained in lvPPA were compared to findings in svPPA and nfvPPA. RESULTS: In lvPPA, the magnitude of deficits in attention, math, visuospatial memory, and executive functioning were as prominent as language deficits. Within the language domain, lvPPA patients demonstrated greater naming than repetition deficits. Compared to svPPA and nfvPPA, lvPPA patients demonstrated greater neuropsychological deficits overall and greater impairment on attention, math, and visual set-shifting tests. CONCLUSIONS: Tests of attention, delayed visuospatial memory, visual set-shifting, and math distinguish lvPPA from svPPA and nfvPPA likely reflecting the posterior temporoparietal atrophy observed early in the course of lvPPA. These findings support the inclusion of these measures in the clinical neuropsychological assessment of lvPPA and underscore the need for additional clinicopathological and longitudinal studies of arithmetic and visuospatial memory across the PPA variants.

Neural correlates of altered insight in frontotemporal dementia: a systematic review.

Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

Parkinsonism in frontotemporal dementias.

Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders, with progressive impairment of behavior and language. They can be closely related to amyotrophic lateral sclerosis, clinically and through shared genetics and similar pathology. Approximately 40% of people with frontotemporal dementia report a family history of dementia, motor neuron disease or parkinsonism, and half of these familial cases are attributed to mutations in three genes (C9orf72, MAPT and PGRN). Akinetic-rigidity is a common feature in several types of frontotemporal dementia, particularly the behavioral variant and the non-fluent agrammatic variant of primary progressive aphasia, and the familial dementias. The majority of patients develop a degree of parkinsonism during the course of the illness, and signs may be present at the time of initial diagnosis. However, the parkinsonism of frontotemporal dementia is very different from that observed in idiopathic Parkinson's disease: it may be symmetric, axial, and poorly responsive to levodopa. Tremor is uncommon, and may be postural, action or occasionally rest tremor. The emergence of parkinsonism is often part of an evolving phenotype, in which frontotemporal dementia comes to resemble corticobasal syndrome or progressive supranuclear palsy. This chapter describes the prevalence and phenomenology of parkinsonism in each of the major syndromes, and according to the common genetic forms of frontotemporal dementia. We discuss the changing nosology and terminology surrounding the diagnoses, and the significance of parkinsonism as a core feature of frontotemporal dementia, relevant to clinical management and the design of future clinical trials.

The use of spelling for variant classification in primary progressive aphasia: Theoretical and practical implications.

Currently, variant subtyping in primary progressive aphasia (PPA) requires an expert neurologist and extensive language and cognitive testing. Spelling impairments appear early in the development of the disorder, and the three PPA variants (non-fluent - nfvPPA; semantic - svPPA; logopenic - lvPPA) reportedly show fairly distinct spelling profiles. Given the theoretical and empirical evidence indicating that spelling may serve as a proxy for spoken language, the current study aimed to determine whether spelling performance alone, when evaluated with advanced statistical analyses, allows for accurate PPA variant classification. A spelling to dictation task (with real words and pseudowords) was administered to 33 PPA individuals: 17 lvPPA, 10 nfvPPA, 6 svPPA. Using machine learning classification algorithms, we obtained pairwise variant classification accuracies that ranged between 67 and 100%. In additional analyses that assumed no prior knowledge of each case's variant, classification accuracies ranged between 59 and 70%. To our knowledge, this is the first time that all the PPA variants, including the most challenging logopenic variant, have been classified with such high accuracy when using information from a single language task. These results underscore the rich structure of the spelling process and support the use of a spelling task in PPA variant classification.

Atypical clinical features associated with mixed pathology in a case of non-fluent variant primary progressive aphasia.

A 66-year-old woman presented with agrammatism and apraxia of speech, meeting criteria for non-fluent/agrammatic variant primary progressive aphasia (nfvPPA). However, three years later, she developed frontal/executive, short-term phonological memory, visuospatial, and visual memory deficits suggesting involvement of multiple brain networks. Multimodal neuroimaging showed damage of both fronto-striatal and posterior brain regions. She was found to have multiple pathological processes: corticobasal degeneration (CBD), Alzheimer's disease (AD), and TAR DNA-binding protein (TDP)-43 type A. We hypothesize that cognitive and neuroimaging findings consistent with damage to multiple brain networks, each associated with vulnerability to certain molecular disease subtypes, could indicate mixed pathology.

Findings of Impaired Hearing in Patients With Nonfluent/Agrammatic Variant Primary Progressive Aphasia.

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.

Emergence of artistic talent in progressive nonfluent aphasia: a case report.

Some patients with frontotemporal lobar degeneration have developed artistic skills after the onset mainly in painting and music. Most of these cases have semantic dementia (SD), one of the frontotemporal lobar degeneration subtypes. In previously reported cases, the paintings made by patients with SD were usually hyper realistic, without a significant symbolic or abstract component. Here, we report on a patient with progressive nonfluent aphasia (PNFA), another frontotemporal lobar degeneration subtype, who started making creative bamboo crafts after PNFA onset. His techniques were completely his original; he devised the shapes of the crafts and made them without samples. His work did not become an obsessive preoccupation. The artistic style expressed by patients with PNFA differs from that expressed by patients with SD. Therefore, the underlying mechanisms for the emergence of artistic talent might differ between SD and PNFA.

Altered topology of the functional speech production network in non-fluent/agrammatic variant of PPA.

Non-fluent/agrammatic primary progressive aphasia (nfvPPA) is caused by neurodegeneration within the left fronto-insular speech and language production network (SPN). Graph theory is a branch of mathematics that studies network architecture (topology) by quantifying features based on its elements (nodes and connections). This approach has been recently applied to neuroimaging data to explore the complex architecture of the brain connectome, though few studies have exploited this technique in PPA. Here, we used graph theory on functional MRI resting state data from a group of 20 nfvPPA patients and 20 matched controls to investigate topological changes in response to focal neurodegeneration. We hypothesized that changes in the network architecture would be specific to the affected SPN in nfvPPA, while preserved in the spared default mode network (DMN). Topological configuration was quantified by hub location and global network metrics. Our findings showed a less efficiently wired and less optimally clustered SPN, while no changes were detected in the DMN. The SPN in the nfvPPA group showed a loss of hubs in the left fronto-parietal-temporal area and new critical nodes in the anterior left inferior-frontal and right frontal regions. Behaviorally, speech production score and rule violation errors correlated with the strength of functional connectivity of the left (lost) and right (new) regions respectively. This study shows that focal neurodegeneration within the SPN in nfvPPA is associated with network-specific topological alterations, with the loss and gain of crucial hubs and decreased global efficiency that were better accounted for through functional rather than structural changes. These findings support the hypothesis of selective network vulnerability in nfvPPA and may offer biomarkers for future behavioral intervention.

Functional Connectivity Changes in Behavioral, Semantic, and Nonfluent Variants of Frontotemporal Dementia.

Frontotemporal dementia (FTD) affects behavior, language, and personality. This study aims to explore functional connectivity changes in three FTD variants: behavioral (bvFTD), semantic (svPPA), and nonfluent variant (nfvPPA). Seventy-six patients diagnosed with FTD by international criteria and thirty-two controls were investigated. Functional connectivity from resting functional magnetic resonance imaging (fMRI) was estimated for the whole brain. Two types of analysis were done: network basic statistic and topological measures by graph theory. Several hubs in the limbic system and basal ganglia were compromised in the behavioral variant apart from frontal networks. Nonfluent variants showed a major disconnection with respect to the behavioral variant in operculum and parietal inferior. The global efficiency had lower coefficients in nonfluent variants than behavioral variants and controls. Our results support an extensive disconnection among frontal, limbic, basal ganglia, and parietal hubs.

Sentence composition ability in two patients with non-fluent/agrammatic variant primary progressive aphasia.

Agrammatism is one of the core clinical features of non-fluent/agrammatic variant primary progressive aphasia, and it has traditionally been considered the hallmark of non-fluent aphasia in Western countries. However, agrammatic speech may remain undetected in Japanese patients because of the agglutinative structure of the language and high flexibility in word order. In the present study, we aimed to analyze agrammatism in the speech production of Japanese patients with aphasia due to neurodegenerative disease using an anagram test generated by our laboratory. Four patients were recruited from the dementia clinic at Tohoku University Hospital between December 2014 and August 2015: two patients with non-fluent/agrammatic variant primary progressive aphasia, one with semantic variant primary progressive aphasia, and one with probable Alzheimer's disease experiencing episodic memory impairment accompanied by transcortical sensory aphasia. All patients underwent thorough neurological and neuropsychological testing before performing a Japanese anagram task based on the Northwestern Anagram Test. Our findings indicated that the two patients with non-fluent/agrammatic variant primary progressive aphasia exhibited poorer performance on the anagram task than the remaining two patients. Therefore, the anagram test used in the present study may aid in detecting output aspects of agrammatism in Japanese patients with aphasia, although future studies are required to develop a standardized version of test.

Evidence for causal top-down frontal contributions to predictive processes in speech perception.

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.

Typical and atypical pathology in primary progressive aphasia variants.

OBJECTIVE: To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. METHODS: Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. RESULTS: A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants. INTERPRETATION: Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430-443.

A physiological signature of sound meaning in dementia.

The meaning of sensory objects is often behaviourally and biologically salient and decoding of semantic salience is potentially vulnerable in dementia. However, it remains unclear how sensory semantic processing is linked to physiological mechanisms for coding object salience and how that linkage is affected by neurodegenerative diseases. Here we addressed this issue using the paradigm of complex sounds. We used pupillometry to compare physiological responses to real versus synthetic nonverbal sounds in patients with canonical dementia syndromes (behavioural variant frontotemporal dementia - bvFTD, semantic dementia - SD; progressive nonfluent aphasia - PNFA; typical Alzheimer's disease - AD) relative to healthy older individuals. Nonverbal auditory semantic competence was assessed using a novel within-modality sound classification task and neuroanatomical associations of pupillary responses were assessed using voxel-based morphometry (VBM) of patients' brain MR images. After taking affective stimulus factors into account, patients with SD and AD showed significantly increased pupil responses to real versus synthetic sounds relative to healthy controls. The bvFTD, SD and AD groups had a nonverbal auditory semantic deficit relative to healthy controls and nonverbal auditory semantic performance was inversely correlated with the magnitude of the enhanced pupil response to real versus synthetic sounds across the patient cohort. A region of interest analysis demonstrated neuroanatomical associations of overall pupil reactivity and differential pupil reactivity to sound semantic content in superior colliculus and left anterior temporal cortex respectively. Our findings suggest that autonomic coding of auditory semantic ambiguity in the setting of a damaged semantic system may constitute a novel physiological signature of neurodegenerative diseases.

Profiling Speech and Pausing in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD).

OBJECTIVE: This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. DESIGN: 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA). Participants with ALS were further divided into 4 non-overlapping subgroups--mild, respiratory, bulbar (with oral-motor deficit) and bulbar-respiratory--based on the presence and severity of motor bulbar or respiratory signs. All participants read a passage aloud. Custom-made software was used to perform speech and pause analyses, and this provided measures of speaking and articulatory rates, duration of speech, and number and duration of pauses. These measures were statistically compared in different subgroups of patients. RESULTS: The results revealed clear differences between patient groups and healthy controls on the passage reading task. A speech-based motor function measure (i.e., articulatory rate) was able to distinguish patients with bulbar ALS or FTD-PNFA from those with respiratory ALS or FTD-BV. Distinguishing the disordered groups proved challenging based on the pausing measures. CONCLUSIONS AND RELEVANCE: This study demonstrated the use of speech measures in the identification of those with an oral-motor deficit, and showed the usefulness of performing a relatively simple reading test to assess speech versus pause behaviors across the ALS-FTD disease continuum. The findings also suggest that motor speech assessment should be performed as part of the diagnostic workup for patients with FTD.

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis.

Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.