Background:Recent work has delineated the semantic behavioral variant of frontotemporal dementia (sbvFTD; or right temporal variant of FTD, which is thought to preferentially impair semantic knowledge for emotional concepts. However, this proposed core feature has not yet been empirically validated, and no clinical tool exists to assess it. Establishing reliable markers is essential to clinically differentiate sbvFTD from behavioral variant FTD (bvFTD), which is critical given their overlapping behavioral symptoms but divergent underlying pathologies. Furthermore, contrasting sbvFTD with semantic variant primary progressive aphasia (svPPA) can advance our understanding of semantic memory, revealing how the right and left anterior temporal lobes (ATLs) support emotion- versus tool-related knowledge, highlighting the graded, lateralized organization of the semantic system. Methods:We studied 15 patients with sbvFTD, 15 with svPPA, 18 with bvFTD, and 37 healthy controls. A novel multimodal semantic battery, the Fear and Spider Test (FST), which assesses tool- and emotion-related concepts across word-based semantic associations, picture-based semantic associations, and sound-to-picture matching, was administered. Stimuli were matched on psycholinguistic and perceptual features, and emotional items were drawn from multicultural facial expressions validated with the Facial Action Coding System. Neural correlates of semantic performance were investigated using voxel-based morphometry. Results:As expected, patients with both sbvFTD and svPPA showed greater deficits in all semantic tasks compared to controls and bvFTD, and bilateral anterior temporal lobe (ATL) volumes were broadly associated with performance across all semantic tasks. Interactions between modality and categories were necessary for the emergence of differences between sbvFTD and svPPA and right and left ATL atrophy: performance on the Words-Tools condition was more impaired in svPPA and correlated with left ATL volume, while performance on the Pictures-Emotions condition was more impaired in sbvFTD and correlated with right ATL volume. Conclusion:The FST provides the first clear dissociation of sbvFTD from bvFTD, a distinction of critical clinical importance given their divergent pathological substrates and the absence of frontotemporal lobar degeneration specific biomarkers. The study also refines our understanding of semantic memory: contrasting sbvFTD with svPPA reveals complementary roles of the right and left ATLs in supporting emotion and tool knowledge, underscoring the graded, lateralized organization of the semantic system.

Some children are slower than average to acquire early spoken language milestones. Little is known about how this heterogeneity in expressive language impacts later childhood language and reading outcomes in children with dyslexia. We investigated oral language and reading differences in 63 children with dyslexia aged 8–12 years, comparing those with (35

More precise subtyping within dementia syndromes leads to better prediction of pathology, supporting individualized, disease-specific treatments, and measuring emotion recognition abilities is particularly important for disorders like semantic behavioural variant frontotemporal dementia (sbvFTD). To evaluate current tools' effectiveness, we compared two dynamic video-based affect labelling tests-the Dynamic Affect Recognition Test (DART), The Awareness of Social Inference Test-Emotion Evaluation Test (TASIT-EET)-and a static image-based Comprehensive Affect Testing System-Name Affect (CATS-NA) test. A total of 555 persons with dementia (PwD), diagnosed with Alzheimer's disease (n = 154), progressive supranuclear palsy syndrome (n = 88), non-fluent variant primary progressive aphasia (nfvPPA) (n = 77), semantic variant PPA (svPPA) (n = 53), bvFTD (n = 124), sbvFTD (n = 65) and 133 healthy participants underwent emotion testing and MRI. All emotion labelling tests differentiated PwD from healthy controls, and FTD with social cognition deficits (sbvFTD, bvFTD and svPPA) from other PwDs. DART outperformed TASIT-EET and CATS-NA in differentiating sbvFTD from bvFTD and svPPA. Beyond emotion reading, TASIT-EET performance was also mediated by verbal memory and semantics, and CATS-NA was predicted by visuospatial and executive functions, while DART required only semantic knowledge. DART corresponded to expected structural anatomy of emotion, including predominantly right insula, anterior temporal and orbitofrontal lobes. While both TASIT-EET and CATS-NA shared that pattern, TASIT-EET additionally correlated with left temporal structures and CATS-NA associated with more dorsal frontoparietal regions. Careful selection of tests that utilize dynamic stimuli, reflect key neural circuits related to emotion and minimize demands from other cognitive domains may yield more accurate diagnoses.

Close relational partners play a critical role in shaping each other's emotions during social interactions, a process known as interpersonal emotion regulation. We examined how different forms of dementia (i.e., Alzheimer's disease, behavioral variant frontotemporal dementia, primary progressive aphasia) affect interpersonal emotion regulation. We assessed how caregivers perceived their partners' prosocial regulatory efforts and tracked real-time changes in caregivers' affect during a dyadic interaction. We also investigated how these processes relate to caregivers' mental health. Informal caregivers (N = 62) reported on their own mental health symptoms (depression, anxiety) and how their care recipients, who had different forms of dementia, use prosocial interpersonal emotion regulation (i.e., efforts to make their partner feel better). Dyads then engaged in a 10-min unrehearsed discussion about a conflict in their relationship. Following this, caregivers viewed a video recording of the interaction and used a rating dial to provide continuous ratings of their own affective valence (negative-neutral-positive) during the conversation. Results revealed that among care recipients with Alzheimer's disease, primary progressive aphasia, and behavioral variant frontotemporal dementia, those with behavioral variant frontotemporal dementia showed the lowest use of prosocial interpersonal emotion regulation, and their caregivers experienced the greatest increases in negative affect during the interaction. Across diagnoses, greater increases in caregiver negativity during the interaction were associated with greater caregiver depression (but not anxiety). These findings provide new information about interpersonal emotion regulation in dementia and highlight how the emotional changes that occur during dyadic interactions are tied to caregiver depressive symptoms. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Research linking facial muscle movement to emotion and other affective experience has been central to affective science throughout the field’s history. Though the study of facial affect has often been contentious, it is possible that researchers currently working in this field agree on more than is commonly recognized. In the present study, 55 actively publishing facial affect researchers indicated their agreement, agreement with reservations, or disagreement with 23 statements regarding the nature of and best practices for research on facial affect, generated through a process akin to the Delphi method for developing consensus statements. Agreement (with or without reservations) exceeded 95

INTRODUCTION:Intrinsic functional connectivity network abnormalities in C9orf72 hexanucleotide repeat expansion carriers emerge during the asymptomatic phase, yet longitudinal studies remain limited. We examined cross-sectional abnormalities and longitudinal connectivity changes across clinical stages. METHODS:We analyzed task-free functional magnetic resonance imaging (fMRI) and structural MRI data in 36 asymptomatic (aSxC9), 17 prodromal (proC9), and 29 symptomatic (SxC9) carriers, and 107 healthy controls (HCs). Functional networks previously found altered in C9orf72, including salience, sensorimotor, default mode, and medial pulvinar thalamic networks, were examined. Associations between longitudinal connectivity and gray matter decline with baseline neurofilament light chain (NfL) concentrations and symptom severity were assessed. RESULTS:aSxC9 and SxC9 showed longitudinal connectivity changes within specific networks. In aSxC9, connectivity changes correlated with baseline NfL. In proC9 and SxC9, changes in connectivity and gray matter were associated with baseline NfL and symptom severity. DISCUSSION:C9orf72 expansion carriers demonstrate stage-specific network connectivity changes.

Previous studies demonstrate that certain asymptomatic MAPT variant carriers (Asymp- MAPT ) exhibit altered baseline gray matter volume (GMV) and functional connectivity (FC) profiles. It remains unclear whether these imaging measures may herald risk for earlier conversion to the symptomatic phase. To address this, we stratified Asymp- MAPT based on baseline GMV and longitudinal FC changes to assess whether any Asymp- MAPT subgroups showed signs of longitudinal neurodegeneration or cognitive decline. We studied 25 Asymp- MAPT recruited from the UCSF Memory and Aging Center and ALLFTD Consortia. Using a median split, we divided Asymp- MAPT into groups with smaller (LowGMV; n  = 12) and larger baseline GMV (HighGMV; n  = 13) within regions atrophied in symptomatic MAPT carriers ( n  = 20). Next, we stratified Asymp- MAPT based on longitudinal FC changes using k-means clustering on rates of change in FC for four intrinsic connectivity networks associated with common MAPT -related syndromes: salience (SN), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and default mode (DMN) networks. We compared Asymp- MAPT subgroups from each stratification on baseline and longitudinal changes in demographics, plasma neurofilament light (NfL) concentration, GMV within 246 Brainnetome regions, and neuropsychological test scores. Stratification of Asymp- MAPT based on baseline GMV showed that LowGMV had higher education levels compared to HighGMV, with no other demographic differences. Though LowGMV and HighGMV did not differ in baseline NfL, LowGMV showed greater longitudinal NfL increases. These groups did not differ in baseline or longitudinal GMV changes. LowGMV had lower baseline attention and working memory scores, and greater longitudinal decline in set-shifting and visuospatial performance. Stratification based on FC changes yielded one group (DecFC; n  = 17) exhibiting longitudinal decreases in the SN, PSP, and DMN and another (IncFC; n  = 8) showing increases in each network. DecFC and IncFC did not differ in demographics, baseline or longitudinal NfL, or baseline GMV. Longitudinally, DecFC showed greater decline in posterior superior temporal and inferior parietal cortices. DecFC showed lower baseline attention and semantic fluency scores, and greater longitudinal decline in set-shifting and visuospatial memory performance. Lower baseline GMV within regions atrophied during the symptomatic phase and longitudinal FC declines within MAPT -relevant networks may signal earlier symptomatic conversion in Asymp- MAPT .

Practical, neurologically validated measures of emotion identification are still needed in the dementia field. The Dynamic Affect Recognition Test (DART) was designed to identify emotion reading deficits in persons with dementia (PWD). Participants included 257 early-stage PWD and 115 healthy controls (HC) who underwent DART and magnetic resonance imaging (MRI). DART performance was worse in PWD than in HC, with the lowest scores observed in the semantic behavioral variant of frontotemporal dementia (sbvFTD). DART showed strong diagnostic specificity (areas under the curve (AUCs) ≥82% comparing syndromes), with the highest performance distinguishing syndromes with prominent socioemotional impairment, particularly sbvFTD. DART performance was associated with other emotion identification measures and predicted real-world socioemotional sensitivity. Poorer DART performance predominantly correlated with focal atrophy in right-sided emotion processing areas, including the insula, temporal pole, and caudate head. The DART is a brief, clinically practical, video-based test of emotion identification designed for PWD that accurately reflects the neuroanatomy involved in emotion.

A central unresolved issue in affective neuroscience is whether human emotions have unique biological signatures in the brain and body. Despite decades of debate, a consensus is lacking on whether emotions are patterned (similar across contexts and characterized by distinct features) or flexible (variable across contexts and lacking distinct features). Studies in other species have revealed the ubiquity of autonomic and motor patterns, and these investigations have elucidated the biology of central pattern generation at the levels of networks, neurons, and synapses. Here, we integrate the knowledge gained from this research and introduce the Dynamic Emotion Fabric Theory (DEFT), a new model of emotions biology. DEFT proposes that, just as fabrics are comprised of both patterns and textures, emotions are accompanied by stereotyped responses that are distinct and recognizable, yet also nuanced and malleable. A neurobiological system that is both automatic-generating patterned reactions essential for survival-and flexible-texturizing each response in context-is equipped to produce the spectrum of human emotions. DEFT provides new insights into the biological basis of emotions and identifies novel areas that warrant further study in humans and other species. This framework has implications for basic affective neuroscience and clinical studies of affective symptoms.

Physiological linkage, which refers to the degree that people's peripheral physiological responses change in coordinated ways, has been linked to a variety of psychiatric and developmental conditions. In contrast, physiological linkage in neurological conditions has been understudied. Behavioral variant frontotemporal dementia (bvFTD) is characterized by debilitating impairments in socioemotional functioning, including connections with others. We hypothesized that physiological linkage during interactions with loved ones would be reduced in bvFTD. During unrehearsed 10-min discussions of an area of disagreement in 86 dyads (n = 40 bvFTD; n = 35 Alzheimer's disease [AD]; n = 11 healthy controls), we computed dyadic physiological linkage using a composite of six peripheral physiological measures (i.e., heart rate, skin conductance, finger pulse amplitude, finger pulse transmission time, ear pulse transmission time, somatic activity). Specifically, we computed in-phase, anti-phase, and combined physiological linkage to examine each dyad's coordinated physiological changes that occur exclusively in the same direction (i.e., positively correlated), opposite direction (i.e., negatively correlated), or in either direction (i.e., correlated regardless of whether the correlation is positive or negative). Results indicate that bvFTD dyads had significantly lower combined (but not in-phase or anti-phase) physiological linkage compared to AD and healthy control dyads. To the extent that physiological linkage reflects social connection, these findings are consistent with the deficits in socio-emotional functioning that characterize bvFTD. We offer several possible explanations for this finding and consider implications for future research and clinical assessment of dyadic interpersonal processes in dementia and related disorders.

OBJECTIVE:Autosomal dominant progranulin (GRN) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. METHODS:Utilizing T1 and task-free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole-brain degree, and GRN-relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive-compulsive disorder symptom severity, and gray matter volume. RESULTS:Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive-compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN-frontotemporal dementia. INTERPRETATION:In asymptomatic carriers, the co-occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

Dyslexia is a neurodevelopmental condition characterized by reading difficulties, yet there is growing evidence for coinciding social and emotional strengths. In our previous work, we found children with dyslexia displayed greater emotional facial behavior to affective stimuli than their well-reading peers, an enhancement that related to better social skills. Traditional measures provide static “snapshots” of emotional facial behavior but overlook important dynamic information about the face’s movements that may confer interpersonal advantages. Here, we examined whether variability in emotional facial behavior was heightened in children with dyslexia and associated with social communication benefits. We coded the second-by-second intensities of ten emotional facial behaviors in 54 children (ages 7–14) with (n = 33) and without (n = 21) dyslexia while they watched five emotion-inducing film clips. For each trial, we calculated two facial behavior variability scores: a within-emotion variability score (the second-by-second intensity changes within each category of emotional behavior) and a between-emotions variability score (the total number of changes between categories of emotional behavior). Parents also reported on children’s real-world communication skills. Linear mixed-effects models (controlling for age, sex, and total facial behavior) revealed that children with dyslexia had higher within-emotion facial behavior variability but not higher between-emotions facial behavior variability than those without dyslexia. Across the sample, greater total within-emotion facial behavior variability correlated with higher parent-reported functional communication—the ability to express ideas in ways that others can easily understand. These findings suggest nuanced emotional facial behavior dynamics contribute to social strengths in dyslexia.

Frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominant atrophy is an emerging area of interest. Recent findings by the International Working Group (IWG) have identified this subtype as having a distinct clinical profile within the FTD spectrum (Ulugut et al., 2024, A&D). However, its genetic and pathological underpinnings remain unexplored in large, multicultural cohorts. Retrospective analyses encompassing clinical, genetic, pathological, and neuroimaging data from 23 IWG sites across 13 countries in Asia, Middle East, Europe, North and South America were conducted. The study included 444 patients with FTD exhibiting predominant RATL atrophy. Genetic screening was performed on 51% ( n  = 225) of the cohort for at least the major frontotemporal lobar degeneration (FTLD) mutations including microtubule-associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ), or dementia panels encompassing extended sets of genes. Of these, 81% were sporadic, showing negative results for the screened genes and a modified Goldman Score of ≥ 3, indicating a negative family history for dementia. The MAPT mutation was the most common genetic variant, identified in 7% of the screened cases (Figure 1). Pathological confirmation was available for 63 patients. Among the sporadic cases, transactive response DNA-binding protein 43 type C (TDP-C) pathology was most prevalent (60%, n  = 32), while tau-MAPT pathology was most common in the genetic cases (38%, n  = 16). Fifteen cases did not fit neatly into genetic or sporadic categories, displaying heterogeneous pathologies (Figure 2). At the initial visit, compared to genetic cases, patients with TDP-C pathology were older, and more frequently exhibited semantic deficits, with less frequent attention difficulties and executive dysfunction. No differences were observed in sex distribution, symptom duration or disease severity between genetic and sporadic TDP-C cases. However, left handedness was more common in TDP-C cases (14%) compared to genetic cases (5%). While FTD with RATL atrophy primarily appears sporadic, a significant proportion of cases exhibit genetic variants. These sporadic and genetic subtypes display distinct neuropathological features and clinical manifestations. Given the implications for therapeutic strategies, precise clinical and molecular subtyping is critical for enhancing patient management and ensuring appropriate enrollment in clinical trials.

Autonomic dysfunction has been linked to empathy deficits in symptomatic frontotemporal degeneration (FTD), but less is known about pre-symptomatic FTD mutation carriers (preFTD+). Our prior work found that increasing resting heart rate (RHR) over time predicts decline in emotional empathy in preFTD+. Here, we replicate previous findings in a large, multi-site consortium sample and assess relationships between RHR and empathy loss across disease stages. RHR and Interpersonal Reactivity Index (IRI) were obtained serially for up to 7 years in 348 preFTD+, 202 symptomatic FTD mutation carriers (FTD+), and 311 non-carrier family members (FTD-) enrolled in ALLFTD. IRI Perspective Taking (IRI-PT) and Empathic Concern (IRI-EC) subscales measured cognitive and emotional empathy, respectively. Separate multiple linear regressions related mutation status and annualized change in RHR to annualized change in IRI subscales and assessed interactions between RHR change and phenoconversion status among mutation carriers. Logistic regression was used to assess the association between change in RHR and phenoconversion among mutation carriers, and Wilcoxon signed-rank tests were used to examine differences in change in RHR between all study groups. In asymptomatic participants (preFTD+ and FTD-), increase in RHR over time was associated with greater decline in IRI-EC (ß = -0.07, p<.001) and IRI-PT (ß = -0.03, p = .011), regardless of mutation status. Among mutation carriers (preFTD+ and FTD+), increase in RHR was associated with greater decline in IRI-EC (ß = -0.04, p = .041), and this effect was stronger in FTD+ compared to PreFTD+ (ß = -0.07, p = .038), while an increase in RHR was associated with decline in IRI-PT only in FTD+ (ß = -0.07, p = .046). Change in RHR did not predict phenoconversion in mutation carriers (PreFTD+ and FTD+), but PreFTD+ showed less change in RHR over time relative to FTD+. Changes in empathy in asymptomatic preFTD+ and FTD- are linked to variability in RHR regardless of genetic status, likely reflecting a non-specific impact of autonomic functioning on empathy and prosocial behavior. In contrast, increasing RHR predicts decline in cognitive and emotional empathy in FTD mutation carriers but primarily after phenoconversion, suggesting that autonomic contributions to empathy in familial FTD increase with disease progression and could be an early marker of manifest disease.

Emotion regulation emerges during childhood and engages prefrontal brain systems. While most developmental studies focus on the neural underpinnings of negative emotion regulation, less is known about the neuroanatomical correlates of positive emotion regulation. In adults, prefrontal areas in the left hemisphere are critical for positive emotion regulation, but whether this association is present in children is unknown. We investigated whether smaller gray matter volume in left prefrontal regions related to worse positive emotion regulation in children with and without dyslexia. Because dyslexia is a neurodevelopmental disorder of reading in which there may be greater variability in left prefrontal structures, it offers a unique window into the neural basis of positive emotion regulation. Sixty-nine children (ages 7–13) were asked to hide their feelings while watching film clips that elicited either amusement or disgust, and evaluate their emotion regulation performance. Parents reported on children’s everyday emotion regulation. Across the sample, children with smaller volumes in left prefrontal regions (i.e., lateral orbitofrontal cortex and dorsolateral prefrontal cortex) had greater facial behavior (i.e., suggesting worse positive emotion regulation) yet more positive self-reported emotion regulation success during the amusement trial (i.e., suggesting more favorable self-evaluation). These regions did not relate to disgust regulation, however. Children with more positive views of their emotion regulation success also had better everyday parent-reported emotion regulation. Results suggest that positive emotion regulation in childhood relies on left prefrontal regions and a more optimistic view of one’s emotion regulation abilities, regardless of one’s actual emotional behavior, may confer real-world advantages.

The experience of interpersonal space may be altered in Alzheimer's disease (AD) due to atrophy in brain systems that support emotion and reward processing. Seventy participants (AD = 36, healthy controls = 34) underwent structural neuroimaging and completed a modified stop-distance paradigm, an established interpersonal distance task, in which they indicated at which distance they preferred to have a conversation with the experimenter. After estimating the distance between themselves and the experimenter, participants rated their emotional experience. Feelings of physical closeness were calculated as the discrepancy between the perceived and actual distance between the participant and experimenter. Participants also estimated their distance from the wall, which served as a non-social control task. Unlike the healthy controls, the participants with AD felt physically closer to the experimenter than they were (despite no differences in objective interpersonal distance) and reported greater positive emotional experience. Voxel-based morphometry analyses revealed greater feelings of physical closeness related to smaller gray matter volume in the right ventral striatum and right medial orbitofrontal cortex (p(FWE)<.05). These results suggest that reward system atrophy influences how people with AD experience interpersonal space. Individuals with AD may feel physically closer to others than they are and find social proximity more enjoyable than healthy controls.

BACKGROUND:Poor affect recognition is an early sign of frontotemporal dementia (FTD). Here, we applied the abbreviated version of the Comprehensive Affect Testing System (CATS-A) battery to Italian FTD cases and healthy controls (HC) to provide cut-offs of emotional dysfunction in the whole group and in different FTD clinical syndromes. METHODS:One hundred thirty-nine FTD patients (60 behavioural variant [bvFTD],13 semantic behavioural variant of FTD [sbvFTD], 28 progressive supranuclear palsy [PSP], 21 semantic [svPPA] and 17 nonfluent [nfvPPA] variants of primary progressive aphasia) and 116 HC were administered the CATS-A, yielding an Affective Recognition Quotient (ARQ), which was used as outcome measure. Age- and education-adjusted, regression-based norms were derived in HC. In patients, the ARQ was assessed for its internal reliability, factorial validity and construct validity by testing its association with another social cognition paradigm, the Story-Based Empath Task (SET). The diagnostic accuracy of the ARQ in discriminating patients from HC, genetic cases from HC and patient groups among each other was tested via ROC analyses. RESULTS:In the whole FTD cohort, CATS-A proved to be underpinned by a mono-component factor (51.1%) and was internally consistent (McDonald's ω = 0.76). Moreover, the ARQ converged with the SET (r(122) = 0.50; p < 0.001) and optimally discriminated HC from both the whole cohort (AUC = 0.89) and each clinical syndrome (AUC range: 0.83-0.92). Conversely, CATS-A subtests were able to distinguish patient groups. CONCLUSIONS:The ARQ score from the CATS-A distinguishes FTD clinical syndromes from HC with high accuracy, making it an excellent tool for immediate use in clinical practice.

BACKGROUND AND OBJECTIVES:Frontotemporal dementia (FTD) includes behavioral-variant FTD (bvFTD) with predominant frontal atrophy and semantic behavioral-variant FTD (sbvFTD) with predominant right anterior temporal lobe (rATL) atrophy. These variants present diagnostic challenges because of overlapping symptoms and neuroanatomy. Accurate differentiation is crucial for clinical trial inclusion targeting TDP-43 proteinopathies. This study investigated whether automated speech analysis can distinguish between FTD-related rATL and frontal atrophy, potentially offering a noninvasive diagnostic tool. METHODS:This cross-sectional study used data from the University of California, San Francisco Memory and Aging Center. Using stepwise logistic regression and receiver-operating characteristic curve analysis, we analyzed 16 linguistic and acoustic features that were extracted automatically from audio-recorded picture description tasks. Voxel-based morphometry was used to investigate brain-behavior relationships. RESULTS:We evaluated 62 participants: 16 with FTD-related predominant frontal atrophy, 24 with predominant rATL atrophy, and 22 healthy controls (mean age 68.3 years, SD = 9.2; 53.2% female). Logistic regression identified 3 features (content units, lexical frequency, and familiarity) differentiating the overall FTD group from controls (area under the curve [AUC] = 0.973), adjusted for age. Within the FTD group, 5 features (adpositions/total words ratio, arousal, syllable pause duration, restarts, and words containing "thing") differentiated frontal from rATL atrophy (AUC = 0.943). Neuroimaging analyses showed that semantic features (lexical frequency, content units, and "thing" words) were linked to bilateral inferior temporal lobe structures, speech and lexical features (syllable pause duration, and adpositions/total words ratio) to bilateral inferior frontal gyri, and socioemotional features (arousal) to areas known to mediate social cognition including the right insula and bilateral anterior temporal structures. As a composite score, this set of 5 features was uniquely associated with rATL atrophy. DISCUSSION:Automated speech analysis demonstrated high accuracy in differentiating FTD subtypes and provided insights into the neural basis of language impairments. Automated speech analysis could enhance early diagnosis and monitoring of FTD, offering a scalable, noninvasive alternative to traditional methods, particularly in resource-limited settings. Future research should focus on further clinical validation with other neuroimaging or fluid biomarkers and longitudinal cognitive data, as well as external validation in larger and more diverse populations.