Multisite ALLFTD study modeling progressive empathy loss from the earliest stages of behavioral variant frontotemporal dementia.

INTRODUCTION: Empathy relies on fronto-cingular and temporal networks that are selectively vulnerable in behavioral variant frontotemporal dementia (bvFTD). This study modeled when in the disease process empathy changes begin, and how they progress. METHODS: Four hundred thirty-one individuals with asymptomatic genetic FTD (n = 114), genetic and sporadic bvFTD (n = 317), and 163 asymptomatic non-carrier controls were enrolled. In sub-samples, we investigated empathy measured by the informant-based Interpersonal Reactivity Index (IRI) at each disease stage and over time (n = 91), and its correspondence to underlying atrophy (n = 51). RESULTS: Empathic concern (estimate = 4.38, 95% confidence interval [CI] = 2.79, 5.97; p < 0.001) and perspective taking (estimate = 5.64, 95% CI = 3.81, 7.48; p < 0.001) scores declined between the asymptomatic and very mild symptomatic stages regardless of pathogenic variant status. More rapid loss of empathy corresponded with subcortical atrophy. DISCUSSION: Loss of empathy is an early and progressive symptom of bvFTD that is measurable by IRI informant ratings and can be used to monitor behavior in neuropsychiatry practice and treatment trials.

Influence of periaqueductal gray on other salience network nodes predicts social sensitivity.

The intrinsic connectivity of the salience network (SN) plays an important role in social behavior, however the directional influence that individual nodes have on each other has not yet been fully determined. In this study, we used spectral dynamic causal modeling to characterize the effective connectivity patterns in the SN for 44 healthy older adults and for 44 patients with behavioral variant frontotemporal dementia (bvFTD) who have focal SN dysfunction. We examined the relationship of SN effective connections with individuals' socioemotional sensitivity, using the revised self-monitoring scale, an informant-facing questionnaire that assesses sensitivity to expressive behavior. Overall, average SN effective connectivity for bvFTD patients differs from healthy older adults in cortical, hypothalamic, and thalamic nodes. For the majority of healthy individuals, strong periaqueductal gray (PAG) output to right cortical (p < .01) and thalamic nodes (p < .05), but not PAG output to other central pattern generators contributed to sensitivity to socioemotional cues. This effect did not exist for the majority of bvFTD patients; PAG output toward other SN nodes was weak, and this lack of output negatively influenced socioemotional sensitivity. Instead, input to the left vAI from other SN nodes supported patients' sensitivity to others' socioemotional behavior (p < .05), though less effectively. The key role of PAG output to cortical and thalamic nodes for socioemotional sensitivity suggests that its core functions, that is, generating autonomic changes in the body, and moreover representing the internal state of the body, is necessary for optimal social responsiveness, and its breakdown is central to bvFTD patients' social behavior deficits.

Clinical, neuroimaging, and neuropathological characterization of a patient with Alzheimer's disease syndrome due to Pick's pathology.

The most common neurodegenerative syndrome associated with Pick's disease pathology (PiD) is behavioral variant frontotemporal dementia (bvFTD), which features profound social behavioral changes. Rarely, PiD can manifest as an Alzheimer's disease (AD)-type dementia with early memory impairment. We describe a patient with AD-type dementia and pure PiD pathology who showed slowly progressive memory impairment, early social changes, and paucity of motor symptoms. Atrophy and PiD were found mainly in frontotemporal regions underlying social behavior. This report may help predict the pathology of patients with atypical AD, which will ultimately be critical for enrolling suitable subjects into disease-modifying clinical trials.

Salience driven attention is pivotal to understanding others' intentions.

Interpreting others' beliefs, desires and intentions is known as "theory of mind" (ToM), and is often evaluated using simplified measurement tools, which may not correctly reflect the brain circuits that are required for real-life ToM functioning. We aimed to identify the brain structures necessary to correctly infer intentions from realistic scenarios by administering The Awareness of Social Inference Test, Enriched subtest to 47 patients with behavioural variant frontotemporal dementia, 24 patients with progressive supranuclear palsy syndrome, 31 patients with Alzheimer's syndrome, and 77 older healthy controls. Neuroimaging data was analyzed using voxel based morphometry, and participants' understanding of intentions was correlated with voxel-wise and region-of interest data. We found that structural integrity of the cinguloinsular cortex in the salience network (SN) was more pivotal for accurate ToM than previously described, emphasizing the importance of the SN for selectively recognizing and attending to social cues during ToM inferences.

Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia.

Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.

State and trait characteristics of anterior insula time-varying functional connectivity.

The human anterior insula (aINS) is a topographically organized brain region, in which ventral portions contribute to socio-emotional function through limbic and autonomic connections, whereas the dorsal aINS contributes to cognitive processes through frontal and parietal connections. Open questions remain, however, regarding how aINS connectivity varies over time. We implemented a novel approach combining seed-to-whole-brain sliding-window functional connectivity MRI and k-means clustering to assess time-varying functional connectivity of aINS subregions. We studied three independent large samples of healthy participants and longitudinal datasets to assess inter- and intra-subject stability, and related aINS time-varying functional connectivity profiles to dispositional empathy. We identified four robust aINS time-varying functional connectivity modes that displayed both "state" and "trait" characteristics: while modes featuring connectivity to sensory regions were modulated by eye closure, modes featuring connectivity to higher cognitive and emotional processing regions were stable over time and related to empathy measures.

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology.

TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.

Nonvisual spatial navigation fMRI lateralizes mesial temporal lobe epilepsy in a patient with congenital blindness.

Nonvisual spatial navigation functional magnetic resonance imaging (fMRI) may help clinicians determine memory lateralization in blind individuals with refractory mesial temporal lobe epilepsy (MTLE). We report on an exceptional case of a congenitally blind woman with late-onset left MTLE undergoing presurgical memory fMRI. To activate mesial temporal structures despite the lack of visual memory, the patient was requested to recall familiar routes using nonvisual multisensory and verbal cues. Our findings demonstrate the diagnostic value of a nonvisual fMRI task to lateralize MTLE despite congenital blindness and may therefore contribute to the risk assessment for postsurgical amnesia in rare cases with refractory MTLE and accompanying congenital blindness.

Right uncinate fasciculus supports socioemotional sensitivity in health and neurodegenerative disease.

The uncinate fasciculus (UF) connects fronto-insular and temporal gray matter regions involved in visceral emotional reactivity and semantic appraisal, but the precise role of this tract in socioemotional functioning is not well-understood. Using the Revised-Self Monitoring (RSMS) informant questionnaire, we examined whether fractional anisotropy (FA) in the right UF corresponded to socioemotional sensitivity during face-to-face interactions in 145 individuals (40 healthy older adults [NC], and 105 patients with frontotemporal lobar degeneration [FTLD] syndromes in whom this tract is selectively vulnerable, including 31 behavioral variant frontotemporal dementia [bvFTD], 39 semantic variant primary progressive aphasia [svPPA], and 35 nonfluent variant primary progressive aphasia [nfvPPA]). Voxelwise and region-of-interest-based DWI analyses revealed that FA in the right but not left UF significantly predicted RSMS score in the full sample, and in NC and svPPA subgroups alone. Right UF integrity did not predict RSMS score in the bvFTD group, but gray matter volume in the right orbitofrontal cortex adjacent to the UF was a significant predictor. Our results suggest that better socioemotional sensitivity is specifically supported by right UF white matter, highlighting a key neuro-affective relationship found in both healthy aging and neurologically affected individuals. The finding that poorer socioemotional sensitivity corresponded to right UF damage in svPPA but was more robustly influenced by gray matter atrophy adjacent to the UF in bvFTD may have important implications for endpoint selection in clinical trial design for patients with FTLD.

Diminished preparatory physiological responses in frontotemporal lobar degeneration syndromes.

Researchers typically study physiological responses either after stimulus onset or when the emotional valence of an upcoming stimulus is revealed. Yet, participants may also respond when they are told that an emotional stimulus is about to be presented even without knowing its valence. Increased physiological responding during this time may reflect a 'preparation for action'. The generation of such physiological responses may be supported by frontotemporal regions of the brain that are vulnerable to damage in frontotemporal lobar degeneration. We examined preparatory physiological responses and their structural and functional neural correlate in five frontotemporal lobar degeneration clinical subtypes (behavioural variant frontotemporal dementia, n = 67; semantic variant primary progressive aphasia, n = 35; non-fluent variant primary progressive aphasia, n = 30; corticobasal syndrome, n = 32; progressive supranuclear palsy, n = 30). Comparison groups included patients with Alzheimer's disease (n = 56) and healthy controls (n = 35). Preparatory responses were quantified as cardiac interbeat interval decreases (i.e. heart rate increases) from baseline to an 'instruction period', during which participants were told to watch the upcoming emotional film but not provided the film's valence. Patients' behavioural symptoms (apathy and disinhibition) were also evaluated via a caregiver-reported measure. Compared to healthy controls and Alzheimer's disease, the frontotemporal lobar degeneration group showed significantly smaller preparatory responses. When comparing each frontotemporal lobar degeneration clinical subtype with healthy controls and Alzheimer's disease, significant group differences emerged for behavioural variant frontotemporal dementia and progressive supranuclear palsy. Behavioural analyses revealed that frontotemporal lobar degeneration patients showed greater disinhibition and apathy compared to Alzheimer's disease patients. Further, these group differences in disinhibition (but not apathy) were mediated by patients' smaller preparatory responses. Voxel-based morphometry and resting-state functional MRI analyses revealed that across patients and healthy controls, smaller preparatory responses were associated with smaller volume and lower functional connectivity in a circuit that included the ventromedial prefrontal cortex and cortical and subcortical regions of the salience network. Diminished preparatory physiological responding in frontotemporal lobar degeneration may reflect a lack of preparation for actions that are appropriate for an upcoming situation, such as approaching or withdrawing from emotional stimuli. The ventromedial prefrontal cortex and salience network are critical for evaluating stimuli, thinking about the future, triggering peripheral physiological responses, and processing and interpreting interoceptive signals. Damage to these circuits in frontotemporal lobar degeneration may impair preparatory responses and help explain often-observed clinical symptoms such as disinhibition in these patients.

Anticholinergic and Sedative Medications Are Associated With Neurocognitive Performance of Well Treated People With Human Immunodeficiency Virus.

Background: We previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation. Methods: A medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome. Results: A total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference -0.26 to -0.14, P < .001 and P = .06) and binary (odds ratio [OR], ≥1.67; P < .05) models. Their combined use was associated with deficits in overall neurocognitive functions in both models (mean z-score difference -0.12, P = .002 and OR = 1.54, P = .03). These associations were unchanged in a subgroup analysis of participants without depression (n = 824). Conclusions: Anticholinergic and sedative medications contribute to NCI. Clinicians need to consider these drugs when assessing NCI in PWH.

Sensitivity of the Social Behavior Observer Checklist to Early Symptoms of Patients With Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes. METHODS: Asymptomatic individuals and neurodegenerative disease patients were selected from the multisite ALLFTD cohort study. In a sample of participants with at least one timepoint of SBOCL data, we investigated whether the Disorganized, Reactive, and Insensitive subscales of the SBOCL change as a function of disease stage within and between these syndromes. In a longitudinal subsample with both SBOCL and neuroimaging data, we examined whether change over time on each subscale corresponds to progressive gray matter atrophy. RESULTS: 1082 FTLD mutation carriers and non-carriers were enrolled (282 asymptomatic, 341 behavioral variant frontotemporal dementia, 114 semantic and 95 non-fluent variant primary progressive aphasia, 137 progressive supranuclear palsy, 113 Alzheimer's clinical syndrome). The Disorganized score increased between asymptomatic to very mild (p=0.016, estimate=-1.10, 95%CI=[-1.99, -0.22]), very mild to mild (p=0.013, -1.17, [-2.08, -0.26]), and mild to moderate/severe (p<0.001, -2.00, [-2.55, -1.45]) disease stages in behavioral variant frontotemporal dementia regardless of mutation status. Asymptomatic GRN pathogenic gene variant carriers showed more Reactive behaviors (preoccupation with time: p=0.001, 1.11, [1.06, 1.16]; self-consciousness: p=0.003, 1.77, [1.52, 2.01]) than asymptomatic non-carriers (1.01, [0.98, 1.03]; 1.31, [1.20, 1.41]). Insensitive score increased to a clinically abnormal level in advanced stages of behavioral variant frontotemporal dementia (p=0.003, -0.73, [-1.18, -0.29]). Higher scores on each subscale corresponded with higher caregiver burden (p<0.001). Greater change over time corresponded to greater fronto-subcortical atrophy in the semantic-appraisal and fronto-parietal intrinsically connected networks. DISCUSSION: The SBOCL is sensitive to early symptoms and reflects disease severity, with some evidence for progression across asymptomatic and symptomatic stages of FTLD syndromes; thus it may hold promise for early measurement and monitoring of behavioral symptoms in clinical practice and treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the Social Behavior Observer Checklist is sensitive to early behavioral changes in FTLD pathogenic variants and early symptomatic individuals in a highly educated patient cohort.

Computationally derived anatomic subtypes of behavioral variant frontotemporal dementia show temporal stability and divergent patterns of longitudinal atrophy.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) can be computationally divided into four distinct anatomic subtypes based on patterns of frontotemporal and subcortical atrophy. To more precisely predict disease trajectories of individual patients, the temporal stability of each subtype must be characterized. METHODS: We investigated the longitudinal stability of the four previously identified anatomic subtypes in 72 bvFTD patients. We also applied a voxel-wise mixed effects model to examine subtype differences in atrophy patterns across multiple timepoints. RESULTS: Our results demonstrate the stability of the anatomic subtypes at baseline and over time. While they had common salience network atrophy, each subtype showed distinctive baseline and longitudinal atrophy patterns. DISCUSSION: Recognizing these anatomically heterogeneous subtypes and their different patterns of atrophy progression in early bvFTD will improve disease course prediction in individual patients. Longitudinal volumetric predictions based on these anatomic subtypes may be used as a more accurate endpoint in treatment trials.

Resting functional connectivity in the semantic appraisal network predicts accuracy of emotion identification.

OBJECTIVE: Structural and task-based functional studies associate emotion reading with frontotemporal brain networks, though it remains unclear whether functional connectivity (FC) alone predicts emotion reading ability. The predominantly frontotemporal salience and semantic appraisal (SAN) networks are selectively impacted in neurodegenerative disease syndromes like behavioral-variant frontotemporal dementia (bvFTD) and semantic-variant primary progressive aphasia (svPPA). Accurate emotion identification diminishes in some of these patients, but studies investigating the source of this symptom in patients have predominantly examined structural rather than functional brain changes. Thus, we investigated the impact of altered connectivity on their emotion reading. METHODS: One-hundred-eighty-five participants (26 bvFTD, 21 svPPA, 24 non-fluent variant PPA, 24 progressive supranuclear palsy, 49 Alzheimer's disease, 41 neurologically healthy older controls) underwent task-free fMRI, and completed the Emotion Evaluation subtest of The Awareness of Social Inference Test (TASIT-EET), watching videos and selecting labels for actors' emotions. RESULTS: As expected, patients averaged significantly worse on emotion reading, but with wide inter-individual variability. Across all groups, lower mean FC in the SAN, but not other ICNs, predicted worse TASIT-EET performance. Node-pair analysis revealed that emotion identification was predicted by FC between 1) right anterior temporal lobe (RaTL) and right anterior orbitofrontal (OFC), 2) RaTL and right posterior OFC, and 3) left basolateral amygdala and left posterior OFC. CONCLUSION: Emotion reading test performance predicts FC in specific SAN regions mediating socioemotional semantics, personalized evaluations, and salience-driven attention, highlighting the value of emotion testing in clinical and research settings to index neural circuit dysfunction in patients with neurodegeneration and other neurologic disorders.

Social Behavior Observer Checklist: Patterns of Spontaneous Behaviors Differentiate Patients With Neurodegenerative Disease From Healthy Older Adults.

Neurodegenerative disease syndromes often affect personality and interpersonal behavior in addition to cognition, but there are few structured observational measures of altered social demeanor validated for this population. We developed the Social Behavior Observer Checklist (SBOCL), a 3-min checklist tool, to facilitate identification of patterns of interpersonal behavior that are diagnostically relevant to different neurodegenerative syndromes. Research assistants without formal clinical training in dementia used the SBOCL to describe participants' behavior, including 125 healthy older adults and 357 patients diagnosed with one of five neurodegenerative disease syndromes: 135 behavioral variant frontotemporal dementia (bvFTD), 57 semantic variant primary progressive aphasia (svPPA), 51 non-fluent variant PPA (nfvPPA), 65 progressive supranuclear palsy (PSP), and 49 amyloid-positive Alzheimer's disease syndrome (AD), all of whom had concurrent 3D T1 MRI scans available for voxel-based morphometry analysis. SBOCL item interrater reliability ranged from moderate to very high, and score elevations showed syndrome-specific patterns. Subscale scores derived from a degree*frequency product of the items had excellent positive predictive value for identifying patients. Specifically, scores above 2 on the Disorganized subscale, and above 3 on the Reactive and Insensitive subscales, were not seen in any healthy controls but were found in many patients with bvFTD, svPPA, nfvPPA, PSP, and AD syndromes. Both the Disorganized and Reactive subscale scores showed significant linear relationships with frontal and temporal gray matter volume that generalized across syndromes. With these initial psychometric characteristics, the SBOCL may be a useful measure to help non-experts identify patients who are appropriate for additional specialized dementia evaluation, without adding time to patient encounters or requiring the presence of an informant.

Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. METHODS: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. RESULTS: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. INTERPRETATION: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

Revised Self-Monitoring Scale: A potential endpoint for frontotemporal dementia clinical trials.

OBJECTIVE: To investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD). METHODS: We investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation-, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation-). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation-, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy. RESULTS: RSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F 4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] -1.90 to -0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI -0.30 to -0.11). CONCLUSIONS: The RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

Divergent patterns of loss of interpersonal warmth in frontotemporal dementia syndromes are predicted by altered intrinsic network connectivity.

Loss of warmth is well-documented in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) at a group level, and has been linked to salience (SN) and semantic-appraisal (SAN) network atrophy. However, clinical observations of individual patients show much greater heterogeneity, thus measuring this clinical variability and identifying the underlying neurologic mechanisms is a critical step for understanding the symptom profile of any one patient. We used reliable change indexes with premorbid and current informant-based evaluations to characterize patterns of change on the warmth subscale of the Interpersonal Adjective Scale (IAS) questionnaire in 132 patients (21 bvFTD, 19 svPPA, 22 nonfluent variant primary progressive aphasia [nfvPPA], 37 Alzheimer's disease [AD]) and 33 healthy older adults. We investigated whether individual differences in warmth change were reflected in SN or SAN functional connectivity, or structural volume of individual brain regions in these two networks. Though one subset of patients showed significant drop in warmth to abnormally low levels (bvFTD: 38%; svPPA: 21%; nfvPPA: 5%; AD: 11%), a second subset significantly dropped but remained within the clinically normal range (bvFTD: 33%; svPPA: 21%; nfvPPA: 9%; AD: 5%), and a third subset did not drop and stayed in the clinically normal range (bvFTD: 29%; svPPA: 58%; nfvPPA: 86%; AD: 84%). Furthermore, interpersonal warmth score was strongly predicted by SN functional connectivity (p < .01), but not by SAN functional connectivity or by structural volume in these networks. Our results extend earlier group-level findings by showing wide individual variability in degree of disease-related reduction of interpersonal warmth and SN functional connectivity in bvFTD and svPPA, and highlight new approaches to revealing how brain connectivity predicts behavior on an individual patient level. Our findings suggest that measures of interpersonal warmth can provide important clinical information about changes in underlying brain networks, and help clinicians and clinical researchers better identify which bvFTD and svPPA patients are at greater risk for interpersonal disruption.

Individual differences in socioemotional sensitivity are an index of salience network function.

Connectivity in intrinsically connected networks (ICNs) may predict individual differences in cognition and behavior. The drastic alterations in socioemotional awareness of patients with behavioral variant frontotemporal dementia (bvFTD) are presumed to arise from changes in one such ICN, the salience network (SN). We examined how individual differences in SN connectivity are reflected in overt social behavior in healthy individuals and patients, both to provide neuroscientific insight into this key brain-behavior relationship, and to provide a practical tool to diagnose patients with early bvFTD. We measured SN functional connectivity and socioemotional sensitivity in 65 healthy older adults and 103 patients in the earliest stage [Clinical Dementia Rating (CDR) Scale score ≤1] of five neurodegenerative diseases [14 bvFTD, 29 Alzheimer's disease (AD), 20 progressive supranuclear palsy (PSP), 21 semantic variant primary progressive aphasia (svPPA), and 19 non-fluent variant primary progressive aphasia (nfvPPA)]. All participants underwent resting-state functional imaging and an informant described their responsiveness to subtle emotional expressions using the Revised Self-Monitoring Scale (RSMS). Higher functional connectivity in the SN, predominantly between the right anterior insula (AI) and both "hub" cortical and "interoceptive" subcortical nodes, predicted socioemotional sensitivity among healthy individuals, showing that socioemotional sensitivity is a behavioral marker of SN function, and particularly of right AI functional connectivity. The continuity of this relationship in both healthy and neurologically affected individuals highlights the role of socioemotional sensitivity as an early diagnostic marker of SN connectivity. Clinically, this is particularly important for identification of patients in the earliest stage of bvFTD, where the SN is selectively vulnerable.

Mesial temporal lobe epilepsy diminishes functional connectivity during emotion perception.

OBJECTIVES: Unilateral mesial temporal lobe epilepsy (MTLE) has been associated with impaired recognition of emotional facial expressions. Correspondingly, imaging studies showed decreased activity of the amygdala and cortical face processing regions in response to emotional faces. However, functional connectivity among regions involved in emotion perception has not been studied so far. METHODS: To address this, we examined intrinsic functional connectivity (FC) modulated by the perception of dynamic fearful faces among the amygdala and limbic, frontal, temporal and brainstem regions. Regions of interest were identified in an activation analysis by presenting a block-design with dynamic fearful faces and dynamic landscapes to 15 healthy individuals. This led to 10 predominately right-hemispheric regions. Functional connectivity between these regions during the perception of fearful faces was examined in drug-refractory patients with left- (n=16) or right-sided (n=17) MTLE, epilepsy patients with extratemporal seizure onset (n=15) and a second group of 15 healthy controls. RESULTS: Healthy controls showed a widespread functional network modulated by the perception of fearful faces that encompassed bilateral amygdalae, limbic, cortical, subcortical and brainstem regions. In patients with left MTLE, a downsized network of frontal and temporal regions centered on the right amygdala was present. Patients with right MTLE showed almost no significant functional connectivity. A maintained network in the epilepsy control group indicates that findings in mesial temporal lobe epilepsy could not be explained by clinical factors such as seizures and antiepileptic medication. CONCLUSION: Functional networks underlying facial emotion perception are considerably changed in left and right MTLE. Alterations are present for both hemispheres in either MTLE group, but are more pronounced in right MTLE. Disruption of the functional network architecture possibly contributes to deficits in facial emotion recognition frequently reported in MTLE.