Human Anterior Insular Cortex Encodes Multiple Electrophysiological Representations of Anxiety-Related Behaviors.

Anxiety is a common symptom across psychiatric disorders, but the neurophysiological underpinnings of these symptoms remain unclear. This knowledge gap has prevented the development of circuit-based treatments that can target the neural substrates underlying anxiety. Here, we conducted an electrophysiological mapping study to identify neurophysiological activity associated with self-reported state anxiety in 17 subjects implanted with intracranial electrodes for seizure localization. Participants had baseline anxiety traits ranging from minimal to severe. Subjects volunteered to participate in an anxiety induction task in which they were temporarily exposed to the threat of unpredictable shock during intracranial recordings. We found that anterior insular beta oscillatory activity was selectively elevated during epochs when unpredictable aversive stimuli were being delivered, and this enhancement in insular beta was correlated with increases in self-reported anxiety. Beta oscillatory activity within the frontoinsular region was also evoked selectively by cues-predictive of threat, but not safety cues. Anterior insular gamma responses were less selective than gamma, strongly evoked by aversive stimuli and had weaker responses to salient threat and safety cues. On longer timescales, this gamma signal also correlated with increased skin conductance, a measure of autonomic state. Lastly, we found that direct electrical stimulation of the anterior insular cortex in a subset of subjects elicited self-reported increases in anxiety that were accompanied by enhanced frontoinsular beta oscillations. Together, these findings suggest that electrophysiologic representations of anxiety- related states and behaviors exist within anterior insular cortex. The findings also suggest the potential of reducing anterior insular beta activity as a therapeutic target for refractory anxiety-spectrum disorders.

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n = 19) compared to controls (n = 23). Lastly, we explored whether genes with significant C9orf72 imaging transcriptomic correlations (i.e., "C9orf72 imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others. Conclusion: Considered together, we identified a network of C9orf72 associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Diminished baseline autonomic outflow in semantic dementia relates to left-lateralized insula atrophy.

In semantic dementia (SD), asymmetric degeneration of the anterior temporal lobes is associated with loss of semantic knowledge and alterations in socioemotional behavior. There are two clinical variants of SD: semantic variant primary progressive aphasia (svPPA), which is characterized by predominant atrophy in the anterior temporal lobe and insula in the left hemisphere, and semantic behavioral variant frontotemporal dementia (sbvFTD), which is characterized by predominant atrophy in those structures in the right hemisphere. Previous studies of behavioral variant frontotemporal dementia, an associated clinical syndrome that targets the frontal lobes and anterior insula, have found impairments in baseline autonomic nervous system activity that correlate with left-lateralized frontotemporal atrophy patterns and disruptions in socioemotional functioning. Here, we evaluated whether there are similar impairments in resting autonomic nervous system activity in SD that also reflect left-lateralized atrophy and relate to diminished affiliative behavior. A total of 82 participants including 33 people with SD (20 svPPA and 13 sbvFTD) and 49 healthy older controls completed a laboratory-based assessment of respiratory sinus arrhythmia (RSA; a parasympathetic measure) and skin conductance level (SCL; a sympathetic measure) during a two-minute resting baseline period. Participants also underwent structural magnetic resonance imaging, and informants rated their current affiliative behavior on the Interpersonal Adjective Scale. Results indicated that baseline RSA and SCL were lower in SD than in healthy controls, with significant impairments present in both svPPA and sbvFTD. Voxel-based morphometry analyses revealed left-greater-than-right atrophy related to diminished parasympathetic and sympathetic outflow in SD. While left-lateralized atrophy in the mid-to-posterior insula correlated with lower RSA, left-lateralized atrophy in the ventral anterior insula correlated with lower SCL. In SD, lower baseline RSA, but not lower SCL, was associated with lower gregariousness/extraversion. Neither autonomic measure related to warmth/agreeableness, however. Through the assessment of baseline autonomic nervous system physiology, the present study contributes to expanding conceptualizations of the biological basis of socioemotional alterations in svPPA and sbvFTD.

Medial Temporal Lobe Tau Aggregation Relates to Divergent Cognitive and Emotional Empathy Abilities in Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease (AD), the gradual accumulation of amyloid-ß (Aß) and tau proteins may underlie alterations in empathy. OBJECTIVE: To assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others' perspectives) and emotional empathy (the ability to experience others' feelings) in AD. METHODS: Older adults (n = 105) completed molecular Aß positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aß positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer's type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aß negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aß positive and negative participants. The Aß positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. RESULTS: Aß positive participants had lower perspective-taking and higher empathic concern than Aß negative healthy controls. Medial temporal tau aggregation in the Aß positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. CONCLUSIONS: Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.

Authenticity and brain health: a values-based perspective and cultural education approach.

This perspective paper discusses the concept of authenticity in relation to brain health and neurodegenerative diseases. We define authenticity as being true to oneself and consider it a social value of relevance to neuroscientists, clinicians, and caregivers. From a biological perspective, behaviors that can be interpreted as expressions of authenticity are produced by distributed brain networks. By understanding it as a dynamic process, we argue that harnessing authenticity across the lifespan can be protective by promoting resilience. We discuss the idea of authentic aging, which appreciates the complexity of human life within the world and can enhance positive views of later life. Authenticity is additionally applicable to caring for people with neurodegenerative diseases, both when understanding the behavior of people with dementia and the response of caregivers. Tailoring care to an individual's personality and strengths may improve their brain health. Finally, we describe an interdisciplinary learning event, themed around masks, designed to engage participants in identifying authenticity in their own work. For scientists, care professionals, and caregivers, reflecting upon authenticity can aid understanding of the person with dementia and therefore improve care.

Neuropsychiatric symptoms and imbalance of atrophy in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia is characterized by heterogeneous frontal, insular, and anterior temporal atrophy patterns that vary along left-right and dorso-ventral axes. Little is known about how these structural imbalances impact clinical symptomatology. The goal of this study was to assess the frequency of frontotemporal asymmetry (right- or left-lateralization) and dorsality (ventral or dorsal predominance of atrophy) and to investigate their clinical correlates. Neuropsychiatric symptoms and structural images were analyzed for 250 patients with behavioral variant frontotemporal dementia. Frontotemporal atrophy was most often symmetric while left-lateralized (9%) and right-lateralized (17%) atrophy were present in a minority of patients. Atrophy was more often ventral (32%) than dorsal (3%) predominant. Patients with right-lateralized atrophy were characterized by higher severity of abnormal eating behavior and hallucinations compared to those with left-lateralized atrophy. Subsequent analyses clarified that eating behavior was associated with right atrophy to a greater extent than a lack of left atrophy, and hallucinations were driven mainly by right atrophy. Dorsality analyses showed that anxiety, euphoria, and disinhibition correlated with ventral-predominant atrophy. Agitation, irritability, and depression showed greater severity with a lack of regional atrophy, including in dorsal regions. Aberrant motor behavior and apathy were not explained by asymmetry or dorsality. This study provides additional insight into how anatomical heterogeneity influences the clinical presentation of patients with behavioral variant frontotemporal dementia. Behavioral symptoms can be associated not only with the presence or absence of focal atrophy, but also with right/left or dorsal/ventral imbalance of gray matter volume.

C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.

Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., 'C9orf72 gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. Conclusions: Considered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.

OBJECTIVE: Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers. METHODS: We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles. RESULTS: Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline. INTERPRETATION: Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy.

BACKGROUND: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. METHODS: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau (n = 8), and healthy non-carrier controls (n = 8). Primary findings from our scRNA-seq analyses were confirmed and extended via flow cytometry, droplet digital (dd)PCR, and secondary analyses of publicly available transcriptomics datasets. RESULTS: Analysis of ~ 181,000 individual PBMC transcriptomes demonstrated striking differential expression in monocytes and natural killer (NK) cells in MAPT pathogenic variant carriers. In particular, we observed a marked reduction in the expression of CX3CR1-the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models-in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia but with unclear function in peripheral monocytes. We confirmed the reduction in nonclassical monocytes by flow cytometry and the differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using ddPCR. CONCLUSIONS: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

Higher emotional granularity relates to greater inferior frontal cortex cortical thickness in healthy, older adults.

Individuals with high emotional granularity make fine-grained distinctions between their emotional experiences. To have greater emotional granularity, one must acquire rich conceptual knowledge of emotions and use this knowledge in a controlled and nuanced way. In the brain, the neural correlates of emotional granularity are not well understood. While the anterior temporal lobes, angular gyri, and connected systems represent conceptual knowledge of emotions, inhibitory networks with hubs in the inferior frontal cortex (i.e., posterior inferior frontal gyrus, lateral orbitofrontal cortex, and dorsal anterior insula) guide the selection of this knowledge during emotions. We investigated the structural neuroanatomical correlates of emotional granularity in 58 healthy, older adults (ages 62-84 years), who have had a lifetime to accrue and deploy their conceptual knowledge of emotions. Participants reported on their daily experience of 13 emotions for 8 weeks and underwent structural magnetic resonance imaging. We computed intraclass correlation coefficients across daily emotional experience surveys (45 surveys on average per participant) to quantify each participant's overall emotional granularity. Surface-based morphometry analyses revealed higher overall emotional granularity related to greater cortical thickness in inferior frontal cortex (pFWE < 0.05) in bilateral clusters in the lateral orbitofrontal cortex and extending into the left dorsal anterior insula. Overall emotional granularity was not associated with cortical thickness in the anterior temporal lobes or angular gyri. These findings suggest individual differences in emotional granularity relate to variability in the structural neuroanatomy of the inferior frontal cortex, an area that supports the controlled selection of conceptual knowledge during emotional experiences.

Expressive Prosody in Patients With Focal Anterior Temporal Neurodegeneration.

BACKGROUND AND OBJECTIVES: Progressive focal anterior temporal lobe (ATL) neurodegeneration has been historically called semantic dementia. More recently, semantic variant primary progressive aphasia (svPPA) and semantic behavioral variant frontotemporal dementia (sbvFTD) have been linked with predominant left and right ATL neurodegeneration, respectively. Nonetheless, clinical tools for an accurate diagnosis of sbvFTD are still lacking. Expressive prosody refers to the modulation of pitch, loudness, tempo, and quality of voice used to convey emotional and linguistic information and has been linked to bilateral but right-predominant frontotemporal functioning. Changes in expressive prosody can be detected with semiautomated methods and could represent a useful diagnostic marker of socioemotional functioning in sbvFTD. METHODS: Participants underwent a comprehensive neuropsychological and language evaluation and a 3T MRI at the University of California San Francisco. Each participant provided a verbal description of the picnic scene from the Western Aphasia Battery. The fundamental frequency (f0) range, an acoustic measure of pitch variability, was extracted for each participant. We compared the f0 range between groups and investigated associations with an informant-rated measure of empathy, a facial emotion labeling task, and gray matter (GM) volumes using voxel-based morphometry. RESULTS: Twenty-eight patients with svPPA, 18 with sbvFTD, and 18 healthy controls (HCs) were included. f0 range was significantly different across groups: patients with sbvFTD showed reduced f0 range in comparison with both patients with svPPA (mean difference of -1.4 ± 2.4 semitones; 95% CI -2.4 to -0.4]; p < 0.005) and HCs (mean difference of -1.9 ± 3.0 semitones; 95% CI -3.0 to -0.7]; p < 0.001). A higher f0 range was correlated with a greater informant-rated empathy (r = 0.355; p ≤ 0.05), but not facial emotion labeling. Finally, the lower f0 range was correlated with lower GM volume in the right superior temporal gyrus, encompassing anterior and posterior portions (p < 0.05 FWE cluster corrected). DISCUSSION: Expressive prosody may be a useful clinical marker of sbvFTD. Reduced empathy is a core symptom in sbvFTD; the present results extend this to prosody, a core component of social interaction, at the intersection of speech and emotion. They also inform the long-standing debate on the lateralization of expressive prosody in the brain, highlighting the critical role of the right superior temporal lobe.

Behavioural subphenotypes and their anatomic correlates in neurodegenerative disease.

Patients with neurodegenerative disorders experience a range of neuropsychiatric symptoms. The neural correlates have been explored for many individual symptoms, such as apathy and disinhibition. Atrophy patterns have also been associated with broadly recognized syndromes that bring together multiple symptoms, such as the behavioural variant of frontotemporal dementia. There is substantial heterogeneity of symptoms, with partial overlap of behaviour and affected neuroanatomy across and within dementia subtypes. It is not well established if there are anatomically distinct behavioural subphenotypes in neurodegenerative disease. The objective of this study was to identify shared behavioural profiles in frontotemporal dementia-spectrum and Alzheimer's disease-related syndromes. Additionally, we sought to determine the underlying neural correlates of these symptom clusters. Two hundred and eighty-one patients diagnosed with one of seven different dementia syndromes, in addition to healthy controls and individuals with mild cognitive impairment, completed a 109-item assessment capturing the severity of a range of clinical behaviours. A principal component analysis captured distinct clusters of related behaviours. Voxel-based morphometry analyses were used to identify regions of volume loss associated with each component. Seven components were identified and interpreted as capturing the following behaviours: Component 1-emotional bluntness, 2-emotional lability and disinhibition, 3-neuroticism, 4-rigidity and impatience, 5-indiscriminate consumption, 6-psychosis and 7-Geschwind syndrome-related behaviours. Correlations with structural brain volume revealed distinct neuroanatomical patterns associated with each component, including after controlling for diagnosis, suggesting that localized neurodegeneration can lead to the development of behavioural symptom clusters across various dementia syndromes.

Increasing empathic concern relates to salience network hyperconnectivity in cognitively healthy older adults with elevated amyloid-ß burden.

Enhanced emotional empathy, the ability to share others' affective experiences, can be a feature of Alzheimer's disease (AD), but whether emotional empathy increases in the preclinical phase of the disease is unknown. We measured emotional empathy over time (range = 0 - 7.3 years, mean = 2.4 years) in 86 older adults during a period in which they were cognitively healthy, functionally normal, and free of dementia symptoms. For each participant, we computed longitudinal trajectories for empathic concern (i.e., an other-oriented form of emotional empathy that promotes prosocial actions) and emotional contagion (i.e., a self-focused form of emotional empathy often accompanied by feelings of distress) from informant ratings of participants' empathy on the Interpersonal Reactivity Index. Amyloid-ß (Aß) positron emission tomography (PET) scans were used to classify participants as either Aß positive (Aß+, n = 23) or negative (Aß-, n = 63) based on Aß-PET cortical binding. Participants also underwent structural and task-free functional magnetic resonance imaging approximately two years on average after their last empathy assessment, at which time most participants remained cognitively healthy. Results indicated that empathic concern, but not emotional contagion, increased more over time in Aß+ participants than in Aß- participants despite no initial group difference at the first measurement. Higher connectivity between certain salience network node-pairs (i.e., pregenual anterior cingulate cortex and periaqueductal gray) predicted longitudinal increases in empathic concern in the Aß+ group but not in the Aß- group. The Aß+ participants also had higher overall salience network connectivity than Aß- participants despite no differences in gray matter volume. These results suggest gains in empathic concern may be a very early feature of AD pathophysiology that relates to hyperconnectivity in the salience network, a system that supports emotion generation and interoception. A better understanding of emotional empathy trajectories in the early stages of AD pathophysiology will broaden the lens on preclinical AD changes and help clinicians to identify older adults who should be screened for AD biomarkers.

Radiogenomics of C9orf72 Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment.

Hexanucleotide repeat expansion (HRE) within C9orf72 is the most common genetic cause of frontotemporal dementia (FTD). Thalamic atrophy occurs in both sporadic and familial FTD but is thought to distinctly affect HRE carriers. Separately, emerging evidence suggests widespread derepression of transposable elements (TEs) in the brain in several neurodegenerative diseases, including C9orf72 HRE-mediated FTD (C9-FTD). Whether TE activation can be measured in peripheral blood and how the reduction in peripheral C9orf72 expression observed in HRE carriers relates to atrophy and clinical impairment remain unknown. We used FreeSurfer software to assess the effects of C9orf72 HRE and clinical diagnosis (n = 78 individuals, male and female) on atrophy of thalamic nuclei. We also generated a novel, human, whole-blood RNA-sequencing dataset to determine the relationships among peripheral C9orf72 expression, TE activation, thalamic atrophy, and clinical severity (n = 114 individuals, male and female). We confirmed global thalamic atrophy and reduced C9orf72 expression in HRE carriers. Moreover, we identified disproportionate atrophy of the right mediodorsal lateral nucleus in HRE carriers and showed that C9orf72 expression associated with clinical severity, independent of thalamic atrophy. Strikingly, we found global peripheral activation of TEs, including the human endogenous LINE-1 element L1HS L1HS levels were associated with atrophy of multiple pulvinar nuclei, a thalamic region implicated in C9-FTD. Integration of peripheral transcriptomic and neuroimaging data from human HRE carriers revealed atrophy of specific thalamic nuclei, demonstrated that C9orf72 levels relate to clinical severity, and identified marked derepression of TEs, including L1HS, which predicted atrophy of FTD-relevant thalamic nuclei.SIGNIFICANCE STATEMENT Pathogenic repeat expansion in C9orf72 is the most frequent genetic cause of FTD and amyotrophic lateral sclerosis (ALS; C9-FTD/ALS). The clinical, neuroimaging, and pathologic features of C9-FTD/ALS are well characterized, whereas the intersections of transcriptomic dysregulation and brain structure remain largely unexplored. Herein, we used a novel radiogenomic approach to examine the relationship between peripheral blood transcriptomics and thalamic atrophy, a neuroimaging feature disproportionately impacted in C9-FTD/ALS. We confirmed reduction of C9orf72 in blood and found broad dysregulation of transposable elements-genetic elements typically repressed in the human genome-in symptomatic C9orf72 expansion carriers, which associated with atrophy of thalamic nuclei relevant to FTD. C9orf72 expression was also associated with clinical severity, suggesting that peripheral C9orf72 levels capture disease-relevant information.

Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits.

BACKGROUND: Elevated blood pressure (BP) variability is predictive of increased risk for stroke, cerebrovascular disease, and other vascular brain injuries, independent of traditionally studied average BP levels. However, no studies to date have evaluated whether BP variability is related to diminished cerebrovascular reactivity, which may represent an early marker of cerebrovascular dysfunction presaging vascular brain injury. METHODS: The present study investigated BP variability and cerebrovascular reactivity in a sample of 41 community-dwelling older adults (mean age 69.6 [SD 8.7] years) without a history of dementia or stroke. Short-term BP variability was determined from BP measurements collected continuously during a 5-minute resting period followed by cerebrovascular reactivity during 5-minute hypocapnia and hypercapnia challenge induced by visually guided breathing conditions. Cerebrovascular reactivity was quantified as percent change in cerebral perfusion by pseudo-continuous arterial spin labeling (pCASL)-MRI per unit change in end-tidal CO2. RESULTS: Elevated systolic BP variability was related to lower whole brain cerebrovascular reactivity during hypocapnia (ß = -0.43 [95% CI -0.73, -0.12]; P = 0.008; adjusted R2 =.11) and hypercapnia (ß = -0.42 [95% CI -0.77, -0.06]; P = 0.02; adjusted R2 = 0.19). CONCLUSIONS: Findings add to prior work linking BP variability and cerebrovascular disease burden and suggest BP variability may also be related to prodromal markers of cerebrovascular dysfunction and disease, with potential therapeutic implications.

Dynamic autonomic nervous system states arise during emotions and manifest in basal physiology.

The outflow of the autonomic nervous system (ANS) is continuous and dynamic, but its functional organization is not well understood. Whether ANS patterns accompany emotions, or arise in basal physiology, remain unsettled questions in the field. Here, we searched for brief ANS patterns amidst continuous, multichannel physiological recordings in 45 healthy older adults. Participants completed an emotional reactivity task in which they viewed video clips that elicited a target emotion (awe, sadness, amusement, disgust, or nurturant love); each video clip was preceded by a pre-trial baseline period and followed by a post-trial recovery period. Participants also sat quietly for a separate 2-min resting period to assess basal physiology. Using principal components analysis and unsupervised clustering algorithms to reduce the second-by-second physiological data during the emotional reactivity task, we uncovered five ANS states. Each ANS state was characterized by a unique constellation of patterned physiological changes that differentiated among the trials of the emotional reactivity task. These ANS states emerged and dissipated over time, with each instance lasting several seconds on average. ANS states with similar structures were also detectable in the resting period but were intermittent and of smaller magnitude. Our results offer new insights into the functional organization of the ANS. By assembling short-lived, patterned changes, the ANS is equipped to generate a wide range of physiological states that accompany emotions and that contribute to the architecture of basal physiology.

The neuroscience of respect: insights from cross-cultural perspectives.

Cultural values such as respect influence cognition, emotion, and behavior by modulating brain functioning. This mini-review discusses the cultural differences of respect as an essential human value, and the neural underpinnings accompanying them. Although neuroscientific studies are limited, we outline potential brain structures and networks that contribute to respect and use clinical examples to illustrate how behavior changes when these neural systems fail. A better understanding of the neuroanatomical basis of respect and its neural manifestations across cultures will help to advance current conceptualizations of the biology of human values.

Visual and social differences in dyslexia: deep phenotyping of four cases with spared phonology.

Diagnostic criteria for dyslexia describe specific reading difficulties, and single-deficit models, including the phonological deficit theory, have prevailed. Children seeking diagnosis, however, do not always show phonological deficits, and may present with strengths and challenges beyond reading. Through extensive neurological, neuropsychological, and academic evaluation, we describe four children with visuospatial, socio-emotional, and attention impairments and spared phonology, alongside long-standing reading difficulties. Diffusion tensor imaging revealed white matter alterations in inferior longitudinal, uncinate, and superior longitudinal fasciculi versus neurotypical children. Findings emphasize that difficulties may extend beyond reading in dyslexia and underscore the value of deep phenotyping in learning disabilities.

Blood pressure variability and plasma Alzheimer's disease biomarkers in older adults.

Blood pressure variability is an emerging risk factor for Alzheimer's disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer's disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with plasma Alzheimer's disease markers have not been investigated. In this cross-sectional study of 54 community-dwelling older adults (aged 55-88, mean age 69.9 [8.2 SD]), elevated blood pressure variability over 5 min was associated with lower levels of plasma Aß1-42 (standardized ß = - 0.36 [95% CI - 0.61, - 0.12]; p = 0.005; adjusted R2 = 0.28) and Aß1-42: Aß1-40 ratio (ß = - 0.49 [95% CI - 0.71, - 0.22]; p < 0.001; adjusted R2 = 0.28), and higher levels of total tau (ß = 0.27 [95% CI 0.01, 0.54]; p = 0.04; adjusted R2 = 0.19) and Ptau181:Aß1-42 ratio (ß = 0.26 [95% CI 0.02, 0.51]; p = 0.04; adjusted R2 = 0.22). Findings suggest higher blood pressure variability is linked to plasma biomarkers of increased Alzheimer's disease pathophysiology.

Enhanced positive emotional reactivity in frontotemporal dementia reflects left-lateralized atrophy in the temporal and frontal lobes.

In frontotemporal dementia (FTD), left-lateralized atrophy patterns have been associated with elevations in certain positive emotions. Here, we investigated whether positive emotional reactivity was enhanced in semantic variant primary progressive aphasia (svPPA), an FTD syndrome that targets the left anterior temporal lobe. Sixty-one participants (16 people with svPPA, 24 people with behavioral variant FTD, and 21 healthy controls) viewed six 90-sec trials that were comprised of a series of photographs; each trial was designed to elicit a specific positive emotion, negative emotion, or no emotion. Participants rated their positive emotional experience after each trial, and their smiling behavior was coded with the Facial Action Coding System. Results indicated that positive emotional experience and smiling were elevated in svPPA in response to numerous affective and non-affective stimuli. Voxel-based morphometry analyses revealed that greater positive emotional experience and greater smiling in the patients were both associated with smaller gray matter volume in the left superior temporal gyrus (pFWE < .05), among other left-lateralized frontotemporal regions. Whereas enhanced positive emotional experience related to atrophy in middle superior temporal gyrus and structures that promote cognitive control and emotion regulation, heightened smiling related to atrophy in posterior superior temporal gyrus and structures that support motor control. Our results suggest positive emotional reactivity is elevated in svPPA and offer new evidence that atrophy in left-lateralized emotion-relevant systems relates to enhanced positive emotions in FTD.