44 results on '"Sturm, Virginia E"'
Search Results
2. Elevated unanticipated acoustic startle reactivity in dyslexia.
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Palser, Eleanor R., Veziris, Christina R., Morris, Nathaniel A., Roy, Ashlin R. K., Watson‐Pereira, Christa, Holley, Sarah R., Miller, Bruce L., Gorno‐Tempini, Maria Luisa, and Sturm, Virginia E.
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PEOPLE with dyslexia ,READING disability ,CHILDREN with dyslexia ,AUTONOMIC nervous system ,GALVANIC skin response - Abstract
People with dyslexia, a neurodevelopmental disorder of reading, are highly attuned to the emotional world. Compared with their typically developing peers, children with dyslexia exhibit greater autonomic nervous system reactivity and facial behaviour to emotion‐ and empathy‐inducing film clips. Affective symptoms, such as anxiety, are also more common in children with dyslexia than in those without. Here, we investigated whether the startle response, an automatic reaction that lies at the interface of emotion and reflex, is elevated in dyslexia. We measured facial behaviour, electrodermal reactivity (a sympathetic nervous system measure) and emotional experience in response to a 100 ms, 105 dB unanticipated acoustic startle task in 30 children with dyslexia and 20 comparison children without dyslexia (aged 7–13) who were matched on age, sex and nonverbal reasoning. Our results indicated that the children with dyslexia had greater total facial behaviour and electrodermal reactivity to the acoustic startle task than the children without dyslexia. Across the sample, greater electrodermal reactivity during the startle predicted greater parent‐reported anxiety symptoms. These findings contribute to an emerging picture of heightened emotional reactivity in dyslexia and suggest accentuated sympathetic nervous system reactivity may contribute to the elevated anxiety that is often seen in this population. [ABSTRACT FROM AUTHOR]
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- 2024
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3. C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types.
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Broce, Iris J., Sirkis, Daniel W., Nillo, Ryan M., Bonham, Luke W., Lee, Suzee E., Miller, Bruce L., Castruita, Patricia A., Sturm, Virginia E., Sugrue, Leo S., Desikan, Rahul S., and Yokoyama, Jennifer S.
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BRAIN cortical thickness ,GENE regulatory networks ,MEDIUM spiny neurons ,DNA repair ,GENE expression ,COAT proteins (Viruses) ,AUTOPHAGY ,GENE ontology - Abstract
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 coexpressed 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. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Medial Temporal Lobe Tau Aggregation Relates to Divergent Cognitive and Emotional Empathy Abilities in Alzheimer's Disease.
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Chow, Tiffany E., Veziris, Christina R., Mundada, Nidhi, Martinez-Arroyo, Alexis I., Kramer, Joel H., Miller, Bruce L., Rosen, Howard J., Gorno-Tempini, Maria Luisa, Rankin, Katherine P., Seeley, William W., Rabinovici, Gil D., La Joie, Renaud, and Sturm, Virginia E.
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PERSPECTIVE taking ,ALZHEIMER'S disease ,TEMPORAL lobe ,TAU proteins ,INTERPERSONAL Reactivity Index ,EMPATHY - Abstract
Background: In Alzheimer's disease (AD), the gradual accumulation of amyloid-β (Aβ) 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 Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ 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 Aβ 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 Aβ positive and negative participants. The Aβ 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: Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ 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. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Neuropsychiatric symptoms and imbalance of atrophy in behavioral variant frontotemporal dementia.
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Sokołowski, Andrzej, Roy, Ashlin R. K., Goh, Sheng‐Yang M., Hardy, Emily G., Datta, Samir, Cobigo, Yann, Brown, Jesse A., Spina, Salvatore, Grinberg, Lea, Kramer, Joel, Rankin, Katherine P., Seeley, William W., Sturm, Virginia E., Rosen, Howard J., Miller, Bruce L., and Perry, David C.
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FRONTOTEMPORAL dementia ,ATROPHY ,APATHY ,FOOD habits ,GRAY matter (Nerve tissue) ,SYMPTOMS ,FRONTOTEMPORAL lobar degeneration - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Network Connectivity Alterations across the MAPT Mutation Clinical Spectrum.
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Zhang, Liwen, Flagan, Taru M., Häkkinen, Suvi, Chu, Stephanie A., Brown, Jesse A., Lee, Alex J., Pasquini, Lorenzo, Mandelli, Maria Luisa, Gorno‐Tempini, Maria Luisa, Sturm, Virginia E., Yokoyama, Jennifer S., Appleby, Brian S., Cobigo, Yann, Dickerson, Bradford C., Domoto‐Reilly, Kimiko, Geschwind, Daniel H., Ghoshal, Nupur, Graff‐Radford, Neill R., Grossman, Murray, and Hsiung, Ging‐Yuek Robin
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PROGRESSIVE supranuclear palsy ,FUNCTIONAL magnetic resonance imaging ,FRONTOTEMPORAL lobar degeneration ,EARLY diagnosis ,GRAY matter (Nerve tissue) ,VERBAL memory - Abstract
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 [ABSTRACT FROM AUTHOR]
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- 2023
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7. Higher emotional granularity relates to greater inferior frontal cortex cortical thickness in healthy, older adults.
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Lukic, Sladjana, Kosik, Eena L., Roy, Ashlin R. K., Morris, Nathaniel, Sible, Isabel J., Datta, Samir, Chow, Tiffany, Veziris, Christina R., Holley, Sarah R., Kramer, Joel H., Miller, Bruce L., Keltner, Dacher, Gorno-Tempini, Maria Luisa, and Sturm, Virginia E.
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FRONTAL lobe ,EMOTIONAL experience ,OLDER people ,PREFRONTAL cortex ,INTRACLASS correlation ,MAGNETIC resonance imaging - Abstract
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 (p
FWE < 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. [ABSTRACT FROM AUTHOR]- Published
- 2023
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8. Authenticity and brain health: a values-based perspective and cultural education approach.
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Stirland, Lucy E., Ayele, Biniyam A., Correa-Lopera, Catherine, and Sturm, Virginia E.
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CULTURAL education ,LARGE-scale brain networks ,NEURODEGENERATION ,SOCIAL values ,CAREGIVERS - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy.
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Sirkis, Daniel W., Warly Solsberg, Caroline, Johnson, Taylor P., Bonham, Luke W., Sturm, Virginia E., Lee, Suzee E., Rankin, Katherine P., Rosen, Howard J., Boxer, Adam L., Seeley, William W., Miller, Bruce L., Geier, Ethan G., and Yokoyama, Jennifer S.
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MONONUCLEAR leukocytes ,TAUOPATHIES ,CHEMOKINE receptors ,MONOCYTES ,GENE expression - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Dynamic autonomic nervous system states arise during emotions and manifest in basal physiology.
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Pasquini, Lorenzo, Noohi, Fatemeh, Veziris, Christina R., Kosik, Eena L., Holley, Sarah R., Lee, Alex, Brown, Jesse A., Roy, Ashlin R. K., Chow, Tiffany E., Allen, Isabel, Rosen, Howard J., Kramer, Joel H., Miller, Bruce L., Saggar, Manish, Seeley, William W., and Sturm, Virginia E.
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AUTONOMIC nervous system ,PHYSIOLOGY ,EMOTIONS ,PRINCIPAL components analysis ,VIDEO excerpts ,SADNESS - Abstract
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. Despite decades of research, many questions remain regarding the functional organization of the autonomic nervous system. By leveraging the rich temporal fluctuations of multichannel physiological recordings, we uncovered five autonomic states that distinguished among five trials of an emotional reactivity task. These dynamic autonomic states were also present in basal physiology. Our results help to elucidate how the autonomic nervous system generates brief physiological patterns during emotions and rest. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Behavioural subphenotypes and their anatomic correlates in neurodegenerative disease.
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Roy, Ashlin R. K., Datta, Samir, Hardy, Emily, Sturm, Virginia E., Kramer, Joel H., Seeley, William W., Rankin, Katherine P., Rosen, Howard J., Miller, Bruce L., and Perry, David C.
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- 2023
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12. Radiogenomics of C9orf72 Expansion Carriers Reveals Global Transposable Element Derepression and Enables Prediction of Thalamic Atrophy and Clinical Impairment.
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Bonham, Luke W., Geier, Ethan G., Sirkis, Daniel W., Leong, Josiah K., Ramos, Eliana Marisa, Qing Wang, Karydas, Anna, Lee, Suzee E., Sturm, Virginia E., Sawyer, Russell P., Friedberg, Adit, Ichida, Justin K., Gitler, Aaron D., Sugrue, Leo, Cordingley, Michael, Bee, Walter, Weber, Eckard, Kramer, Joel H., Rankin, Katherine P., and Rosen, Howard J.
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ATROPHY ,THALAMIC nuclei ,FRONTOTEMPORAL dementia ,GENE expression ,RNA sequencing - Abstract
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 Free Surfer 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. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Older Adults With Higher Blood Pressure Variability Exhibit Cerebrovascular Reactivity Deficits.
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Sible, Isabel J, Jang, Jung Yun, Dutt, Shubir, Yew, Belinda, Alitin, John Paul M, Li, Yanrong, Blanken, Anna E, Ho, Jean K, Marshall, Anisa J, Kapoor, Arunima, Shenasa, Fatemah, Gaubert, Aimée, Nguyen, Amy, Sturm, Virginia E, Mather, Mara, Rodgers, Kathleen E, Shao, Xingfeng, Wang, Danny J, and Nation, Daniel A
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HYPERTENSION ,OLDER people ,CEREBROVASCULAR disease ,BLOOD pressure ,STROKE - Abstract
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 CO
2 . 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. [ABSTRACT FROM AUTHOR]- Published
- 2023
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14. Blood pressure variability and plasma Alzheimer's disease biomarkers in older adults.
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Sible, Isabel J., Yew, Belinda, Jang, Jung Yun, Alitin, John Paul M., Li, Yanrong, Gaubert, Aimée, Nguyen, Amy, Dutt, Shubir, Blanken, Anna E., Ho, Jean K., Marshall, Anisa J., Kapoor, Arunima, Shenasa, Fatemah, Rodgers, Kathleen E., Sturm, Virginia E., Head, Elizabeth, Martini, Alessandra, and Nation, Daniel A.
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ALZHEIMER'S disease ,OLDER people ,DISEASE risk factors ,CEREBROSPINAL fluid ,TAU proteins ,POSITRON emission tomography ,BLOOD pressure - Abstract
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 Aβ
1–42 (standardized ß = − 0.36 [95% CI − 0.61, − 0.12]; p = 0.005; adjusted R2 = 0.28) and Aβ1–42 : Aβ1–40 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 :Aβ1–42 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. [ABSTRACT FROM AUTHOR]- Published
- 2022
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15. Visual and social differences in dyslexia: deep phenotyping of four cases with spared phonology.
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Palser, Eleanor R., Miller, Zachary A., Licata, Abigail E., Yabut, Nicole A., Sudarsan, Swati P., Tee, Boon Lead, Deleon, Jessica A., Mandelli, Maria Luisa, Caverzasi, Eduardo, Sturm, Virginia E., Hendren, Robert, Possin, Katherine L., Miller, Bruce L., Gorno Tempini, Maria Luisa, and Watson Pereira, Christa
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DYSLEXIA ,DIFFUSION tensor imaging ,PHONOLOGY ,WHITE matter (Nerve tissue) ,LEARNING disabilities ,DEEP learning - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Decoding naturalistic affective behaviour from spectro-spatial features in multiday human iEEG.
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Bijanzadeh, Maryam, Khambhati, Ankit N., Desai, Maansi, Wallace, Deanna L., Shafi, Alia, Dawes, Heather E., Sturm, Virginia E., and Chang, Edward F.
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- 2022
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17. Influence of periaqueductal gray on other salience network nodes predicts social sensitivity.
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Rijpma, Myrthe G., Yang, Winson F.Z., Toller, Gianina, Battistella, Giovanni, Sokolov, Arseny A., Sturm, Virginia E., Seeley, William W., Kramer, Joel H., Miller, Bruce L., and Rankin, Katherine P.
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SALIENCE network ,CENTRAL pattern generators ,SELF-monitoring (Psychology) ,FRONTOTEMPORAL dementia ,OLDER people - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2022
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18. 96 Short-Term Blood Pressure Variability and Cerebrovascular Health in OlderaAdults.
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Sible, Isabel J, Yew, Belinda, Kapoor, Arunima, Jang, Jung Y, Alitin, John Paul M, Dutt, Shubir, Li, Yanrong, Blanken, Anna E, Ho, Jean K, Marshall, Anisa J, Shenasa, Fatemah, Gaubert, Aimee, Nguyen, Amy, Rodgers, Kathleen E, Sturm, Virginia E, and Nation, Daniel A
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CEREBROVASCULAR disease ,BLOOD pressure ,VASCULAR endothelial growth factors ,DISEASE risk factors - Abstract
Objective: Blood pressure variability (BPV), independent of traditionally targeted average blood pressure levels, is an emerging vascular risk factor for stroke, cerebrovascular disease, and dementia, possibly through links with vascular-endothelial injury. Recent evidence suggests visit-to-visit (e.g., over months, years) BPV is associated with cerebrovascular disease severity, but less is known about relationships with short-term (e.g., < 24 hours) fluctuations in blood pressure. Additionally, it is unclear how BPV may be related to angiogenic growth factors that play a role in cerebral arterial health. Participants and Methods: We investigated relationships between short-term BPV, white matter hyperintensities on MRI, and levels of plasma vascular endothelial growth factor (VEGF) in a sample of community-dwelling older adults (n = 57, ages 55-88) without history of dementia or stroke. Blood pressure was collected continuously during a 5-minute resting period. BPV was calculated as variability independent of mean, a commonly used index of BPV uncorrelated with average blood pressure levels. Participants underwent T2-FLAIR MRI to determine severity of white matter lesion burden. Severity of lesions was classified as Fazekas scores (0-3). Participants also underwent venipuncture to determine levels of plasma VEGF. Ordinal logistic regression examined the association between BPV and Fazekas scores. Multiple linear regression explored relationships between BPV and VEGF. Models controlled for age, sex, and average blood pressure. Results: Elevated BPV was related to greater white matter lesion burden (i.e., Fazekas score) (systolic: OR = 1.17 [95% CI 1.01, 1.37]; p =.04; diastolic: OR = 2.47 [95% CI 1.09, 5.90]; p =.03) and increased levels of plasma VEGF (systolic: ß =.39 [95% CI.11,.67]; adjusted R2 =.16; p =.007; diastolic: ß =.48 [95% CI.18,.78]; adjusted R2 =.18; p =.003). Conclusions: Findings suggest short-term BPV may be related to cerebrovascular disease burden and angiogenic growth factors relevant to cerebral arterial health, independent of average blood pressure. Understanding the role of BPV in cerebrovascular disease and vascular-endothelial health may help elucidate the increased risk for stroke and dementia associated with elevated BPV. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Brain volumetric deficits in MAPT mutation carriers: a multisite study.
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Chu, Stephanie A., Flagan, Taru M., Staffaroni, Adam M., Jiskoot, Lize C., Deng, Jersey, Spina, Salvatore, Zhang, Liwen, Sturm, Virginia E., Yokoyama, Jennifer S., Seeley, William W., Papma, Janne M., Geschwind, Dan H., Rosen, Howard J., Boeve, Bradley F., Boxer, Adam L., Heuer, Hilary W., Forsberg, Leah K., Brushaber, Danielle E., Grossman, Murray, and Coppola, Giovanni
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FRONTOTEMPORAL lobar degeneration ,FRONTOTEMPORAL dementia ,MILD cognitive impairment ,CORPUS callosum ,PARKINSON'S disease ,GRAY matter (Nerve tissue) - Abstract
Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration. [ABSTRACT FROM AUTHOR]
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- 2021
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20. Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia.
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Pasquini, Lorenzo, Nana, Alissa L, Toller, Gianina, Brown, Jesse A, Deng, Jersey, Staffaroni, Adam, Kim, Eun-Joo, Hwang, Ji-Hye L, Li, Libo, Park, Youngsoon, Gaus, Stephanie E, Allen, Isabel, Sturm, Virginia E, Spina, Salvatore, Grinberg, Lea T, Rankin, Katherine P, Kramer, Joel H, Rosen, Howard J, Miller, Bruce L, and Seeley, William W
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- 2020
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21. Depressive Symptom Profiles Predict Specific Neurodegenerative Disease Syndromes in Early Stages.
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Shdo, Suzanne M., Ranasinghe, Kamalini G., Sturm, Virginia E., Possin, Katherine L., Bettcher, Brianne M., Stephens, Melanie L., Foley, Jessica M., You, Shou-Chin Christine, Rosen, Howard J., Miller, Bruce L., Kramer, Joel H., and Rankin, Katherine P.
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NEURODEGENERATION ,PROGRESSIVE supranuclear palsy ,GERIATRIC Depression Scale ,FRONTOTEMPORAL dementia ,ALZHEIMER'S disease ,FRONTOTEMPORAL lobar degeneration - Abstract
Background: During early stages, patients with neurodegenerative diseases (NDG) often present with depressive symptoms. However, because depression is a heterogeneous disorder, more precise delineation of the specific depressive symptom profiles that arise early in distinct NDG syndromes is necessary to enhance patient diagnosis and care. Methods and Findings: Five-hundred and sixty four participants self-reported their depressive symptoms using the Geriatric Depression Scale (GDS), including 111 healthy older control subjects (NC) and 453 patients diagnosed with one of six NDGs who were at the mild stage of disease (CDR® Dementia Staging Instrument ≤ 1) [186 Alzheimer's disease (AD), 76 behavioral variant frontotemporal dementia (bvFTD), 52 semantic variant primary progressive aphasia (svPPA), 46 non-fluent variant PPA (nfvPPA), 49 progressive supranuclear palsy syndrome (PSPS), 44 corticobasal syndrome (CBS)]. The GDS was divided into subscales based on a previously published factor analysis, representing five symptoms (dysphoria, hopelessness, withdrawal, worry, and cognitive concerns). Mixed models were created to examine differences in depression subscale by group, and logistic regression analyses were performed to determine if patterns of depressive symptoms could predict a patient's NDG syndrome. PSPS patients presented with a hopeless, dysphoric, and withdrawn pattern, while patients with CBS presented with a similar but less severe pattern. Worry was a key symptom in the profile of patients with svPPA, while ADs only had abnormally elevated cognitive concerns. Depressive profile accurately predicted NDG diagnosis at a rate of between 70 and 84% accuracy. Conclusions: These results suggest that attention to specific depressive symptom profile can improve diagnostic sensitivity and can be used to provide more individualized patient care. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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22. Comparing two facets of emotion perception across multiple neurodegenerative diseases.
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Brown, Casey L, Hua, Alice Y, Coster, Lize De, Sturm, Virginia E, Kramer, Joel H, Rosen, Howard J, Miller, Bruce L, and Levenson, Robert W
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Deficits in emotion perception (the ability to infer others' emotions accurately) can occur as a result of neurodegeneration. It remains unclear how different neurodegenerative diseases affect different forms of emotion perception. The present study compares performance on a dynamic tracking task of emotion perception (where participants track the changing valence of a film character's emotions) with performance on an emotion category labeling task (where participants label specific emotions portrayed by film characters) across seven diagnostic groups (N = 178) including Alzheimer's disease (AD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent variant primary progressive aphasia (nfvPPA), progressive supranuclear palsy (PSP), corticobasal syndrome and healthy controls. Consistent with hypotheses, compared to controls, the bvFTD group was impaired on both tasks. The svPPA group was impaired on the emotion labeling task, whereas the nfvPPA, PSP and AD groups were impaired on the dynamic tracking task. Smaller volumes in bilateral frontal and left insular regions were associated with worse labeling, whereas smaller volumes in bilateral medial frontal, temporal and right insular regions were associated with worse tracking. Findings suggest labeling and tracking facets of emotion perception are differentially affected across neurodegenerative diseases due to their unique neuroanatomical correlates. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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23. Relationship Turmoil and Emotional Empathy in Frontotemporal Dementia.
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Takeda, Akitoshi, Sturm, Virginia E., Rankin, Katherine P., Ketelle, Robin, Miller, Bruce L., and Perry, David C.
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- 2019
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24. Network Architecture Underlying Basal Autonomic Outflow: Evidence from Frontotemporal Dementia.
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Sturm, Virginia E., Brown, Jesse A., Hua, Alice Y., Lwi, Sandy J., Zhou, Juan, Kurth, Florian, Eickhoff, Simon B., Rosen, Howard J., Kramer, Joel H., Miller, Bruce L., Levenson, Robert W., and Seeley, William W.
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FRONTOTEMPORAL dementia ,AUTONOMIC nervous system ,SINUS arrhythmia ,TEMPORAL lobe ,SOCIAL skills - Abstract
The salience network is a distributed neural system that maintains homeostasis by regulating autonomic nervous system activity and social-emotional function. Here we examined how within-network connectivity relates to individual differences in human (including males and females) baseline parasympathetic and sympathetic nervous activity. We measured resting autonomic nervous system physiology in 24 healthy controls and 23 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by baseline autonomic deficits. Participants also underwent structural and task-free fMRI. First, we used voxel-based morphometry to determine whether salience network atrophy was associated with lower baseline respiratory sinus arrhythmia (a parasympathetic measure) and skin conductance level (a sympathetic measure) in bvFTD. Next, we examined whether functional connectivity deficits in 21 autonomic-relevant, salience network node-pairs related to baseline autonomic dysfunction. Lower baseline respiratory sinus arrhythmia was associated with smaller volume in left ventral anterior insula (vAI), weaker connectivity between bilateral vAI and bilateral anterior cingulate cortex (ACC), and stronger connectivity between bilateral ACC and bilateral hypothalamus/ amygdala. Lower baseline skin conductance level, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal mid-insula, and hypothalamus; weaker connectivity between bilateral ACC and right hypothalamus/amygdala; and stronger connectivity between bilateral dorsal anterior insula and periaqueductal gray. Our results suggest that baseline parasympathetic and sympathetic tone depends on the integrity of lateralized salience network hubs (left vAI for parasympathetic and right hypothalamus/amygdala for sympathetic) and highly calibrated ipsilateral and contralateral network connections. In bvFTD, deficits in this system may underlie resting parasympathetic and sympathetic disruption. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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25. Enhanced Positive Emotional Reactivity Undermines Empathy in Behavioral Variant Frontotemporal Dementia.
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Hua, Alice Y., Sible, Isabel J., Perry, David C., Rankin, Katherine P., Kramer, Joel H., Miller, Bruce L., Rosen, Howard J., and Sturm, Virginia E.
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FRONTOTEMPORAL dementia ,EMPATHY ,EMOTIONS - Abstract
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease characterized by profound changes in emotions and empathy. Although most patients with bvFTD become less sensitive to negative emotional cues, some patients become more sensitive to positive emotional stimuli. We investigated whether dysregulated positive emotions in bvFTD undermine empathy by making it difficult for patients to share (emotional empathy), recognize (cognitive empathy), and respond (real-world empathy) to emotions in others. Fifty-one participants (26 patients with bvFTD and 25 healthy controls) viewed photographs of neutral, positive, negative, and self-conscious emotional faces and then identified the emotions displayed in the photographs. We used facial electromyography to measure automatic, sub-visible activity in two facial muscles during the task: Zygomaticus major (ZM), which is active during positive emotional reactions (i.e., smiling), and Corrugator supercilii (CS), which is active during negative emotional reactions (i.e., frowning). Participants rated their baseline positive and negative emotional experience before the task, and informants rated participants' real-world empathic behavior on the Interpersonal Reactivity Index. The majority of participants also underwent structural magnetic resonance imaging. A mixed effects model found a significant diagnosis X trial interaction: patients with bvFTD showed greater ZM reactivity to neutral, negative (disgust and surprise), self-conscious (proud), and positive (happy) faces than healthy controls. There was no main effect of diagnosis or diagnosis X trial interaction on CS reactivity. Compared to healthy controls, patients with bvFTD had impaired emotion recognition. Multiple regression analyses revealed that greater ZM reactivity predicted worse negative emotion recognition and worse real-world empathy. At baseline, positive emotional experience was higher in bvFTD than healthy controls and also predicted worse negative emotion recognition. Voxel-based morphometry analyses found that smaller volume in the thalamus, midcingulate cortex, posterior insula, anterior temporal pole, amygdala, precentral gyrus, and inferior frontal gyrus--structures that support emotion generation, interoception, and emotion regulation--was associated with greater ZM reactivity in bvFTD. These findings suggest that dysregulated positive emotional reactivity may relate to reduced empathy in bvFTD by making patients less likely to tune their reactions to the social context and to share, recognize, and respond to others' feelings and needs. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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26. Reward deficits in behavioural variant frontotemporal dementia include insensitivity to negative stimuli.
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Perry, David C., Datta, Samir, Sturm, Virginia E., Wood, Kristie A., Zakrzewski, Jessica, Seeley, William W., Miller, Bruce L., Kramer, Joel H., and Rosen, Howard J.
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FRONTOTEMPORAL dementia ,REWARD (Psychology) ,STIMULUS & response (Psychology) ,PLEASANTNESS & unpleasantness (Psychology) ,AMYGDALOID body - Abstract
During reward processing individuals weigh positive and negative features of a stimulus to determine whether they will pursue or avoid it. Though patients with behavioural variant frontotemporal dementia display changes in their pursuit of rewards, such as food, alcohol, money, and sex, the basis for these shifts is not clearly established. In particular, it is unknown whether patients' behaviour results from excessive focus on rewards, insensitivity to punishment, or to dysfunction in a particular stage of reward processing, such as anticipation, consumption, or action selection. Our goal was to determine the nature of the reward deficit in behavioural variant frontotemporal dementia and its underlying anatomy. We devised a series of tasks involving pleasant, unpleasant, and neutral olfactory stimuli, designed to separate distinct phases of reward processing. In a group of 25 patients with behavioural variant frontotemporal dementia and 21 control subjects, diagnosis by valence interactions revealed that patients with behavioural variant frontotemporal dementia rated unpleasant odours as less aversive than did controls and displayed lower skin conductance responses when anticipating an upcoming aversive odour. Subjective pleasantness ratings and skin conductance responses did not differ between behavioural variant frontotemporal dementia and controls for pleasant or neutral smells. In a task designed to measure the effort subjects would expend to smell or avoid smelling a stimulus, patients with behavioural variant frontotemporal dementia were less motivated, and therefore less successful than control subjects, at avoiding what they preferred not to smell, but had equivalent success at obtaining stimuli they found rewarding. Voxel-based morphometry of patients with behavioural variant frontotemporal dementia revealed that the inability to subjectively differentiate the valence of pleasant and unpleasant odours correlated with atrophy in right ventral mid-insula and right amygdala. High pleasantness ratings of unpleasant stimuli correlated with left dorsal anterior insula and frontal pole atrophy. These findings indicate that insensitivity to negative information may be a key component of the reward-seeking behaviours in behavioural variant frontotemporal dementia, and may relate to degeneration of structures that are involved in representing the emotional salience of sensory information. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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27. Clinicopathological correlations in behavioural variant frontotemporal dementia.
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Perry, David C., Brown, Jesse A., Possin, Katherine L., Datta, Samir, Trujillo, Andrew, Radke, Anneliese, Karydas, Anna, Kornak, John, Sias, Ana C., Rabinovici, Gil D., Gorno-Tempini, Maria Luisa, Boxer, Adam L., De May, Mary, Rankin, Katherine P., Sturm, Virginia E., Lee, Suzee E., Matthews, Brandy R., Kao, Aimee W., Vossel, Keith A., and Tartaglia, Maria Carmela
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FRONTOTEMPORAL dementia ,NEUROLOGICAL disorders ,BRAIN imaging ,CEREBRAL atrophy ,FOLLOW-up studies (Medicine) - Abstract
Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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28. Prosocial deficits in behavioral variant frontotemporal dementia relate to reward network atrophy.
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Sturm, Virginia E., Perry, David C., Wood, Kristie, Hua, Alice Y., Alcantar, Oscar, Datta, Samir, Rankin, Katherine P., Rosen, Howard J., Miller, Bruce L., and Kramer, Joel H.
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- 2017
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29. Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia.
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Guo, Christine C., Sturm, Virginia E., Juan Zhou, Gennatas, Efstathios D., Trujillo, Andrew J., Hua, Alice Y., Crawford, Richard, Stables, Lara, Kramer, Joel H., Rankin, Katherine, Levenson, Robert W., Rosen, Howard J., Miller, Bruce L., and Seeley, William W.
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CEREBRAL dominance ,PARASYMPATHETIC nervous system ,FRONTOTEMPORAL dementia ,CINGULATE cortex ,NEUROSCIENCES - Abstract
The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical formaintaining an adaptive level of baseline parasympathetic outflow. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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30. Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage.
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Ranasinghe, Kamalini G., Rankin, Katherine P., Lobach, Iryna V., Kramer, Joel H., Sturm, Virginia E., Bettcher, Brianne M., Possin, Katherine, You, S. Christine, Lamarre, Amanda K., Stephens, Melanie L., Perry, David C., Lee, Suzee E., Miller, Zachary A., Gorno-Tempini, Maria L., Rosen, Howard J., Boxer, Adam, Seeley, William W., Rabinovici, Gil D., Vossel, Keith A., and Miller, Bruce L.
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- 2016
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31. Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis.
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Perry, David C., Sturm, Virginia E., Peterson, Matthew J., Pieper, Carl F., Bullock, Thomas, Boeve, Bradley F., Miller, Bruce L., Guskiewicz, Kevin M., Berger, Mitchel S., Kramer, Joel H., and Welsh-Bohmer, Kathleen A.
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- 2016
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32. Divergent Processing of Monetary and Social Reward in Behavioral Variant Frontotemporal Dementia and Alzheimer Disease.
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Perry, David C., Sturm, Virginia E., Wood, Kristie A., Miller, Bruce L., and Kramer, Joel H.
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- 2015
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33. Variation in longevity gene KLOTHO is associated with greater cortical volumes.
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Yokoyama, Jennifer S., Sturm, Virginia E., Bonham, Luke W., Klein, Eric, Arfanakis, Konstantinos, Yu, Lei, Coppola, Giovanni, Kramer, Joel H., Bennett, David A., Miller, Bruce L., and Dubal, Dena B.
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GENETICS of longevity ,COGNITION ,AGING ,BRAIN research ,HETEROZYGOSITY - Abstract
Objective Identifying genetic variation associated with brain structures in aging may elucidate new biologic mechanisms underlying resilience to cognitive decline. We investigated whether carrying one copy of the protective haplotype ' KL- VS' in longevity gene KLOTHO ( KL) is associated with greater gray matter volume in healthy human aging compared to carrying no copies. Methods We performed unbiased whole-brain analysis in cognitively normal older adults from two independent cohorts to assess the relationship between KL- VS and gray matter volume using voxel-based morphometry. Results We found that KL- VS heterozygosity was associated with greater volume in right dorsolateral prefrontal cortex ( rDLPFC). Because rDLPFC is important for executive function, we analyzed working memory and processing speed in individuals. KL- VS heterozygosity was associated with enhanced executive function. Larger rDLPFC volume correlated with better executive function across the lifespan examined. Statistical analysis suggested that volume partially mediates the effect of genotype on cognition. Interpretation These results suggest that variation in KL is associated with bigger brain volume and better function. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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34. Neuropsychological Assessment of Primary Progressive Aphasia (PPA).
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Bettcher, Brianne M. and Sturm, Virginia E.
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- 2014
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35. Anatomical correlates of reward-seeking behaviours in behavioural variant frontotemporal dementia.
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Perry, David C., Sturm, Virginia E., Seeley, William W., Miller, Bruce L., Kramer, Joel H., and Rosen, Howard J.
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FRONTOTEMPORAL dementia ,REWARD (Psychology) ,NEURAL circuitry ,BRAIN anatomy ,STIMULUS & response (Biology) ,HYPERPHAGIA ,FOOD preferences - Abstract
Behavioural variant frontotemporal dementia is characterized by an increase in primary reward-seeking behaviours, including pursuit of food, drug, and sexual rewards. Perry et al. reveal that increased reward-seeking correlates with lower volume in the right ventral putamen and pallidum, which are known reward circuit structures.Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0–3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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36. Life Extension Factor Klotho Enhances Cognition.
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Dubal, Dena B., Yokoyama, Jennifer S., Zhu, Lei, Broestl, Lauren, Worden, Kurtresha, Wang, Dan, Sturm, Virginia E., Kim, Daniel, Klein, Eric, Yu, Gui-Qiu, Ho, Kaitlyn, Eilertson, Kirsten E., Yu, Lei, Kuro-o, Makoto, De Jager, Philip L., Coppola, Giovanni, Small, Gary W., Bennett, David A., Kramer, Joel H., and Abraham, Carmela R.
- Abstract
Summary: Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages. [Copyright &y& Elsevier]
- Published
- 2014
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37. Emotional and behavioral symptoms in neurodegenerative disease: a model for studying the neural bases of psychopathology.
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Levenson, Robert W, Sturm, Virginia E, and Haase, Claudia M
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- 2014
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38. Emotional and Behavioral Symptoms in Neurodegenerative Disease: A Model for Studying the Neural Bases of Psychopathology.
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Levenson, Robert W., Sturm, Virginia E., and Haase, Claudia M.
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- 2014
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39. TDP-43 frontotemporal lobar degeneration and autoimmune disease.
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Miller, Zachary A., Rankin, Katherine P., Graff-Radford, Neill R., Takada, Leonel T., Sturm, Virginia E., Cleveland, Clare M., Criswell, Lindsey A., Jaeger, Philipp A., Stan, Trisha, Heggeli, Kristin A., Sandy Chan Hsu, Karydas, Anna, Khan, Baber K., Grinberg, Lea T., Gorno-Tempini, Maria Luisa, Boxer, Adam L., Rosen, Howard J., Kramer, Joel H., Coppola, Giovanni, and Geschwind, Daniel H.
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FRONTAL lobe diseases ,AUTOIMMUNE diseases ,ETIOLOGY of diseases ,FRONTOTEMPORAL dementia ,INFLAMMATION ,NEURODEGENERATION - Abstract
Background The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. Objective To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls. Design Case control. Setting Academic medical centres. Participants 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor a (TNF-a) levels. Outcome measures ?² Comparison of autoimmune prevalence and follow-up logistic regression. Results There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-a levels were observed in svPPA and PGRN compared with NC. Conclusions svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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40. Heightened emotional contagion in mild cognitive impairment and Alzheimer's disease is associated with temporal lobe degeneration.
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Sturm, Virginia E., Yokoyama, Jennifer S., Seeley, William W., Kramer, Joel H., Miller, Bruce L., and Rankin, Katherine P.
- Subjects
EMOTIONAL contagion ,MILD cognitive impairment ,ALZHEIMER'S disease ,TEMPORAL lobe ,DISEASE progression - Abstract
Emotional changes are common in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Intrinsic connectivity imaging studies suggest that default mode network degradation in AD is accompanied by the release of an emotion-relevant salience network. We investigated whether emotional contagion, an evolutionarily conserved affect-sharing mechanism, is higher in MCI and AD secondary to biological alterations in neural networks that support emotion. We measured emotional contagion in 237 participants (111 healthy controls, 62 patients with MCI, and 64 patients with AD) with the Interpersonal Reactivity Index Personal Distress subscale. Depressive symptoms were evaluated with the Geriatric Depression Scale. Participants underwent structural MRI, and voxel-based morphometry was used to relate whole-brain maps to emotional contagion. Analyses of covariance found significantly higher emotional contagion at each stage of disease progression [controls < MCI (P < 0.01) and MCI < AD (P < 0.001)]. Depressive symptoms were also higher in patients compared with controls [controls < MCI (P < 0.01) and controls < AD (P < 0.0001)]. Higher emotional contagion (but not depressive symptoms) was associated with smaller volume in right inferior, middle, and superior temporal gyri (P
FWE < 0.05); right temporal pole, anterior hippocampus, parahippocampal gyrus; and left middle temporal gyrus (all P < 0.001, uncorrected). These findings suggest that in MCI and AD, neurodegeneration of temporal lobe structures important for affective signal detection and emotion inhibition are associated with up-regulation of emotion-generating mechanisms. Emotional contagion, a quantifiable index of empathic reactivity that is present in other species, may be a useful tool with which to study emotional alterations in animal models of AD. [ABSTRACT FROM AUTHOR]- Published
- 2013
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41. Role of right pregenual anterior cingulate cortex in self-conscious emotional reactivity.
- Author
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Sturm, Virginia E., Sollberger, Marc, Seeley, William W., Rankin, Katherine P., Ascher, Elizabeth A., Rosen, Howard J., Miller, Bruce L., and Levenson, Robert W.
- Subjects
NEURODEGENERATION ,SELF-consciousness (Awareness) ,FRONTOTEMPORAL dementia ,AUTONOMIC nervous system ,NEURAL circuitry ,MAGNETIC resonance imaging of the brain - Abstract
Self-conscious emotions such as embarrassment arise when one’s actions fail to meet salient social expectations and are accompanied by marked physiological and behavioral activation. We investigated the neural correlates of self-conscious emotional reactivity in 27 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease that disrupts self-conscious emotion and targets brain regions critical for emotional functioning early in the disease course, and in 33 healthy older controls. Subjects participated in an embarrassing karaoke task in which they watched a video clip of themselves singing. They also watched a sad film clip; these data were used to control for non-self-conscious emotional reactivity in response to audiovisual stimuli. Using Freesurfer to quantify regional brain volumes from structural magnetic resonance imaging, right pregenual anterior cingulate cortex (pACC) gray matter volume was the only brain region that was a significant predictor of self-conscious emotion. Smaller pACC volume was associated with attenuated physiological and behavioral self-conscious emotional reactivity, and this relationship was not specific to diagnosis. We argue that these results reflect the significant role that right pACC plays in the visceromotor responding that accompanies self-conscious emotion and that neurodegeneration in this region may underlie the self-conscious emotional decline seen in bvFTD. [ABSTRACT FROM PUBLISHER]
- Published
- 2013
- Full Text
- View/download PDF
42. Mutual gaze in Alzheimer's disease, frontotemporal and semantic dementia couples.
- Author
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Sturm, Virginia E., McCarthy, Megan E., Yun, Ira, Madan, Anita, Yuan, Joyce W., Holley, Sarah R., Ascher, Elizabeth A., Boxer, Adam L., Miller, Bruce L., and Levenson, Robert W.
- Subjects
GAZE ,ALZHEIMER'S disease ,FRONTOTEMPORAL dementia ,INTERPERSONAL relations ,AUTONOMIC nervous system - Abstract
Alzheimer’s disease (AD), frontotemporal dementia (FTD) and semantic dementia (SD) are neurodegenerative diseases that differ in their socioemotional presentations. Mutual gaze (i.e. when two individuals make eye contact) is a building block of social behavior that may be differentially affected by these diseases. We studied 13 AD patients, 11 FTD patients, 9 SD patients and 22 normal controls as they engaged in conversations with partners about relationship conflicts. Physiological reactivity was monitored during the conversations and trained raters coded mutual gaze from videotaped recordings. Results indicated that mutual gaze was preserved in AD couples. Mutual gaze was diminished in FTD couples while SD couples showed evidence of greater mutual gaze. SD couples also showed lower physiological reactivity compared to controls. Across patient groups, reduced mutual gaze was associated with greater behavioral disturbance as measured by the Neuropsychiatric Inventory, especially on the disinhibition and apathy subscales. These results point to subtle differences between the three types of dementia in the social realm that help to illuminate the nature of the disease process and could aid in differential diagnosis. [ABSTRACT FROM PUBLISHER]
- Published
- 2011
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43. Relationship Satisfaction and Emotional Language in Frontotemporal Dementia and Alzheimer Disease Patients and Spousal Caregivers.
- Author
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Ascher, Elizabeth A., Sturm, Virginia E., Seider, Benjamin H., Holley, Sarah R., Miller, Bruce L., and Levenson, Robert W.
- Published
- 2010
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44. Cognition and neuropsychiatry in behavioral variant frontotemporal dementia by disease stage.
- Author
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Bertoux, Maxime, Sarazin, Marie, Pasquier, Florence, Bottlaender, Michel, de Souza, Leonardo Cruz, Horizonte, Belo, Mioshi, Eneida, Hornberger, Michael, Ranasinghe, Kamalini G., Rankin, Katherine P., Lobach, Iryna V., Kramer, Joel H., Sturm, Virginia E., Bettcher, Brianne M., Possin, Katherine, You, S. Christine, Lamarre, Amanda K., Shany-Ur, Tal, Stephens, Melanie L., and Perry, David C.
- Published
- 2016
- Full Text
- View/download PDF
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