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1.  Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes 
Nature medicine  2013;19(10):1325-1330.
Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain–containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes1. Although Hif regulates many metabolic pathways2, it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3, also known as Egln3, improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.
doi:10.1038/nm.3294
PMCID: PMC4089950  PMID: 24037093
2.  Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene 
Background
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability.
Results
We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]).
Conclusions
Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.
Electronic supplementary material
The online version of this article (doi:10.1186/1750-1326-9-38) contains supplementary material, which is available to authorized users.
doi:10.1186/1750-1326-9-38
PMCID: PMC4190282  PMID: 25239657
C9ORF72; Frontotemporal dementia; Motor neuron disease; Genetic modifier; Repeat expansion
3.  Psychosis and Hallucinations in FTD with C9ORF72 mutation: A detailed clinical cohort 
OBJECTIVE
To describe in detail the presenting symptoms and clinical course of a cohort of patients with Frontotemporal dementia and the recently described C9ORF72 repeat expansion.
BACKGROUND
Recent discovery of the C9ORF72 repeat expansion linked to familial frontotemporal dementia and ALS has permitted retrospective evaluation of potential defining clinical characteristics that may distinguish C9ORF72 mutation carriers from other patients with FTD. Prior reports have identified a subset of patients with an increased incidence of psychosis, specifically delusions, though the detailed nature of these symptoms is not yet well described.
METHODS
We conducted a retrospective chart review of to report the detailed case histories of 7 patients with C9ORF72 mutations from a cohort of 61 patients with FTD.
Results
Detailed histories available from these patients reveal an increased incidence of psychosis, including visual and auditory hallucinations and delusions compared to sporadic FTD patients in our cohort.
CONCLUSIONS
This cohort confirms and adds symptom-related details to prior reports of increased incidence of psychotic phenomenon in FTD and ALS patients with C9ORF72 mutations, to enhance future clinical identification and diagnosis of patients presenting with these symptoms.
doi:10.1097/WNN.0000000000000008
PMCID: PMC4090685  PMID: 24077574
frontotemporal dementia; psychosis; C9ORF72 mutation; motor neuron disease
4.  TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia 
Journal of neurochemistry  2013;126(6):781-791.
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLDTDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and TMEM106B protein regulation.
First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of PGRN levels showed similar effects upon T185 and S185 TMEM106B overexpression. However, overexpression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk.
doi:10.1111/jnc.12329
PMCID: PMC3766501  PMID: 23742080
TMEM106B; frontotemporal dementia; progranulin; glycosylation
5.  Empathic responsiveness in amygdala and anterior cingulate cortex in youths with psychopathic traits 
Background
Psychopathic traits are associated with increases in antisocial behaviors such as aggression and are characterized by reduced empathy for others’ distress. This suggests that psychopathic traits may also impair empathic pain sensitivity. However, whether psychopathic traits affect responses to the pain of others versus the self has not been previously assessed.
Method
We used whole-brain functional magnetic resonance imaging (fMRI) scanning to measure neural activation in 14 adolescents with Oppositional Defiant Disorder or Conduct Disorder and psychopathic traits, as well as 21 healthy controls matched on age, sex, and intelligence. Activation in structures associated with empathic pain perception was assessed as adolescents viewed photographs of pain-inducing injuries. Adolescents imagined either that the body in each photograph was their own or that it belonged to another person. Behavioral and neuroimaging data were analyzed using random-effects analysis of variance.
Results
Youths with psychopathic traits showed reduced activity within regions associated with empathic pain as the depicted pain increased. These regions included rostral anterior cingulate cortex, ventral striatum (putamen), and amygdala. Reductions in amygdala activity particularly occurred when the injury was perceived as occurring to another. Empathic pain responses within both amygdala and rostral anterior cingulate cortex were negatively correlated with the severity of psychopathic traits as indexed by PCL:YV scores.
Conclusions
Youths with psychopathic traits show less responsiveness in regions implicated in the affective response to another’s pain as the perceived intensity of this pain increases. Moreover, this reduced responsiveness appears to predict symptom severity.
doi:10.1111/jcpp.12063
PMCID: PMC3716835  PMID: 23488588
Psychopathy; adolescents; empathy; pain; amygdala; Conduct Disorder
6.  Hypoxia, inflammation, and the tumor microenvironment in metastatic disease 
Cancer metastasis reviews  2010;29(2):285-293.
Metastasis, the leading cause of cancer deaths, is an intricate process involving many important tumor and stromal proteins that have yet to be fully defined. This review discusses critical components necessary for the metastatic cascade, including hypoxia, inflammation, and the tumor microenvironment. More specifically, this review focuses on tumor cell and stroma interactions, which allow cell detachment from a primary tumor, intravasation to the blood stream, and extravasation at a distant site where cells can seed and tumor metastases can form. Central players involved in this process and discussed in this review include integrins, matrix metalloproteinases, and soluble growth factors/matrix proteins, including the connective tissue growth factor and lysyl oxidase.
doi:10.1007/s10555-010-9224-5
PMCID: PMC4012531  PMID: 20393783
Connective tissue growth factor; Lysyl oxidase; Metastasis; Hypoxia
7.  C9ORF72 repeat expansions in cases with previously identified pathogenic mutations 
Neurology  2013;81(15):1332-1341.
Objective:
To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases.
Methods:
A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72. For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology.
Results:
We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin (GRN: p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau (MAPT: p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations.
Conclusions:
Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.
doi:10.1212/WNL.0b013e3182a8250c
PMCID: PMC3806926  PMID: 24027057
8.  Dissociable Roles of Medial Orbitofrontal Cortex in Human Operant Extinction Learning 
NeuroImage  2008;43(4):748-755.
Operant extinction, which features modification of instrumental responses to stimuli following a change in associated reinforcement, is an important form of learning for organisms in dynamic environments. Animal studies have highlighted orbital and medial prefrontal cortex and amygdala as mediators of operant extinction. Yet little is known about the neural mediators of operant extinction learning in humans. Using a novel fMRI paradigm, we report dissociable functional responses in distinct regions of medial orbitofrontal cortex (mOFC) during successful appetitive and aversive based operant extinction. During successful operant extinction, increased activity was observed in frontopolar OFC, while decreased activity was observed in caudal mOFC and rostral anterior cingulate cortex (rACC) relative to both (i) successful control trials where the reinforcement associated with the stimulus does not change; and (ii) successful acquisition trials during initial learning of the stimulus- reinforcement associations. Functional connectivity analysis demonstrated inverse connectivity between frontopolar OFC and both rACC and the amygdala. These data support animal models suggesting the importance of mOFC - amygdala interaction during operant extinction and expand our knowledge of the neural systems in humans. These findings suggest that in humans, frontopolar OFC modulates activity in caudal mOFC, rACC and amygdala during successful operant extinction learning.
doi:10.1016/j.neuroimage.2008.08.021
PMCID: PMC3941699  PMID: 18793731
frontopolar; amygdala; instrumental; anterior cingulate cortex
9.  Disrupted Reinforcement Signaling in Orbital Frontal Cortex and Caudate in Youths with Conduct Disorder/Oppositional Defiant Disorder and High Psychopathic Traits 
The American journal of psychiatry  2010;168(2):152-162.
OBJECTIVE
Dysfunction in amygdala and orbital frontal cortex functioning has been reported in youths and adults with psychopathic traits. However, the specific nature of the computational irregularities within these brain structures remains poorly understood. The current study used the passive avoidance task to examine responsiveness of these systems to early stimulus-reinforcement exposure, when prediction errors are greatest and learning maximized, and to reward in youths with psychopathic traits and comparison youths.
METHOD
30 youths (N=15 with conduct disorder or oppositional defiant disorder plus high psychopathic traits and N=15 comparison subjects) completed a 3.0 T fMRI scan while performing a passive avoidance learning task.
RESULTS
Relative to comparison youth, youths with conduct disorder or oppositional defiant disorder plus psychopathic traits showed reduced orbitofrontal cortex responsiveness both to early stimulus-reinforcement exposure and to rewards, as well as reduced caudate response to early stimulus-reinforcement exposure. Contrary to other predictions, however, there were no group differences in amygdala responsiveness specifically to these two task parameters. However, amygdala responsiveness throughout the task was reduced in the youths with conduct disorder or oppositional defiant disorder plus psychopathic traits.
CONCLUSIONS
This study demonstrates that youths with conduct disorder or oppositional defiant disorder plus psychopathic traits are marked by a compromised sensitivity to early reinforcement information in both orbitofrontal cortex and caudate and to reward outcome information within orbitofrontal cortex. They further suggest that the integrated functioning of the amygdala, caudate and orbitofrontal cortex may be disrupted in individuals with this disorder.
doi:10.1176/appi.ajp.2010.10010129
PMCID: PMC3908480  PMID: 21078707
10.  Nature and extent of person recognition impairments associated with Capgras syndrome in Lewy body dementia 
Patients with Capgras syndrome (CS) adopt the delusional belief that persons well-known to them have been replaced by an imposter. Several current theoretical models of CS attribute such misidentification problems to deficits in covert recognition processes related to the generation of appropriate affective autonomic signals. These models assume intact overt recognition processes for the imposter and, more broadly, for other individuals. As such, it has been suggested that CS could reflect the “mirror-image” of prosopagnosia. The purpose of the current study was to determine whether overt person recognition abilities are indeed always spared in CS. Furthermore, we examined whether CS might be associated with any impairments in overt affective judgments of facial expressions. We pursued these goals by studying a patient with Dementia with Lewy bodies (DLB) who showed clear signs of CS, and by comparing him to another patient with DLB who did not experience CS, as well as to a group of healthy control participants. Clinical magnetic resonance imaging scans revealed medial prefrontal cortex (mPFC) atrophy that appeared to be uniquely associated with the presence CS. We assessed overt person recognition with three fame recognition tasks, using faces, voices, and names as cues. We also included measures of confidence and probed pertinent semantic knowledge. In addition, participants rated the intensity of fearful facial expressions. We found that CS was associated with overt person recognition deficits when probed with faces and voices, but not with names. Critically, these deficits were not present in the DLB patient without CS. In addition, CS was associated with impairments in overt judgments of affect intensity. Taken together, our findings cast doubt on the traditional view that CS is the mirror-image of prosopagnosia and that it spares overt recognition abilities. These findings can still be accommodated by models of CS that emphasize deficits in autonomic responding, to the extent that the potential role of interoceptive awareness in overt judgments is taken into account.
doi:10.3389/fnhum.2014.00726
PMCID: PMC4173644  PMID: 25309399
Capgras syndrome; Lewy body dementia; interoceptive awareness; person recognition; affect perception
11.  Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype 
Neurobiology of aging  2012;33(12):2950.e5-2950.e7.
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
doi:10.1016/j.neurobiolaging.2012.07.005
PMCID: PMC3617405  PMID: 22840558
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
12.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases 
Coppola, Giovanni | Chinnathambi, Subashchandrabose | Lee, Jason JiYong | Dombroski, Beth A. | Baker, Matt C. | Soto-Ortolaza, Alexandra I. | Lee, Suzee E. | Klein, Eric | Huang, Alden Y. | Sears, Renee | Lane, Jessica R. | Karydas, Anna M. | Kenet, Robert O. | Biernat, Jacek | Wang, Li-San | Cotman, Carl W. | DeCarli, Charles S. | Levey, Allan I. | Ringman, John M. | Mendez, Mario F. | Chui, Helena C. | Le Ber, Isabelle | Brice, Alexis | Lupton, Michelle K. | Preza, Elisavet | Lovestone, Simon | Powell, John | Graff-Radford, Neill | Petersen, Ronald C. | Boeve, Bradley F. | Lippa, Carol F. | Bigio, Eileen H. | Mackenzie, Ian | Finger, Elizabeth | Kertesz, Andrew | Caselli, Richard J. | Gearing, Marla | Juncos, Jorge L. | Ghetti, Bernardino | Spina, Salvatore | Bordelon, Yvette M. | Tourtellotte, Wallace W. | Frosch, Matthew P. | Vonsattel, Jean Paul G. | Zarow, Chris | Beach, Thomas G. | Albin, Roger L. | Lieberman, Andrew P. | Lee, Virginia M. | Trojanowski, John Q. | Van Deerlin, Vivianna M. | Bird, Thomas D. | Galasko, Douglas R. | Masliah, Eliezer | White, Charles L. | Troncoso, Juan C. | Hannequin, Didier | Boxer, Adam L. | Geschwind, Michael D. | Kumar, Satish | Mandelkow, Eva-Maria | Wszolek, Zbigniew K. | Uitti, Ryan J. | Dickson, Dennis W. | Haines, Jonathan L. | Mayeux, Richard | Pericak-Vance, Margaret A. | Farrer, Lindsay A. | Ross, Owen A. | Rademakers, Rosa | Schellenberg, Gerard D. | Miller, Bruce L. | Mandelkow, Eckhard | Geschwind, Daniel H.
Human Molecular Genetics  2012;21(15):3500-3512.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
doi:10.1093/hmg/dds161
PMCID: PMC3392107  PMID: 22556362
13.  Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits 
Psychiatry research  2012;202(3):239-244.
Youths with conduct disorder or oppositional defiant disorder and psychopathic traits (CD/ODD+PT) are at high risk of adult anti-social behaviour and psychopathy. Neuroimaging studies demonstrate functional abnormalities in orbitofrontal cortex and the amygdala in both youths and adults with psychopathic traits. Diffusion tensor imaging in psychopathic adults demonstrates disrupted structural connectivity between these regions (uncinate fasiculus). The current study examined whether functional neural abnormalities present in youths with CD/ODD+PT are associated with similar white matter abnormalities. Youths with CD/ODD+PT and comparison participants completed 3.0 T diffusion tensor scans and functional MRI scans. Diffusion tensor imaging did not reveal disruption in structural connections within the uncinate fasiculus or other white matter tracts in youths with CD/ODD+PT, despite the demonstration of disrupted amygdala-prefrontal functional connectivity in these youths. These results suggest that disrupted amygdala-frontal white matter connectivity as measured by fractional anisotropy is less sensitive than imaging measurements of functional perturbations in youths with psychopathic traits. If white matter tracts are intact in youths with this disorder, childhood may provide a critical window for intervention and treatment, before significant structural brain abnormalities solidify.
doi:10.1016/j.pscychresns.2011.11.002
PMCID: PMC3423593  PMID: 22819939
Psychopathic traits; conduct disorder; oppositional defiant disorder; diffusion tensor imaging; functional connectivity
14.  TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease 
Background
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
Results
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Conclusions
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
doi:10.1186/1750-1326-8-19
PMCID: PMC3691612  PMID: 23800361
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
15.  Functional neural correlates of emotional expression processing deficits in behavioural variant frontotemporal dementia 
Background
Frontotemporal dementia (FTD) is a neurodegenerative disorder resulting in social-cognitive deficits partially attributed to abnormalities processing social cues, such as facial expressions. However, to our knowledge, the functional neuroanatomy of deficient social cue processing in individuals with FTD has not been examined. The objective of this study was to delineate the functional abnormalities underlying altered facial expression processing in individuals with FTD using functional magnetic resonance imaging (fMRI).
Methods
Patients meeting Neary criteria for behavioural variant FTD (bvFTD) with supportive neuroimaging and 18 age-matched healthy controls completed an implicit facial expression task during fMRI. We conducted volumetric brain morphometry to correct functional imaging data for volume differences.
Results
We included 20 patients with bvFTD and 18 controls in our study. The results demonstrate emotion-specific functional abnormalities in frontal and limbic regions in patients with bvFTD. Patients also showed decreased activity in posterior ventral visual regions, specifically the fusiform cortex, possibly reflecting reduced afferent input from limbic regions. Finally, bvFTD was associated with increased activity in posterior regions, including the inferior parietal cortex.
Limitations
Autopsy validation of frontotemporal dementia is not yet available for this cohort.
Conclusion
Together, these findings suggest that fMRI combined with tasks targeting social-cognitive deficits is a powerful technique to objectively measure neural systems involved in emotion processing in individuals with bvFTD. As viewing emotional expressions is known to engage many of the same neural systems that are active when experiencing the emotion itself, fMRI during expression processing provides a novel window into the emotions of patients with FTD.
doi:10.1503/jpn.120008
PMCID: PMC3633710  PMID: 23031250
16.  Reduced amygdala-orbitofrontal connectivity during moral judgments in youths with disruptive behavior disorders and psychopathic traits 
Psychiatry research  2011;194(3):279-286.
We used functional magnetic resonance imaging (fMRI) to investigate dysfunction in the amygdala and orbitofrontal cortex in adolescents with disruptive behavior disorders and psychopathic traits during a moral judgment task. Fourteen adolescents with psychopathic traits and 14 healthy controls were assessed using fMRI while they categorized illegal and legal behaviors in a moral judgment implicit association task. fMRI data were then analyzed using random-effects analysis of variance and functional connectivity. Youths with psychopathic traits showed reduced amygdala activity when making judgments about legal actions and reduced functional connectivity between the amygdala and orbitofrontal cortex during task performance. These results suggest that psychopathic traits are associated with amygdala and orbitofrontal cortex dysfunction. This dysfunction may relate to previous findings of disrupted moral judgment in this population.
doi:10.1016/j.pscychresns.2011.07.008
PMCID: PMC3225495  PMID: 22047730
Conduct disorder; psychopathy; moral reasoning; fMRI
17.  Ataxin-2 repeat-length variation and neurodegeneration 
Human Molecular Genetics  2011;20(16):3207-3212.
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
doi:10.1093/hmg/ddr227
PMCID: PMC3140823  PMID: 21610160
18.  Adolescents with psychopathic traits report reductions in physiological responses to fear 
Background
Psychopathy is characterized by profound affective deficits, including shallow affect and reduced empathy. Recent research suggests that these deficits may apply particularly to negative emotions, or to certain negative emotions such as fear. Despite increased focus on the cognitive and neural underpinnings of psychopathy, little is known about how psychopathy is associated with emotional deficits across a range of emotions. In addition, the relationship between psychopathy and the subjective experience of emotion has not yet been assessed.
Methods
Eighteen 10-17-year-olds with psychopathic traits and 24 comparison children and adolescents reported on their subjective experiences of emotion during five recent emotionally evocative life events, following a paradigm developed by Scherer and colleagues (Scherer & Wallbott, 1994). Group comparisons were then performed to assess variations in subjective experiences across emotions.
Results
As predicted, psychopathy was associated with reductions in the subjective experience of fear relative to other emotions. Children and adolescents with psychopathic traits reported fewer symptoms associated with sympathetic nervous system arousal during fear-evoking experiences.
Conclusions
Rather than being related to uniformly impoverished emotional experience, psychopathic traits appear to be associated with greater deficits in subjective experiences of fear. This pattern of responding supports and extends previous observations that psychopathy engenders deficits in fear learning, physiological responses to threats, and the recognition of fear in others.
doi:10.1111/j.1469-7610.2010.02353.x
PMCID: PMC3116087  PMID: 21155775
Psychopathy; emotion; fear; antisocial behavior; autonomic
19.  Altered neural function in pediatric bipolar disorder during reversal learning 
Bipolar Disorders  2010;12(7):707-719.
Objective
Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial-and-error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event-related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls.
Method
We compared euthymic pediatric BD participants (n = 16) versus age-, sex-, and IQ-matched controls (n = 16). Our main outcome measure was blood oxygen level-dependent (BOLD) signal measured with fMRI during an event-related probabilistic reversal task.
Results
Pediatric BD participants had significantly greater neural activity than controls in fronto-parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons).
Conclusions
Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.
doi:10.1111/j.1399-5618.2010.00863.x
PMCID: PMC3391027  PMID: 21040288
adolescent; bipolar disorder; child; magnetic resonance imaging; reversal learning
20.  Abnormal Ventromedial Prefrontal Cortex Function in Children With Psychopathic Traits During Reversal Learning 
Archives of general psychiatry  2008;65(5):586-594.
Context
Children and adults with psychopathic traits and conduct or oppositional defiant disorder demonstrate poor decision making and are impaired in reversal learning. However, the neural basis of this impairment has not previously been investigated. Furthermore, despite high comorbidity of psychopathic traits and attention-deficit/hyperactivity disorder, to our knowledge, no research has attempted to distinguish neural correlates of childhood psychopathic traits and attention-deficit/hyperactivity disorder.
Objective
To determine the neural regions that underlie the reversal learning impairments in children with psychopathic traits plus conduct or oppositional defiant disorder.
Design
Case-control study.
Setting
Government clinical research institute.
Participants
Forty-two adolescents aged 10 to 17 years: 14 with psychopathic traits and oppositional defiant disorder or conduct disorder, 14 with attention-deficit/hyperactivity disorder only, and 14 healthy controls.
Main Outcome Measure
Blood oxygenation level–dependent signal as measured via functional magnetic resonance imaging during a probabilistic reversal task.
Results
Children with psychopathic traits showed abnormal responses within the ventromedial prefrontal cortex (Brodmann area 10) during punished reversal errors compared with children with attention-deficit/hyperactivity disorder and healthy children (P < .05 corrected for multiple comparisons).
Conclusions
To our knowledge, this study provides the first evidence of abnormal ventromedial prefrontal cortex responsiveness in children with psychopathic traits and demonstrates this dysfunction was not attributable to comorbid attention-deficit/hyperactivity disorder. These findings suggest that reversal learning impairments in patients with developmental psychopathic traits relate to abnormal processing of reinforcement information.
doi:10.1001/archpsyc.65.5.586
PMCID: PMC3104600  PMID: 18458210
21.  Altered neural function in pediatric bipolar disorder during reversal learning 
Bipolar disorders  2007;9(7):679-692.
Objective
Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial-and-error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event-related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls.
Method
We compared euthymic pediatric BD participants (n = 16) versus age-, sex-, and IQ-matched controls (n = 16). Our main outcome measure was blood oxygen level-dependent (BOLD) signal measured with fMRI during an event-related probabilistic reversal task.
Results
Pediatric BD participants had significantly greater neural activity than controls in fronto-parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons).
Conclusions
Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.
doi:10.1111/j.1399-5618.2007.00418.x
PMCID: PMC2946159  PMID: 17988357
adolescent; bipolar disorder; child; magnetic resonance imaging; reversal learning
22.  Response to Emotional Expressions in Generalized Social Phobia and Generalized Anxiety Disorder: Evidence for Separate Disorders 
The American journal of psychiatry  2008;165(9):1193-1202.
Objective
Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder.
Method
Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N= 17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment.
Results
The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder.
Conclusions
These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder.
doi:10.1176/appi.ajp.2008.07071060
PMCID: PMC2855133  PMID: 18483136

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