Browsing by Author "Murrell, Jill"

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    APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba
    (Cambridge University Press, 2014-06) Hendrie, Hugh C.; Murrell, Jill; Baiyewu, Olusegun; Lane, Kathleen A.; Purnell, Christianna; Ogunniyi, Adesola; Unverzagt, Frederick W.; Hall, Kathleen; Callahan, Christopher M.; Saykin, Andrew J.; Gureje, Oye; Hake, Ann; Foroud, Tatiana; Gao, Sujuan; Department of Psychiatry, IU School of Medicine
    Background There is little information on the association of the APOEe4 allele and AD risk in African populations. In previous analyses from the Indianapolis-Ibadan dementia project, we have reported that APOE ε4 increased the risk for Alzheimer’s disease (AD) in African Americans but not in Yoruba. This study represents a replication of this earlier work using enriched cohorts and extending the analysis to include cognitive decline. Methods In this longitudinal study of two community dwelling cohorts of elderly Yoruba and African Americans, APOE genotyping was conducted from blood samples taken on or before 2001 (1,871 African Americans & 2,200 Yoruba). Mean follow up time was 8.5 years for African Americans and 8.8 years for Yoruba. The effects of heterozygosity or homozygosity of ε4 and of the possession of e4 on time to incident AD and on cognitive decline were determined using Cox’s proportional hazards regression and mixed effects models. Results After adjusting for covariates, one or two copies of the APOE ε4 allele were significant risk factors for incident AD (p < 0.0001) and cognitive decline in the African-American population (p < 0001). In the Yoruba, only homozygosity for APOE ε4 was a significant risk factor for AD (p = 0.0002) but not for cognitive decline (p = 0.2346), however, possession of an e4 allele was significant for both incident AD (p = 0.0489) and cognitive decline (p = 0.0425). Conclusions In this large longitudinal comparative study, APOE ε4 had a significant, but weaker, effect on incident AD and on cognitive decline in Yoruba than in African Americans. The reasons for these differences remain unclear.
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    Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior
    (Elsevier, 2021) Harris, Holly K.; Nakayama, Tojo; Lai, Jenny; Zhao, Boxun; Argyrou, Nikoleta; Gubbels, Cynthia S.; Soucy, Aubrie; Genetti, Casie A.; Suslovitch, Victoria; Rodan, Lance H.; Tiller, George E.; Lesca, Gaetan; Gripp, Karen W.; Asadollahi, Reza; Hamosh, Ada; Applegate, Carolyn D.; Turnpenny, Peter D.; Simon, Marleen E.H.; Volker-Touw, Catharina M.L.; van Gassen, Koen L.I.; van Binsbergen, Ellen; Pfundt, Rolph; Gardeitchik, Thatjana; de Vries, Bert B.A.; Immken, LaDonna L.; Buchanan, Catherine; Willing, Marcia; Toler, Tomi L.; Fassi, Emily; Baker, Laura; Vansenne, Fleur; Wang, Xiadong; Ambrus, Julian L., Jr.; Fannemel, Madeleine; Posey, Jennifer E.; Agolini, Emanuele; Novelli, Antonio; Rauch, Anita; Boonsawat, Paranchai; Fagerberg, Christina R.; Larsen, Martin J.; Kibaek, Maria; Labalme, Audrey; Poisson, Alice; Payne, Katelyn K.; Walsh, Laurence E.; Aldinger, Kimberly A.; Balciuniene, Jorune; Skraban, Cara; Gray, Christopher; Murrell, Jill; Bupp, Caleb P.; Pascolini, Giulia; Grammatico, Paola; Broly, Martin; Küry, Sébastien; Nizon, Mathilde; Rasool, Iqra Ghulam; Zahoor, Muhammad Yasir; Kraus, Cornelia; Reis, André; Iqbal, Muhammad; Uguen, Kevin; Audebert-Bellanger, Severine; Ferec, Claude; Redon, Sylvia; Baker, Janice; Wu, Yunhong; Zampino, Guiseppe; Syrbe, Steffan; Brosse, Ines; Jamra, Rami Abou; Dobyns, William B.; Cohen, Lilian L.; Blomhoff, Anne; Mignot, Cyril; Keren, Boris; Courtin, Thomas; Agrawal, Pankaj B.; Beggs, Alan H.; Yu, Timothy W.; Neurology, School of Medicine
    Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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    The effects of DAT1 genotype on fMRI activation in an emotional go/no-go task
    (Springer, 2017-02) Brown, Brenna K.; Murrell, Jill; Karne, Harish; Anand, Amit; Pathology and Laboratory Medicine, School of Medicine
    Dopaminergic brain circuits participate in emotional processing and impulsivity. The dopamine transporter (DAT) modulates dopamine reuptake. A variable number tandem repeat (VNTR) in the dopamine transporter gene (DAT1) affects DAT expression. The influence of DAT1 genotype on neural activation during emotional processing and impulse inhibition has not been examined. Forty-two healthy subjects were classified as 9DAT (n = 17) or 10DAT (n = 25) based on DAT1 genotype (9DAT = 9R/9R and 9R/10R; 10DAT = 10R/10R). Subjects underwent fMRI during non-emotional and emotional go/no-go tasks. Subjects were instructed to inhibit responses to letters, happy faces, or sad faces in separate blocks. Accuracy and reaction time did not differ between groups. Within group results showed activation in regions previously implicated in emotional processing and response inhibition. Between groups results showed increased activation in 9DAT individuals during inhibition. During letter inhibition, 9DAT individuals exhibited greater activation in right inferior parietal regions. During sad inhibition, 9DAT Individuals exhibited greater activation in frontal, posterior cingulate, precuneus, right cerebellar, left paracentral, and right occipital brain regions. The interaction between DAT genotype and response type in sad versus letter stimuli showed increased activation in 9DAT individuals during sad no-go responses in the anterior cingulate cortex, extending into frontal-orbital regions. 9DAT individuals have greater activation than 10DAT individuals during neutral and sad inhibition, showing that genotypic variation influencing basal dopamine levels can alter the neural basis of emotional processing and response inhibition. This may indicate that 9R carriers exert more effort to overcome increased basal dopamine activation when inhibiting responses in emotional contexts.
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    Effects of Lithium Monotherapy for Bipolar Disorder on Gene Expression in Peripheral Lymphocytes
    (Karger Publishers, 2016-10) Anand, Amit; McClintick, Jeanette N.; Murrell, Jill; Karne, Harish; Nurnberger, John I.; Edenberg, Howard J.; Psychiatry, School of Medicine
    Background This study investigated the effect of lithium monotherapy on peripheral lymphocyte gene expression in bipolar disorder (BD). Method Twenty-two medication-free bipolar subjects (11 hypomanic, 11 depressed) were started on lithium monotherapy. Closely matched healthy subjects (n = 15) were included as controls but did not receive treatment. Blood RNA samples were collected at baseline and after 2 and 8 weeks of treatment. RNA expression was measured using the Affymetrix GeneChip® Human Gene 1.0 ST Array followed by Ingenuity pathways analysis. The results for the contrast of weeks 2 and 8 were not significantly different and were combined. Results In BD subjects, 56 genes showed significant (false discovery rate <0.1) expression changes from baseline; the effect sizes and directions for all of these were similar at weeks 2 and 8. Among these were immune-related genes (IL5RA, MOK, IFI6, and RFX2), purinergic receptors (P2RY14, P2RY2, and ADORA3) and signal transduction-related genes (CAMK1 and PIK3R6). Pathway and upstream regulator analysis also revealed that lithium altered several immune- and signal transduction-related functions. Differentially expressed genes did not correlate with week 8 clinical response, but other genes involved in protein synthesis and degradation did. Conclusion Peripheral gene expression may serve as a biomarker of lithium effect.
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    Enlarging the Nosological Spectrum of Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids (HDLS)
    (Wiley, 2014-09) Hoffmann, Sarah; Murrell, Jill; Harms, Lutz; Miller, Kelly; Meisel, Andreas; Brosch, Thomas; Scheel, Michael; Ghetti, Bernardino; Goebel, Hans-Hilmar; Stenzel, Werner; Pathology and Laboratory Medicine, School of Medicine
    Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.
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    Genetic architecture of age-related cognitive decline in African Americans
    (American Academy of Neurology, 2016-12-21) Raj, Towfique; Chibnik, Lori B.; McCabe, Cristin; Wong, Andus; Replogle, Joseph M.; Yu, Lei; Gao, Sujuan; Unverzagt, Frederick W.; Stranger, Barbara; Murrell, Jill; Barnes, Lisa; Hendrie, Hugh C.; Foroud, Tatiana; Krichevsky, Anna; Bennett, David A.; Hall, Kathleen S.; Evans, Denis A.; De Jager, Philip L.; Department of Biostatistics, Richard M. Fairbanks School of Public Health
    OBJECTIVE: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs). METHODS: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS. RESULTS: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility. CONCLUSIONS: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.
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    Homocysteine levels and dementia risk in Yoruba and African Americans
    (Elsevier, 2013) Hendrie, Hugh C.; Baiyewu, Olusegun; Lane, Kathleen A.; Purnell, Christianna; Gao, Sujuan; Hake, Ann; Ogunniyi, Adesola; Gureje, Oye; Unverzagt, Frederick W.; Murrell, Jill; Deeg, Mark A.; Hall, Kathleen; Psychiatry, School of Medicine
    Background: High levels of homocysteine have been associated with increased risk for dementia although results have been inconsistent. There are no reported studies from the developing world including Africa. Methods: In this longitudinal study of two community-dwelling cohorts of elderly Yoruba and African Americans, levels of homocysteine, vitamin B12 and folate were measured from blood samples taken in 2001. These levels were compared in two groups, participants who developed incident dementia in the follow-up until 2009 (59 Yoruba and 101 African Americans) and participants who were diagnosed as cognitively normal or in the good performance category at their last follow-up (760 Yoruba and 811 African Americans). Homocysteine levels were divided into quartiles for each site. Results: After adjusting for age, education, possession of ApoE, smoking, and time of enrollment the higher quartiles of homocysteine were associated with a non-significant increase in dementia risk in the Yoruba (homocysteine quartile 4 vs. 1 OR: 2.19, 95% CI 0.95-5.07, p = 0.066). For the African Americans, there was a similar but non-significant relationship between higher homocysteine levels and dementia risk. There were no significant relationships between levels of vitamin B12 and folate and incident dementia in either site although folate levels were lower and vitamin B12 levers were higher in the Yoruba than in the African Americans. Conclusions: Increased homocysteine levels were associated with a similar but non-significant increase in dementia risk for both Yoruba and African Americans despite significant differences in folate levels between the two sites.
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    Increased Tau Phosphorylation and Tau Truncation, and Decreased Synaptophysin Levels in Mutant BRI2/Tau Transgenic Mice
    (Public Library of Science, 2013) Garringer, Holly J.; Murrell, Jill; Sammeta, Neeraja; Gnezda, Anita; Ghetti, Bernardino; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
    Familial Danish dementia (FDD) is an autosomal dominant neurodegenerative disease caused by a 10-nucleotide duplication-insertion in the BRI(2) gene. FDD is clinically characterized by loss of vision, hearing impairment, cerebellar ataxia and dementia. The main neuropathologic findings in FDD are the deposition of Danish amyloid (ADan) and the presence of neurofibrillary tangles (NFTs). Here we investigated tau accumulation and truncation in double transgenic (Tg-FDD-Tau) mice generated by crossing transgenic mice expressing human Danish mutant BRI(2) (Tg-FDD) with mice expressing human 4-repeat mutant Tau-P301S (Tg-Tau). Compared to Tg-Tau mice, we observed a significant enhancement of tau deposition in Tg-FDD-Tau mice. In addition, a significant increase in tau cleaved at aspartic acid (Asp) 421 was observed in Tg-FDD-Tau mice. Tg-FDD-Tau mice also showed a significant decrease in synaptophysin levels, occurring before widespread deposition of fibrillar ADan and tau can be observed. Thus, the presence of soluble ADan/mutant BRI(2) can lead to significant changes in tau metabolism and synaptic dysfunction. Our data provide new in vivo insights into the pathogenesis of FDD and the pathogenic pathway(s) by which amyloidogenic peptides, regardless of their primary amino acid sequence, can cause neurodegeneration.
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    Modeling familial British and Danish dementia
    (SpringerLink, 2010-03) Garringer, Holly J.; Murrell, Jill; D’Adamio, Luciano; Ghetti, Bernardino; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
    Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI ( 2 ) gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles. Transgenic mice expressing wild-type and mutant forms of the BRI(2) protein, Bri ( 2 ) knock-in mutant mice, and Bri ( 2 ) gene knock-out mice have been developed. Transgenic mice expressing a human FDD-mutated form of the BRI ( 2 ) gene have partially reproduced the neuropathological lesions observed in FDD. These mice develop extensive CAA, parenchymal amyloid deposition, and neuroinflammation in the central nervous system. These animal models allow the study of the molecular mechanism(s) underlying the neuronal dysfunction in these diseases and allow the development of potential therapeutic approaches for these and related neurodegenerative conditions. In this review, a comprehensive account of the advances in the development of animal models for FBD and FDD and of their relevance to the study of Alzheimer disease is presented.
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    Statin Use, Incident Dementia and Alzheimer Disease in Elderly African Americans
    (International Society on Hypertension in Blacks, 2015) Hendrie, Hugh C.; Hake, Ann; Lane, Kathleen; Purnell, Christianna; Unverzagt, Frederick; Smith-Gamble, Valerie; Murrell, Jill; Ogunniyi, Adesola; Baiyewu, Olusegun; Callahan, Chris; Saykin, Andrew J.; Taylor, Stanley; Hall, Kathleen; Gao, Su; Department of Neurology, IU School of Medicine
    OBJECTIVE: To investigate the association between statin use, incident dementia, and Alzheimer disease (AD) in a prospective elderly African American cohort. DESIGN: Two stage design with a screening interview followed by a comprehensive in-home assessment conducted over an eight-year period. Diagnoses of incident AD and dementia were made by consensus. Statin use was collected at each evaluation. Measurements of low-density lipoprotein cholesterol (LDL), C-reactive protein (CRP) and APOE genotype were obtained from baseline blood samples. Logistic regression models were used to test the association of statin use on incident dementia and AD and its possible association with lipid and CRP levels. SETTING: Indianapolis, Indiana. PARTICIPANTS: From an original cohort of 2629 participants, a subsample of 974 African Americans aged >70 years with normal cognition, at least one follow up evaluation, complete statin information, and biomarker availability were included. MAIN OUTCOME MEASURES: Incident dementia and incident AD. RESULTS: After controlling for age at diagnosis, sex, education level, presence of the APOE ε4 allele and history of stroke for the incident dementia model, baseline use of statins was associated with a significantly decreased risk of incident dementia (OR=.44, P=.029) and incident AD (OR=.40, P=.029). The significant effect of statin use on reduced AD risk and trend for dementia risk was found only for those participants who reported consistent use over the observational period (incident AD: P=.034; incident dementia: P=.061). Additional models found no significant interaction between baseline statin use, baseline LDL, or CRP level and incident dementia/AD. CONCLUSIONS: Consistent use of statin medications during eight years of follow-up resulted in significantly reduced risk for incident AD and a trend toward reduced risk for incident dementia.