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1. Study protocol for a randomized controlled trial of telephone-delivered cognitive behavior therapy compared with befriending for treating depression and anxiety in older adults with COPD

Author

Doyle C, Dunt D, Ames D, Fearn M, You E, and Bhar S

Subjects
chronic obstructive pulmonary disease (COPD), depression, anxiety, telephone, cognitive behaviour therapy (CBT), befriending, Diseases of the respiratory system, RC705-779
Abstract

Colleen Doyle,1 David Dunt,2 David Ames,3 Marcia Fearn,3 Emily (Chuanmei) You,1 Sunil Bhar41Australian Catholic University, Melbourne, VIC, Australia; 2Centre for Health Policy, The University of Melbourne, Melbourne, VIC, Australia; 3National Ageing Research Institute, Melbourne, VIC, Australia; 4Department of Psychological Sciences, Swinburne University of Technology, Hawthorn, VIC, AustraliaBackground: COPD is an umbrella term to describe chronic lung diseases that cause limitations in lung airflow, including emphysema and chronic bronchitis. The prevalence of depression and anxiety in people with COPD is high, although these comorbidities are often undiagnosed, untreated, or undertreated. There is a need to identify efficacious treatments for depression and anxiety in people with COPD. Cognitive behavior therapy (CBT) for the treatment of anxiety and depression has a strong evidence base. There has been some success delivering this treatment over the telephone in limited studies. The aim of this study is to evaluate the efficacy of both telephone-administered CBT and befriending on outcomes for patients with diagnosed COPD who have at least mild levels of depression and/or anxiety.Methods: The protocol described in this paper is of a pragmatic randomized controlled trial comparing eight sessions of telephone CBT to an active social control, referred to as befriending. Primary outcome measures will include depression and anxiety symptoms, and secondary outcome measures will include quality of life, self-efficacy, and COPD symptom severity. Participants’ satisfaction with the intervention and therapeutic alliance will also be assessed. Measures will be taken pre- and postdelivery of the intervention and again at 8 weeks following the intervention.Conclusion: People with COPD often have limitations to their mobility because of their breathlessness. They are often already attending many medical appointments and could be reluctant to attend for face-to-face psychological treatment. The results of this study should identify the relative efficacy of CBT delivered over the telephone to this population, which, if successful, may be a cost-effective and more palatable alternative to face-to-face treatment of depression or anxiety for this population.Keywords: chronic obstructive pulmonary disease (COPD), depression, anxiety, telephone, cognitive behavior therapy (CBT), befriending

Published
2016

2. Managing mood disorders in patients attending pulmonary rehabilitation clinics

Author

Selvarajah S, Ames D, Dunt D, and Doyle C

Subjects
Diseases of the respiratory system, RC705-779
Abstract

Colleen Doyle,1–3 David Dunt,2 David Ames,1 Suganya Selvarajah11National Ageing Research Institute, Royal Melbourne Hospital Royal Park Campus, Parkville, Victoria, Australia; 2Centre for Health Policy, Programs and Economics, University of Melbourne, Parkville, Victoria, Australia; 3Australian Catholic University, Fitzroy, Victoria, AustraliaBackground: There is good evidence for the positive benefits of pulmonary rehabilitation (PR) in the prevention of hospital admissions, lower mortality, and improved health-related quality of life. There is also increasing evidence about the impact of PR on mental health and, in particular, mood disorders. We aimed to identify how depression in chronic obstructive pulmonary disease (COPD) patients in Victoria, Australia, is being managed in PR, to identify the prevalence of depressive symptoms among COPD patients who attend PR, and to determine whether patients with depressive symptoms or anxiety symptoms dropped out of PR early.Method: Of 61 PR clinics, 44 were invited and 22 agreed to participate. Telephone interviews were conducted to see how depression and anxiety in COPD patients were being recognized and managed in these clinics. A total of 294 questionnaires were distributed to patients by clinic coordinators to determine the prevalence of anxiety/depression, as measured by the Hospital Anxiety and Depression Scale. Coordinators were contacted to provide information on whether respondents dropped out of rehabilitation early or continued with their treatment at 2–4 months post program.Results: Seven clinics were not aware of local guidelines on assessment/treatment/management of mood. Four clinics did not use any screening tools or other aids in the recognition and management of depression and/or anxiety. Overall, eight clinics participating in this study requested advice on suitable screening tools. The patient survey indicated that the mean depression score on the Hospital Anxiety and Depression Scale was 5.0 (standard deviation 3.0, range 1–13). The mean anxiety score was 5.5 (standard deviation 3.4, range 0–18). There was no evidence of a link between failure to complete rehabilitation and depression or anxiety scores, as only three of 105 patients failed to complete their rehabilitation.Discussion: Awareness of management guidelines for depression and anxiety in COPD patients was variable across the clinics recruited into our study. We found no link between compliance with rehabilitation and depression, but our sample had limitations.Conclusion: Future research needs to investigate how best to encourage more use of available guidelines regarding integrating psychological and psychosocial support to supplement the exercise and education that are currently offered routinely by all PR clinics studied in Victoria, Australia.Keywords: chronic obstructive pulmonary disease, depression, anxiety, pulmonary rehabilitation

Published
2013

4. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Author

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF

Subjects
Generation Scotland, Humans, Genetic Predisposition to Disease, HMGN1 Protein, Cohort Studies, Cognition, Cognition Disorders, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Scotland, Female, Male, Atherosclerosis, Genome-Wide Association Study, and over, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015

12. Vulnerability, social value and the equitable sharing of benefits from research: beyond the placebo and access debates

Author

Chieko Kurihara, Dirceu Greco, Ames Dhai, Kotone Matsuyama, and Varvara Baroutsou

Subjects
vulnerability, social value, post-trial access, global health, Declaration of Helsinki, Medicine (General), R5-920
Abstract

The vulnerability of research participants is a critical topic for the 2024 revision of the Declaration of Helsinki, with the proposal to include “social value. ” However, this proposal has been withdrawn and the relationship between the two concepts has not been clarified. This paper attempts to clarify: (1) the recent reform for the ethical inclusion of vulnerable study participants to promote diversity; (2) the social value, prerequisite for everyone, especially for those who are vulnerable and the most in need; (3) the requirements for promoting the inclusion of vulnerable participants, in particular the review of the norms for placebo-controlled trials and post-trial access; (4) finally, the direction of research ethics reform to achieve social value and equitable global health.

Published
2024
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21. Alzheimer's disease progression and risk factors: A standardized comparison between six large data sets

Author

Evans, S, McRae-McKee, K, Hadjichrysanthou, C, Wong, MM, Ames, D, Lopez, O, De Wolf, F, Anderson, RM, Australian Imaging Biomarkers and Lifestyle flagship study of ageing, Predictors of Cognitive Decline Among Normal Individuals (BIOCARD) study, Add Neuro Med Consortium, and Janssen Vaccines & Prevention B.V

Subjects
0301 basic medicine, medicine.medical_specialty, Epidemiology, Add Neuro Med Consortium, Disease, Markov model, 03 medical and health sciences, 0302 clinical medicine, Medicine, Dementia, Mixed regression, business.industry, Biological risk factors, Disease progression, Modeling, Mild cognitive impairment, Predictors of Cognitive Decline Among Normal Individuals (BIOCARD) study, Featured Article, medicine.disease, Clinical trial, Psychiatry and Mental health, 030104 developmental biology, Statistical analysis, Australian Imaging Biomarkers and Lifestyle flagship study of ageing, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study, Demography
Abstract

There exist a large number of cohort studies that have been used to identify genetic and biological risk factors for developing Alzheimer's disease (AD). However, there is a disagreement between studies as to how strongly these risk factors affect the rate of progression through diagnostic groups toward AD. We have calculated the probability of transitioning through diagnostic groups in six studies and considered how uncertainty around the strength of the effect of these risk factors affects estimates of the distribution of individuals in each diagnostic group in an AD clinical trial simulator. In this work, we identify the optimal choice of widely collected variables for comparing data sets and calculating probabilities of progression toward AD. We use the estimated transition probabilities to inform stochastic simulations of AD progression that are based on a Markov model and compare predicted incidence rates to those in a community-based study, the Cardiovascular Health Study.

Published
2019

25. Cerebral small vessel disease genomics and its implications across the lifespan

Author

Sargurupremraj, M., Suzuki, H., Jian, X.Q., Sarnowski, C., Evans, T.E., Bis, J.C., Eiriksdottir, G., Sakaue, S., Terzikhan, N., Habes, M., Zhao, W., Armstrong, N.J., Hofer, E., Yanek, L.R., Hagenaars, S.P., Kumar, R.B., Akker, E.B. van den, McWhirter, R.E., Trompet, S., Mishra, A., Saba, Y., Satizabal, C.L., Beaudet, G., Petit, L., Tsuchida, A., Zago, L., Schilling, S., Sigurdsson, S., Gottesman, R.F., Lewis, C.E., Aggarwal, N.T., Lopez, O.L., Smith, J.A., Hernandez, M.C.V., Grond, J. van der, Wright, M.J., Knol, M.J., Dorr, M., Thomson, R.J., Bordes, C., Grand, Q. le, Duperron, M.G., Smith, A.V., Knopman, D.S., Schreiner, P.J., Evans, D.A., Rotter, J.I., Beiser, A.S., Maniega, S.M., Beekman, M., Trollor, J., Stott, D.J., Vernooij, M.W., Wittfeld, K., Niessen, W.J., Soumare, A., Boerwinkle, E., Sidney, S., Turner, S.T., Davies, G., Thalamuthu, A., Volker, U., Buchem, M.A. van, Bryan, R.N., Dupuis, J., Bastin, M.E., Ames, D., Teumer, A., Amouyel, P., Kwok, J.B., Bulow, R., Deary, I.J., Schofield, P.R., Brodaty, H., Jiang, J.Y., Tabara, Y., Setoh, K., Miyamoto, S., Yoshida, K., Nagata, M., Kamatani, Y., Matsuda, F., Psaty, B.M., Bennett, D.A., Jager, P.L. de, Mosley, T.H., Sachdev, P.S., Schmidt, R., Warren, H.R., Evangelou, E., Tregouet, D.A., Ikram, M.A., Wen, W., DeCarli, C., Srikanth, V.K., Jukema, J.W., Slagboom, E.P., Kardia, S.L.R., Okada, Y., Mazoyer, B., Wardlaw, J.M., Nyquist, P.A., Mather, K.A., Grabe, H.J., Schmidt, H., Duijn, C.M. van, Gudnason, V., Longstreth, W.T., Launer, L.J., Lathrop, M., Seshadri, S., Tzourio, C., Adams, H.H., Matthews, P.M., Fornage, M., Debette, S., Int Network Thrombosis INVENT Cons, and Int Headache Genomics Consortium I

Subjects
Adult, Male, Science, BLOOD-PRESSURE, Risk Assessment, behavioral disciplines and activities, GENETIC ARCHITECTURE, Young Adult, Alzheimer Disease, Risk Factors, mental disorders, WHITE-MATTER HYPERINTENSITIES, WIDE ASSOCIATION, Humans, International Headache Genomics Consortium (IHGC), CELL-TYPES, Medical History Taking, METAANALYSIS, AGING RESEARCH, Aged, RISK, Aged, 80 and over, Science & Technology, Mendelian Randomization Analysis, Middle Aged, COGNITIVE IMPAIRMENT, White Matter, Multidisciplinary Sciences, Stroke, Diffusion Tensor Imaging, Genetic Loci, Cerebral Small Vessel Diseases, Hypertension, MENDELIAN RANDOMIZATION, Science & Technology - Other Topics, Female, International Network against Thrombosis (INVENT) Consortium, Genome-Wide Association Study
Abstract

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Published
2020

29. Integrated care improves risk-factor modification after stroke: initial results of the Integrated Care for the Reduction of Secondary Stroke Model

Author

Joubert, J., Reid, C., Barton, D., Cumming, T., McLean, A., Joubert, L., Barlow, J., Ames, D., and Davis, S.

Subjects
Interdisciplinary approach in education -- Models, Interdisciplinary approach in education -- Research, Stroke (Disease) -- Care and treatment, Stroke (Disease) -- Complications and side effects, Stroke (Disease) -- Risk factors, Stroke (Disease) -- Research, Practice guidelines (Medicine) -- Usage, Diseases -- Relapse, Diseases -- Risk factors, Diseases -- Prevention, Diseases -- Research, Health, Psychology and mental health
Published
2009

32. Cereb Cortex

Author

Shin, J., Ma, S., Hofer, E., Patel, Y., VOSBERG, D. E., TILLEY, S., ROSHCHUPKIN, G. V., SOUSA, A. M. M., JIAN, X., GOTTESMAN, R., MOSLEY, T. H., FORNAGE, M., SABA, Y., PIRPAMER, L., Schmidt, R., Schmidt, H., CARRION-CASTILLO, A., Crivello, F., Mazoyer, B., BIS, J. C., Li, S., Yang, Q., LUCIANO, M., Karama, S., Lewis, L., BASTIN, M. E., HARRIS, M. A., WARDLAW, J. M., DEARY, I. E., Scholz, M., Loeffler, M., WITTE, A. V., Beyer, F., VILLRINGER, A., ARMSTRONG, N. J., MATHER, K. A., Ames, D., Jiang, J., KWOK, J. B., SCHOFIELD, P. R., THALAMUTHU, A., TROLLOR, J. N., WRIGHT, M. J., BRODATY, H., Wen, W., SACHDEV, P. S., TERZIKHAN, N., EVANS, T. E., ADAMS, Hhhh, Ikram, M. A., FRENZEL, S., AUWERA-PALITSCHKA, S. V., WITTFELD, K., BULOW, R., Grabe, H. J., Tzourio, Christophe, Mishra, Aniket, MAINGAULT, S., Debette, Stéphanie, GILLESPIE, N. A., FRANZ, C. E., KREMEN, W. S., Ding, L., JAHANSHAD, N., Sestan, N., PAUSOVA, Z., SESHADRI, S., PAUS, T., Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
endocrine system, VINTAGE, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.

Published
2020

33. Genetic architecture of subcortical brain structures in 38,854 individuals worldwide

Author

Satizabal, C., Adams, H., Hibar, D., White, C., Knol, M., Stein, J., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G., Smith, A., Bis, J., Jian, X., Luciano, M., Hofer, E., Teumer, A., Van der Lee, S., Yang, J., Yanek, L., Lee, T., Li, S., Hu, Y., Koh, J., Eicher, J., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M., Kim, S., Höhn, D., Armstrong, N., Chen, Q., Holmes, A., Den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A., Jones, H., Pike, G., Stein, D., Stevens, A., Bralten, J., Vernooij, M., Harris, T., Filippi, I., Witte, A., Guadalupe, T., Wittfeld, K., Mosley, T., Becker, J., Doan, N., Hagenaars, S., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Karbalai, N., Arfanakis, K., Becker, D., Ames, D., Goldman, A., Lee, P., Boomsma, D., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M., Kasperaviciute, D., Schmaal, L., Lawrie, S., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G., Shin, J., Ipser, J., Vinke, L., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U., Aribisala, B., Schmidt, H., Strike, L., Cheng, C., Risacher, S., Pütz, B., Fleischman, D., Assareh, A., Mattay, V., Buckner, R., Mecocci, P., Dale, A., Cichon, S., Boks, M., Matarin, M., Penninx, B., Calhoun, V., Chakravarty, M., Marquand, A., Macare, C., Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J., Schork, A., Liewald, D., De Zubicaray, G., Wong, T., Shen, L., Sämann, P., Brodaty, H., Roffman, J., De Geus, E., Tsolaki, M., Erk, S., Van Eijk, K., Cavalleri, G., Van der Wee, N., McIntosh, A., Gollub, R., Bulayeva, K., Bernard, M., Richards, J., Himali, J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L., Valdés Hernández, M., Hansell, N., Van Erp, T., Wolf, C., Kwok, J., Vellas, B., Heinz, A., Olde Loohuis, L., Delanty, N., Ho, B., Ching, C., Shumskaya, E., Singh, B., Hofman, A., Van der Meer, D., Homuth, G., Psaty, B., Bastin, M., Montgomery, G., Foroud, T., Reppermund, S., Hottenga, J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C., Van Donkelaar, M., Yang, Q., Hosten, N., Green, R., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H., Lin, H., Jack Jr., C., Schofield, P., Mühleisen, T., Maillard, P., Potkin, S., Wen, W., Fletcher, E., Toga, A., Gruber, O., Huentelman, M., Smith, G., Launer, L., Nyberg, L., Jönsson, E., Crespo-Facorro, B., Koen, N., Greve, D., Uitterlinden, A., Weinberger, D., Steen, V., Fedko, I., Groenewold, N., Niessen, W., Toro, R., Tzourio, C., Longstreth Jr., W., Ikram, M., Smoller, J., Van Tol, M., Sussmann, J., Paus, T., Lemaître, H., Schroeter, M., Mazoyer, B., Andreassen, O., Holsboer, F., Depondt, C., Veltman, D., Turner, J., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I., McMahon, K., Müller-Myhsok, B., Brouwer, R., Soininen, H., Pandolfo, M., Wassink, T., Cheung, J., Wolfers, T., Martinot, J., Zwiers, M., Nauck, M., Melle, I., Martin, N., Kanai, R., Westman, E., Kahn, R., Sisodiya, S., White, T., Saremi, A., Van Bokhoven, H., Brunner, H., Völzke, H., Wright, M., Van 't Ent, D., Nöthen, M., Ophoff, R., Buitelaar, J., Fernández, G., Sachdev, P., Rietschel, M., Van Haren, N., Fisher, S., Beiser, A., Francks, C., Saykin, A., Mather, K., Romanczuk-Seiferth, N., Hartman, C., DeStefano, A., Heslenfeld, D., Weiner, M., Walter, H., Hoekstra, P., Nyquist, P., Franke, B., Bennett, D., Grabe, H., Johnson, A., Chen, C., Van Duijn, C., Lopez, O., Fornage, M., Wardlaw, J., Schmidt, R., DeCarli, C., De Jager, P., Villringer, A., Debette, S., Gudnason, V., Medland, S., Shulman, J., Thompson, P., and Seshadri, S.

Subjects
nervous system
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

34. Enantioselective inhibitory abilities of enantiomers of notoamides against RANKL-induced formation of multinuclear osteoclasts

Author

Sunderhaus, James D., McAfoos, Timothy J., Finefield, Jennifer M., Williams, Robert M., Hikaru, Kato, Aika, Kai, Tetsuro, Kawabata, ames D. , SunderhausJ, Timothy J. , McAfoos, Jennifer M. , Finefield, Yukihiko, Sugimoto, Robert M. , Williams, and Sachiko, Tsukamoto

Subjects
Osteoclastogenesis, Stereochemistry, Clinical Biochemistry, Osteoclasts, Pharmaceutical Science, 010402 general chemistry, 01 natural sciences, Biochemistry, Indole Alkaloids, Notoamide, 474.73, Inhibitory Concentration 50, Mice, Prenylation, 499.3, Drug Discovery, Animals, Receptor, Molecular Biology, IC50, Indole test, Fungus, biology, Enantiomer, 010405 organic chemistry, Chemistry, Activator (genetics), RANK Ligand, Organic Chemistry, Fungi, Cell Differentiation, Stereoisomerism, Ligand (biochemistry), 0104 chemical sciences, RAW 264.7 Cells, Aspergillus, RANKL, biology.protein, Molecular Medicine
Abstract

The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (−)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)–induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (−)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7 μM.

Published
2017

50. The interactive effect of demographic and clinical factors on hippocampal volume: A multicohort study on 1958 cognitively normal individuals

Author

Ferreira, D, Hansson, O, Barroso, J, Molina, Y, Machado, A, Hernández-Cabrera, J, Muehlboeck, J, Stomrud, E, Nägga, K, Lindberg, O, Ames, D, Kalpouzos, G, Fratiglioni, L, Bäckman, L, Graff, C, Mecocci, P, Vellas, B, Tsolaki, M, Kłoszewska, I, Soininen, H, Lovestone, S, Ahlström, H, Lind, L, Larsson, E, Wahlund, L, Simmons, A, Westman, E, consortium, AddNeuroMed, (ADNI), Alzheimer's Disease Neuroimaging Initiative, and group, Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL) research

Subjects
Aging, medicine.medical_specialty, Neurology, Cognitive Neuroscience, Multicohort, Population, Disease, Hippocampus, 050105 experimental psychology, Cohort Studies, 03 medical and health sciences, Magnetic resonance imaging, 0302 clinical medicine, Global brain atrophy, medicine, Humans, 0501 psychology and cognitive sciences, education, Analysis of covariance, education.field_of_study, Alzheimer's disease, Hippocampal volume, 05 social sciences, Contrast (statistics), Organ Size, Analysis of variance, Psychology, Neuroscience, 030217 neurology & neurosurgery, Cohort study
Abstract

Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.

Published
2017

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