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3. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Author

Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, Debette, S, Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, and Debette, S

Abstract

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

Published
2023

4. Genetic variants associated with longitudinal changes in brain structure across the lifespan

Author

Brouwer, RM, Klein, M, Grasby, KL, Schnack, HG, Jahanshad, N, Teeuw, J, Thomopoulos, SI, Sprooten, E, Franz, CE, Gogtay, N, Kremen, WS, Panizzon, MS, Olde Loohuis, LM, Whelan, CD, Aghajani, M, Alloza, C, Alanaes, D, Artiges, E, Ayesa-Arriola, R, Barker, GJ, Bastin, ME, Blok, E, Boen, E, Breukelaar, IA, Bright, JK, Buimer, EEL, Bulow, R, Cannon, DM, Ciufolini, S, Crossley, NA, Damatac, CG, Dazzan, P, de Mol, CL, de Zwarte, SMC, Desrivieres, S, Diaz-Caneja, CM, Doan, NT, Dohm, K, Froehner, JH, Goltermann, J, Grigis, A, Grotegerd, D, Han, LKM, Harris, MA, Hartman, CA, Heany, SJ, Heindel, W, Heslenfeld, DJ, Hohmann, S, Ittermann, B, Jansen, PR, Janssen, J, Jia, T, Jiang, J, Jockwitz, C, Karali, T, Keeser, D, Koevoets, MGJC, Lenroot, RK, Malchow, B, Mandl, RCW, Medel, V, Meinert, S, Morgan, CA, Muehleisen, TW, Nabulsi, L, Opel, N, de la Foz, VO-G, Overs, BJ, Paillere Martinot, M-L, Redlich, R, Marques, TR, Repple, J, Roberts, G, Roshchupkin, GV, Setiaman, N, Shumskaya, E, Stein, F, Sudre, G, Takahashi, S, Thalamuthu, A, Tordesillas-Gutierrez, D, van der Lugt, A, van Haren, NEM, Wardlaw, JM, Wen, W, Westeneng, H-J, Wittfeld, K, Zhu, AH, Zugman, A, Armstrong, NJ, Bonfiglio, G, Bralten, J, Dalvie, S, Davies, G, Di Forti, M, Ding, L, Donohoe, G, Forstner, AJ, Gonzalez-Penas, J, Guimaraes, JPOFT, Homuth, G, Hottenga, J-J, Knol, MJ, Kwok, JBJ, Le Hellard, S, Mather, KA, Milaneschi, Y, Morris, DW, Noethen, MM, Papiol, S, Rietschel, M, Santoro, ML, Steen, VM, Stein, JL, Streit, F, Tankard, RM, Teumer, A, van 't Ent, D, van der Meer, D, van Eijk, KR, Vassos, E, Vazquez-Bourgon, J, Witt, SH, Adams, HHH, Agartz, I, Ames, D, Amunts, K, Andreassen, OA, Arango, C, Banaschewski, T, Baune, BT, Belangero, SI, Bokde, ALW, Boomsma, DI, Bressan, RA, Brodaty, H, Buitelaar, JK, Cahn, W, Caspers, S, Cichon, S, Crespo-Facorro, B, Cox, SR, Dannlowski, U, Elvsashagen, T, Espeseth, T, Falkai, PG, Fisher, SE, Flor, H, Fullerton, JM, Garavan, H, Gowland, PA, Grabe, HJ, Hahn, T, Heinz, A, Hillegers, M, Hoare, J, Hoekstra, PJ, Ikram, MA, Jackowski, AP, Jansen, A, Jonsson, EG, Kahn, RS, Kircher, T, Korgaonkar, MS, Krug, A, Lemaitre, H, Malt, UF, Martinot, J-L, McDonald, C, Mitchell, PB, Muetzel, RL, Murray, RM, Nees, F, Nenadic, I, Oosterlaan, J, Ophoff, RA, Pan, PM, Penninx, BWJH, Poustka, L, Sachdev, PS, Salum, GA, Schofield, PR, Schumann, G, Shaw, P, Sim, K, Smolka, MN, Stein, DJ, Trollor, JN, van den Berg, LH, Veldink, JH, Walter, H, Westlye, LT, Whelan, R, White, T, Wright, MJ, Medland, SE, Franke, B, Thompson, PM, Hulshoff Pol, HE, Brouwer, RM, Klein, M, Grasby, KL, Schnack, HG, Jahanshad, N, Teeuw, J, Thomopoulos, SI, Sprooten, E, Franz, CE, Gogtay, N, Kremen, WS, Panizzon, MS, Olde Loohuis, LM, Whelan, CD, Aghajani, M, Alloza, C, Alanaes, D, Artiges, E, Ayesa-Arriola, R, Barker, GJ, Bastin, ME, Blok, E, Boen, E, Breukelaar, IA, Bright, JK, Buimer, EEL, Bulow, R, Cannon, DM, Ciufolini, S, Crossley, NA, Damatac, CG, Dazzan, P, de Mol, CL, de Zwarte, SMC, Desrivieres, S, Diaz-Caneja, CM, Doan, NT, Dohm, K, Froehner, JH, Goltermann, J, Grigis, A, Grotegerd, D, Han, LKM, Harris, MA, Hartman, CA, Heany, SJ, Heindel, W, Heslenfeld, DJ, Hohmann, S, Ittermann, B, Jansen, PR, Janssen, J, Jia, T, Jiang, J, Jockwitz, C, Karali, T, Keeser, D, Koevoets, MGJC, Lenroot, RK, Malchow, B, Mandl, RCW, Medel, V, Meinert, S, Morgan, CA, Muehleisen, TW, Nabulsi, L, Opel, N, de la Foz, VO-G, Overs, BJ, Paillere Martinot, M-L, Redlich, R, Marques, TR, Repple, J, Roberts, G, Roshchupkin, GV, Setiaman, N, Shumskaya, E, Stein, F, Sudre, G, Takahashi, S, Thalamuthu, A, Tordesillas-Gutierrez, D, van der Lugt, A, van Haren, NEM, Wardlaw, JM, Wen, W, Westeneng, H-J, Wittfeld, K, Zhu, AH, Zugman, A, Armstrong, NJ, Bonfiglio, G, Bralten, J, Dalvie, S, Davies, G, Di Forti, M, Ding, L, Donohoe, G, Forstner, AJ, Gonzalez-Penas, J, Guimaraes, JPOFT, Homuth, G, Hottenga, J-J, Knol, MJ, Kwok, JBJ, Le Hellard, S, Mather, KA, Milaneschi, Y, Morris, DW, Noethen, MM, Papiol, S, Rietschel, M, Santoro, ML, Steen, VM, Stein, JL, Streit, F, Tankard, RM, Teumer, A, van 't Ent, D, van der Meer, D, van Eijk, KR, Vassos, E, Vazquez-Bourgon, J, Witt, SH, Adams, HHH, Agartz, I, Ames, D, Amunts, K, Andreassen, OA, Arango, C, Banaschewski, T, Baune, BT, Belangero, SI, Bokde, ALW, Boomsma, DI, Bressan, RA, Brodaty, H, Buitelaar, JK, Cahn, W, Caspers, S, Cichon, S, Crespo-Facorro, B, Cox, SR, Dannlowski, U, Elvsashagen, T, Espeseth, T, Falkai, PG, Fisher, SE, Flor, H, Fullerton, JM, Garavan, H, Gowland, PA, Grabe, HJ, Hahn, T, Heinz, A, Hillegers, M, Hoare, J, Hoekstra, PJ, Ikram, MA, Jackowski, AP, Jansen, A, Jonsson, EG, Kahn, RS, Kircher, T, Korgaonkar, MS, Krug, A, Lemaitre, H, Malt, UF, Martinot, J-L, McDonald, C, Mitchell, PB, Muetzel, RL, Murray, RM, Nees, F, Nenadic, I, Oosterlaan, J, Ophoff, RA, Pan, PM, Penninx, BWJH, Poustka, L, Sachdev, PS, Salum, GA, Schofield, PR, Schumann, G, Shaw, P, Sim, K, Smolka, MN, Stein, DJ, Trollor, JN, van den Berg, LH, Veldink, JH, Walter, H, Westlye, LT, Whelan, R, White, T, Wright, MJ, Medland, SE, Franke, B, Thompson, PM, and Hulshoff Pol, HE

Abstract

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

Published
2022

6. Thrombolysis outcomes according to arterial characteristics of acute ischemic stroke by alteplase dose and blood pressure target

Author

Zhou, Z, Xia, C, Mair, G, Delcourt, C, Yoshimura, S, Liu, X, Chen, Z, Malavera, A, Carcel, C, Chen, X, Wang, X, Al-Shahi Salman, R, Robinson, TG, Lindley, RI, Chalmers, J, Wardlaw, JM, Parsons, MW, Demchuk, AM, Anderson, CS, Zhou, Z, Xia, C, Mair, G, Delcourt, C, Yoshimura, S, Liu, X, Chen, Z, Malavera, A, Carcel, C, Chen, X, Wang, X, Al-Shahi Salman, R, Robinson, TG, Lindley, RI, Chalmers, J, Wardlaw, JM, Parsons, MW, Demchuk, AM, and Anderson, CS

Abstract

Background: We explored the influence of low-dose intravenous alteplase and intensive blood pressure lowering on outcomes of acute ischemic stroke according to status/location of vascular obstruction in participants of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods: ENCHANTED was a multicenter, quasi-factorial, randomized trial to determine efficacy and safety of low- versus standard-dose intravenous alteplase and intensive- versus guideline-recommended blood pressure lowering in acute ischemic stroke patients. In those who had baseline computed tomography or magnetic resonance imaging angiography, the degree of vascular occlusion was grouped according to being no (NVO), medium (MVO), or large (LVO). Logistic regression models were used to determine 90-day outcomes (modified Rankin scale [mRS] shift [primary], other mRS cut-scores, intracranial hemorrhage, early neurologic deterioration, and recanalization) by vascular obstruction status/site. Heterogeneity in associations for outcomes across subgroups was estimated by adding an interaction term to the models. Results: There were 940 participants: 607 in alteplase arm only, 243 in blood pressure arm only, and 90 assigned to both arms. Compared to the NVO group, functional outcome was worse in LVO (mRS shift, adjusted OR [95% CI] 2.13 [1.56–2.90]) but comparable in MVO (1.34 [0.96–1.88]) groups. There were no differences in associations of alteplase dose or blood pressure lowering and outcomes across NVO/MVO/LVO groups (mRS shift: low versus standard alteplase dose 0.84 [0.54–1.30]/0.48 [0.25–0.91]/0.99 [0.75–2.09], Pinteraction = 0.28; intensive versus standard blood pressure lowering 1.32 [0.74–2.38]/0.78 [0.31–1.94]/1.24 [0.64–2.41], Pinteraction = 0.41), except for a borderline significant difference for intensive blood pressure lowering and increased early neurologic deterioration (0.63 [0.14–2.72]/0.17 [0.02–1.47]/2.69 [0.90–8.04], Pinteraction = 0.05). Conclusions: Func

Published
2021

7. Intensive versus guideline-recommended blood pressure reduction in acute lacunar stroke with intravenous thrombolysis therapy: The ENCHANTED trial

Author

Zhou, Z, Xia, C, Carcel, C, Yoshimura, S, Wang, X, Delcourt, C, Malavera, A, Chen, X, Mair, G, Woodward, M, Chalmers, J, Demchuk, AM, Lindley, RI, Robinson, TG, Parsons, MW, Wardlaw, JM, Anderson, CS, Zhou, Z, Xia, C, Carcel, C, Yoshimura, S, Wang, X, Delcourt, C, Malavera, A, Chen, X, Mair, G, Woodward, M, Chalmers, J, Demchuk, AM, Lindley, RI, Robinson, TG, Parsons, MW, Wardlaw, JM, and Anderson, CS

Abstract

Background and purpose: This was an investigation of the differential effects of early intensive versus guideline-recommended blood pressure (BP) lowering between lacunar and non-lacunar acute ischaemic stroke (AIS) in the BP arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods: In 1,632 participants classified as having definite or probable lacunar (n = 454 [27.8%]) or non-lacunar AIS according to pre-specified definitions based upon clinical and adjudicated imaging findings, mean BP changes over days 0–7 were plotted, and systolic BP differences by treatment between subgroups were estimated in generalized linear models. Logistic regression models were used to estimate the BP treatment effects on 90-day outcomes (primary, an ordinal shift of modified Rankin scale scores) across lacunar and non-lacunar AIS after adjustment for baseline covariables. Results: Most baseline characteristics, acute BP and other management differed between lacunar and non-lacunar AIS, but mean systolic BP differences by treatment were comparable at each time point (all pinteraction > 0.12) and over 24 h post-randomization (−5.5, 95% CI −6.5, −4.4 mmHg in lacunar AIS vs. −5.6, 95% CI −6.3, −4.8 mmHg in non-lacunar AIS, pinteraction = 0.93). The neutral effect of intensive BP lowering on functional outcome and the beneficial effect on intracranial haemorrhage were similar for the two subgroups (all pinteraction > 0.19). Conclusions: There were no differences in the treatment effect of early intensive versus guideline-recommended BP lowering across lacunar and non-lacunar AIS.

Published
2021

8. Low Dose versus Standard Dose Alteplase in Acute Lacunar Ischemic Stroke.

Author

Zhou, Z, Delcourt, C, Xia, C, Yoshimura, S, Carcel, C, Torii-Yoshimura, T, You, S, Malavera, A, Chen, X, Hackett, M, Woodward, M, Chalmers, J, Xu, J, Robinson, TG, Parsons, MW, Demchuk, AM, Lindley, R, Mair, G, Wardlaw, JM, Anderson, CS, Zhou, Z, Delcourt, C, Xia, C, Yoshimura, S, Carcel, C, Torii-Yoshimura, T, You, S, Malavera, A, Chen, X, Hackett, M, Woodward, M, Chalmers, J, Xu, J, Robinson, TG, Parsons, MW, Demchuk, AM, Lindley, R, Mair, G, Wardlaw, JM, and Anderson, CS

Abstract

Objective: To identify any differential efficacy and safety of low- versus standard-dose intravenous alteplase for lacunar versus non-lacunar acute ischemic stroke (AIS) in the alteplase dose-arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED).Methods: In a cohort of 3297 ENCHANTED participants, we identified those with lacunar or non-lacunar AIS with different levels of confidence (definite/probable/possible) according to pre-specified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration [END] or death) and treatment effects of low- versus standard-dose alteplase across lacunar and non-lacunar AIS with adjustment for baseline covariables.Results: Of 2588 participants with available imaging and clinical data, we classified cases as definite or probable lacunar (n=490) or non-lacunar AIS (n=2098) for primary analyses. Regardless of the alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% CI] 0.60 [0.47-0.77]) and other clinical or safety outcomes, compared to participants with non-lacunar AIS. Overall, low-dose alteplase (compared to standard) had no differential effect on the functional outcome (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of ICH. There were no differential treatment effects of low- versus standard-dose alteplase on all outcomes across lacunar and non-lacunar AIS (all Pinteraction ≥0.07).Conclusions: We found no clear evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard-dose for definite/probable lacunar AIS.

Published
2021

9. Early decompressive hemicraniectomy in thrombolyzed acute ischemic stroke patients from the international ENCHANTED trial

Author

Xia, C, Wang, X, Lindley, RI, Delcourt, C, Chen, X, Zhou, Z, Guo, R, Carcel, C, Malavera, A, Calic, Z, Mair, G, Wardlaw, JM, Robinson, TG, Anderson, CS, Xia, C, Wang, X, Lindley, RI, Delcourt, C, Chen, X, Zhou, Z, Guo, R, Carcel, C, Malavera, A, Calic, Z, Mair, G, Wardlaw, JM, Robinson, TG, and Anderson, CS

Abstract

Decompressive hemicraniectomy (DHC) can improve outcomes for patients with severe forms of acute ischemic stroke (AIS), but the evidence is mainly derived from non-thrombolyzed patients. We aimed to determine the characteristics and outcomes of early DHC in thrombolyzed AIS participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Post-hoc analyses of ENCHANTED, an international, partial-factorial, open, blinded outcome-assessed, controlled trial in 4557 thrombolysis-eligible AIS patients randomized to low- versus standard-dose intravenous alteplase (Arm A, n = 2350), intensive versus guideline-recommended blood pressure control (Arm B, n = 1280), or both (Arms A + B, n = 947). Logistic regression models were used to identify baseline variables associated with DHC, with inverse probability of treatment weights employed to eliminate baseline imbalances between those with and without DHC. Logistic regression was also used to determine associations of DHC and clinical outcomes of death/disability, major disability, and death (defined by scores 2–6, 3–5, and 6, respectively, on the modified Rankin scale) at 90 days post-randomization. There were 95 (2.1%) thrombolyzed AIS patients who underwent DHC, who were significantly younger, of non-Asian ethnicity, and more likely to have had prior lipid-lowering treatment and severe neurological impairment from large vessel occlusion than other patients. DHC patients were more likely to receive other management interventions and have poor functional outcomes than non-DHC patients, with no relation to different doses of intravenous alteplase. Compared to other thrombolyzed AIS patients, those who received DHC had a poor prognosis from more severe disease despite intensive in-hospital management.

Published
2021

10. Low-Dose vs Standard-Dose Alteplase in Acute Lacunar Ischemic Stroke: The ENCHANTED Trial

Author

Zhou, Z, Delcourt, C, Xia, C, Yoshimura, S, Carcel, C, Torii-Yoshimura, T, You, S, Malavera, A, Chen, X, Hackett, ML, Woodward, M, Chalmers, J, Xu, J, Robinson, TG, Parsons, MW, Demchuk, AM, Lindley, RI, Mair, G, Wardlaw, JM, Anderson, CS, Zhou, Z, Delcourt, C, Xia, C, Yoshimura, S, Carcel, C, Torii-Yoshimura, T, You, S, Malavera, A, Chen, X, Hackett, ML, Woodward, M, Chalmers, J, Xu, J, Robinson, TG, Parsons, MW, Demchuk, AM, Lindley, RI, Mair, G, Wardlaw, JM, and Anderson, CS

Abstract

OBJECTIVE: To determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm. METHODS: In a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables. RESULTS: Of 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all pinteraction ≥0.07). CONCLUSIONS: We found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safe

Published
2021

11. Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

Author

Jia, T, Chu, C, Liu, Y, van Dongen, J, Papastergios, E, Armstrong, NJ, Bastin, ME, Carrillo-Roa, T, den Braber, A, Harris, M, Jansen, R, Liu, J, Luciano, M, Ori, APS, Santianez, RR, Ruggeri, B, Sarkisyan, D, Shin, J, Sungeun, K, Gutierrez, DT, van't Ent, D, Ames, D, Artiges, E, Bakalkin, G, Banaschewski, T, Bokde, ALW, Brodaty, H, Bromberg, U, Brouwer, R, Buchel, C, Quinlan, EB, Cahn, W, de Zubicaray, G, Ehrlich, S, Ekstrom, TJ, Flor, H, Frohner, JH, Frouin, V, Garavan, H, Gowland, P, Heinz, A, Hoare, J, Ittermann, B, Jahanshad, N, Jiang, J, Kwok, JB, Martin, NG, Martinot, J-L, Mather, KA, McMahon, KL, McRae, AF, Nees, F, Orfanos, DP, Paus, T, Poustka, L, Samann, PG, Schofield, PR, Smolka, MN, Stein, DJ, Strike, LT, Teeuw, J, Thalamuthu, A, Trollor, J, Walter, H, Wardlaw, JM, Wen, W, Whelan, R, Apostolova, LG, Binder, EB, Boomsma, D, Calhoun, V, Crespo-Facorro, B, Deary, IJ, Pol, HH, Ophoff, RA, Pausova, Z, Sachdev, PS, Saykin, A, Wright, MJ, Thompson, PM, Schumann, G, Desrivieres, S, Jia, T, Chu, C, Liu, Y, van Dongen, J, Papastergios, E, Armstrong, NJ, Bastin, ME, Carrillo-Roa, T, den Braber, A, Harris, M, Jansen, R, Liu, J, Luciano, M, Ori, APS, Santianez, RR, Ruggeri, B, Sarkisyan, D, Shin, J, Sungeun, K, Gutierrez, DT, van't Ent, D, Ames, D, Artiges, E, Bakalkin, G, Banaschewski, T, Bokde, ALW, Brodaty, H, Bromberg, U, Brouwer, R, Buchel, C, Quinlan, EB, Cahn, W, de Zubicaray, G, Ehrlich, S, Ekstrom, TJ, Flor, H, Frohner, JH, Frouin, V, Garavan, H, Gowland, P, Heinz, A, Hoare, J, Ittermann, B, Jahanshad, N, Jiang, J, Kwok, JB, Martin, NG, Martinot, J-L, Mather, KA, McMahon, KL, McRae, AF, Nees, F, Orfanos, DP, Paus, T, Poustka, L, Samann, PG, Schofield, PR, Smolka, MN, Stein, DJ, Strike, LT, Teeuw, J, Thalamuthu, A, Trollor, J, Walter, H, Wardlaw, JM, Wen, W, Whelan, R, Apostolova, LG, Binder, EB, Boomsma, D, Calhoun, V, Crespo-Facorro, B, Deary, IJ, Pol, HH, Ophoff, RA, Pausova, Z, Sachdev, PS, Saykin, A, Wright, MJ, Thompson, PM, Schumann, G, and Desrivieres, S

Abstract

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Published
2021

14. Cerebral Small Vessel Disease Burden and Longitudinal Cognitive Decline from age 73 to 82: the Lothian Birth Cohort 1936

Author

Hamilton, OKL, primary, Cox, SR, additional, Okely, JA, additional, Conte, F, additional, Ballerini, L, additional, Bastin, ME, additional, Corley, J, additional, Taylor, AM, additional, Page, D, additional, Gow, AJ, additional, Muñoz Maniega, S, additional, Redmond, P, additional, Valdés-Hernández, M del C, additional, Wardlaw, JM, additional, and Deary, IJ, additional

Published
2021
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16. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author

Hofer, E, Roshchupkin, GV, Adams, HHH, Knol, MJ, Lin, H, Li, S, Zare, H, Ahmad, S, Armstrong, NJ, Satizabal, CL, Bernard, M, Bis, JC, Gillespie, NA, Luciano, M, Mishra, A, Scholz, M, Teumer, A, Xia, R, Jian, X, Mosley, TH, Saba, Y, Pirpamer, L, Seiler, S, Becker, JT, Carmichael, O, Rotter, JI, Psaty, BM, Lopez, OL, Amin, N, van der Lee, SJ, Yang, Q, Himali, JJ, Maillard, P, Beiser, AS, Decarli, C, Karama, S, Lewis, L, Harris, M, Bastin, ME, Deary, IJ, Witte, AV, Beyer, F, Loeffler, M, Mather, KA, Schofield, PR, Thalamuthu, A, Kwok, JB, Wright, MJ, Ames, D, Trollor, J, Jiang, J, Brodaty, H, Wen, W, Vernooij, MW, Hofman, A, Uitterlinden, AG, Niessen, WJ, Wittfeld, K, Bülow, R, Völker, U, Pausova, Z, Pike, GB, Maingault, S, Crivello, F, Tzourio, C, Amouyel, P, Mazoyer, B, Neale, MC, Franz, CE, Lyons, MJ, Panizzon, MS, Andreassen, OA, Dale, AM, Logue, M, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Stein, JL, Thompson, PM, Medland, SE, Sachdev, PS, Kremen, WS, Wardlaw, JM, Villringer, A, van Duijn, CM, Grabe, HJ, Longstreth, WT, Fornage, M, Paus, T, Debette, S, Ikram, MA, Schmidt, H, Schmidt, R, Seshadri, S, Ching, CRK, Hofer, E, Roshchupkin, GV, Adams, HHH, Knol, MJ, Lin, H, Li, S, Zare, H, Ahmad, S, Armstrong, NJ, Satizabal, CL, Bernard, M, Bis, JC, Gillespie, NA, Luciano, M, Mishra, A, Scholz, M, Teumer, A, Xia, R, Jian, X, Mosley, TH, Saba, Y, Pirpamer, L, Seiler, S, Becker, JT, Carmichael, O, Rotter, JI, Psaty, BM, Lopez, OL, Amin, N, van der Lee, SJ, Yang, Q, Himali, JJ, Maillard, P, Beiser, AS, Decarli, C, Karama, S, Lewis, L, Harris, M, Bastin, ME, Deary, IJ, Witte, AV, Beyer, F, Loeffler, M, Mather, KA, Schofield, PR, Thalamuthu, A, Kwok, JB, Wright, MJ, Ames, D, Trollor, J, Jiang, J, Brodaty, H, Wen, W, Vernooij, MW, Hofman, A, Uitterlinden, AG, Niessen, WJ, Wittfeld, K, Bülow, R, Völker, U, Pausova, Z, Pike, GB, Maingault, S, Crivello, F, Tzourio, C, Amouyel, P, Mazoyer, B, Neale, MC, Franz, CE, Lyons, MJ, Panizzon, MS, Andreassen, OA, Dale, AM, Logue, M, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Stein, JL, Thompson, PM, Medland, SE, Sachdev, PS, Kremen, WS, Wardlaw, JM, Villringer, A, van Duijn, CM, Grabe, HJ, Longstreth, WT, Fornage, M, Paus, T, Debette, S, Ikram, MA, Schmidt, H, Schmidt, R, Seshadri, S, and Ching, CRK

Abstract

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Published
2020

17. Thrombolysis Outcomes in Acute Ischemic Stroke by Fluid-Attenuated Inversion Recovery Hyperintense Arteries

Author

Zhou, Z, Yoshimura, S, Delcourt, C, Lindley, RI, You, S, Malavera, A, Torii-Yoshimura, T, Carcel, C, Wang, X, Chen, X, Parsons, MW, Demchuk, AM, Wardlaw, JM, Mair, G, Robinson, TG, Chalmers, J, Xu, J, Anderson, CS, Zhou, Z, Yoshimura, S, Delcourt, C, Lindley, RI, You, S, Malavera, A, Torii-Yoshimura, T, Carcel, C, Wang, X, Chen, X, Parsons, MW, Demchuk, AM, Wardlaw, JM, Mair, G, Robinson, TG, Chalmers, J, Xu, J, and Anderson, CS

Abstract

Background and Purpose: To determine factors associated with fluid-attenuated inversion recovery (FLAIR) hyperintense arteries (FLAIR-HAs) on magnetic resonance imaging and their prognostic significance in thrombolysis-treated patients with acute ischemic stroke from the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) trial alteplase-dose arm. Methods: Patients with acute ischemic stroke (N=293) with brain magnetic resonance imaging (FLAIR and diffusion-weighted imaging sequences) scanned <4.5 hours of symptom onset were assessed for location and extent (score) of FLAIR-HAs, infarct volume, large vessel occlusion (LVO), and other ischemic signs. Logistic regression models were used to determine predictors of FLAIR-HAs and the association of FLAIR-HAs with 90-day outcomes: favorable functional outcome (primary; modified Rankin Scale scores, 0-1), other modified Rankin Scale scores, and intracerebral hemorrhage. Results: Prior atrial fibrillation, LVO, large infarct volume, and anterior circulation infarction were independently associated with FLAIR-HAs. The rate of modified Rankin Scale scores 0 to 1 was numerically lower in patients with FLAIR-HAs versus without (69/152 [45.4%] versus 75/131 [57.3%]), as was the subset of LVO (37/93 [39.8%] versus 9/16 [56.3%]), but not in those without LVO (25/36 [69.4%] versus 60/106 [56.6%]). After adjustment for covariables, FLAIR-HAs were independently associated with increased primary outcome (adjusted odds ratio [95% CI]: overall 4.14 [1.63-10.50]; with LVO 4.92 [0.87-27.86]; no LVO 6.16 [1.57-24.14]) despite an increased risk of hemorrhagic infarct (4.77 [1.12-20.26]). Conclusions: FLAIR-HAs are more frequent in acute ischemic stroke with cardioembolic features and indicate potential for a favorable prognosis in thrombolysis-treated patients possibly mediated by LVO. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01422616.

Published
2020

18. Clinical prognosis of FLAIR hyperintense arteries in ischaemic stroke patients: A systematic review and meta-analysis

Author

Zhou, Z, Malavera, A, Yoshimura, S, Delcourt, C, Mair, G, Al-Shahi Salman, R, Demchuk, AM, Wardlaw, JM, Lindley, RI, Anderson, CS, Zhou, Z, Malavera, A, Yoshimura, S, Delcourt, C, Mair, G, Al-Shahi Salman, R, Demchuk, AM, Wardlaw, JM, Lindley, RI, and Anderson, CS

Abstract

Objective We performed a systematic review and meta-analysis to determine the association of fluid-attenuated inversion recovery (FLAIR) hyperintense arteries (FLAIR-HAs) on brain MRI and prognosis after acute ischaemic stroke (AIS). Methods We searched Medline, Embase and Cochrane Central Register of Controlled Trials for studies reporting clinical or imaging outcomes with presence of FLAIR-HAs after AIS. Two researchers independently assessed eligibility of retrieved studies and extracted data, including from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Outcomes were unfavourable functional outcome (primary, modified Rankin scale scores 3-6 or 2-6), death, intermediate clinical and imaging outcomes. We performed subgroup analyses by treatment or types of FLAIR-HAs defined by location (at proximal/distal middle cerebral artery (MCA), within/beyond diffusion-weighted imaging (DWI) lesion) or extent. Results We included 36 cohort studies (33 prospectively collected) involving 3577 patients. FLAIR-HAs were not associated with functional outcome overall (pooled risk ratio 0.87, 95% CI 0.71 to 1.06), but were significantly associated with better outcome in those receiving endovascular therapy (0.56, 95% CI 0.41 to 0.75). Contrary to FLAIR-HAs at proximal MCA or within DWI lesions, FLAIR-HAs beyond DWI lesions were associated with better outcome (0.67, 95% CI 0.57 to 0.79). FLAIR-HAs favoured recanalisation (1.21, 95% CI 1.06 to 1.38) with increased risk of intracerebral haemorrhage (2.07, 95% CI 1.37 to 3.13) and early neurological deterioration (1.93, 95% CI 1.30 to 2.85). Conclusions FLAIR-HAs were not associated with functional outcome overall but were associated with outcome after endovascular therapy for AIS. FLAIR-HAs were also associated with early recanalisation or haemorrhagic complications, and early neurologic deterioration. PROSPERO registration number CRD42019131168.

Published
2020

19. Age-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study

Author

Beaudet, G, Tsuchida, A, Petit, L, Tzourio, C, Caspers, S, Schreiber, J, Pausova, Z, Patel, Y, Paus, T, Schmidt, R, Pirpamer, L, Sachdev, PS, Brodaty, H, Kochan, N, Trollor, J, Wen, W, Armstrong, NJ, Deary, IJ, Bastin, ME, Wardlaw, JM, Munõz Maniega, S, Witte, AV, Villringer, A, Duering, M, Debette, S, Mazoyer, B, Beaudet, G, Tsuchida, A, Petit, L, Tzourio, C, Caspers, S, Schreiber, J, Pausova, Z, Patel, Y, Paus, T, Schmidt, R, Pirpamer, L, Sachdev, PS, Brodaty, H, Kochan, N, Trollor, J, Wen, W, Armstrong, NJ, Deary, IJ, Bastin, ME, Wardlaw, JM, Munõz Maniega, S, Witte, AV, Villringer, A, Duering, M, Debette, S, and Mazoyer, B

Abstract

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant incre

Published
2020

20. Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes

Author

Shin, J, Ma, S, Hofer, E, Patel, Y, Vosberg, DE, Tilley, S, Roshchupkin, G, Sousa, AMM, Jian, X, Gottesman, R, Mosley, TH, Fornage, M, Saba, Y, Pirpamer, L, Schmidt, R, Schmidt, H, Carrion-Castillo, A, Crivello, F, Mazoyer, B, Bis, JC, Li, S, Yang, Q, Luciano, M, Karama, S, Lewis, L, Bastin, ME, Harris, MA, Wardlaw, JM, Deary, IE, Scholz, M, Loeffler, M, Witte, AV, Beyer, F, Villringer, A, Armstrong, NJ, Mather, KA, Ames, D, Jiang, J, Kwok, JB, Schofield, PR, Thalamuthu, A, Trollor, JN, Wright, MJ, Brodaty, H, Wen, W, Sachdev, PS, Terzikhan, N, Evans, TE, Adams, HHHH, Ikram, MA, Frenzel, S, Van der Auwera-Palitschka, S, Wittfeld, K, Bulow, R, Grabe, HJ, Tzourio, C, Mishra, A, Maingault, S, Debette, S, Gillespie, NA, Franz, CE, Kremen, WS, Ding, L, Jahanshad, N, Sestan, N, Pausova, Z, Seshadri, S, Paus, T, Shin, J, Ma, S, Hofer, E, Patel, Y, Vosberg, DE, Tilley, S, Roshchupkin, G, Sousa, AMM, Jian, X, Gottesman, R, Mosley, TH, Fornage, M, Saba, Y, Pirpamer, L, Schmidt, R, Schmidt, H, Carrion-Castillo, A, Crivello, F, Mazoyer, B, Bis, JC, Li, S, Yang, Q, Luciano, M, Karama, S, Lewis, L, Bastin, ME, Harris, MA, Wardlaw, JM, Deary, IE, Scholz, M, Loeffler, M, Witte, AV, Beyer, F, Villringer, A, Armstrong, NJ, Mather, KA, Ames, D, Jiang, J, Kwok, JB, Schofield, PR, Thalamuthu, A, Trollor, JN, Wright, MJ, Brodaty, H, Wen, W, Sachdev, PS, Terzikhan, N, Evans, TE, Adams, HHHH, Ikram, MA, Frenzel, S, Van der Auwera-Palitschka, S, Wittfeld, K, Bulow, R, Grabe, HJ, Tzourio, C, Mishra, A, Maingault, S, Debette, S, Gillespie, NA, Franz, CE, Kremen, WS, Ding, L, Jahanshad, N, Sestan, N, Pausova, Z, Seshadri, S, and Paus, T

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

21. Association between Computed Tomographic Biomarkers of Cerebral Small Vessel Diseases and Long-Term Outcome after Spontaneous Intracerebral Hemorrhage

Author

Rodrigues, MA, E. Samarasekera, N, Lerpiniere, C, Perry, LA, Moullaali, TJ, J. M. Loan, J, Wardlaw, JM, Al-Shahi Salman, R, Rodrigues, MA, E. Samarasekera, N, Lerpiniere, C, Perry, LA, Moullaali, TJ, J. M. Loan, J, Wardlaw, JM, and Al-Shahi Salman, R

Abstract

OBJECTIVE: A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long-term outcome after intracerebral hemorrhage. METHODS: We performed a prospective, community-based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May 31, 2013. A neuroradiologist rated the diagnostic brain CT for acute intracerebral hemorrhage features and SVD biomarkers. We used severity of white matter lucencies and cerebral atrophy, and the number of lacunes to calculate the CT SVD score. We assessed the association between CT SVD biomarkers and either death, or death or dependence (modified Rankin Scale scores = 4-6) 1 year after first-ever intracerebral hemorrhage using logistic regression, adjusting for known predictors of outcome. RESULTS: Within 1 year of intracerebral hemorrhage, 224 (56%) of 402 patients died. In separate models, 1-year death was associated with severe atrophy (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.44-4.49, p = 0.001) but not lacunes or severe white matter lucencies, and CT SVD sum score ≥ 1 (aOR = 2.50, 95% CI = 1.40-4.45, p = 0.002). Two hundred seventy-seven (73%) of 378 patients with modified Rankin Scale data were dead or dependent at 1 year. In separate models, 1-year death or dependence was associated with severe atrophy (aOR = 3.67, 95% CI = 1.71-7.89, p = 0.001) and severe white matter lucencies (aOR = 2.18, 95% CI = 1.06-4.51, p = 0.035) but not lacunes, and CT SVD sum score ≥ 1 (aOR = 2.81, 95% CI = 1.45-5.46, p = 0.002). INTERPRETATION: SVD biomarkers on the diagnostic brain CT are associated with 1-year death and dependence after intracerebral hemorrhage, independent of known predictors of outcome. ANN NEUROL 2021;89:266-279.

Published
2020

22. The genetic architecture of the human cerebral cortex

Author

Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, Medland, SE, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, and Medland, SE

Abstract

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Published
2020

23. Intensive versus guideline-recommended blood pressure reduction in acute lacunar stroke with intravenous thrombolysis therapy: The ENCHANTED trial

Author

Zhou, Z, Xia, C, Carcel, C, Yoshimura, S, Wang, X, Delcourt, C, Malavera, A, Chen, X, Mair, G, Woodward, M, Chalmers, J, Demchuk, AM, Lindley, RI, Robinson, TG, Parsons, MW, Wardlaw, JM, Anderson, CS, Zhou, Z, Xia, C, Carcel, C, Yoshimura, S, Wang, X, Delcourt, C, Malavera, A, Chen, X, Mair, G, Woodward, M, Chalmers, J, Demchuk, AM, Lindley, RI, Robinson, TG, Parsons, MW, Wardlaw, JM, and Anderson, CS

Abstract

BACKGROUND AND PURPOSE: This was an investigation of the differential effects of early intensive versus guideline-recommended blood pressure (BP) lowering between lacunar and non-lacunar acute ischaemic stroke (AIS) in the BP arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: In 1,632 participants classified as having definite or probable lacunar (n = 454 [27.8%]) or non-lacunar AIS according to pre-specified definitions based upon clinical and adjudicated imaging findings, mean BP changes over days 0-7 were plotted, and systolic BP differences by treatment between subgroups were estimated in generalized linear models. Logistic regression models were used to estimate the BP treatment effects on 90-day outcomes (primary, an ordinal shift of modified Rankin scale scores) across lacunar and non-lacunar AIS after adjustment for baseline covariables. RESULTS: Most baseline characteristics, acute BP and other management differed between lacunar and non-lacunar AIS, but mean systolic BP differences by treatment were comparable at each time point (all pinteraction > 0.12) and over 24 h post-randomization (-5.5, 95% CI -6.5, -4.4 mmHg in lacunar AIS vs. -5.6, 95% CI -6.3, -4.8 mmHg in non-lacunar AIS, pinteraction = 0.93). The neutral effect of intensive BP lowering on functional outcome and the beneficial effect on intracranial haemorrhage were similar for the two subgroups (all pinteraction > 0.19). CONCLUSIONS: There were no differences in the treatment effect of early intensive versus guideline-recommended BP lowering across lacunar and non-lacunar AIS.

Published
2020

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

Author

Sargurupremraj, M, Suzuki, H, Jian, X, Sarnowski, C, Evans, TE, Bis, JC, Eiriksdottir, G, Sakaue, S, Terzikhan, N, Habes, M, Zhao, W, Armstrong, NJ, Hofer, E, Yanek, LR, Hagenaars, SP, Kumar, RB, van den Akker, EB, McWhirter, RE, Trompet, S, Mishra, A, Saba, Y, Satizabal, CL, Beaudet, G, Petit, L, Tsuchida, A, Zago, L, Schilling, S, Sigurdsson, S, Gottesman, RF, Lewis, CE, Aggarwal, NT, Lopez, OL, Smith, JA, Hernandez, MCV, van der Grond, J, Wright, MJ, Knol, MJ, Dorr, M, Thomson, RJ, Bordes, C, Le Grand, Q, Duperron, M-G, Smith, A, Knopman, DS, Schreiner, PJ, Evans, DA, Rotter, J, Beiser, AS, Maniega, SM, Beekman, M, Trollor, J, Stott, DJ, Vernooij, MW, Wittfeld, K, Niessen, WJ, Soumare, A, Boerwinkle, E, Sidney, S, Turner, ST, Davies, G, Thalamuthu, A, Volker, U, van Buchem, MA, Bryan, RN, Dupuis, J, Bastin, ME, Ames, D, Teumer, A, Amouyel, P, Kwok, JB, Bulow, R, Deary, IJ, Schofield, PR, Brodaty, H, Jiang, J, Tabara, Y, Setoh, K, Miyamoto, S, Yoshida, K, Nagata, M, Kamatani, Y, Matsuda, F, Psaty, BM, Bennett, DA, De Jager, PL, Mosley, TH, Sachdev, PS, Schmidt, R, Warren, HR, Evangelou, E, Tregouet, D-A, Ikram, MA, Wen, W, DeCarli, C, Srikanth, VK, Jukema, JW, Slagboom, EP, Kardia, SLR, Okada, Y, Mazoyer, B, Wardlaw, JM, Nyquist, PA, Mather, KA, Grabe, HJ, Schmidt, H, Van Duijn, CM, Gudnason, V, Longstreth, WT, Launer, LJ, Lathrop, M, Seshadri, S, Tzourio, C, Adams, HH, Matthews, PM, Fornage, M, Debette, S, Sargurupremraj, M, Suzuki, H, Jian, X, Sarnowski, C, Evans, TE, Bis, JC, Eiriksdottir, G, Sakaue, S, Terzikhan, N, Habes, M, Zhao, W, Armstrong, NJ, Hofer, E, Yanek, LR, Hagenaars, SP, Kumar, RB, van den Akker, EB, McWhirter, RE, Trompet, S, Mishra, A, Saba, Y, Satizabal, CL, Beaudet, G, Petit, L, Tsuchida, A, Zago, L, Schilling, S, Sigurdsson, S, Gottesman, RF, Lewis, CE, Aggarwal, NT, Lopez, OL, Smith, JA, Hernandez, MCV, van der Grond, J, Wright, MJ, Knol, MJ, Dorr, M, Thomson, RJ, Bordes, C, Le Grand, Q, Duperron, M-G, Smith, A, Knopman, DS, Schreiner, PJ, Evans, DA, Rotter, J, Beiser, AS, Maniega, SM, Beekman, M, Trollor, J, Stott, DJ, Vernooij, MW, Wittfeld, K, Niessen, WJ, Soumare, A, Boerwinkle, E, Sidney, S, Turner, ST, Davies, G, Thalamuthu, A, Volker, U, van Buchem, MA, Bryan, RN, Dupuis, J, Bastin, ME, Ames, D, Teumer, A, Amouyel, P, Kwok, JB, Bulow, R, Deary, IJ, Schofield, PR, Brodaty, H, Jiang, J, Tabara, Y, Setoh, K, Miyamoto, S, Yoshida, K, Nagata, M, Kamatani, Y, Matsuda, F, Psaty, BM, Bennett, DA, De Jager, PL, Mosley, TH, Sachdev, PS, Schmidt, R, Warren, HR, Evangelou, E, Tregouet, D-A, Ikram, MA, Wen, W, DeCarli, C, Srikanth, VK, Jukema, JW, Slagboom, EP, Kardia, SLR, Okada, Y, Mazoyer, B, Wardlaw, JM, Nyquist, PA, Mather, KA, Grabe, HJ, Schmidt, H, Van Duijn, CM, Gudnason, V, Longstreth, WT, Launer, LJ, Lathrop, M, Seshadri, S, Tzourio, C, Adams, HH, Matthews, PM, Fornage, M, and Debette, S

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 = 2.5×10-7) 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.

Published
2020

25. Association of common genetic variants with brain microbleeds: A genome-wide association study

Author

Knol, Maria, Lu, Difei, Traylor, M, Adams, Hieab, Romero, JR, Smith, AV, Fornage, M, Hofer, E, Liu, Jun, Hostettler, IC, Luciano, M, Trompet, S, Giese, A K, Hilal, S, van den Akker, EB, Vojinovic, Dina, Li, S, Sigurdsson, S, van der Lee, Sven, Jack, CR, Wilson, D, Yilmaz, Pinar, Satizabal, CL, Liewald, DCM, van der Grond, J, Chen, C, Saba, Y, van der Lugt, Aad, Bastin, ME, Windham, BG, Cheng, CY (Ching-Yu), Pirpamer, L, Kantarci, K, Himali, JJ, Yang, Q, Morris, Z, Beiser, AS, Tozer, DJ, Vernooij, Meike, Amin, Najaf, Beekman, M, Koh, JY, Stott, DJM, Houlden, H, Schmidt, R, Gottesman, RF, MacKinnon, AD, DeCarli, C, Gudnason, V, Deary, IJ, Duijn, Cornelia, Slagboom, PE, Wong, TY, Rost, NS, Jukema, JW, Mosley, TH, Jr, Werring, DJ, Schmidt, H, Wardlaw, JM, Ikram, Arfan, Seshadri, S, Launer, LJ, Markus, HS, Knol, Maria, Lu, Difei, Traylor, M, Adams, Hieab, Romero, JR, Smith, AV, Fornage, M, Hofer, E, Liu, Jun, Hostettler, IC, Luciano, M, Trompet, S, Giese, A K, Hilal, S, van den Akker, EB, Vojinovic, Dina, Li, S, Sigurdsson, S, van der Lee, Sven, Jack, CR, Wilson, D, Yilmaz, Pinar, Satizabal, CL, Liewald, DCM, van der Grond, J, Chen, C, Saba, Y, van der Lugt, Aad, Bastin, ME, Windham, BG, Cheng, CY (Ching-Yu), Pirpamer, L, Kantarci, K, Himali, JJ, Yang, Q, Morris, Z, Beiser, AS, Tozer, DJ, Vernooij, Meike, Amin, Najaf, Beekman, M, Koh, JY, Stott, DJM, Houlden, H, Schmidt, R, Gottesman, RF, MacKinnon, AD, DeCarli, C, Gudnason, V, Deary, IJ, Duijn, Cornelia, Slagboom, PE, Wong, TY, Rost, NS, Jukema, JW, Mosley, TH, Jr, Werring, DJ, Schmidt, H, Wardlaw, JM, Ikram, Arfan, Seshadri, S, Launer, LJ, and Markus, HS

Published
2020

27. Three major dimensions of human brain cortical ageing in relation to cognitive decline across the 8thdecade of life

Author

Cox, SR, primary, Harris, MA, additional, Ritchie, SJ, additional, Buchanan, CR, additional, Valdés Hernández, MC, additional, Corley, J, additional, Taylor, AM, additional, Madole, JW, additional, Harris, SE, additional, Whalley, HC, additional, McIntosh, AM, additional, Russ, TC, additional, Bastin, ME, additional, Wardlaw, JM, additional, Deary, IJ, additional, and Tucker-Drob, EM, additional

Published
2020
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28. Brain age predicts mortality

Author

Cole, JH, Ritchie, SJ, Bastin, ME, Valdes Hernandez, MC, Munoz Maniega, S, Royle, N, Corely, J, Pattie, A, Harris, SE, Zhang, Q, Wray, N, Redmond, P, Marioni, RE, Starr, JM, Cox, SR, Wardlaw, JM, Sharp, DJ, Deary, IJ, Commission of the European Communities, and National Institute for Health Research

Subjects
Psychiatry, Adult, Aged, 80 and over, Epigenomics, Male, Aging, Brain, Neuroimaging, 11 Medical And Health Sciences, 06 Biological Sciences, Middle Aged, Epigenesis, Genetic, 17 Psychology And Cognitive Sciences, Machine Learning, Cognition, Journal Article, Humans, Original Article, Female, Longitudinal Studies, Biomarkers, Aged
Abstract

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, 'brain-predicted age', derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death.Molecular Psychiatry advance online publication, 25 April 2017; doi:10.1038/mp.2017.62.

Published
2017

29. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Author

Al-Shahi Salman, Rustam, Dennis, MS, Sandercock, PAG, Sudlow, CLM, Wardlaw, JM, Whiteley, WN, Murray, GD, Stephen, J, Newby, DE, Sprigg, N, Werring, DJ, White, PM, Baigent, Colin, Lasserson, Daniel, Sullivan, Frank, Carrie, Johanna, Rojas, Javier, Amoils, Shannon, Bamford, John, Armitage, Jane, Rinkel, Gabriel, Lowe, Gordon, Emberson, Jonathan, Innes, Karen, Dinsmore, Lynn, Drever, Jonathan, Williams, Carol, Perry, David, McGill, Connor, Buchanan, David, Walker, Allan, Hutchison, Aidan, Matthews, Christopher, Fraser, Ruth, McGrath, Aileen, Deary, Ann, Anderson, Rosemary, Walker, Pauli, Hansen, Christian, Parker, Richard, Rodriguez, Aryelly, Macleod, MR, Gattringer, Thomas, Palmer, Jeb, Sakka, Eleni, Adil-Smith, Jennifer, Minks, David, Mitra, Dipayan, Bhatnagar, Priya, du Plessis, Johannes, Joshi, Yogish, Lerpiniere, Christine, O'Brien, Richard, Burgess, Seona, Mead, Gillian, Paulton, Ruth, Doubal, Fergus, McCormick, Katrina, Hunter, Neil, Taylor, Pat, Parakramawansha, Ruwan, Perry, Jack, Blair, Gordon, MacRaild, Allan, Parry-Jones, Adrian, Johnes, Mary, Lee, Stephanie, Shaw, Kelly Marie, Burger, Ilse, Punter, Martin, Ingham, Andrea, Perez, Jane, Naing, Zin, Morell, Jordi, Marsden, Tracy, Hall, Andrea, Marshall, Sally, Harrison, Louise, Jarapa, Rowilson, Wood, Edith, O'Loughlin, Victoria, Cohen, David, Davies, Silvie, Njoku, Kelechi, Mpelembue, Mushiya, Burgess, Laura, Licenik, Radim, Ngwako, Mmua, Nisar, Nabeela, Niranchanan, Rangah, Roganova, Tatjana, Bathula, Rajaram, Devine, Joseph, David, Anette, Oshodi, Anne, Guo, Fenglin, Owoyele, Emmanuelle, Sukdeo, Varthi, Ballantine, Robert, Abbdul-saheb, Mudhar, Chamberlain, Angela, Chandrakumar, Aberami, Poku, Philip, Harkness, Kirsty, Blank, Catrin, Richards, Emma, Ali, Ali, Kibutu, Faith, Balitska, Olesia, Birchall, Kathryn, Bayliss, Pauline, Doyle, Clare, Stocks, Kathy, Majis, Arshad, Howe, Jo, Kamara, Christine, Barron, Luke, Maatouk, Ahmad, Lindert, Ralf, Dakin, Katy, Redgrave, Jessica, Bhaskaran, Biju, Salih, Isam, Kelly, Debs, Szabo, Susan, Tomlin, Dawn, Bearne, Helen, Buxton, Jean, Fitzell, Pauline, Ayres, Georgina, Saulat, Afaq, Horan, Kathleen, Garfield-Smith, Joanne, Bhakri, Harbens, Guyler, Paul, Sinha, Devesh, Loganathan, Thayalini, Siddiqui, Amber, Siddiqui, Anwer, Coward, Lucy, Kunhunny, Swapna, Tysoe, Sharon, Orath Prabakaran, Rajalakshmi, Kelavkar, Shyam, Rashmi, Sindhu, Ngo, David, Ng, Kheng Xiong, Menon, Nisha, Shah, Sweni, Barber, Mark, Esson, Derek, Brodie, Fiona, Anjum, Talat, Wani, Mushtaq, Krishnan, Manju, Quinn, Leanne, Spencer, Jayne, Jones, Terry, Thompson-Jones, Helen, Dacey, Lynne, Chenna, Srikanth, Storton, Sharon, Thomas, Sarah, Beaty, Teresa, Treadwell, Shelley, Davies, Caroline, Tucker, Susan, Connor, Lynda, Slade, Peter, Gainard, Glyn, Muddegowda, Girish, Sanyal, Ranjan, Remegoso, Alda, Abano, Nenette, Causley, Chelsea, Carpio, Racquel, Stevens, Stephanie, Butler, Adrian, Varquez, Resti, Denic, Hayley, Alipio, Francis, Moores, Andrew, Barry, Adrian, Maguire, Holly, Grocott, Jeanette, Finney, Kay, Lyjko, Sue, Roffe, Christine, Hiden, Joanne, Ferdinand, Phillip, Cvoro, Vera, Ullah, Khalil, Chapman, Nicola, Couser, Mandy, Pound, Susan, Mcauley, Sean, Raghunathan, Senthil, Shelton, Faye, Hedstrom, Amanda, Godfrey, Margi, Havard, Diane, Buck, Amanda, Krishnan, Kailash, Gilzeane, Nicola, Roffe, Jack, Clarke, Judith, Whittamore, Katherine, Sheikh, Saima, Keshvara, Rekha, Jordan, Carla, Jackson, Benjamin, Wilkes, Gwendoline, Appleton, Jason, Law, Zhe, Matias, Oliver, Vasileiadis, Evangelos, Mason, Cathy, Parry, Anthea, Landers, Geraldine, Holden, Melinda, Aweid, Basaam, Rashed, Khalid, Balian, Linda, Vickers, Carinna, Keeling, Elizabeth, Board, Sarah, Allison, Joanna, Buckley, Clare, Williams-Yesson, Barbara, Board, Joanne, Pitt-Kerby, Tressy, Tanate, Alfonso, Wood, Diane, Kini, Manohar, Chadha, Dinesh, Walstow, Deborah, Fong, Rosanna, Luder, Robert, Adesina, Tolu, Gallagher, Jill, Bridger, Hayley, Murali, Elodie, Bhargava, Maneesh, van Someren, Chloe, Harrington, Frances, Mate, Abhijit, James, Ali, Courtauld, Gillian, Schofield, Christine, Adie, Katja, Lucas, Linda, Bond, Kirsty, Maund, Bev, Ellis, Sam, Mudd, Paul, James, Martin, Keenan, Samantha, Bowring, Angela, Cageao, Julie, Kingwell, Hayley, Roughan, Caroline, Hemsley, Anthony, Sword, Jane, Strain, David, Miller, Keniesha, Goff, Anita, Gupwell, Karin, Thorpe, Kevin, Emsley, Hedley, Punekar, Shuja, McLoughlin, Alison, Sultan, Sulaiman, Gregory, Bindu, Raj, Sonia, Doyle, Donna, Muir, Keith, Smith, Wilma, Welch, Angela, Moreton, Fiona, Cheripelli, Bharath Kumar, El Tawil, Salwa, Kalladka, Dheeraj, Huang, Xuya, Day, Nicola, Ramachandran, Sankaranarayana, Crosbie, Caroline, Elliot, Jennifer, Rudd, Tony, Marks, Katherine, Bhalla, Ajay, Birns, Jonathan, Kullane, Sagal, Weir, Nic, Allen, Christopher, Pressly, Vanessa, Crawford, Pam, Battersby-Wood, Emma, Blades, Alex, Egerton, Shuna, Walters, Ashleigh, Evans, Sue, Marigold, James Richard, Smith, Fiona, Howard, Gabriella, Gartrell, Imogen, Smith, Simon, Creeden, Robyn, Cox, Chloe, Boxall, Cherish, Hewitt, Jonathan, Nott, Claire, Sarah, Procter, Whiteman, Jessica, Buckle, Steve, Wallace, Rebecca, Mardania, Rina, Gray, Jane, Triscott, Claire, Nair, Anand, Greig, Jill, Rana, Pratap, Robinson, Matthew, Alam, Mohammad Irfan, Wilson, Duncan, Watchurst, Caroline, Brezitski, Maria, Crook, Luci, Jones, Ifan, Banaras, Azra, Patel, Krishna, Erande, Renuka, Hogan, Caroline, Hostettler, Isabel, Ashton, Amy, Feerick, Shez, Francia, Nina, Oji, Nnebuife, Elliott, Emma, Al-Mayhani, Talal, Dutta, Dipankar, Brown, Pauline, Ward, Deborah, Davis, Fiona, Turfrey, Jennifer, Hughes, Chloe, Collins, Kayleigh, Bakawala, Rehana, O'Connell, Susan, Glass, Jon, Broughton, David, Tryambake, Dinesh, Dixon, Lynn, Chapman, Kath, Young, Andrew, Bergin, Adrian, Sigsworth, Andrew, Manoj, Aravind, Fletcher, Glyn, Lopez, Paula, Cox, Penelope, Wilkinson, Mark, Fitzsimmons, Paul, Sharma, Nikhil, Choulerton, James, Button, Denise, Dow, Lindsey, Gbadamoshi, Lukuman, Avis, Joanne, Madigan, Barbara, McCann, Stephanie, Shaw, Louise, Howcroft, Deborah, Lucas, Suzanne, Stone, Andrew, Cluckie, Gillian, Lovelock, Caroline, Clarke, Brian, Chopra, Neha, Clarke, Natasha, Patel, Bhavini, Kennedy, Kate, Williams, Rebecca, Blight, Adrian, O'Reilly, Joanna, Orefo, Chukwuka, Dayal, Nilofer, Ghatala, Rita, Adedoyin, Temi, Watson, Fran, Trippier, Sarah, Choy, Lillian, Moynihan, Barry, Khan, Usman, Jones, Val, Jeyaraj, Naomi, Kerin, Lourda, Thavanesan, Kamy, Tiwari, Divya, Cox, Chantel, Ljubez, Anja, Tucker, Laura, Iqbal, Arshi, Bagnall, Caroline, Keltos, Marketa, Roberts, Josh, Jupp, Becky, Ovington, Catherine, Rogers, Emily, David, Owen, Bell, Jo, Longland, Barbara, Hann, Gail, Cooper, Martin, Nasar, Mohammad, Rajapakse, Anoja, Wynter, Inez, Anwar, Ijaz, Skinner, Helen, Nozedar, Tarn, McArdle, Damian, Kumar, Balakrishna, Crawford, Susan, Annamalai, Arunkumar, Ramshaw, Alex, Holmes, Clare, Caine, Sarah, Osborn, Mairead, Dodd, Emily, Murphy, Peter, Devitt, Nicola, Baker, Pauline, Steele, Amy, Guthrie, Lucy Belle, Clarke, Samantha, Hassan, Ahamad, Waugh, Dean, Veraque, Emelda, Makawa, Linetty, Kambafwile, Mary, Randall, Marc, Papavasileiou, Vasileios, Cullen, Claire, Peters, Jenny, Thant, Hlaing, Ingram, Tanya, Zoe, Mellor, Durairaj, Ramesh, Harrison, Melanie, Stevenson, Sarah, Shackcloth, Daniela, Ewing, Jordan, Sutton, Victoria, McCarron, Mark, McKee, Jacqueline, Doherty, Mandy, McVerry, Ferghal, Blair, Caroline, MacLeod, Mary, Irvine, Janice, Gow, Heather, Furnace, Jacqueline, Joyson, Anu, Jagpal, Baljit, Ross, Sarah, Klaasen, Katrina, Nelson, Sandra, Clarke, Rebecca, Crouch, Nichola, MacLennan, Beverly, Taylor, Vicky, Epstein, Daniel, Shukla, Avani, Krishnamurthy, Vinodh, Nicholas, Paul, Qureshi, Sammie, Webber, Adam, Penge, Justin, Ramadan, Hawraman, Maguire, Stuart, Patterson, Chris, Bellfield, Ruth, Hairsine, Brigid, Stewart, Kelvin, Hooley, Michaela, Quinn, Outi, Richard, Bella, Moseley, Sally, Edwards, Mandy, Lawson, Heidi, Tayler, Michelle, Pai, Yogish, Dhakal, Mahesh, Esisi, Bernard, Dima, Sofia, Smith, Gemma Marie, Garside, Mark, Naeem, Muhammad, Baliga, Vidya, Rogers, Gill, Brown, Ellen, Bruce, David, Hayman, Rachel, Clayton, Susan, Gamble, Ed, Grue, Rebecca, Charles, Bethan, Hague, Adam, Blane, Sujata, Lambert, Caroline, Chaudhry, Afnan, Harrison, Thomas, Saastamoinen, Kari, Hove, Dionne, Howaniec, Laura, Grimwood, Gemma, Redjep, Ozlem, Humphries, Fiona, Argandona, Lucia, Cuenoud, Larissa, Erumere, Esther, Amlani, Sageet, Auld, Grace, Salek-Haddadi, Afraim, Schulz, Ursula, Kennedy, James, Ford, Gary, Mathieson, Philip, Reckless, Ian, Teal, Rachel, Lenti, Giulia, Harston, George, O'Brien, Eoin, Mcgee, Joanne, Mitchell, Jennifer, Amis, Elaine, Handley, Dominic, Kelly, Siobhan, Zachariah, George, Francis, Jobbin, Crisp, Sarah, Sesay, Juliana, Finlay, Sarah, Hayhoe, Helen, Hannon, Niamh, Hughes, Tom, Morse, Bethan, De Berker, Henry, Tallantyre, Emma, Osman, Ahmed, White, Susan, Schwarz, Stefan, Jelley, Benjamin, Yadava, Rajendra, Azhar, Khalid, Reddan, Julie, Sangombe, Mirriam, Stafford, Samantha, Fotherby, Ken, Morgan, Debbie, Baig, Farrukh, Jennings-Preece, Karla, Butler, Donna, Ahmad, Nasar, Willberry, Angela, Stevens, Angela, Rai, Baljinder, Siddegowda, Prasad, Howard, Peter, Hyatt, Lisa, Dobson, Tracey, Jarrett, David, Ponnambath, Suheil, Tandy, Jane, Harrington-Davies, Yasmin, Butler, Rebecca, James, Claire, Valentine, Stacey, Suttling, Anne, Langhorne, Peter, Kerr, Gillian, Wright, Fiona, Graham, Ruth, McAlpine, Christine, Iqbal, Mohammad Shahzad, Humphreys, Louise, Pasco, Kath, Balazikova, Olga, Nasim, Ashraf, Peixoto, Cassilda, Gallagher, Louise, Shahmehri, Shahrzad, Ghosh, Sandip, Barrie, Elizabeth, Gilmour, Danielle, Henry, Margo, Webb, Tom, Cowie, Linda, Rudenko, Hannah, McDonald, Shanni, Schumacher, Natasha, Walker, Susannah, Cosier, Tracey, Verrion, Anna, Beranova, Eva, Thomson, Audrey, Venter, Marius, Kar, Arindam, Mashate, Sheila, Harvey, Kirsten, Gardener, Léjeune, Nguyen, Vinh, Halse, Omid, Geraghty, Olivia, Hazel, Beth, Wilding, Peter, Tilley, Victoria, Cassidy, Tim, McClelland, Beverley, Bokhari, Maria, England, Timothy, Maddula, Mohana, Donnelly, Richard, Findlay, Paul, Macaden, Ashish, Shread, Ian, Barr, Charlotte, Mohd Nor, Azlisham, Brown, Claire, Persad, Nicola, Eglinton, Charlotte, Weinling, Marie, Hyams, Benjamin, Shah, Alex, Baker, John, Byrne, Anthony, McGhee, Caroline, Smart, Amanda, Copeland, Claire, Carpenter, Michael, Walker, Marion, Davey, Richard, Needle, Ann, Fathima, Razik, Bateman, Gavin, Datta, Prabal, Stanners, Andrew, Jackson, Linda, Ball, Julie, Davis, Michelle, Atkinson, Natalie, Fawcett, Michelle, Thompson, Teresa, Guy, Helen, Hogg, Valerie, Hays, Carole, Woodward, Stephen, Haque, Mohammad, Hakim, Eluzai, Symonds, Stuart, Maanoosi, Mehran, Herman, Jane, Black, Toby, Miriam, Skelton, Clarke, Caroline, Anthony, Alpha, Tribbeck, Michele, Cronin, Julie, Mead, Denise, Fennelly, Ruth, McIlmoyle, James, Dickinson, Christina, Jeffs, Carol, Anwar, Sajjad, Howard, Joanne, Jones, Kirsty, Dhar, Saikat, Clay, Caroline, Siddiq, Muhammad, Ivatts, Simone, Baird, Yolanda, Sally, Moore, Amey, Isobel, Newton, Sophie, Clayton-Evans, Lisa, Chadbourn, Indra, Rayessa, Rayessa, Naylor, Charde, Rodgers, Alicia, Wilson, Lisa, Wilson, Sarah, Clarkson, Emma, Davies, Ruth, Owings, Paula, Sangster, Graeme, Gott, Valerie, Little, Victoria, Weir, Pauline, Cherian, Suja, Jose, Deepa, Moroney, Helen, Downham, Susan, Dodd, Angela, Vettimootal Johnson, Venetia, Codd, Laura, Robinson, Naomi, Ahmed, Ashraf, Albazzaz, Mo, Johnson, Sharon, Denniss, Carol, Cunningham, Mishell, Zahoor, Tajammal, Webster, Timothy, Leason, Sandra, Haider, Syed, Chatterjee, Kausic, Nallasivan, Arumugam, Perkins, Charlotte, Seagrave, Samantha, Jenkins, Colin, Price, Fiona, Hughes, Claire, Mercer, Lily, Hussain, Malik, Brown, Sarah, Harvey, Miriam, Homan, Jane, Khan, Mohammad, Whiting, Robert, Foote, Leanne, Hunt, Nicholas, Durman, Helen, Brotherton, Lucy, Foot, Jayne, Pawley, Corinne, Foster, Eliza, Whitcher, Alison, Metcalf, Kneale, Jagger, Jenny, McDonald, Susan, Waterfield, Kelly, Sutton, Patrick, Shinh, Naval, Anversha, Ajmal, Ravenhill, Garth, Greenwood, Richard, Saada, Janak, Wiltshire, Alison, Perfitt, Rebekah, Andole, Sreeman, Gadapa, Naveen, Dunne, Karen, Krommyda, Magdalini, Burssens, Evelyne, King, Sam, Plewa, Catherine, Smyth, Nigel, Wilson, Jenny, Giallombardo, Elio, Sykes, Lucy, Kumar, Pradeep, Barker, James, Huggett, Isabel, Dunn, Linda, Culmsee, Charlotte, Thomas, Philip, Myint, Min, Brew, Helen, Majmudar, Nikhil, O'Connell, Janice, Bunea, George, Fox, Charlotte, Gulliver, Diane, Smith, Andrew, Mokoena, Betty, Sattar, Naweed, Krishnamurthy, Ramesh, Osborne, Emily, Wilson, David, Wroath, Belinda, Dynan, Kevin, Power, Michael, Thompson, Susan, Adell, Victoria, Orugun, Enoch, Poultney, Una, Glover, Rachel, Crowther, Hannah, Thornthwaite, Sarah, Wiggam, Ivan, Wallace, Aine, Kerr, Enda, Fulton, Ailsa, Hunter, Annemarie, Tauro, Suzanne, Cuddy, Sarah, Mangion, David, Hardwick, Anne, Markova, Skarlet, Lawrence, Tara, Constantin, Carmen, Fletcher, Jo, Thomas, Isobel, Pettitt, Kerry, Sekaran, Lakshmanan, Tate, Margaret, Bharaj, Kiranjit, Simon, Rohan, Justin, Frances, Sethuraman, Sakthivel, Phiri, Duke, Mohammed, Niaz, Chauhan, Meena, Elfandi, Khaled, Khan, Uzma, Eveson, David, Mistri, Amit, Manning, Lisa, Khan, Shagufta, Patel, Champa, Moqsith, Mohammed, Sattar, Saira, Lam, Man Yee, Musarrat, Kashif, Stephens, Claire, Kalathil, Latheef, Miller, Richard, Salehin, Maqsud, Gautam, Nikki, Bailey, Duncan, Amor, Kelly, Meir, Julie, Nicolson, Anne, Imam, Javed, Wood, Lisa, White, Julie, Sajid, Mahmud, Ghaly, George, Ball, Margaret, Gascoyne, Rachel, Proeschel, Harald, Sharpe, Simon, Horton, Sarah, Beaves, Emily, Jones, Stephanie, Yip, Brigitte, Bell, Murdina, MacLiver, Linda, MacInnes, Brian, Sims, Don, Hurley, Jennifer, Willmot, Mark, Sutton, Claire, Littleton, Edward, Maiden, Susan, Jones, Rachael, Cunningham, James, Green, Carole, Bates, Michelle, Shekhar, Raj, Gilham, Ellie, Ahmed, Iman, Crown, Rachel, Fuller, Tracy, Goorah, Neetish, Bell, Angela, Kelly, Christine, Singh, Arun, Walford, Jamie, Tomlinson, Benjamin, Patel, Farzana, Duberley, Stephen, Kane, Ingrid, Rajkumar, Chakravarthi, Gaylard, Jane, Breeds, Joanna, Gainsborough, Nicola, Pitt-Ford, Alexandra, Barbon, Emma, Latter, Laura, Thompson, Philip, Hervey, Simon, Krishnamoorthy, Shrivakumar, Vassallo, Joseph, Walter, Deborah, Cochrane, Helen, Srinivasan, Meena, Campbell, Robert, Donaldson, Denise, Motherwell, Nichola, Hurford, Frances, Mukherjee, Indranil, Kenton, Antony, Nyabadza, Sheila, Martin, Irene, Hunt, Benjamin, Hassan, Hardi, O'Toole, Sarah, Dallol, Bander, Putterill, Janet, Jha, Ratneshwari, Gallifent, Rachel, Kakar, Puneet, Pusalkar, Aparna, Chan, Kelly, Dangri, Puneet, Beadle, Hannah, Cook, Angela, Crabtree, Karen, Subramonian, Santhosh, Owusu-Agyei, Peter, Temple, Natalie, Butterworth-Cowin, Nicola, Ragab, Suzanne, Knops, Kerstin, Jinks, Emma, Dickson, Christine, Gleave, Laura, Dube, Judith, Leggett, Jacqui, Garcia, Tatiana, Ispoglou, Sissy, Evans, Rachel, Ankolekar, Sandeep, Hayes, Anne, Ni, Hlaing, Rahman, Bithi, Milligan, Josette, Graham, Carol, Jose, Josin, Keegan, Breffni, Kelly, Jim, Dewar, Richard, White, James, and Thomas, Kelly

Abstract

Background:\ud Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.\ud \ud Methods:\ud The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).\ud \ud Findings:\ud Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).\ud \ud Interpretation:\ud These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.

Published
2019

30. Prehospital transdermal glyceryl trinitrate for ultra-acute intracerebral hemorrhage: Data from the RIGHT-2 trial

Author

Bath, PM, Woodhouse, LJ, Krishnan, K, Appleton, JP, Anderson, CS, Berge, E, Cala, L, Dixon, M, England, TJ, Godolphin, PJ, Hepburn, T, Mair, G, Montgomery, AA, Phillips, SJ, Potter, J, Price, CI, Randall, M, Robinson, TG, Roffe, C, Rothwell, PM, Sandset, EC, Sanossian, N, Saver, JL, Siriwardena, AN, Venables, G, Wardlaw, JM, and Sprigg, N

Subjects
cardiovascular system, circulatory and respiratory physiology
Abstract

Background and Purpose- Pilot trials suggest that glyceryl trinitrate (GTN; nitroglycerin) may improve outcome when administered early after stroke onset. Methods- We undertook a multicentre, paramedic-delivered, ambulance-based, prospective randomized, sham-controlled, blinded-end point trial in adults with presumed stroke within 4 hours of ictus. Participants received transdermal GTN (5 mg) or a sham dressing (1:1) in the ambulance and then daily for three days in hospital. The primary outcome was the 7-level modified Rankin Scale at 90 days assessed by central telephone treatment-blinded follow-up. This prespecified subgroup analysis focuses on participants with an intracerebral hemorrhage as their index event. Analyses are intention-to-treat. Results- Of 1149 participants with presumed stroke, 145 (13%; GTN, 74; sham, 71) had an intracerebral hemorrhage: time from onset to randomization median, 74 minutes (interquartile range, 45-110). By admission to hospital, blood pressure tended to be lower with GTN as compared with sham: mean, 4.4/3.5 mm Hg. The modified Rankin Scale score at 90 days was nonsignificantly higher in the GTN group: adjusted common odds ratio for poor outcome, 1.87 (95% CI, 0.98-3.57). A prespecified global analysis of 5 clinical outcomes (dependency, disability, cognition, quality of life, and mood) was worse with GTN; Mann-Whitney difference, 0.18 (95% CI, 0.01-0.35; Wei-Lachin test). GTN was associated with larger hematoma and growth, and more mass effect and midline shift on neuroimaging, and altered use of hospital resources. Death in hospital but not at day 90 was increased with GTN. There were no significant between-group differences in serious adverse events. Conclusions- Prehospital treatment with GTN worsened outcomes in patients with intracerebral hemorrhage. Since these results could relate to the play of chance, confounding, or a true effect of GTN, further randomized evidence on the use of vasodilators in ultra-acute intracerebral hemorrhage is needed. Clinical Trial Registration- URL: http://www.controlled-trials.com. Unique identifier: ISRCTN26986053.

Published
2019

32. Lowering blood pressure after acute intracerebral haemorrhage: Protocol for a systematic review and meta-analysis using individual patient data from randomised controlled trials participating in the Blood Pressure in Acute Stroke Collaboration (BASC)

Author

Moullaali, TJ, Wang, X, Woodhouse, LJ, Law, ZK, Delcourt, C, Sprigg, N, Krishnan, K, Robinson, TG, Wardlaw, JM, Al-Shahi Salman, R, Berge, E, Sandset, EC, Anderson, CS, Bath, PM, Moullaali, TJ, Wang, X, Woodhouse, LJ, Law, ZK, Delcourt, C, Sprigg, N, Krishnan, K, Robinson, TG, Wardlaw, JM, Al-Shahi Salman, R, Berge, E, Sandset, EC, Anderson, CS, and Bath, PM

Abstract

Introduction Conflicting results from multiple randomised trials indicate that the methods and effects of blood pressure (BP) reduction after acute intracerebral haemorrhage (ICH) are complex. The Blood pressure in Acute Stroke Collaboration is an international collaboration, which aims to determine the optimal management of BP after acute stroke including ICH. Methods and analysis A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient's demographic, clinical and prestroke neuroradiological characteristics. Ethics and dissemination No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted; therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals. PROSPERO registration number CRD42019141136.

Published
2019

33. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, YC, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Guðnason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, CY, Wong, TY, Ikram, MK, van der Lee, SJ, Amin, N, Chouraki, V, Destefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, Decarli, C, Wardlaw, JM, Del C. Valdés Hernández, M, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, HW, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Völker, U, Levi, C, Jimenez-Conde, J, Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, YC, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Guðnason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, CY, Wong, TY, Ikram, MK, van der Lee, SJ, Amin, N, Chouraki, V, Destefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, Decarli, C, Wardlaw, JM, Del C. Valdés Hernández, M, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, HW, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Völker, U, Levi, C, and Jimenez-Conde, J

Abstract

Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI]= 4.4 × 10-10; p [SSBI] = 1.2 × 10 -4), diabetes (p[BI] = 1.7 × 10 -8; p [SSBI] = 2.8 × 10 -3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significan

Published
2019

34. Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies

Author

Wilson, D, Ambler, G, Lee, K-J, Lim, J-S, Shiozawa, M, Koga, M, Li, L, Lovelock, C, Chabriat, H, Hennerici, M, Wong, YK, Mak, HKF, Prats-Sanchez, L, Martinez-Domeno, A, Inamura, S, Yoshifuji, K, Arsava, EM, Horstmann, S, Purrucker, J, Lam, BYK, Wong, A, Kim, YD, Song, T-J, Schrooten, M, Lemmens, R, Eppinger, S, Gattringer, T, Uysal, E, Tanriverdi, Z, Bornstein, NM, Ben Assayag, E, Hallevi, H, Tanaka, J, Hara, H, Coutts, SB, Hert, L, Polymeris, A, Seiffge, DJ, Lyrer, P, Algra, A, Kappelle, J, Salman, RA-S, Jager, HR, Lip, GYH, Mattle, HP, Panos, LD, Mas, J-L, Legrand, L, Karayiannis, C, Phan, T, Gunkel, S, Christ, N, Abrigo, J, Leung, T, Chu, W, Chappell, F, Makin, S, Hayden, D, Williams, DJ, Kooi, ME, van Dam-Nolen, DHK, Barbato, C, Browning, S, Wiegertjes, K, Tuladhar, AM, Maaijwee, N, Guevarra, C, Yatawara, C, Mendyk, A-M, Delmaire, C, Kohler, S, van Oostenbrugge, R, Zhou, Y, Xu, C, Hilal, S, Gyanwali, B, Chen, C, Lou, M, Staals, J, Bordet, R, Kandiah, N, de Leeuw, F-E, Simister, R, van der Lugt, A, Kelly, PJ, Wardlaw, JM, Soo, Y, Fluri, F, Srikanth, V, Calvet, D, Jung, S, Kwa, VIH, Engelter, ST, Peters, N, Smith, EE, Yakushiji, Y, Orken, DN, Fazekas, F, Thijs, V, Heo, JH, Mok, V, Veltkamp, R, Ay, H, Imaizumi, T, Gomez-Anson, B, Lau, KK, Jouvent, E, Rothwell, PM, Toyoda, K, Bae, H-J, Marti-Fabregas, J, Werring, DJ, Wilson, D, Ambler, G, Lee, K-J, Lim, J-S, Shiozawa, M, Koga, M, Li, L, Lovelock, C, Chabriat, H, Hennerici, M, Wong, YK, Mak, HKF, Prats-Sanchez, L, Martinez-Domeno, A, Inamura, S, Yoshifuji, K, Arsava, EM, Horstmann, S, Purrucker, J, Lam, BYK, Wong, A, Kim, YD, Song, T-J, Schrooten, M, Lemmens, R, Eppinger, S, Gattringer, T, Uysal, E, Tanriverdi, Z, Bornstein, NM, Ben Assayag, E, Hallevi, H, Tanaka, J, Hara, H, Coutts, SB, Hert, L, Polymeris, A, Seiffge, DJ, Lyrer, P, Algra, A, Kappelle, J, Salman, RA-S, Jager, HR, Lip, GYH, Mattle, HP, Panos, LD, Mas, J-L, Legrand, L, Karayiannis, C, Phan, T, Gunkel, S, Christ, N, Abrigo, J, Leung, T, Chu, W, Chappell, F, Makin, S, Hayden, D, Williams, DJ, Kooi, ME, van Dam-Nolen, DHK, Barbato, C, Browning, S, Wiegertjes, K, Tuladhar, AM, Maaijwee, N, Guevarra, C, Yatawara, C, Mendyk, A-M, Delmaire, C, Kohler, S, van Oostenbrugge, R, Zhou, Y, Xu, C, Hilal, S, Gyanwali, B, Chen, C, Lou, M, Staals, J, Bordet, R, Kandiah, N, de Leeuw, F-E, Simister, R, van der Lugt, A, Kelly, PJ, Wardlaw, JM, Soo, Y, Fluri, F, Srikanth, V, Calvet, D, Jung, S, Kwa, VIH, Engelter, ST, Peters, N, Smith, EE, Yakushiji, Y, Orken, DN, Fazekas, F, Thijs, V, Heo, JH, Mok, V, Veltkamp, R, Ay, H, Imaizumi, T, Gomez-Anson, B, Lau, KK, Jouvent, E, Rothwell, PM, Toyoda, K, Bae, H-J, Marti-Fabregas, J, and Werring, DJ

Abstract

BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intr

Published
2019

37. Associations between vascular risk factors and brain MRI indices in UK Biobank

Author

Cox, SR, primary, Lyall, DM, additional, Ritchie, SJ, additional, Bastin, ME, additional, Harris, MA, additional, Buchanan, CR, additional, Fawns-Ritchie, C, additional, Barbu, MC, additional, de Nooij, L, additional, Reus, LM, additional, Alloza, C, additional, Shen, X, additional, Neilson, E, additional, Alderson, HL, additional, Hunter, S, additional, Liewald, DC, additional, Whalley, HC, additional, McIntosh, AM, additional, Lawrie, SJ, additional, Pell, JP, additional, Tucker-Drob, EM, additional, Wardlaw, JM, additional, Gale, CR, additional, and Deary, IJ, additional

Published
2019
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38. Maximising the Potential of Longitudinal Cohorts for Research in Neurodegenerative Diseases: A Community Perspective

Author

Brayne, CEG, Moody, CJ, Mitchell, D, Kiser, G, Aarsland, D, Berg, D, Brayne, C, Costa, A, Ikram, MA, Mountain, G, Rohrer, JD, Teunissen, CE, van den Berg, LH, Wardlaw, JM, Brayne, Carol [0000-0001-5307-663X], and Apollo - University of Cambridge Repository

Subjects
joint programming, research, flexible funding mechanism, neurodegenerative disease, longitudinal cohort studies, transnational working groups
Abstract

Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilise scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape (Alzheimer’s, Parkinson’s, frontotemporal degeneration, amyotrophic lateral sclerosis, Lewy-body and vascular dementia) were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.

Published
2017
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39. Impact of detecting potentially serious incidental findings during multi-modal imaging [version 3; peer review: 2 approved, 1 approved with reservations]

Author

Gibson, LM, Littlejohns, TJ, Adamska, L, Garratt, S, Doherty, N, UK Biobank Imaging Working Group, Wardlaw, JM, Maskell, G, Parker, M, Brownsword, R, Matthews, PM, Collins, R, Allen, NE, Sellors, J, and Sudlow, CL

Subjects
incidental findings, false negatives, research ethics, false positives, magnetic resonance imaging, UK Biobank Imaging Working Group, dual-energy X-ray absorptiometry
Abstract

Background: There are limited data on the impact of feedback of incidental findings (IFs) from research imaging. We evaluated the impact of UK Biobank's protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer 'flagging' with radiologist confirmation of potentially serious IFs) compared with systematic radiologist review of all images. Methods: Brain, cardiac and body magnetic resonance, and dual-energy x-ray absorptiometry scans from the first 1000 imaged UK Biobank participants were independently assessed for potentially serious IFs using both protocols. We surveyed participants with potentially serious IFs and their GPs up to six months after imaging to determine subsequent clinical assessments, final diagnoses, emotional, financial and work or activity impacts. Results: Compared to systematic radiologist review, radiographer flagging resulted in substantially fewer participants with potentially serious IFs (179/1000 [17.9%] versus 18/1000 [1.8%]) and a higher proportion with serious final diagnoses (21/179 [11.7%] versus 5/18 [27.8%]). Radiographer flagging missed 16/21 serious final diagnoses (i.e., false negatives), while systematic radiologist review generated large numbers of non-serious final diagnoses (158/179) (i.e., false positives). Almost all (90%) participants had further clinical assessment (including invasive procedures in similar numbers with serious and non-serious final diagnoses [11 and 12 respectively]), with additional impact on emotional wellbeing (16.9%), finances (8.9%), and work or activities (5.6%). Conclusions: Compared with systematic radiologist review, radiographer flagging missed some serious diagnoses, but avoided adverse impacts for many participants with non-serious diagnoses. While systematic radiologist review may benefit some participants, UK Biobank's responsibility to avoid both unnecessary harm to larger numbers of participants and burdening of publicly-funded health services suggests that radiographer flagging is a justifiable approach in the UK Biobank imaging study. The potential scale of non-serious final diagnoses raises questions relating to handling IFs in other settings, such as commercial and public health screening.

Published
2017

40. Effects of alteplase for acute stroke according to criteria defining the EU and US marketing authorizations: individual-patient-data meta-analysis of randomized trials

Author

Hacke, W, Lyden, P, Emberson, J, Baigent, C, Blackwell, L, Albers, G, Bluhmki, E, Brott, T, Cohen, G, Davis, SM, Donnan, GA, Grotta, JC, Howard, G, Kaste, M, Koga, M, von Kummer, R, Lansberg, MG, Lindley, RI, Olivot, J-M, Parsons, M, Sandercock, PAG, Toni, D, Toyoda, K, Wahlgren, N, Wardlaw, JM, Whiteley, WN, del Zoppo, G, and Lees, KR

Abstract

Background: The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke (AIS) each differ between Europe (EU) and United States (US). Aims: To compare the effects of alteplase according to cohorts defined by current EU or US marketing approval labels, or by hypothetical revisions of the labels that would remove the EU upper age limit or extend the US treatment time window to 4.5 hours. Methods: Individual-patient-data meta-analysis of 8 randomized trials of intravenous alteplase (0.9 mg/kg) versus control for AIS. Outcomes included excellent outcome (modified Rankin score [mRS] 0-1) at 3-6 months, the distribution of mRS, symptomatic intracerebral hemorrhage, and 90 day mortality. Results: Among 2449/6136 (40%) patients who met the current EU label and 3491 (57%) patients who met the age-revised label, alteplase increased the odds of mRS 0-1 (odds ratio 1.42, 95% CI 1.21−1.68 and 1.43, 1.23−1.65, respectively) but not in those outside the age-revised label (1.06, 0.90−1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76−1.25 and 1.01, 0.86–1.19 respectively) but mortality remained higher outside the age-revised label (1.19, 0.99–1.42). Similarly, among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-hour revised approval, alteplase increased the odds of mRS 0-1 (OR 1.55, 1.19−2.01 and 1.37, 1.17−1.59, respectively) but not for those outside the 4.5-hour revised approval (1.14, 0.97−1.34). By 90 days no increased mortality remained for the current and 4.5-hour revised label cohorts (hazard ratios 0.99, 0.77−1.26 and 1.02, 0.87–1.20 respectively) but mortality remained higher outside the 4.5-hour revised approval (1.17, 0.98–1.41). Conclusions: An age-revised EU label or 4.5-hour-revised US label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality.

Published
2017

41. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Author

Vojinovic, D, Adams, HH, Jian, X, Yang, Q, Smith, AV, Bis, JC, Teumer, A, Scholz, M, Armstrong, NJ, Hofer, E, Saba, Y, Luciano, M, Bernard, M, Trompet, S, Yang, J, Gillespie, NA, van der Lee, SJ, Neumann, A, Ahmad, S, Andreassen, OA, Ames, D, Amin, N, Arfanakis, K, Bastin, ME, Becker, DM, Beiser, AS, Beyer, F, Brodaty, H, Bryan, RN, Bülow, R, Dale, AM, De Jager, PL, Deary, IJ, DeCarli, C, Fleischman, DA, Gottesman, RF, van der Grond, J, Gudnason, V, Harris, TB, Homuth, G, Knopman, DS, Kwok, JB, Lewis, CE, Li, S, Loeffler, M, Lopez, OL, Maillard, P, El Marroun, H, Mather, KA, Mosley, TH, Muetzel, RL, Nauck, M, Nyquist, PA, Panizzon, MS, Pausova, Z, Psaty, BM, Rice, K, Rotter, JI, Royle, N, Satizabal, CL, Schmidt, R, Schofield, PR, Schreiner, PJ, Sidney, S, Stott, DJ, Thalamuthu, A, Uitterlinden, AG, Valdés Hernández, MC, Vernooij, MW, Wen, W, White, T, Witte, AV, Wittfeld, K, Wright, MJ, Yanek, LR, Tiemeier, H, Kremen, WS, Bennett, DA, Jukema, JW, Paus, T, Wardlaw, JM, Schmidt, H, Sachdev, PS, Villringer, A, Grabe, HJ, Longstreth, WT, van Duijn, CM, Launer, LJ, Seshadri, S, Ikram, MA, Fornage, M, Vojinovic, D, Adams, HH, Jian, X, Yang, Q, Smith, AV, Bis, JC, Teumer, A, Scholz, M, Armstrong, NJ, Hofer, E, Saba, Y, Luciano, M, Bernard, M, Trompet, S, Yang, J, Gillespie, NA, van der Lee, SJ, Neumann, A, Ahmad, S, Andreassen, OA, Ames, D, Amin, N, Arfanakis, K, Bastin, ME, Becker, DM, Beiser, AS, Beyer, F, Brodaty, H, Bryan, RN, Bülow, R, Dale, AM, De Jager, PL, Deary, IJ, DeCarli, C, Fleischman, DA, Gottesman, RF, van der Grond, J, Gudnason, V, Harris, TB, Homuth, G, Knopman, DS, Kwok, JB, Lewis, CE, Li, S, Loeffler, M, Lopez, OL, Maillard, P, El Marroun, H, Mather, KA, Mosley, TH, Muetzel, RL, Nauck, M, Nyquist, PA, Panizzon, MS, Pausova, Z, Psaty, BM, Rice, K, Rotter, JI, Royle, N, Satizabal, CL, Schmidt, R, Schofield, PR, Schreiner, PJ, Sidney, S, Stott, DJ, Thalamuthu, A, Uitterlinden, AG, Valdés Hernández, MC, Vernooij, MW, Wen, W, White, T, Witte, AV, Wittfeld, K, Wright, MJ, Yanek, LR, Tiemeier, H, Kremen, WS, Bennett, DA, Jukema, JW, Paus, T, Wardlaw, JM, Schmidt, H, Sachdev, PS, Villringer, A, Grabe, HJ, Longstreth, WT, van Duijn, CM, Launer, LJ, Seshadri, S, Ikram, MA, and Fornage, M

Abstract

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (?genetic = -0.59, p-value = 3.14 × 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Published
2018

42. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author

Franceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkanen, N, Franzen, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, S-J, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Fava, C, Baldassarre, D, O'Leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Voelzke, H, Markus, HS, Deary, IJ, Jukema, JW, de Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Doer, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-Ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, Giral, P, Anugu, P, Wong, Q, Malik, R, Rauramaa, R, Burkhardt, R, Hardy, R, Schmidt, R, de Mutsert, R, Morris, RW, Strawbridge, RJ, Wannamethee, SG, Hagg, S, Shah, S, McLachlan, S, Trompet, S, Seshadri, S, Kurl, S, Heckbert, SR, Ring, S, Harris, TB, Lehtimaki, T, Galesloot, TE, Shah, T, de Faire, U, Plagnol, V, Rosamond, WD, Post, W, Zhu, X, Zhang, X, Guo, X, Saba, Y, Dehghan, A, Seldenrijk, A, Morrison, AC, Hamsten, A, Psaty, BM, van Duijn, CM, Lawlor, DA, Mook-Kanamori, DO, Bowden, DW, Schmidt, H, Wilson, JF, Wilson, JG, Rotter, JI, Wardlaw, JM, Deanfield, J, Halcox, J, Lyytikainen, L-P, Loeffler, M, Evans, MK, Debette, S, Humphries, SE, Voelker, U, Gudnason, V, Hingorani, AD, Bjorkegren, JLM, Casas, JP, O'Donnell, CJ, Franceschini, N, Giambartolomei, C, de Vries, PS, Finan, C, Bis, JC, Huntley, RP, Lovering, RC, Tajuddin, SM, Winkler, TW, Graff, M, Kavousi, M, Dale, C, Smith, AV, Hofer, E, van Leeuwen, EM, Nolte, IM, Lu, L, Scholz, M, Sargurupremraj, M, Pitkanen, N, Franzen, O, Joshi, PK, Noordam, R, Marioni, RE, Hwang, S-J, Musani, SK, Schminke, U, Palmas, W, Isaacs, A, Correa, A, Zonderman, AB, Hofman, A, Teumer, A, Cox, AJ, Uitterlinden, AG, Wong, A, Smit, AJ, Newman, AB, Britton, A, Ruusalepp, A, Sennblad, B, Hedblad, B, Pasaniuc, B, Penninx, BW, Langefeld, CD, Wassel, CL, Tzourio, C, Fava, C, Baldassarre, D, O'Leary, DH, Teupser, D, Kuh, D, Tremoli, E, Mannarino, E, Grossi, E, Boerwinkle, E, Schadt, EE, Ingelsson, E, Veglia, F, Rivadeneira, F, Beutner, F, Chauhan, G, Heiss, G, Snieder, H, Campbell, H, Voelzke, H, Markus, HS, Deary, IJ, Jukema, JW, de Graaf, J, Price, J, Pott, J, Hopewell, JC, Liang, J, Thiery, J, Engmann, J, Gertow, K, Rice, K, Taylor, KD, Dhana, K, Kiemeney, LALM, Lind, L, Raffield, LM, Launer, LJ, Holdt, LM, Doer, M, Dichgans, M, Traylor, M, Sitzer, M, Kumari, M, Kivimaki, M, Nalls, MA, Melander, O, Raitakari, O, Franco, OH, Rueda-Ochoa, OL, Roussos, P, Whincup, PH, Amouyel, P, Giral, P, Anugu, P, Wong, Q, Malik, R, Rauramaa, R, Burkhardt, R, Hardy, R, Schmidt, R, de Mutsert, R, Morris, RW, Strawbridge, RJ, Wannamethee, SG, Hagg, S, Shah, S, McLachlan, S, Trompet, S, Seshadri, S, Kurl, S, Heckbert, SR, Ring, S, Harris, TB, Lehtimaki, T, Galesloot, TE, Shah, T, de Faire, U, Plagnol, V, Rosamond, WD, Post, W, Zhu, X, Zhang, X, Guo, X, Saba, Y, Dehghan, A, Seldenrijk, A, Morrison, AC, Hamsten, A, Psaty, BM, van Duijn, CM, Lawlor, DA, Mook-Kanamori, DO, Bowden, DW, Schmidt, H, Wilson, JF, Wilson, JG, Rotter, JI, Wardlaw, JM, Deanfield, J, Halcox, J, Lyytikainen, L-P, Loeffler, M, Evans, MK, Debette, S, Humphries, SE, Voelker, U, Gudnason, V, Hingorani, AD, Bjorkegren, JLM, Casas, JP, and O'Donnell, CJ

Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018

43. Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

Author

Vojinovic, Dina, Adams, Hieab, Jian, XQ, Yang, Q, Smith, AV, Bis, JC, Teumer, A, Scholz, M, Armstrong, NJ, Hofer, E, Saba, Y, Luciano, M, Bernard, M, Trompet, S, Yang, JY, Gillespie, NA, van der Lee, Sven, Neumann, Alexander, Ahmad, Shahzad, Andreassen, OA, Ames, D, Amin, Najaf, Arfanakis, K, Bastin, ME, Becker, DM, Beiser, AS, Beyer, F, Brodaty, H, Bryan, RN, Bulow, R, Dale, AM, De Jager, PL, Deary, IJ, DeCarli, C, Fleischman, DA, Gottesman, RF, van der Grond, J, Gudnason, V, Harris, TB, Homuth, G, Knopman, DS, Kwok, JB, Lewis, CE, Li, S, Loeffler, M, Lopez, OL, Maillard, P, El Marroun, Hanan, Mather, KA, Mosley, TH, Muetzel, Ryan, Nauck, M, Nyquist, PA, Panizzon, MS, Pausova, Z, Psaty, BM, Rice, K, Rotter, JI, Royle, N, Satizabal, CL, Schmidt, R, Schofield, PR, Schreiner, PJ, Sidney, S, Stott, DJ, Thalamuthu, A, Uitterlinden, André, Hernandez, MCV, Vernooij, Meike, Wen, W, White, Tonya, Witte, AV, Wittfeld, K, Wright, MJ, Yanek, LR, Tiemeier, Henning, Kremen, WS, Bennett, DA, Jukema, JW, Paus, T, Wardlaw, JM, Schmidt, H, Sachdev, PS, Villringer, A, Grabe, HJ, Longstreth, WT, Duijn, Cornelia, Launer, LJ, Seshadri, S, Ikram, Arfan, Fornage, M, Vojinovic, Dina, Adams, Hieab, Jian, XQ, Yang, Q, Smith, AV, Bis, JC, Teumer, A, Scholz, M, Armstrong, NJ, Hofer, E, Saba, Y, Luciano, M, Bernard, M, Trompet, S, Yang, JY, Gillespie, NA, van der Lee, Sven, Neumann, Alexander, Ahmad, Shahzad, Andreassen, OA, Ames, D, Amin, Najaf, Arfanakis, K, Bastin, ME, Becker, DM, Beiser, AS, Beyer, F, Brodaty, H, Bryan, RN, Bulow, R, Dale, AM, De Jager, PL, Deary, IJ, DeCarli, C, Fleischman, DA, Gottesman, RF, van der Grond, J, Gudnason, V, Harris, TB, Homuth, G, Knopman, DS, Kwok, JB, Lewis, CE, Li, S, Loeffler, M, Lopez, OL, Maillard, P, El Marroun, Hanan, Mather, KA, Mosley, TH, Muetzel, Ryan, Nauck, M, Nyquist, PA, Panizzon, MS, Pausova, Z, Psaty, BM, Rice, K, Rotter, JI, Royle, N, Satizabal, CL, Schmidt, R, Schofield, PR, Schreiner, PJ, Sidney, S, Stott, DJ, Thalamuthu, A, Uitterlinden, André, Hernandez, MCV, Vernooij, Meike, Wen, W, White, Tonya, Witte, AV, Wittfeld, K, Wright, MJ, Yanek, LR, Tiemeier, Henning, Kremen, WS, Bennett, DA, Jukema, JW, Paus, T, Wardlaw, JM, Schmidt, H, Sachdev, PS, Villringer, A, Grabe, HJ, Longstreth, WT, Duijn, Cornelia, Launer, LJ, Seshadri, S, Ikram, Arfan, and Fornage, M

Abstract

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (?genetic?=?-0.59, p-value?=?3.14?×?10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology

Published
2018

45. Arterial Obstruction on Computed Tomographic or Magnetic Resonance Angiography and Response to Intravenous Thrombolytics in Ischemic Stroke

Author

Mair, G, von Kummer, R, Adami, A, White, PM, Adams, ME, Yan, B, Demchuk, AM, Farrall, AJ, Sellar, RJ, Sakka, E, Palmer, J, Perry, D, Lindley, RI, Sandercock, PAG, Wardlaw, JM, Mair, G, von Kummer, R, Adami, A, White, PM, Adams, ME, Yan, B, Demchuk, AM, Farrall, AJ, Sellar, RJ, Sakka, E, Palmer, J, Perry, D, Lindley, RI, Sandercock, PAG, and Wardlaw, JM

Abstract

BACKGROUND AND PURPOSE: Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data. METHODS: We analyzed angiograms from the IST-3 (Third International Stroke Trial), an international, multicenter, prospective, randomized controlled trial of intravenous alteplase. Readers, masked to clinical, treatment, and outcome data, assessed prerandomization computed tomographic angiography and magnetic resonance angiography for presence, extent, location, and completeness of obstruction and collaterals. We compared angiography findings to 6-month functional outcome (Oxford Handicap Scale) and tested for interactions with alteplase, using ordinal regression in adjusted analyses. We also meta-analyzed all available angiography data from other randomized controlled trials of intravenous thrombolytics. RESULTS: In IST-3, 300 patients had prerandomization angiography (computed tomographic angiography=271 and magnetic resonance angiography=29). On multivariable analysis, more extensive angiographic obstruction and poor collaterals independently predicted poor outcome (P<0.01). We identified no significant interaction between angiography findings and alteplase effect on Oxford Handicap Scale (P≥0.075) in IST-3. In meta-analysis (5 trials of alteplase or desmoteplase, including IST-3, n=591), there was a significantly increased benefit of thrombolytics on outcome (odds ratio>1 indicates benefit) in patients with (odds ratio, 2.07; 95% confidence interval, 1.18-3.64; P=0.011) versus without (odds ratio, 0.88; 95% confidence interval, 0.58-1.35; P=0.566) arterial obstruction (P for interaction 0.017). CONCLUSIONS: Intravenous thrombolytics provide benefit to stroke patients with computed tomographic angiography or magnetic resonance angiography

Published
2017

46. Novel genetic loci associated with hippocampal volume

Author

Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, Ikram, MA, Hibar, DP, Adams, HHH, Jahanshad, N, Chauhan, G, Stein, JL, Hofer, E, Renteria, ME, Bis, JC, Arias-Vasquez, A, Ikram, MK, Desrivieres, S, Vernooij, MW, Abramovic, L, Alhusaini, S, Amin, N, Andersson, M, Arfanakis, K, Aribisala, BS, Armstrong, NJ, Athanasiu, L, Axelsson, T, Beecham, AH, Beiser, A, Bernard, M, Blanton, SH, Bohlken, MM, Boks, MP, Bralten, J, Brickman, AM, Carmichael, O, Chakravarty, MM, Chen, Q, Ching, CRK, Chouraki, V, Cuellar-Partida, G, Crivello, F, Den Braber, A, Nhat, TD, Ehrlich, S, Giddaluru, S, Goldman, AL, Gottesman, RF, Grimm, O, Griswold, ME, Guadalupe, T, Gutman, BA, Hass, J, Haukvik, UK, Hoehn, D, Holmes, AJ, Hoogman, M, Janowitz, D, Jia, T, Jorgensen, KN, Karbalai, N, Kasperaviciute, D, Kim, S, Klein, M, Kraemer, B, Lee, PH, Liewald, DCM, Lopez, LM, Luciano, M, Macare, C, Marquand, AF, Matarin, M, Mather, KA, Mattheisen, M, McKay, DR, Milaneschi, Y, Maniega, SM, Nho, K, Nugent, AC, Nyquist, P, Loohuis, LMO, Oosterlaan, J, Papmeyer, M, Pirpamer, L, Puetz, B, Ramasamy, A, Richards, JS, Risacher, SL, Roiz-Santianez, R, Rommelse, N, Ropele, S, Rose, EJ, Royle, NA, Rundek, T, Saemann, PG, Saremi, A, Satizabal, CL, Schmaal, L, Schork, AJ, Shen, L, Shin, J, Shumskaya, E, Smith, AV, Sprooten, E, Strike, LT, Teumer, A, Tordesillas-Gutierrez, D, Toro, R, Trabzuni, D, Trompet, S, Vaidya, D, Van der Grond, J, Van der Lee, SJ, Van der Meer, D, Van Donkelaar, MMJ, Van Eijk, KR, Van Erp, TGM, Van Rooij, D, Walton, E, Westlye, LT, Whelan, CD, Windham, BG, Winkler, AM, Wittfeld, K, Woldehawariat, G, Wolf, C, Wolfers, T, Yanek, LR, Yang, J, Zijdenbos, A, Zwiers, MP, Agartz, I, Almasy, L, Ames, D, Amouyel, P, Andreassen, OA, Arepalli, S, Assareh, AA, Barral, S, Bastin, ME, Becker, DM, Becker, JT, Bennett, DA, Blangero, J, van Bokhoven, H, Boomsma, DI, Brodaty, H, Brouwer, RM, Brunner, HG, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cahn, W, Calhoun, VD, Cannon, DM, Cavalleri, GL, Cheng, C-Y, Cichon, S, Cookson, MR, Corvin, A, Crespo-Facorro, B, Curran, JE, Czisch, M, Dale, AM, Davies, GE, De Craen, AJM, De Geus, EJC, De Jager, PL, De Zubicaray, GI, Deary, IJ, Debette, S, DeCarli, C, Delanty, N, Depondt, C, DeStefano, A, Dillman, A, Djurovic, S, Donohoe, G, Drevets, WC, Duggirala, R, Dyer, TD, Enzinger, C, Erk, S, Espeseth, T, Fedko, IO, Fernandez, G, Ferrucci, L, Fisher, SE, Fleischman, DA, Ford, I, Fornage, M, Foroud, TM, Fox, PT, Francks, C, Fukunaga, M, Gibbs, JR, Glahn, DC, Gollub, RL, Goring, HHH, Green, RC, Gruber, O, Gudnason, V, Guelfi, S, Haberg, AK, Hansell, NK, Hardy, J, Hartman, CA, Hashimoto, R, Hegenscheid, K, Heinz, A, Le Hellard, S, Hernandez, DG, Heslenfeld, DJ, Ho, B-C, Hoekstra, PJ, Hoffmann, W, Hofman, A, Holsboer, F, Homuth, G, Hosten, N, Hottenga, J-J, Huentelman, M, Pol, HEH, Ikeda, M, Jack, CR, Jenkinson, M, Johnson, R, Joensson, EG, Jukema, JW, Kahn, RS, Kanai, R, Kloszewska, I, Knopman, DS, Kochunov, P, Kwok, JB, Lawrie, SM, Lemaitre, H, Liu, X, Longo, DL, Lopez, OL, Lovestone, S, Martinez, O, Martinot, J-L, Mattay, VS, McDonald, C, McIntosh, AM, McMahon, FJ, McMahon, KL, Mecocci, P, Melle, I, Meyer-Lindenberg, A, Mohnke, S, Montgomery, GW, Morris, DW, Mosley, TH, Muhleisen, TW, Mueller-Myhsok, B, Nalls, MA, Nauck, M, Nichols, TE, Niessen, WJ, Nothen, MM, Nyberg, L, Ohi, K, Olvera, RL, Ophoff, RA, Pandolfo, M, Paus, T, Pausova, Z, Penninx, BWJH, Pike, GB, Potkin, SG, Psaty, BM, Reppermund, S, Rietschel, M, Roffman, JL, Romanczuk-Seiferth, N, Rotter, JI, Ryten, M, Sacco, RL, Sachdev, PS, Saykin, AJ, Schmidt, R, Schmidt, H, Schofield, PR, Sigursson, S, Simmons, A, Singleton, A, Sisodiya, SM, Smith, C, Smoller, JW, Soininen, H, Steen, VM, Stott, DJ, Sussmann, JE, Thalamuthu, A, Toga, AW, Traynor, BJ, Troncoso, J, Tsolaki, M, Tzourio, C, Uitterlinden, AG, Hernandez, MCV, Van der Brug, M, van der Lugt, A, van der Wee, NJA, Van Haren, NEM, van't Ent, D, Van Tol, M-J, Vardarajan, BN, Vellas, B, Veltman, DJ, Voelzke, H, Walter, H, Wardlaw, JM, Wassink, TH, Weale, ME, Weinberger, DR, Weiner, MW, Wen, W, Westman, E, White, T, Wong, TY, Wright, CB, Zielke, RH, Zonderman, AB, Martin, NG, Van Duijn, CM, Wright, MJ, Longstreth, WT, Schumann, G, Grabe, HJ, Franke, B, Launer, LJ, Medland, SE, Seshadri, S, Thompson, PM, and Ikram, MA

Abstract

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

Published
2017

47. ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Author

Thompson, PM, Andreassen, OA, Arias-Vasquez, A, Bearden, CE, Boedhoe, PS, Brouwer, RM, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cannon, DM, Cohen, RA, Conrod, PJ, Dale, AM, Deary, IJ, Dennis, EL, de Reus, MA, Desrivieres, S, Dima, D, Donohoe, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Ganjgahi, H, Garavan, H, Glahn, DC, Grabe, HJ, Guadalupe, T, Gutman, BA, Hashimoto, R, Hibar, DP, Holland, D, Hoogman, M, Pol, HEH, Hosten, N, Jahanshad, N, Kelly, S, Kochunov, P, Kremen, WS, Lee, PH, Mackey, S, Martin, NG, Mazoyer, B, McDonald, C, Medland, SE, Morey, RA, Nichols, TE, Paus, T, Pausova, Z, Schmaal, L, Schumann, G, Shen, L, Sisodiya, SM, Smit, DJA, Smoller, JW, Stein, DJ, Stein, JL, Toro, R, Turner, JA, van den Heuvel, MP, van den Heuvel, OL, van Erp, TGM, van Rooij, D, Veltman, DJ, Walter, H, Wang, Y, Wardlaw, JM, Whelan, CD, Wright, MJ, Ye, J, Thompson, PM, Andreassen, OA, Arias-Vasquez, A, Bearden, CE, Boedhoe, PS, Brouwer, RM, Buckner, RL, Buitelaar, JK, Bulayeva, KB, Cannon, DM, Cohen, RA, Conrod, PJ, Dale, AM, Deary, IJ, Dennis, EL, de Reus, MA, Desrivieres, S, Dima, D, Donohoe, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Ganjgahi, H, Garavan, H, Glahn, DC, Grabe, HJ, Guadalupe, T, Gutman, BA, Hashimoto, R, Hibar, DP, Holland, D, Hoogman, M, Pol, HEH, Hosten, N, Jahanshad, N, Kelly, S, Kochunov, P, Kremen, WS, Lee, PH, Mackey, S, Martin, NG, Mazoyer, B, McDonald, C, Medland, SE, Morey, RA, Nichols, TE, Paus, T, Pausova, Z, Schmaal, L, Schumann, G, Shen, L, Sisodiya, SM, Smit, DJA, Smoller, JW, Stein, DJ, Stein, JL, Toro, R, Turner, JA, van den Heuvel, MP, van den Heuvel, OL, van Erp, TGM, van Rooij, D, Veltman, DJ, Walter, H, Wang, Y, Wardlaw, JM, Whelan, CD, Wright, MJ, and Ye, J

Abstract

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

Published
2017

50. The syndrome of transient epileptic amnesia

Author

Butler, CR, Graham, KS, Hodges, JR, Kapur, N, Wardlaw, JM, and Zeman, AZ

Abstract

OBJECTIVE: Transient amnesia can be the principal manifestation of epilepsy. This diagnosis, however, is seldom suspected by clinicians and remains controversial. The amnestic attacks are often associated with persistent memory complaints. This study was designed to provide the first description of transient epileptic amnesia in a substantial series of patients. METHODS: Fifty patients were recruited over 18 months using the following diagnostic criteria: (1) recurrent, witnessed episodes of amnesia; (2) other cognitive functions intact during attacks; and (3) compelling evidence of epilepsy. We assessed clinical features and performed neuropsychological evaluation in cases and 24 matched control subjects. RESULTS: Transient epileptic amnesia develops in later life (mean onset, 62 years). Amnestic episodes are frequent (median, 12/year), brief (median duration, 30-60 minutes), and often occur on waking (37/50 cases). Epilepsy was the initial specialist diagnosis in only 12 of 50 cases. Attacks ceased on anticonvulsant medication in 44 of 47 treated patients. A total of 40 of 50 cases described persistent memory difficulties. Despite normal performance on standard memory tests, patients exhibited accelerated forgetting of verbal and visual material over 3 weeks by comparison with matched control subjects (p < 0.001). They also showed loss of autobiographical memories for events extending back over 40 years (p < 0.05). INTERPRETATION: We propose that transient epileptic amnesia is a distinctive epilepsy syndrome, typically misdiagnosed at presentation and associated with accelerated long-term forgetting and autobiographical amnesia. The syndrome is of clinical and theoretic importance.

Published
2016

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