Bio

Bio


Dr. Montine received his education at Columbia University (BA in Chemistry), the University of Rochester (PhD in Pharmacology), and McGill University (MD and CM). His postgraduate medical training was at Duke University, and he was junior faculty at Vanderbilt University where he was awarded the Thorne Professorship in Pathology. In 2002, Dr. Montine was appointed as the Nancy and Buster Alvord Endowed Professor in Neuropathology and Director of the Division of Neuropathology at the University of Washington. In 2010, Dr. Montine was appointed Chair of the Department of Pathology at the University of Washington, and in 2012 he became Director of the University of Washington Alzheimer?s Disease Research Center. In 2016, Dr. Montine was appointed Chair of the Department of Pathology at Stanford University.

Dr. Montine is the founding Director of the Pacific Udall Center, one of 9 NINDS-funded Morris K. Udall Centers of Excellence for Parkinson?s Disease Research. Our center performs basic, translational, and clinical research focused on cognitive impairment in Parkinson?s disease. The Pacific Udall Center emphasizes a vision for precision health that comprises functional genomics, development of surveillance tools for pre-clinical detection, and discovery of molecularly tailored therapies.

Dr. Montine is among the top recipients of NIH funding for all Department of Pathology faculty in the United States. He was the 2015 President of the American Association of Neuropathologists, and led or co-led recent NIH initiatives to revise diagnostic guidelines for Alzheimer?s disease (NIA), develop research priorities for the National Alzheimer?s Plan (NINDS & NIA), and develop research priorities for Parkinson?s Disease (NINDS).

The focus of the Montine Laboratory is on the structural and molecular bases of cognitive impairment. Our goal is to define key pathogenic steps and thereby identify new therapeutic targets. The Montine Laboratory addresses these prevalent, unmet medical needs through a combination of neuropathology, biomarker development and application early in the course of disease, and experimental studies that test hypotheses concerning specific mechanisms of neuron injury and approaches to neuroprotection. PubMed lists 511 publications for Dr. Montine. In May 2016, Google Scholar calculates Dr. Montine?s citations as > 25,500 and his H-Index as 83.

Clinical Focus


  • Neuropathology

Academic Appointments


Administrative Appointments


  • Department Chair, Stanford University Department of Pathology (2016 - Present)

Professional Education


  • Board Certification: Neuropathology, American Board of Pathology (1997)
  • Board Certification: Anatomic Pathology, American Board of Pathology (1997)
  • Fellowship:Vanderbilt University Medical Center (1996) TN
  • Residency:Duke University Hospital (1995) NC
  • Residency:Duke University Hospital (1994) NC
  • Internship:Duke University Medical Center (1992) NC
  • Medical Education:McGill University Faculty of Medicine (1991) Canada

Publications

All Publications


  • The phosphatase calcineurin regulates pathological TDP-43 phosphorylation. Acta neuropathologica Liachko, N. F., Saxton, A. D., McMillan, P. J., Strovas, T. J., Currey, H. N., Taylor, L. M., Wheeler, J. M., Oblak, A. L., Ghetti, B., Montine, T. J., Keene, C. D., Raskind, M. A., Bird, T. D., Kraemer, B. C. 2016; 132 (4): 545-561

    Abstract

    Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date, several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together, these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

    View details for DOI 10.1007/s00401-016-1600-y

    View details for PubMedID 27473149

  • Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings. JAMA neurology Crane, P. K., Gibbons, L. E., Dams-O'Connor, K., Trittschuh, E., Leverenz, J. B., Keene, C. D., Sonnen, J., Montine, T. J., Bennett, D. A., Leurgans, S., Schneider, J. A., Larson, E. B. 2016; 73 (9): 1062-1069

    Abstract

    The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited.To determine whether TBI with loss of consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias.This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014.Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC.Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies.Of 7130 participants (2879 [40.4%] men; overall mean [SD] age, 79.9 [6.9] years), 865 reported a history of TBI with LOC. In 45?190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC ?1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC ?1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio [OR] for TBI with LOC ?1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ?1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC ?1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35).Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.

    View details for DOI 10.1001/jamaneurol.2016.1948

    View details for PubMedID 27400367

  • Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid- levels in brain. Journal of neurochemistry Henderson, B. W., Gentry, E. G., Rush, T., Troncoso, J. C., Thambisetty, M., Montine, T. J., Herskowitz, J. H. 2016; 138 (4): 525-531

    Abstract

    Alzheimer's disease (AD) is the leading cause of dementia and mitigating amyloid-? (A?) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb A? levels, and mechanisms that underlie ROCK2's effects on A? production are defined. How ROCK1 affects A? generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. A?42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that A?42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous A?40 production in neurons, and A?40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes A? levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat A? production in AD. Mitigating amyloid-? (A?) levels is a rational strategy for Alzheimer's disease (AD) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that A? accumulation in mild cognitive impairment because of AD (MCI) and AD activates the RhoA/ROCK pathway which in turn fuels production of A?. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD.

    View details for DOI 10.1111/jnc.13688

    View details for PubMedID 27246255

  • Mitochondrial DNA mutations increase in early stage Alzheimer disease and are inconsistent with oxidative damage. Annals of neurology Hoekstra, J. G., Hipp, M. J., Montine, T. J., Kennedy, S. R. 2016; 80 (2): 301-306

    Abstract

    Mitochondrial dysfunction and oxidative damage are commonly associated with early stage Alzheimer disease (AD). The accumulation of somatic mutations in mitochondrial DNA (mtDNA) has been hypothesized to be a driver of these phenotypes, but the detection of increased mutation loads has been difficult due to a lack of sensitive methods. We used an ultrasensitive next generation sequencing technique to measure the mutation load of the entire mitochondrial genome. Here, we report a significant increase in the mtDNA mutation frequency in the hippocampus of early stage AD, with the cause of these mutations being consistent with replication errors and not oxidative damage. Ann Neurol 2016;80:301-306.

    View details for DOI 10.1002/ana.24709

    View details for PubMedID 27315116

  • Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition LANCET Murray, C. J., Barber, R. M., Foreman, K. J., Ozgoren, A. A., Abd-Allah, F., Abera, S. F., Aboyans, V., Abraham, J. P., Abubakar, I., Abu-Raddad, L. J., Abu-Rmeileh, N. M., Achoki, T., Ackerman, I. N., Ademi, Z., Adou, A. K., Adsuar, J. C., Afshin, A., Agardh, E. E., Alam, S. S., Alasfoor, D., Albittar, M. I., Alegretti, M. A., Alemu, Z. A., Alfonso-Cristancho, R., Alhabib, S., Ali, R., Alla, F., Allebeck, P., AlMazroa, M. A., Alsharif, U., Alvarez, E., Alvis-Guzman, N., Amare, A. T., Ameh, E. A., Amini, H., Ammar, W., Anderson, H. R., Anderson, B. O., Antonio, C. A., Anwari, P., Arnlov, J., Arsenijevic, V. S., Artaman, A., Asghar, R. J., Assadi, R., Atkins, L. S., Avila, M. A., Awuah, B., Bachman, V. F., Badawi, A., Bahit, M. C., Balakrishnan, K., Banerjee, A., Barker-Collo, S. L., Barquera, S., Barregard, L., Barrero, L. H., Basu, A., Basu, S., Basulaiman, M. O., Beardsley, J., Bedi, N., Beghi, E., Bekele, T., Bell, M. L., Benjet, C., Bennett, D. A., Bensenor, I. M., Benzian, H., Bernabe, E., Bertozzi-Villa, A., Beyene, T. J., Bhala, N., Bhalla, A., Bhutta, Z. A., Bienhoff, K., Bikbov, B., Biryukov, S., Blore, J. D., Blosser, C. D., Blyth, F. M., Bohensky, M. A., Bolliger, I. W., Basara, B. B., Bornstein, N. M., Bose, D., Boufous, S., Bourne, R. R., Boyers, L. N., Brainin, M., Brayne, C. E., Brazinova, A., Breitborde, N. J., Brenner, H., Briggs, A. D., Brooks, P. M., Brown, J. C., Brugha, T. S., Buchbinder, R., Buckle, G. C., Budke, C. M., Bulchis, A., Bulloch, A. G., Campos-Nonato, I. R., Carabin, H., Carapetis, J. R., Cardenas, R., Carpenter, D. O., Caso, V., Castaneda-Orjuela, C. A., Castro, R. E., Catala-Lopez, F., Cavalleri, F., Cavlin, A., Chadha, V. K., Chang, J., Charlson, F. J., Chen, H., Chen, W., Chiang, P. P., Chimed-Ochir, O., Chowdhury, R., Christensen, H., Christophi, C. A., Cirillo, M., Coates, M. M., Coffeng, L. E., Coggeshall, M. S., Colistro, V., Colquhoun, S. M., Cooke, G. S., Cooper, C., Cooper, L. T., Coppola, L. M., Cortinovis, M., Criqui, M. H., Crump, J. A., Cuevas-Nasu, L., Danawi, H., Dandona, L., Dandona, R., Dansereau, E., Dargan, P. I., Davey, G., Davis, A., Davitoiu, D. V., Dayama, A., De Leo, D., Degenhardt, L., Del Pozo-Cruz, B., Dellavalle, R. P., Deribe, K., Derrett, S., Des Jarlais, D. C., Dessalegn, M., Dharmaratne, S. D., Dherani, M. K., Diaz-Torne, C., Dicker, D., Ding, E. L., Dokova, K., Dorsey, E. R., Driscoll, T. R., Duan, L., Duber, H. C., Ebel, B. E., Edmond, K. M., Elshrek, Y. M., Endres, M., Ermakov, S. P., Erskine, H. E., Eshrati, B., Esteghamati, A., Estep, K., Faraon, E. J., Farzadfar, F., Fay, D. F., Feigin, V. L., Felson, D. T., Fereshtehnejad, S., Fernandes, J. G., Ferrari, A. J., Fitzmaurice, C., Flaxman, A. D., Fleming, T. D., Foigt, N., Forouzanfar, M. H., Fowkes, F. G., Paleo, U. F., Franklin, R. C., Fuerst, T., Gabbe, B., Gaffikin, L., Gankpe, F. G., Geleijnse, J. M., Gessner, B. D., Gething, P., Gibney, K. B., Giroud, M., Giussani, G., Gomez Dantes, H., Gona, P., Gonzalez-Medina, D., Gosselin, R. A., Gotay, C. C., Goto, A., Gouda, H. N., Graetz, N., Gugnani, H. C., Gupta, R., Gupta, R., Gutierrez, R. A., Haagsma, J., Hafezi-Nejad, N., Hagan, H., Halasa, Y. A., Hamadeh, R. R., Hamavid, H., Hammami, M., Hancock, J., Hankey, G. J., Hansen, G. M., Hao, Y., Harb, H. L., Maria Haro, J., Havmoeller, R., Hay, S. I., Hay, R. J., Heredia-Pi, I. B., Heuton, K. R., Heydarpour, P., Higashi, H., Hijar, M., Hoek, H. W., Hoffman, H. J., Hosgood, H. D., Hossain, M., Hotez, P. J., Hoy, D. G., Hsairi, M., Hu, G., Huang, C., Huang, J. J., Husseini, A., Huynh, C., Iannarone, M. L., Iburg, K. M., Innos, K., Inoue, M., Islami, F., Jacobsen, K. H., Jarvis, D. L., Jassal, S. K., Jee, S. H., Jeemon, P., Jensen, P. N., Jha, V., Jiang, G., Jiang, Y., Jonas, J. B., Juel, K., Kan, H., Karch, A., Karema, C. K., Karimkhani, C., Karthikeyan, G., Kassebaum, N. J., Kaul, A., Kawakami, N., Kazanjan, K., Kemp, A. H., Kengne, A. P., Keren, A., Khader, Y. S., Khalifa, S. E., Khan, E. A., Khan, G., Khang, Y., Kieling, C., Kim, D., Kim, S., Kim, Y., Kinfu, Y., Kinge, J. M., Kivipelto, M., Knibbs, L. D., Knudsen, A. K., Kokubo, Y., Kosen, S., Krishnaswami, S., Defo, B. K., Bicer, B. K., Kuipers, E. J., Kulkarni, C., Kulkarni, V. S., Kumar, G. A., Kyu, H. H., Lai, T., Lalloo, R., Lallukka, T., Lam, H., Lan, Q., Lansingh, V. C., Larsson, A., Lawrynowicz, A. E., Leasher, J. L., Leigh, J., Leung, R., Levitz, C. E., Li, B., Li, Y., Li, Y., Lim, S. S., Lind, M., Lipshultz, S. E., Liu, S., Liu, Y., Lloyd, B. K., Lofgren, K. T., Logroscino, G., Looker, K. J., Lortet-Tieulent, J., Lotufo, P. A., Lozano, R., Lucas, R. M., Lunevicius, R., Lyons, R. A., Ma, S., MacIntyre, M. F., Mackay, M. T., Majdan, M., Malekzadeh, R., Marcenes, W., Margolis, D. J., Margono, C., Marzan, M. B., Masci, J. R., Mashal, M. T., Matzopoulos, R., Mayosi, B. M., Mazorodze, T. T., McGill, N. W., McGrath, J. J., McKee, M., McLain, A., Meaney, P. A., Medina, C., Mehndiratta, M. M., Mekonnen, W., Melaku, Y. A., Meltzer, M., Memish, Z. A., Mensah, G. A., Meretoja, A., Mhimbira, F. A., Micha, R., Miller, T. R., Mills, E. J., Mitchell, P. B., Mock, C. N., Ibrahim, N. M., Mohammad, K. A., Mokdad, A. H., Mola, G. L., Monasta, L., Montanez Hernandez, J. C., Montico, M., Montine, T. J., Mooney, M. D., Moore, A. R., Moradi-Lakeh, M., Moran, A. E., Mori, R., Moschandreas, J., Moturi, W. N., Moyer, M. L., Mozaffarian, D., Msemburi, W. T., Mueller, U. O., Mukaigawara, M., Mullany, E. C., Murdoch, M. E., Murray, J., Murthy, K. S., Naghavi, M., Naheed, A., Naidoo, K. S., Naldi, L., Nand, D., Nangia, V., Narayan, K. M., Nejjari, C., Neupane, S. P., Newton, C. R., Ng, M., Ngalesoni, F. N., Nguyen, G., Nisar, M. I., Nolte, S., Norheim, O. F., Norman, R. E., Norrving, B., Nyakarahuka, L., Oh, I., Ohkubo, T., Ohno, S. L., Olusanya, B. O., Opio, J. N., Ortblad, K., Ortiz, A., Pain, A. W., Pandian, J. D., Panelo, C. I., Papachristou, C., Park, E., Park, J., Patten, S. B., Patton, G. C., Paul, V. K., Pavlin, B. I., Pearce, N., Pereira, D. M., Perez-Padilla, R., Perez-Ruiz, F., Perico, N., Pervaiz, A., Pesudovs, K., Peterson, C. B., Petzold, M., Phillips, M. R., Phillips, B. K., Phillips, D. E., Piel, F. B., Plass, D., Poenaru, D., Polinder, S., Pope, D., Popova, S., Poulton, R. G., Pourmalek, F., Prabhakaran, D., Prasad, N. M., Pullan, R. L., Qato, D. M., Quistberg, D. A., Rafay, A., Rahimi, K., Rahman, S. U., Raju, M., Rana, S. M., Razavi, H., Reddy, K. S., Refaat, A., Remuzzi, G., Resnikoff, S., Ribeiro, A. L., Richardson, L., Richardus, J. H., Roberts, D. A., Rojas-Rueda, D., Ronfani, L., Roth, G. A., Rothenbacher, D., Rothstein, D. H., Rowley, J. T., Roy, N., Ruhago, G. M., Saeedi, M. Y., Saha, S., Sahraian, M. A., Sampson, U. K., Sanabria, J. R., Sandar, L., Santos, I. S., Satpathy, M., Sawhney, M., Scarborough, P., Schneider, I. J., Schoettker, B., Schumacher, A. E., Schwebel, D. C., Scott, J. G., Seedat, S., Sepanlou, S. G., Serina, P. T., Servan-Mori, E. E., Shackelford, K. A., Shaheen, A., Shahraz, S., Levy, T. S., Shangguan, S., She, J., Sheikhbahaei, S., Shi, P., Shibuya, K., Shinohara, Y., Shiri, R., Shishani, K., Shiue, I., Shrime, M. G., Sigfusdottir, I. D., Silberberg, D. H., Simard, E. P., Sindi, S., Singh, A., Singh, J. A., Singh, L., Skirbekk, V., Slepak, E. L., Sliwa, K., Soneji, S., Soreide, K., Soshnikov, S., Sposato, L. A., Sreeramareddy, C. T., Stanaway, J. D., Stathopoulou, V., Stein, D. J., Stein, M. B., Steiner, C., Steiner, T. J., Stevens, A., Stewart, A., Stovner, L. J., Stroumpoulis, K., Sunguya, B. F., Swaminathan, S., Swaroop, M., Sykes, B. L., Tabb, K. M., Takahashi, K., Tandon, N., Tanne, D., Tanner, M., Tavakkoli, M., Taylor, H. R., Te Ao, B. J., Tediosi, F., Temesgen, A. M., Templin, T., ten Have, M., Tenkorang, E. Y., Terkawi, A. S., Thomson, B., Thorne-Lyman, A. L., Thrift, A. G., Thurston, G. D., Tillmann, T., Tonelli, M., Topouzis, F., Toyoshima, H., Traebert, J., Tran, B. X., Trillini, M., Truelsen, T., Tsilimbaris, M., Tuzcu, E. M., Uchendu, U. S., Ukwaja, K. N., Undurraga, E. A., Uzun, S. B., Van Brakel, W. H., van de Vijver, S., van Gool, C. H., van Os, J., Vasankari, T. J., Venketasubramanian, N., Violante, F. S., Vlassov, V. V., Vollset, S. E., Wagner, G. R., Wagner, J., Waller, S. G., Wan, X., Wang, H., Wang, J., Wang, L., Warouw, T. S., Weichenthal, S., Weiderpass, E., Weintraub, R. G., Wang Wenzhi, W. Z., Werdecker, A., Westerman, R., Whiteford, H. A., Wilkinson, J. D., Williams, T. N., Wolfe, C. D., Wolock, T. M., Woolf, A. D., Wulf, S., Wurtz, B., Xu, G., Yan, L. L., Yano, Y., Ye, P., Yentur, G. K., Yip, P., Yonemoto, N., Yoon, S., Younis, M. Z., Yu, C., Zaki, M. E., Zhao, Y., Zheng, Y., Zonies, D., Zou, X., Salomon, J. A., Lopez, A. D., Vos, T. 2015; 386 (10009): 2145-2191
  • Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 LANCET Vos, T., Barber, R. M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., Charlson, F., Davis, A., Degenhardt, L., Dicker, D., Duan, L., Erskine, H., Feigin, V. L., Ferrari, A. J., Fitzmaurice, C., Fleming, T., Graetz, N., Guinovart, C., Haagsma, J., Hansen, G. M., Hanson, S. W., Heuton, K. R., Higashi, H., Kassebaum, N., Kyu, H., Laurie, E., Liang, X., Lofgren, K., Lozano, R., MacIntyre, M. F., Moradi-Lakeh, M., Naghavi, M., Nguyen, G., Odell, S., Ortblad, K., Roberts, D. A., Roth, G. A., Sandar, L., Serina, P. T., Stanaway, J. D., Steiner, C., Thomas, B., Vollset, S. E., Whiteford, H., Wolock, T. M., Ye, P., Zhou, M., Avila, M. A., Aasvang, G. M., Abbafati, C., Ozgoren, A. A., Abd-Allah, F., Aziz, M. I., Abera, S. F., Aboyans, V., Abraham, J. P., Abraham, B., Abubakar, I., Abu-Raddad, L. J., Abu-Rmeileh, N. M., Aburto, T. C., Achoki, T., Ackerman, I. N., Adelekan, A., Ademi, Z., Adou, A. K., Adsuar, J. C., Arnlov, J., Agardh, E. E., Al Khabouri, M. J., Alam, S. S., Alasfoor, D., Albittar, M. I., Alegretti, M. A., Aleman, A. V., Alemu, Z. A., Alfonso-Cristancho, R., Alhabib, S., Ali, R., Alla, F., Allebeck, P., Allen, P. J., AlMazroa, M. A., Alsharif, U., Alvarez, E., Alvis-Guzman, N., Ameli, O., Amini, H., Ammar, W., Anderson, B. O., Anderson, H. R., Antonio, C. A., Anwari, P., Apfel, H., Arsenijevic, V. S., Artaman, A., Asghar, R. J., Assadi, R., Atkins, L. S., Atkinson, C., Badawi, A., Bahit, M. C., Bakfalouni, T., Balakrishnan, K., Balalla, S., Banerjee, A., Barker-Collo, S. L., Barquera, S., Barregard, L., Barrero, L. H., Basu, S., Basu, A., Baxter, A., Beardsley, J., Bedi, N., Beghi, E., Bekele, T., Bell, M. L., Benjet, C., Bennett, D. A., Bensenor, I. M., Benzian, H., Bernabe, E., Beyene, T. J., Bhala, N., Bhalla, A., Bhutta, Z. Q., Bienhoff, K., Bikbov, B., Bin Abdulhak, A., Blore, J. D., Blyth, F. M., Bohensky, M. A., Basara, B. B., Borges, G., Bornstein, N. M., Bose, D., Boufous, S., Bourne, R. R., Boyers, L. N., Brainin, M., Brauer, M., Brayne, C. E., Brazinova, A., Breitborde, N. J., Brenner, H., Briggs, A. D., Brooks, P. M., Brown, J., Brugha, T. S., Buchbinder, R., Buckle, G. C., Bukhman, G., Bulloch, A. G., Burch, M., Burnett, R., Cardenas, R., Cabral, N. L., Nonato, I. R., Campuzano, J. C., Carapetis, J. R., Carpenter, D. O., Caso, V., Castaneda-Orjuela, C. A., Catala-Lopez, F., Chadha, V. K., Chang, J., Chen, H., Chen, W., Chiang, P. P., Chimed-Ochir, O., Chowdhury, R., Christensen, H., Christophi, C. A., Chugh, S. S., Cirillo, M., Coggeshall, M., Cohen, A., Colistro, V., Colquhoun, S. M., Contreras, A. G., Cooper, L. T., Cooper, C., Cooperrider, K., Coresh, J., Cortinovis, M., Criqui, M. H., Crump, J. A., Cuevas-Nasu, L., Dandona, R., Dandona, L., Dansereau, E., Dantes, H. G., Dargan, P. I., Davey, G., Davitoiu, D. V., Dayama, A., De la Cruz-Gongora, V., de la Vega, S. F., De Leo, D., Del Pozo-Cruz, B., Dellavalle, R. P., Deribe, K., Derrett, S., Des Jarlais, D. C., Dessalegn, M., de Veber, G. A., Dharmaratne, S. D., Diaz-Torne, C., Ding, E. L., Dokova, K., Dorsey, E. R., Driscoll, T. R., Duber, H., Durrani, A. M., Edmond, K. M., Ellenbogen, R. G., Endres, M., Ermakov, S. P., Eshrati, B., Esteghamati, A., Estep, K., Fahimi, S., Farzadfar, F., Fay, D. F., Felson, D. T., Fereshtehnejad, S., Fernandes, J. G., Ferri, C. P., Flaxman, A., Foigt, N., Foreman, K. J., Fowkes, F. G., Franklin, R. C., Furst, T., Futran, N. D., Gabbe, B. J., Gankpe, F. G., Garcia-Guerra, F. A., Geleijnse, J. M., Gessner, B. D., Gibney, K. B., Gillum, R. F., Ginawi, I. A., Giroud, M., Giussani, G., Goenka, S., Goginashvili, K., Gona, P., de Cosio, T. G., Gosselin, R. A., Gotay, C. C., Goto, A., Gouda, H. N., Guerrant, R. L., Gugnani, H. C., Gunnell, D., Gupta, R., Gupta, R., Gutierrez, R. A., Hafezi-Nejad, N., Hagan, H., Halasa, Y., Hamadeh, R. R., Hamavid, H., Hammami, M., Hankey, G. J., Hao, Y., Harb, H. L., Haro, J. M., Havmoeller, R., Hay, R. J., Hay, S., Hedayati, M. T., Pi, I. B., Heydarpour, P., Hijar, M., Hoek, H. W., Hoffman, H. J., Hornberger, J. C., Hosgood, H. D., Hossain, M., Hotez, P. J., Hoy, D. G., Hsairi, M., Hu, H., Hu, G., Huang, J. J., Huang, C., Huiart, L., Husseini, A., Iannarone, M., Iburg, K. M., Innos, K., Inoue, M., Jacobsen, K. H., Jassal, S. K., Jeemon, P., Jensen, P. N., Jha, V., Jiang, G., Jiang, Y., Jonas, J. B., Joseph, J., Juel, K., Kan, H., Karch, A., Karimkhani, C., Karthikeyan, G., Katz, R., Kaul, A., Kawakami, N., Kazi, D. S., Kemp, A. H., Kengne, A. P., Khader, Y. S., Khalifa, S. E., Khan, E. A., Khan, G., Khang, Y., Khonelidze, I., Kieling, C., Kim, D., Kim, S., Kimokoti, R. W., Kinfu, Y., Kinge, J. M., Kissela, B. M., Kivipelto, M., Knibbs, L., Knudsen, A. K., Kokubo, Y., Kosen, S., Kramer, A., Kravchenko, M., Krishnamurthi, R. V., Krishnaswami, S., Defo, B. K., Bicer, B. K., Kuipers, E. J., Kulkarni, V. S., Kumar, K., Kumar, G. A., Kwan, G. F., Lai, T., Lalloo, R., Lam, H., Lan, Q., Lansingh, V. C., Larson, H., Larsson, A., Lawrynowicz, A. E., Leasher, J. L., Lee, J., Leigh, J., Leung, R., Levi, M., Li, B., Li, Y., Li, Y., Liang, J., Lim, S., Lin, H., Lind, M., Lindsay, M. P., Lipshultz, S. E., Liu, S., Lloyd, B. K., Ohno, S. L., Logroscino, G., Looker, K. J., Lopez, A. D., Lopez-Olmedo, N., Lortet-Tieulent, J., Lotufo, P. A., Low, N., Lucas, R. M., Lunevicius, R., Lyons, R. A., Ma, J., Ma, S., Mackay, M. T., Majdan, M., Malekzadeh, R., Mapoma, C. C., Marcenes, W., March, L. M., Margono, C., Marks, G. B., Marzan, M. B., Masci, J. R., Mason-Jones, A. J., Matzopoulos, R. G., Mayosi, B. M., Mazorodze, T. T., McGill, N. W., McGrath, J. J., McKee, M., McLain, A., McMahon, B. J., Meaney, P. A., Mehndiratta, M. M., Mejia-Rodriguez, F., Mekonnen, W., Melaku, Y. A., Meltzer, M., Memish, Z. A., Mensah, G., Meretoja, A., Mhimbira, F. A., Micha, R., Miller, T. R., Mills, E. J., Mitchell, P. B., Mock, C. N., Moffitt, T. E., Ibrahim, N. M., Mohammad, K. A., Mokdad, A. H., Mola, G. L., Monasta, L., Montico, M., Montine, T. J., Moore, A. R., Moran, A. E., Morawska, L., Mori, R., Moschandreas, J., Moturi, W. N., Moyer, M., Mozaffarian, D., Mueller, U. O., Mukaigawara, M., Murdoch, M. E., Murray, J., Murthy, K. S., Naghavi, P., Nahas, Z., Naheed, A., Naidoo, K. S., Naldi, L., Nand, D., Nangia, V., Narayan, K. M., Nash, D., Nejjari, C., Neupane, S. P., Newman, L. M., Newton, C. R., Ng, M., Ngalesoni, F. N., Nhung, N. T., Nisar, M. I., Nolte, S., Norheim, O. F., Norman, R. E., Norrving, B., Nyakarahuka, L., Oh, I. H., Ohkubo, T., Omer, S. B., Opio, J. N., Ortiz, A., Pandian, J. D., Panelo, C. I., Papachristou, C., Park, E., Parry, C. D., Caicedo, A. J., Patten, S. B., Paul, V. K., Pavlin, B. I., Pearce, N., Pedraza, L. S., Pellegrini, C. A., Pereira, D. M., Perez-Ruiz, F. P., Perico, N., Pervaiz, A., Pesudovs, K., Peterson, C. B., Petzold, M., Phillips, M. R., Phillips, D., Phillips, B., Piel, F. B., Plass, D., Poenaru, D., Polanczyk, G. V., Polinder, S., Pope, C. A., Popova, S., Poulton, R. G., Pourmalek, F., Prabhakaran, D., Prasad, N. M., Qato, D., Quistberg, D. A., Rafay, A., Rahimi, K., Rahimi-Movaghar, V., Rahman, S. u., Raju, M., Rakovac, I., Rana, S. M., Razavi, H., Refaat, A., Rehm, J., Remuzzi, G., Resnikoff, S., Ribeiro, A. L., Riccio, P. M., Richardson, L., Richardus, J. H., Riederer, A. M., Robinson, M., Roca, A., Rodriguez, A., Rojas-Rueda, D., Ronfani, L., Rothenbacher, D., Roy, N., Ruhago, G. M., Sabin, N., Sacco, R. L., Ksoreide, K., Saha, S., Sahathevan, R., Sahraian, M. A., Sampson, U., Sanabria, J. R., Sanchez-Riera, L., Santos, I. S., Satpathy, M., Saunders, J. E., Sawhney, M., Saylan, M. I., Scarborough, P., Schoettker, B., Schneider, I. J., Schwebel, D. C., Scott, J. G., Seedat, S., Sepanlou, S. G., Serdar, B., Servan-Mori, E. E., Shackelford, K., Shaheen, A., Shahraz, S., Levy, T. S., Shangguan, S., She, J., Sheikhbahaei, S., Shepard, D. S., Shi, P., Shibuya, K., Shinohara, Y., Shiri, R., Shishani, K., Shiue, I., Shrime, M. G., Sigfusdottir, I. D., Silberberg, D. H., Simard, E. P., Sindi, S., Singh, J. A., Singh, L., Skirbekk, V., Sliwa, K., Soljak, M., Soneji, S., Soshnikov, S. S., Speyer, P., Sposato, L. A., Sreeramareddy, C. T., Stoeckl, H., Stathopoulou, V. K., Steckling, N., Stein, M. B., Stein, D. J., Steiner, T. J., Stewart, A., Stork, E., Stovner, L. J., Stroumpoulis, K., Sturua, L., Sunguya, B. F., Swaroop, M., Sykes, B. L., Tabb, K. M., Takahashi, K., Tan, F., Tandon, N., Tanne, D., Tanner, M., Tavakkoli, M., Taylor, H. R., Ao, B. J., Temesgen, A. M., ten Have, M., Tenkorang, E. Y., Terkawi, A. S., Theadom, A. M., Thomas, E., Thorne-Lyman, A. L., Thrift, A. G., Tleyjeh, I. M., Tonelli, M., Topouzis, F., Towbin, J. A., Toyoshima, H., Traebert, J., Tran, B. X., Trasande, L., Trillini, M., Truelsen, T., Trujillo, U., Tsilimbaris, M., Tuzcu, E. M., Ukwaja, K. N., Undurraga, E. A., Uzun, S. B., Van Brakel, W. H., de Vijver, S. v., Van Dingenen, R., van Gool, C. H., Varakin, Y. Y., Vasankari, T. J., Vavilala, M. S., Veerman, L. J., Velasquez-Melendez, G., Venketasubramanian, N., Vijayakumar, L., Villalpando, S., Violante, F. S., Vlassov, V. V., Waller, S., Wallin, M. T., Wan, X., Wang, L., Wang, J., Wang, Y., Warouw, T. S., Weichenthal, S., Weiderpass, E., Weintraub, R. G., Werdecker, A., Wessells, K. R., Westerman, R., Wilkinson, J. D., Williams, H. C., Williams, T. N., Woldeyohannes, S. M., Wolfe, C. D., Wong, J. Q., Wong, H., Woolf, A. D., Wright, J. L., Wurtz, B., Xu, G., Yang, G., Yano, Y., Yenesew, M. A., Yentur, G. K., Yip, P., Yonemoto, N., Yoon, S., Younis, M., Yu, C., Kim, K. Y., Zaki, M. E., Zhang, Y., Zhao, Z., Zhao, Y., Zhu, J., Zonies, D., Zunt, J. R., Salomon, J. A., Murray, C. J. 2015; 386 (9995): 743-800
  • Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 LANCET Naghavi, M., Wang, H., Lozano, R., Davis, A., Liang, X., Zhou, M., Vollset, S. E., Ozgoren, A. A., Abdalla, S., Abd-Allah, F., Aziz, M. I., Abera, S. F., Aboyans, V., Abraham, B., Abraham, J. P., Abuabara, K. E., Abubakar, I., Abu-Raddad, L. J., Abu-Rmeileh, N. M., Achoki, T., Adelekan, A., Ademi, Z. N., Adofo, K., Adou, A. K., Adsuar, J. C., Aernlov, J., Agardh, E. E., Akena, D., Al Khabouri, M. J., Alasfoor, D., Albittar, M., Alegretti, M. A., Aleman, A. V., Alemu, Z. A., Alfonso-Cristancho, R., Alhabib, S., Ali, M. K., Ali, R., Alla, F., Al Lami, F., Allebeck, P., AlMazroa, M. A., Salman, R. A., Alsharif, U., Alvarez, E., Alviz-Guzman, N., Amankwaa, A. A., Amare, A. T., Ameli, O., Amini, H., Ammar, W., Anderson, H. R., Anderson, B. O., Antonio, C. A., Anwari, P., Apfel, H., Cunningham, S. A., Arsenijevic, V. S., Al Artaman, Asad, M. M., Asghar, R. J., Assadi, R., Atkins, L. S., Atkinson, C., Badawi, A., Bahit, M. C., Bakfalouni, T., Balakrishnan, K., Balalla, S., Banerjee, A., Barber, R. M., Barker-Collo, S. L., Barquera, S., Barregard, L., Barrero, L. H., Barrientos-Gutierrez, T., Basu, A., Basu, S., Basulaiman, M. O., Beardsley, J., Bedi, N., Beghi, E., Bekele, T., Bell, M. L., Benjet, C., Bennett, D. A., Bensenor, I. M., Benzian, H., Bertozzi-Villa, A., Beyene, T. J., Bhala, N., Bhalla, A., Bhutta, Z. A., Bikbov, B., Bin Abdulhak, A., Biryukov, S., Blore, J. D., Blyth, F. M., Bohensky, M. A., Borges, G., Bose, D., Boufous, S., Bourne, R. R., Boyers, L. N., Brainin, M., Brauer, M., Brayne, C. E., Brazinova, A., Breitborde, N., Brenner, H., Briggs, A. D., Brown, J. C., Brugha, T. S., Buckle, G. C., Bui, L. N., Bukhman, G., Burch, M., Nonato, I. R., Carabin, H., Cardenas, R., Carapetis, J., Carpenter, D. O., Caso, V., Castaneda-Orjuela, C. A., Castro, R. E., Catala-Lopez, F., Cavalleri, F., Chang, J., Charlson, F. C., Che, X., Chen, H., Chen, Y., Chen, J. S., Chen, Z., Chiang, P. P., Chimed-Ochir, O., Chowdhury, R., Christensen, H., Christophi, C. A., Chuang, T., Chugh, S. S., Cirillo, M., Coates, M. M., Coffeng, L. E., Coggeshall, M. S., Cohen, A., Colistro, V., Colquhoun, S. M., Colomar, M., Cooper, L. T., Cooper, C., Coppola, L. M., Cortinovis, M., Courville, K., Cowie, B. C., Criqui, M. H., Crump, J. A., Cuevas-Nasu, L., Leite, I. d., Dabhadkar, K. C., Dandona, L., Dandona, R., Dansereau, E., Dargan, P. I., Dayama, A., De la Cruz-Gongora, V., de la Vega, S. F., De Leo, D., Degenhardt, L., Del Pozo-Cruz, B., Dellavalle, R. P., Deribe, K., Jarlais, D. C., Dessalegn, M., deVeber, G. A., Dharmaratne, S. D., Dherani, M., Diaz-Ortega, J., Diaz-Torne, C., Dicker, D., Ding, E. L., Dokova, K., Dorsey, E. R., Driscoll, T. R., Duan, L., Duber, H. C., Durrani, A. M., Ebel, B. E., Edmond, K. M., Ellenbogen, R. G., Elshrek, Y., Ermakov, S. P., Erskine, H. E., Eshrati, B., Esteghamati, A., Estep, K., Fuerst, T., Fahimi, S., Fahrion, A. S., Faraon, E. J., Farzadfar, F., Fay, D. F., Feigl, A. B., Feigin, V. L., Felicio, M. M., Fereshtehnejad, S., Fernandes, J. G., Ferrari, A. J., Fleming, T. D., Foigt, N., Foreman, K., Forouzanfar, M. H., Fowkes, F. G., Fra Paleo, U., Franklin, R. C., Futran, N. D., Gaffikin, L., Gambashidze, K., Gankpe, F. G., Garcia-Guerra, F. A., Garcia, A. C., Geleijnse, J. M., Gessner, B. D., Gibney, K. B., Gillum, R. F., Gilmour, S., Abdelmageem, I., Ginawi, M., Giroud, M., Glaser, E. L., Goenka, S., Dantes, H. G., Gona, P., Gonzalez-Medina, D., Guinovart, C., Gupta, R., Gupta, R., Gosselin, R. A., Gotay, C. C., Goto, A., Gowda, H. N., Graetz, N., Greenwell, K. F., Gugnani, H. C., Gunnell, D., Gutierrez, R. A., Haagsma, J., Hafezi-Nejad, N., Hagan, H., Hagstromer, M., Halasa, Y. A., Hamadeh, R. R., Hamavid, H., Hammami, M., Hancock, J., Hankey, G. J., Hansen, G. M., Harb, H. L., Harewood, H., Haro, J. M., Havmoeller, R., Hay, R. J., Hay, S. I., Hedayati, M. T., Pi, I. B., Heuton, K. R., Heydarpour, P., Higashi, H., Hijar, M., Hoek, H. W., Hoffman, H. J., Hornberger, J. C., Hosgood, H. D., Hossain, M., Hotez, P. J., Hoy, D. G., Hsairi, M., Hu, G., Huang, J. J., Huffman, M. D., Hughes, A. J., Husseini, A., Huynh, C., Iannarone, M., Iburg, K. M., Idrisov, B. T., Ikeda, N., Innos, K., Inoue, M., Islami, F., Ismayilova, S., Jacobsen, K. H., Jassal, S., Jayaraman, S. P., Jensen, P. N., Jha, V., Jiang, G., Jiang, Y., Jonas, J. B., Joseph, J., Juel, K., Kabagambe, E. K., Kan, H., Karch, A., Karimkhani, C., Karthikeyan, G., Kassebaum, N., Kaul, A., Kawakami, N., Kazanjan, K., Kazi, D. S., Kemp, A. H., Kengne, A. P., Keren, A., Kereselidze, M., Khader, Y. S., Khalifa, S. E., Khan, E. A., Khan, G., Khang, Y., Kieling, C., Kinfu, Y., Kinge, J. M., Kim, D., Kim, S., Kivipelto, M., Knibbs, L., Knudsen, A. K., Kokubo, Y., Kosen, S., Kotagal, M., Kravchenko, M. A., Krishnaswami, S., Krueger, H., Defo, B. K., Kuipers, E. J., Bicer, B. K., Kulkarni, C., Kulkarni, V. S., Kumar, K., Kumar, R. B., Kwan, G. F., Kyu, H., Lai, T., Balaji, A. L., Lalloo, R., Lallukka, T., Lam, H., Lan, Q., Lansingh, V. C., Larson, H. J., Larsson, A., Lavados, P. M., Lawrynowicz, A. E., Leasher, J. L., Lee, J., Leigh, J., Leinsalu, M., Leung, R., Levitz, C., Li, B., Li, Y., Li, Y., Liddell, C., Lim, S. S., de Lima, G. M., Lind, M. L., Lipshultz, S. E., Liu, S., Liu, Y., Lloyd, B. K., Lofgren, K. T., Logroscino, G., London, S. J., Lortet-Tieulent, J., Lotufo, P. A., Lucas, R. M., Lunevicius, R., Lyons, R. A., Ma, S., Machado, V. M., MacIntyre, M. F., Mackay, M. T., Maclachlan, J. H., Magis-Rodriguez, C., Mahdi, A. A., Majdan, M., Malekzadeh, R., Mangalam, S., Mapoma, C. C., Marape, M., Marcenes, W., Margono, C., Marks, G. B., Marzan, M. B., Masci, J. R., Mashal, M. T., Masiye, F., Mason-Jones, A. J., Matzopolous, R., Mayosi, B. M., Mazorodze, T. T., McGrath, J. J., Mckay, A. C., McKee, M., McLain, A., Meaney, P. A., Mehndiratta, M. M., Mejia-Rodriguez, F., Melaku, Y. A., Meltzer, M., Memish, Z. A., Mendoza, W., Mensah, G. A., Meretoja, A., Mhimbira, F. A., Miller, T. R., Mills, E. J., Misganaw, A., Mishra, S. K., Mock, C. N., Moffitt, T. E., Ibrahim, N. M., Mohammad, K. A., Mokdad, A. H., Mola, G. L., Monasta, L., Monis, J. d., Hernandez, J. C., Montico, M., Montine, T. J., Mooney, M. D., Moore, A. R., Moradi-Lakeh, M., Moran, A. E., Mori, R., Moschandreas, J., Moturi, W. N., Moyer, M. L., Mozaffarian, D., Mueller, U. O., Mukaigawara, M., Mullany, E. C., Murray, J., Mustapha, A., Naghavi, P., Naheed, A., Naidoo, K. S., Naldi, L., Nand, D., Nangia, V., Narayan, K. M., Nash, D., Nasher, J., Nejjari, C., Nelson, R. G., Neuhouser, M., Neupane, S. P., Newcomb, P. A., Newman, L., Newton, C. R., Ng, M., Ngalesoni, F. N., Nguyen, G., Nhung Thi Trang Nguyen, N. T., Nisar, M. I., Nolte, S., Norheim, O. F., Norman, R. E., Norrving, B., Nyakarahuka, L., Odell, S., O'Donnell, M., Ohkubo, T., Ohno, S. L., Olusanya, B. O., Omer, S. B., Opio, J. N., Orisakwe, O. E., Ortblad, K. F., Ortiz, A., Otayza, M. L., Pain, A. W., Pandian, J. D., Panelo, C. I., Panniyammakal, J., Papachristou, C., Paternina Caicedo, A. J., Patten, S. B., Patton, G. C., Paul, V. K., Pavlin, B., Pearce, N., Pellegrini, C. A., Pereira, D. M., Peresson, S. C., Perez-Padilla, R., Perez-Ruiz, F. P., Perico, N., Pervaiz, A., Pesudovs, K., Peterson, C. B., Petzold, M., Phillips, B. K., Phillips, D. E., Phillips, M. R., Plass, D., Piel, F. B., Poenaru, D., Polinder, S., Popova, S., Poulton, R. G., Pourmalek, F., Prabhakaran, D., Qato, D., Quezada, A. D., Quistberg, D. A., Rabito, F., Rafay, A., Rahimi, K., Rahimi-Movaghar, V., Rahman, S. u., Raju, M., Rakovac, I., Rana, S. M., Refaat, A., Remuzzi, G., Ribeiro, A. L., Ricci, S., Riccio, P. M., Richardson, L., Richardus, J. H., Roberts, B., Roberts, D. A., Robinson, M., Roca, A., Rodriguez, A., Rojas-Rueda, D., Ronfani, L., Room, R., Roth, G. A., Rothenbacher, D., Rothstein, D. H., Rowley, J. T., Roy, N., Ruhago, G. M., Rushton, L., Sambandam, S., Soreide, K., Saeedi, M. Y., Saha, S., Sahathevan, R., Sahraian, M. A., Sahle, B. W., Salomon, J. A., Salvo, D., Samonte, G. M., Sampson, U., Sanabria, J. R., Sandar, L., Santos, I. S., Satpathy, M., Sawhney, M., Saylan, M., Scarborough, P., Schoettker, B., Schmidt, J. C., Schneider, I. J., Schumacher, A. E., Schwebel, D. C., Scott, J. G., Sepanlou, S. G., Servan-Mori, E. E., Shackelford, K., Shaheen, A., Shahraz, S., Shakh-Nazarova, M., Shangguan, S., She, J., Sheikhbahaei, S., Shepard, D. S., Shibuya, K., Shinohara, Y., Shishani, K., Shiue, I., Shivakoti, R., Shrime, M. G., Sigfusdottir, I. D., Silberberg, D. H., Silva, A. P., Simard, E. P., Sindi, S., Singh, J. A., Singh, L., Sioson, E., Skirbekk, V., Sliwa, K., So, S., Soljak, M., Soneji, S., Soshnikov, S. 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R., Waller, S. G., Wang, J., Wang, L., Wang, X., Wang, Y., Warouw, T. S., Weichenthal, S., Weiderpass, E., Weintraub, R. G., Wenzhi, W., Werdecker, A., Wessells, K. R., Westerman, R., Whiteford, H. A., Wilkinson, J. D., Williams, T. N., Woldeyohannes, S. M., Wolfe, C. D., Wolock, T. M., Woolf, A. D., Wong, J. Q., Wright, J. L., Wulf, S., Wurtz, B., Xu, G., Yang, Y. C., Yano, Y., Yatsuya, H., Yip, P., Yonemoto, N., Yoon, S., Younis, M., Yu, C., Jin, K. Y., Zaki, M. E., Zamakhshary, M. F., Zeeb, H., Zhang, Y., Zhao, Y., Zheng, Y., Zhu, J., Zhu, S., Zonies, D., Zou, X. N., Zunt, J. R., Vos, T., Lopez, A. D., Murray, C. J. 2015; 385 (9963): 117-171
  • Low Plasma Leptin in Cognitively Impaired ADNI Subjects: Gender Differences and Diagnostic and Therapeutic Potential CURRENT ALZHEIMER RESEARCH Johnston, J. M., Hu, W. T., Fardo, D. W., Greco, S. J., Perry, G., Montine, T. J., Trojanowski, J. Q., Shaw, L. M., Ashford, J. W., Tezapsidis, N. 2014; 11 (2): 165-174

    Abstract

    Analysis of data derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI) program showed plasma leptin levels in individuals with Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD) to be lower than those of subjects with normal cognition (NC). Approximately 70% of both men and women with MCI have plasma leptin levels lower than the median values of NC. Additionally, half of these subjects carry at least one apolipoprotein-E4 (APOE-?4) allele. A subgroup of participants also had cerebrospinal fluid (CSF) leptin measured. Plasma leptin typically reflected the levels of leptin in CSF in all groups (Control/MCI/AD) in both genders. The data suggest that plasma leptin deficiency provides an indication of potential CNS leptin deficiency, further supporting the exploration of plasma leptin as a diagnostic marker for MCI or AD. The important question is whether leptin deficiency plays a role in the causation of AD and/or its progression. If this is the case, individuals with early AD or MCI with low plasma leptin may benefit from leptin replacement therapy. Thus, these data indicate that trials of leptin in low leptin MCI/early-stage AD patients should be conducted to test the hypothesis.

    View details for DOI 10.2174/1567205010666131212114156

    View details for Web of Science ID 000333195900008

    View details for PubMedID 24359504

  • The future of blood-based biomarkers for Alzheimer's disease ALZHEIMERS & DEMENTIA Henriksen, K., O'Bryant, S. E., Hamper, H., Trojanowski, J. Q., Montine, T. J., Jeromin, A., Blennow, K., Lonneborg, A., Wyss-Coray, T., Soares, H., Bazenet, C., Sjogren, M., Hu, W., Lovestone, S., Karsdal, M. A., Weiner, M. W. 2014; 10 (1): 115-131

    Abstract

    Treatment of Alzheimer's disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the "right" control population, and the blood-brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.

    View details for DOI 10.1016/j.jalz.2013.01.013

    View details for Web of Science ID 000329559300015

    View details for PubMedID 23850333

  • Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease ANNALS OF NEUROLOGY Shi, J., Wang, Q., Johansson, J. U., Liang, X., Woodling, N. S., Priyam, P., Loui, T. M., Merchant, M., Breyer, R. M., Montine, T. J., Andreasson, K. 2012; 72 (5): 788-798

    Abstract

    There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to A? peptide.The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of A?(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1?E9 transgenic mice.Deletion of the PGE(2) EP3 receptor in a model of A?(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1?E9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of A? peptides were significantly decreased, as were ?-secretase and ? C-terminal fragment levels, suggesting that generation of A? peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1?E9 mice.Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.

    View details for DOI 10.1002/ana.23677

    View details for Web of Science ID 000312940300017

    View details for PubMedID 22915243

  • Mutations in Prickle Orthologs Cause Seizures in Flies, Mice, and Humans AMERICAN JOURNAL OF HUMAN GENETICS Tao, H., Manak, J. R., Sowers, L., Mei, X., Kiyonari, H., Abe, T., Dandaleh, N. S., Yang, T., Wu, S., Chen, S., Fox, M. H., Gurnett, C., Montine, T., Bird, T., Shaffer, L. G., Rosenfeld, J. A., McConne, J., Madan-Khetarpal, S., Berry-Kravis, E., Griesbach, H., Saneto, R. P., Scott, M. P., Antic, D., Reed, J., Boland, R., Ehaideb, S. N., El-Shanti, H., Mahajan, V. B., Ferguson, P. J., Axelrod, J. D., Lehesjoki, A., Fritzsch, B., Slusarski, D. C., Wemmie, J., Ueno, N., Bassuk, A. G. 2011; 88 (2): 138-149

    Abstract

    Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.

    View details for DOI 10.1016/j.ajhg.2010.12.012

    View details for Web of Science ID 000287684100002

    View details for PubMedID 21276947

  • The Prostaglandin E-2 E-Prostanoid 4 Receptor Exerts Anti-Inflammatory Effects in Brain Innate Immunity JOURNAL OF IMMUNOLOGY Shi, J., Johansson, J., Woodling, N. S., Wang, Q., Montine, T. J., Andreasson, K. 2010; 184 (12): 7207-7218

    Abstract

    Peripheral inflammation leads to immune responses in brain characterized by microglial activation, elaboration of proinflammatory cytokines and reactive oxygen species, and secondary neuronal injury. The inducible cyclooxygenase (COX), COX-2, mediates a significant component of this response in brain via downstream proinflammatory PG signaling. In this study, we investigated the function of the PGE2 E-prostanoid (EP) 4 receptor in the CNS innate immune response to the bacterial endotoxin LPS. We report that PGE2 EP4 signaling mediates an anti-inflammatory effect in brain by blocking LPS-induced proinflammatory gene expression in mice. This was associated in cultured murine microglial cells with decreased Akt and I-kappaB kinase phosphorylation and decreased nuclear translocation of p65 and p50 NF-kappaB subunits. In vivo, conditional deletion of EP4 in macrophages and microglia increased lipid peroxidation and proinflammatory gene expression in brain and in isolated adult microglia following peripheral LPS administration. Conversely, EP4 selective agonist decreased LPS-induced proinflammatory gene expression in hippocampus and in isolated adult microglia. In plasma, EP4 agonist significantly reduced levels of proinflammatory cytokines and chemokines, indicating that peripheral EP4 activation protects the brain from systemic inflammation. The innate immune response is an important component of disease progression in a number of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In addition, recent studies demonstrated adverse vascular effects with chronic administration of COX-2 inhibitors, indicating that specific PG signaling pathways may be protective in vascular function. This study supports an analogous and beneficial effect of PGE2 EP4 receptor signaling in suppressing brain inflammation.

    View details for DOI 10.4049/jimmunol.0903487

    View details for Web of Science ID 000278516700071

    View details for PubMedID 20483760

  • Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor EXPERIMENTAL NEUROLOGY Savonenko, A., Munoz, P., Melnikova, T., Wang, Q., Liang, X., Breyer, R. M., Montine, T. J., Kirkwood, A., Andreasson, K. 2009; 217 (1): 63-73

    Abstract

    Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.

    View details for DOI 10.1016/j.expneurol.2009.01.016

    View details for Web of Science ID 000265859000009

    View details for PubMedID 19416671

  • The prostaglandin E-2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis ANNALS OF NEUROLOGY Liang, X., Wang, Q., Shi, J., Lokteva, L., Breyer, R. M., Montine, T. J., Andreasson, K. 2008; 64 (3): 304-314

    Abstract

    Inflammation has emerged as an important factor in disease progression in human and transgenic models of amyotrophic lateral sclerosis (ALS). Recent studies demonstrate that the prostaglandin E(2) EP2 receptor is a major regulator of inflammatory oxidative injury in innate immunity. We tested whether EP2 signaling participated in disease pathogenesis in the G93A superoxide dismutase (SOD) model of familial ALS.We examined the phenotype of G93A SOD mice lacking the EP2 receptor and performed immunocytochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western analyses to determine the mechanism of EP2 toxicity in this model.EP2 receptor is significantly induced in G93A SOD mice in astrocytes and microglia in parallel with increases in expression of proinflammatory enzymes and lipid peroxidation. In human ALS, EP2 receptor immunoreactivity was upregulated in astrocytes in ventral spinal cord. In aging G93A SOD mice, genetic deletion of the prostaglandin E(2)EP2 receptor improved motor strength and extended survival. Deletion of the EP2 receptor in G93A SOD mice resulted in significant reductions in levels of proinflammatory effectors, including cyclooxygenase-1, cyclooxygenase-2, inducible nitric oxide synthase, and components of the NADPH oxidase complex. In alternate models of inflammation, including the lipopolysaccharide model of innate immunity and the APPSwe-PS1DeltaE9 model of amyloidosis, deletion of EP2 also reduced expression of proinflammatory genes.These data suggest that prostaglandin E(2) signaling via the EP2 receptor functions in the mutant SOD model and more broadly in inflammatory neurodegeneration to regulate expression of a cassette of proinflammatory genes. Inhibition of EP2 signaling may represent a novel strategy to downregulate the inflammatory response in neurodegenerative disease.

    View details for DOI 10.1002/ana.21437

    View details for Web of Science ID 000259681700013

    View details for PubMedID 18825663

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