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Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes [Original Contribution]
Jun, G., Naj, A. C., Beecham, G. W., Wang, L.-S., Buros, J., Gallins, P. J., Buxbaum, J. D., Ertekin-Taner, N., Fallin, M. D., Friedland, R., Inzelberg, R., Kramer, P., Rogaeva, E., St. George-Hyslop, P., Cantwell, L. B., Dombroski, B. A., Saykin, A. J., Reiman, E. M., Bennett, D. A., Morris, J. C., Lunetta, K. L., Martin, E. R., Montine, T. J., Goate, A. M., Blacker, D., Tsuang, D. W., Beekly, D., Cupples, L. A., Hakonarson, H., Kukull, W., Foroud, T. M., Haines, J., Mayeux, R., Farrer, L. A., Pericak-Vance, M. A., Schellenberg, G. D., Alzheimer's Disease Genetics Consortium, Arnold, Baldwin, Barber, Beach, Bigio, Bird, Boxer, Burke, Cairns, Carroll, Chui, Clark, Cotman, Cummings, DeCarli, Diaz-Arrastia, Dick, Dickson, Ellis, Fallon, Farlow, Ferris, Frosch, Galasko, Gearing, Geschwind, Ghetti, Gilman, Giordani, Glass, Graff-Radford, Green, Growdon, Hamilton, Harrell, Head, Honig, Hulette, Hyman, Jicha, Jin, Johnson, Karlawish, Karydas, Kaye, Kim, Koo, Kowall, Lah, Levey, Lieberman, Lopez, Mack, Markesbery, Marson, Martiniuk, Masliah, McKee, Mesulam, Miller, Miller, Miller, Parisi, Perl, Peskind, Petersen, Poon, Quinn, Raskind, Reisberg, Ringman, Roberson, Rosenberg, Sano, Schneider, Schneider, Seeley, Shelanski, Smith, Spina, Stern, Tanzi, Trojanowski, Troncoso, Van Deerlin, Vinters, Vonsattel, Weintraub, Welsh-Bohmer, Woltjer, Younkin Objectives To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design Association study of AD and CLU, PICALM, CR1, and APOE genotypes. Setting Academic research institutions in the United States, Canada, and Israel. Participants Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE 4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE 4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE 4, and an interaction term showed significant interaction between presence or absence of APOE 4 and PICALM. Conclusions We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE 4–positive subjects. Thus, APOE and PICALM synergistically interact.
Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains [Original Contribution]
Alvarez-Erviti, L., Rodriguez-Oroz, M. C., Cooper, J. M., Caballero, C., Ferrer, I., Obeso, J. A., Schapira, A. H. V. Objective To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD). Design Postmortem observational study. Setting University Department of Clinical Neuroscience, Institute of Neurology, University College London. Subjects Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains. Main Outcome Measure Lysosomal-associated membrane protein 2A (LAMP2A) and heat shock cognate 70 (hsc70) protein levels were compared in the substantia nigra pars compacta and amygdala of PD, AD, and control brain samples. To provide insight into the turnover of -synuclein, degradation pathways for this protein were studied in a dopaminergic cell line. Results The expression levels of the chaperone-mediated autophagy proteins LAMP2A and hsc70 were significantly reduced in the substantia nigra pars compacta and amygdala of PD brains compared with age-matched AD and control brain samples. Lewy bodies in these regions contained autophagy-related proteins. We demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of -synuclein. Conclusions These findings suggest that there is reduced chaperone-mediated autophagy activity in the PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation,
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Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci and Reveals Interactions With APOE Genotypes [Original Contribution]
Jun, G., Naj, A. C., Beecham, G. W., Wang, L.-S., Buros, J., Gallins, P. J., Buxbaum, J. D., Ertekin-Taner, N., Fallin, M. D., Friedland, R., Inzelberg, R., Kramer, P., Rogaeva, E., St. George-Hyslop, P., Cantwell, L. B., Dombroski, B. A., Saykin, A. J., Reiman, E. M., Bennett, D. A., Morris, J. C., Lunetta, K. L., Martin, E. R., Montine, T. J., Goate, A. M., Blacker, D., Tsuang, D. W., Beekly, D., Cupples, L. A., Hakonarson, H., Kukull, W., Foroud, T. M., Haines, J., Mayeux, R., Farrer, L. A., Pericak-Vance, M. A., Schellenberg, G. D., Alzheimer's Disease Genetics Consortium, Arnold, Baldwin, Barber, Beach, Bigio, Bird, Boxer, Burke, Cairns, Carroll, Chui, Clark, Cotman, Cummings, DeCarli, Diaz-Arrastia, Dick, Dickson, Ellis, Fallon, Farlow, Ferris, Frosch, Galasko, Gearing, Geschwind, Ghetti, Gilman, Giordani, Glass, Graff-Radford, Green, Growdon, Hamilton, Harrell, Head, Honig, Hulette, Hyman, Jicha, Jin, Johnson, Karlawish, Karydas, Kaye, Kim, Koo, Kowall, Lah, Levey, Lieberman, Lopez, Mack, Markesbery, Marson, Martiniuk, Masliah, McKee, Mesulam, Miller, Miller, Miller, Parisi, Perl, Peskind, Petersen, Poon, Quinn, Raskind, Reisberg, Ringman, Roberson, Rosenberg, Sano, Schneider, Schneider, Seeley, Shelanski, Smith, Spina, Stern, Tanzi, Trojanowski, Troncoso, Van Deerlin, Vinters, Vonsattel, Weintraub, Welsh-Bohmer, Woltjer, Younkin Objectives To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes. Design Association study of AD and CLU, PICALM, CR1, and APOE genotypes. Setting Academic research institutions in the United States, Canada, and Israel. Participants Seven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals. Results Unadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE 4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE 4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE 4, and an interaction term showed significant interaction between presence or absence of APOE 4 and PICALM. Conclusions We confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE 4–positive subjects. Thus, APOE and PICALM synergistically interact.
Chaperone-Mediated Autophagy Markers in Parkinson Disease Brains [Original Contribution]
Alvarez-Erviti, L., Rodriguez-Oroz, M. C., Cooper, J. M., Caballero, C., Ferrer, I., Obeso, J. A., Schapira, A. H. V. Objective To investigate chaperone-mediated autophagy in the pathogenesis of Parkinson disease (PD). Design Postmortem observational study. Setting University Department of Clinical Neuroscience, Institute of Neurology, University College London. Subjects Postmortem samples from 7 PD, 6 Alzheimer disease (AD), and 8 control brains. Main Outcome Measure Lysosomal-associated membrane protein 2A (LAMP2A) and heat shock cognate 70 (hsc70) protein levels were compared in the substantia nigra pars compacta and amygdala of PD, AD, and control brain samples. To provide insight into the turnover of -synuclein, degradation pathways for this protein were studied in a dopaminergic cell line. Results The expression levels of the chaperone-mediated autophagy proteins LAMP2A and hsc70 were significantly reduced in the substantia nigra pars compacta and amygdala of PD brains compared with age-matched AD and control brain samples. Lewy bodies in these regions contained autophagy-related proteins. We demonstrated that decreased LAMP2A levels in dopaminergic cell lines reduced chaperone-mediated autophagy activity and increased the half-life of -synuclein. Conclusions These findings suggest that there is reduced chaperone-mediated autophagy activity in the PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation,
Sites:
Family Practice Notebook: Neurology: Covers Autonomic, Cerebellum, Chorea, Cranial Nerve, Cognitive, CSF, Demyelinating, Disability, Examination, Headache, Level of Consciousness, Motor, Procedure, Seizure, Sensory, Symptom Evaluation and Tremor. Related chapters from other specialties include Cardiovascular, Dermatology, Ophthalmo...Foundation for Education and Research in Neurological Emergencies: Information about this non-profit organization for improving the care of Emergency Department patients with neurological emergencies. Offers free educational courses and sponsors research for Emergency Physicians.
General Practice Notebook - Neurology: Coverage of this medical specialty.
HowStuffWorks: How Your Brain Works: Every animal you can think of -- mammals, birds, reptiles, fish, amphibians -- all have brains. But the human brain is unique. It gives us the power to think, plan, speak, imagine... Find out all about this amazing organ.
Institute for Nerve Medicine: Presenting information on disorders of the cranial, spinal and peripheral nerves. Includes illustrated descriptions of treatment options.
Iowa Neuroradiology Library: Department of Neurology, University of Iowa Hospitals and Clinics. Radiology teaching file.
National Institute of Neurological Disorders and Stroke: An NIH site with research and clinical information on disorders of the brain and nervous system.
Neuroconsult: Information resource on Clinical Neurology. Covering areas such as alzheimers, epilepsy, migraine, motor neurone, multiple sclerosis, pain, parkinsons, schizophrenia, and stroke.
NeuroExam.com: neuroexam.com is an interactive online guide to the neurologic examination, with video demonstrations. It is a companion to 'The NeuroExam Video' and 'Neuroanatomy Through Clinical Cases', both by Hal Blumenfeld
Neurological Teaching Videos: Digital video of the neurologic exam [Online registration, (free) required] by Wright State University.
Neurology Channel: NeurologyChannel is a comprehensive resource for seizures, stroke, coma, Alzheimer's, headaches, migraines, Parkinson's, and other brain and nervous system disorders. Features patient forum and neurologist search.
Neurology in Clinical Practice, 3e: An online professional neurology reference.
Neurology Jobs: Physician employment opportunities for all specialties in North America.
Neurology-Info.net: Information about the nervous system in health and disease. Part of the ALtruis Biomedical Network.
NeurologyLinx: Neurologist keep current with free medical news and daily newsletters. NeurologyLinx and MDLinx aggregates the most current medical journal news and research from premier medical and healthcare journals and news sources. Comprehensive, specialized content updated every day on the web and in email...
Neurosciences on the Internet: Neurosciences on the Internet contains a searchable and browsable index of neuroscience resources available on the World Wide Web and other parts of the Internet. Neurobiology, neurology, neurosurgery, psychiatry, psychology, cognitive science sites and information on human neurological diseases...
Oregon Nerve Center: The Oregon Nerve Center is a leading center for research in the field of neurology.
This directory is based on the Open Directory and may have been modified