Natalia Vilor-Tejedor1,2,3,4, Iacopo Ciampa5, Grégory Operto6,7,8, Carles Falcón6,7,9, Marc Suárez-Calvet6,7,8,10, Marta Crous-Bou6,11,12, Mahnaz Shekari6,13,7, Eider M Arenaza-Urquijo6,7,8, Marta Milà-Alomà6,13,7,8, Oriol Grau-Rivera6,7,8,10, Carolina Minguillon6,7,8, Gwendlyn Kollmorgen14, Henrik Zetterberg15,16,17,18, Kaj Blennow15,16, Roderic Guigo19,13, José Luis Molinuevo20,21,22,23, Juan Domingo Gispert24,25,26,27. 1. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. nvilor@barcelonabeta.org. 2. Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain. nvilor@barcelonabeta.org. 3. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. nvilor@barcelonabeta.org. 4. Universitat Pompeu Fabra, Barcelona, Spain. nvilor@barcelonabeta.org. 5. Department of Radiology, Hospital Universitari Sagrat Cor, Barcelona, Spain. 6. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. 7. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 8. Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES), Madrid, Spain. 9. Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales Y Nanomedicina, Madrid, Spain. 10. Servei de Neurologia, Hospital del Mar, Barcelona, Spain. 11. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 12. Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Hospitalet del Llobregat, Spain. 13. Universitat Pompeu Fabra, Barcelona, Spain. 14. Roche Diagnostics GmbH, Penzberg, Germany. 15. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden. 16. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 17. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK. 18. Dementia Research Institute At UCL, London, UK. 19. Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Barcelona, Spain. 20. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. jlmolinuevo@barcelonabeta.org. 21. Universitat Pompeu Fabra, Barcelona, Spain. jlmolinuevo@barcelonabeta.org. 22. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. jlmolinuevo@barcelonabeta.org. 23. Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES), Madrid, Spain. jlmolinuevo@barcelonabeta.org. 24. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. jdgispert@barcelonabeta.org. 25. Universitat Pompeu Fabra, Barcelona, Spain. jdgispert@barcelonabeta.org. 26. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. jdgispert@barcelonabeta.org. 27. Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales Y Nanomedicina, Madrid, Spain. jdgispert@barcelonabeta.org.
Abstract
BACKGROUND: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. OBJECTIVE: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. METHODS: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). RESULTS: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. CONCLUSIONS: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
BACKGROUND: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown. OBJECTIVE: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors. METHODS: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071). RESULTS: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants. CONCLUSIONS: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
Authors: Jie Ning; Jing Luo; Zengdong Meng; Chong Luo; Gang Wan; Jie Liu; Sanrong Wang; Xingye Lian; N D Melgiri; Yang Sun; Rongzhong Huang Journal: Oncotarget Date: 2017-11-03
Authors: Joanna M Wardlaw; Eric E Smith; Geert J Biessels; Charlotte Cordonnier; Franz Fazekas; Richard Frayne; Richard I Lindley; John T O'Brien; Frederik Barkhof; Oscar R Benavente; Sandra E Black; Carol Brayne; Monique Breteler; Hugues Chabriat; Charles Decarli; Frank-Erik de Leeuw; Fergus Doubal; Marco Duering; Nick C Fox; Steven Greenberg; Vladimir Hachinski; Ingo Kilimann; Vincent Mok; Robert van Oostenbrugge; Leonardo Pantoni; Oliver Speck; Blossom C M Stephan; Stefan Teipel; Anand Viswanathan; David Werring; Christopher Chen; Colin Smith; Mark van Buchem; Bo Norrving; Philip B Gorelick; Martin Dichgans Journal: Lancet Neurol Date: 2013-08 Impact factor: 44.182