Cerebral microbleeds are related to loss of white matter structural integrity

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Oral Sessions: O1-03: Diagnosis and Prognosis: Cerebral Microhemorrhages—Role of Cerebral Neuropathology

siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (p<0.001) and b-amyloid load (p<0.001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions (Figure). APOE ε4 carriers had greater odds than APOE ε3 homozygotes of having two (p¼0.046) and three (p¼0.03) or more mH. Greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last followup (rank correlation¼0.49;P<0.001). Conclusions: ADNI is an ongoing multi-site prospective study designed to represent cohorts typically recruited to clinical trials for the treatment and prevention of AD. We report that focal hemosiderin deposits are a relatively common imaging finding in the ADNI cohort and are associated with b-amyloid load. The finding of higher number of mH at baseline increasing the risk of subsequent mH is important for planning treatment and prevention trials with amyloid-lowering agents in AD.

O1-03-03

CEREBRAL AMYLOID ANGIOPATHY IN ALZHEIMER’S DISEASE IS ASSOCIATED WITH INCREASED BLOOD-BRAIN BARRIER PERMEABILITY: A QUANTITATIVE [11C]PIB-PET STUDY

Bart van Berckel1, Jeroen Goos2, Danielle M.E. Assema2, Maqsood Yaqub1, Esther Bakker1, Reina Kloet1, Lothar Schwarte1, Philip Scheltens1, Frederik Barkhof1, Adriaan Lammertsma1, Wiesje Van der Flier1, Ronald Boellaard1, 1VU University Medical Center, Amsterdam, Netherlands; 2VU University Medical Center, Department of Neurology and Alzheimer Center, Amsterdam, Netherlands. Contact e-mail: B.Berckel@ VUmc.nl Background: Microbleeds (MBs) and superficial siderosis (SS) are thought to be related to cerebral amyloid angiopathy (CAA). To assess the relation between these CAA markers and amyloid load in vivo and blood-brain barrier (BBB) permeability we used quantitative [11 C]PIB-PET in Alzheimer disease (AD) patients. Methods: We included eight AD patients with MBs or SS (17 MBs and 5 SS areas (CAA+ group)) and five AD patients without (CAA- group) on 1.5T SWI. Dynamic 90 minute [11 C]PIB-PET scans were acquired on the HR+ PET camera with arterial blood sampling to generate metabolite corrected input curves. Data were analysed with a validated two tissue compartment model. We assessed the non-displaceable binding potential (BP ND), reflecting specific amyloid binding, and the K1/k2 ratio, reflecting BBB permeability, on three levels; (i) local volumes of interest (VOIs) drawn manually around MBs/SS and copied contra-laterally serving as control regions, (ii) regional VOIs and (iii) global cortical VOIs. Results: Locally, BP ND did not differ, but K1/k2 ratios were higher in grey matter CAA+ VOIs than in contra-lateral control VOIs (median(range) 2.30(1.33.3) versus 2.13(1.3-2.9); p<0.05), suggesting locally increased BBB permeability.Regional or global VOIs however, showed no differences in BP ND (global: CAA+¼2.29(1.3-8.4), CAA-¼2.65(1.3-5.1); p>0.05) or K1/k2 ratio (global: CAA+¼2.22(1.3-2.8) and CAA-¼2.19(1.7-2.7); p>0.05). Conclusions: Instead of BP ND , K1/k2 ratios surrounding MBs and SS were higher, suggesting that MRI signs of CAA in AD may relate to locally increased BBB permeability, rather than increased amyloid deposition. This has important implications for the use of [11 C]PIB scans in the diagnosis of CAA.

O1-03-04

CEREBRAL MICROBLEEDS ARE RELATED TO LOSS OF WHITE MATTER STRUCTURAL INTEGRITY

Saloua Akoudad, Marius de Groot, Peter Koudstaal, Aad van der Lugt, Wiro Niessen, Albert Hofman, Mohammad Ikram, Meike Vernooij, Erasmus Medical Center, Rotterdam, Netherlands. Contact e-mail: saloua. [email protected] Background: Cerebral small vessel disease (CSVD) indicates diffuse brain damage and is related to stroke, cognitive decline and dementia. Imaging markers for CSVD include white matter lesions and lacunar infarcts. Cerebral microbleeds are increasingly being recognized as a new manifestation of CSVD. However, because cerebral microbleeds appear as focal lesions on imaging, it remains unclear if they also represent diffuse brain pathology. We investigated whether presence, number, and location of microbleeds is related to loss of microstructural integrity of brain white matter, as measured by diffusion tensor imaging (DTI). Methods: A total of 4493 Rotterdam Scan Study participants underwent brain MRI to determine microbleed status. With DTI, global fractional anisotropy (FA) and mean diffusivity (MD) were measured in normal-appearing white matter. Analyses were adjusted for age, sex, cardiovascular risk factors, white matter lesions and infarcts, and were repeated after stratification by APOE ε4 carriership. Results: Presence of microbleeds at any location in the brain was related to a lower mean FA and higher mean MD, reflecting loss of integrity of brain white matter in subjects with microbleeds. Even the presence of a single microbleed associated with a significant lower mean FA and higher mean MD (FA: -0.13, 95% CI -0.21; -0.05; MD: 0.12, 95% CI 0.05; 0.19). The associations became stronger as the microbleed count increased. For lobar microbleeds alterations in DTI measurements was solely driven by APOE ε4 carriers. Conclusions: Presence of microbleeds relates to poorer microstructural integrity of brain white matter. Our data suggests that microbleeds reflect diffuse brain pathology. This pathology may be more severe in APOE ε4 allele carriers who have lobar microbleeds. O1-03-05

PREVALENCE AND GROWTH OF CEREBRAL MICROHEMORRHAGES IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE

Tyler Blazey1, Clifford Jack2, Kejal Kantarci2, Gregory Preboske2, John Ringman3, Adam Brickman4, Marc Raichle1, Russ Hornbeck1, Andrew Saykin1, Stephen Salloway1, Eric McDade5, Martin Rossor6, Nick Fox6, Paul Thompson3, Stephen Correia7, Christopher Rowe8, Michael Weiner9, Richard Mayeux4, Bernardino Ghetti10, Reisa Sperling11, Peter Schofield12, Randall Bateman13, Nigel Cairns1, Alison Goate13, Daniel Marcus13, Anne Fagan13, Chengjie Xiong1, Virginia Buckles14, Krista Moulder13, John Morris1, Tammie Benzinger13, 1Washington University School of Medicine, St. Louis, Missouri, United States; 2Mayo Clinic, Rochester, Minnesota, United States; 3UCLA, Los Angeles, California, United States; 4Columbia University, New York, New York, United States; 5University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States; 6University College London, London, United Kingdom; 7Brown Medical School, Providence, Rhode Island, United States; 8INSERM, Universite de Caen Basse-Normandie, Ecole Pratique des Hautes Etudes, CHU de Caen, Caen, France; 9Center for Imaging of Neurodegenerative Diseases, VA Medical Center and UCSF, San Francisco, California, United States; 10Indiana University School of Medicine, Indianapolis, New York, United States; 11Brigham and Women’s Hospital, Boston, Massachusetts, United States; 12Neuroscience Research Australia, Randwick-Sydney, Australia; 13Washington University, St. Louis, Missouri, United States; 14Alzheimer’s Disease Research Center, St. Louis, Missouri, United States. Contact e-mail: [email protected] Background: Cerebral microhemorrhages (MH), defined as small, hypointense lesions on T2/T2* weighted images, occur in approximately 23% of Alzheimer’s disease (AD) cases. Furthermore, anti-amyloid treatment trials have been associated with the development of MHs . As a response to concerns about the safety of increased MH loads, the Alzheimer’s Association Research Roundtable Workgroup recommended that individuals with more