Deposition of ss-amyloid (Ass) in the cerebral vessels (cerebral amyloid angiopathy or CAA) is a major cause of hemorrhagic stroke, a contributor to vascular cognitive impairment, and a complicating factor in attempts to develop anti-amyloid immunotherapies. Current methods for detecting CAA during life are focused on identifying CAA-associated hemorrhages, typically after major hemorrhagic stroke has occurred. Growing evidence (including the high prevalence of lobar microbleeds in the general elderly population) suggests that advanced CAA is extremely common even in the absence of hemorrhagic stroke. The current proposal seeks to establish the early diagnosis of advanced CAA by validating and applying novel in vivo detection methods for individuals without hemorrhagic stroke. Preliminary data support three candidate detection methods: 1) increased retention of the amyloid ligand Pittsburgh Compound B (PiB) in an occipital-predominant pattern, 2) reduction of cerebrospinal fluid concentrations of the ss-amyloid Ass40 and Ass42 peptides, and 3) blunting of cerebrovascular reactivity to visual stimulation. We will validate these three approaches in two groups of patients with well established diagnoses of advanced CAA: sporadic patients with multiple lobar cerebral microbleeds recruited at Massachusetts General Hospital (Specific Aim 1) and familial patients genetically diagnosed with Dutch-type hereditary CAA recruited at Leiden University Medical Center (Specific Aim 2). Based on the diagnostic cut-points established in these two patients groups, we will then proceed to apply the detection methods to asymptomatic population-based subjects with strictly lobar microbleeds identified by the Rotterdam Scan Study (Specific Aim 3). Each of the three study groups will consist of 20 case subjects and 20 similar aged control subjects from the same site. Receiver operator characteristic techniques will be used to establish optimum methods for distinguishing CAA cases from non-CAA controls, applying results from the two patient groups with established CAA to the population-based Rotterdam Scan subjects where the presence of advanced CAA remains unknown. The three study populations represent the largest and most thoroughly characterized groups of sporadic CAA patients (Massachusetts General Hospital), hereditary CAA patients (Leiden University Medical Center) and population-based subjects scanned by MRI methods optimized for microbleed detection (Rotterdam Scan Study). This proposal also builds on the Principal Investigator's considerable success in developing a range of novel tools for characterizing CAA during life. Successful completion of the proposed studies will have potentially major impact on the fields of hemorrhagic stroke, vascular cognitive impairment, and Ass immunotherapy, by providing new information on an individual's risk of future hemorrhage, defining the true contribution of CAA to age-related cognitive decline, and possibly yielding new safety markers for anti-amyloid immunotherapy.

Public Health Relevance

We propose a study of new detection methods for cerebral amyloid angiopathy (or CAA), an age-related degenerative condition of the blood vessels of the brain. Severe CAA is an important cause of bleeding strokes in the elderly, a likely contributor to memory loss related to impaired circulation, and a possible barrier to ongoing attempts to develop a vaccine for Alzheimer disease. The current proposal seeks to implement newly developed methods for detecting CAA before it causes a bleeding stroke, potentially leading both to improved treatments for stroke prevention and better understanding of how this common degenerative process affects memory.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Koemans, Emma A; van Etten, Ellis S; van Opstal, Anna M et al. (2018) Innovative Magnetic Resonance Imaging Markers of Hereditary Cerebral Amyloid Angiopathy at 7 Tesla. Stroke 49:1518-1520
Greenberg, Steven M; Charidimou, Andreas (2018) Diagnosis of Cerebral Amyloid Angiopathy: Evolution of the Boston Criteria. Stroke 49:491-497
Martinez-Ramirez, Sergi; van Rooden, Sanneke; Charidimou, Andreas et al. (2018) Perivascular Spaces Volume in Sporadic and Hereditary (Dutch-Type) Cerebral Amyloid Angiopathy. Stroke 49:1913-1919
Greenberg, Steven M (2017) William M. Feinberg Award for Excellence in Clinical Stroke: Big Pictures and Small Vessels. Stroke 48:2628-2631
Rentz, Dorene M; Mormino, Elizabeth C; Papp, Kathryn V et al. (2017) Cognitive resilience in clinical and preclinical Alzheimer's disease: the Association of Amyloid and Tau Burden on cognitive performance. Brain Imaging Behav 11:383-390
van Opstal, Anna M; van Rooden, Sanneke; van Harten, Thijs et al. (2017) Cerebrovascular function in presymptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study. Lancet Neurol 16:115-122
Fotiadis, Panagiotis; van Rooden, Sanneke; van der Grond, Jeroen et al. (2016) Cortical atrophy in patients with cerebral amyloid angiopathy: a case-control study. Lancet Neurol 15:811-819
Charidimou, Andreas; Boulouis, Gregoire; Haley, Kellen et al. (2016) White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy. Neurology 86:505-11
Charidimou, Andreas; Ni, Jun; Martinez-Ramirez, Sergi et al. (2016) Cortical Superficial Siderosis in Memory Clinic Patients: Further Evidence for Underlying Cerebral Amyloid Angiopathy. Cerebrovasc Dis 41:156-62
Phuah, Chia-Ling; Raffeld, Miriam R; Ayres, Alison M et al. (2016) Subacute decline in serum lipids precedes the occurrence of primary intracerebral hemorrhage. Neurology 86:2034-41

Showing the most recent 10 out of 32 publications