Cerebral amyloid angiopathy(CAA) is an age-related cerebral small vessel disease that is a common cause of lobar intracerebral hemorrhage (ICH) and vascular cognitive impairment in the elderly. It is characterized by progressive deposition of -amyloid (A) in the walls of cortical and leptomeningeal arteries. Although CAA is a widely recognized cause of lobar ICH, neuropathological studies suggest that milder forms of CAA are far more common in the elderly. In non-demented individuals without ICH, nearly 14% have moderate to severe CAA and greater than 50% have at least mild degrees of CAA that independently contributes to cognitive impairment. Based on these data, it is conceivable that CAA may play an important role in a large percentage of individuals with subtle cognitive symptoms or mild cognitive impairment (MCI). As our preliminary data suggest that strictly lobar MB have high specificity for CAA even in the absence of ICH, individuals with early CAA may be now readily identified. However, an important unanswered question is what additional vascular lesions predispose these individuals to develop cognitive symptoms and what role Alzheimer's disease (AD) pathology plays in cognitive impairment. Indeed, beyond MB, other neuroimaging and laboratory biomarkers appear be associated with vascular A accumulation. Dilated perivascular spaces (DPVS) in the white matter (a recently identified important marker of cerebral small vessel disease), chronic bleeding in the subarachnoid space (known as superficial siderosis) and posterior distribution of white matter hyperintensities (a marker of chronic cerebral ischemia) have all been associated with advanced CAA. This is likely related to increased vascular amyloid deposition in posterior brain regions-supported by evidence showing elevated relative occipital burden of Pittsburgh Compound B (PiB) in patients with CAA, the PET ligand that detects fibrillar and vascular amyloid deposition in vivo. Patients with CAA have also been shown to have depletion of the A40 species of amyloid protein in cerebrospinal fluid (CSF). Finally, cerebral microinfarctions on pathology appear to be very common in CAA. The current application aims to examine the role of A-mediated vascular pathology in cognitive symptoms in the elderly. The key questions motivating this proposal are: 1) Is there a signature of neuroimaging and laboratory biomarkers that can reliably identify patients with early CAA? 2) Do patients early CAA have a particular neuropsychological profile distinct from patients with mild cognitive symptoms due to early AD? and 3) What are the predisposing risk factors that lead to cognitive decline in patients with early CAA?

Public Health Relevance

This project aims to achieve a more detailed understanding of early (even prodromal) stages of CAA prior to the development of dementia or hemorrhagic stroke. Identifying individuals with early and asymptomatic CAA will be critically important in the design of future therapeutic trials to prevent the devastating consequences of this disease. The results from this study could yield important insights for better understanding vascular cognitive impairment in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG047975-01
Application #
8749950
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Petanceska, Suzana
Project Start
2014-09-30
Project End
2019-05-31
Budget Start
2014-09-30
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Xiong, Li; Boulouis, Gregoire; Charidimou, Andreas et al. (2018) Dementia incidence and predictors in cerebral amyloid angiopathy patients without intracerebral hemorrhage. J Cereb Blood Flow Metab 38:241-249
Pasi, Marco; Marini, Sandro; Morotti, Andrea et al. (2018) Cerebellar Hematoma Location: Implications for the Underlying Microangiopathy. Stroke 49:207-210
Xiong, Li; van Veluw, Susanne J; Bounemia, Narimene et al. (2018) Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy. Stroke 49:2330-2336
Charidimou, Andreas; Boulouis, Gregoire; Xiong, Li et al. (2017) Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy. Neurology 88:1607-1614
Charidimou, Andreas; Boulouis, Gregoire; Roongpiboonsopit, Duangnapa et al. (2017) Cortical superficial siderosis multifocality in cerebral amyloid angiopathy: A prospective study. Neurology 89:2128-2135
Reijmer, Yael D; Fotiadis, Panagiotis; Charidimou, Andreas et al. (2017) Relationship between white matter connectivity loss and cortical thinning in cerebral amyloid angiopathy. Hum Brain Mapp :
Boulouis, Gregoire; Charidimou, Andreas; Pasi, Marco et al. (2017) Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers. J Neurol Sci 380:64-67
Valenti, Raffaella; Charidimou, Andreas; Xiong, Li et al. (2017) Visuospatial Functioning in Cerebral Amyloid Angiopathy: A Pilot Study. J Alzheimers Dis 56:1223-1227
Charidimou, Andreas; Imaizumi, Toshio; Moulin, Solene et al. (2017) Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis. Neurology 89:820-829

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