A strong body of evidence implicates cerebrovascular ss-amyloid (cerebral amyloid angiopathy or CAA) as a relatively common independent contributor to cognitive impairment in the elderly, most likely by effects on vessel function. Unlike other common small vessel pathologies, CAA remains both unpreventable and untreatable. This renewal proposal seeks to establish the pathophysiologic mechanisms that lead from vascular amyloid deposition to focal brain injury to neurologic impairment. It builds on the considerable success of the productive initial funding period in establishing a range of novel noninvasive markers for CAA, including increasingly sensitive detection of cerebral microbleeds, surprisingly frequent silent microinfarcts, impaired cerebrovascular reactivity, and detection of vascular amyloid itself by Pittsburgh Compound B. The proposal also takes advantage of the Principal Investigator's expertise in the diagnosis, genetics, clinical course, and pathophysiology of CAA and his group's well-characterized cohort of patients diagnosed with this disorder.
Specific Aim 1 examines the cross-sectional association between location and severity of vascular amyloid and the extent of focal structural lesions, brain atrophy, and neurologic dysfunction.
This aim tests the hypothesis that cortical amyloid accumulation triggers cerebral microbleeds, microinfarcts, increased diffusivity, and focal brain atrophy, which in turn lead to impaired cognitive performance, gait, and functional skills.
Specific Aim 2 tests the specific role in this pathogenic cascade of two candidate vascular mechanisms as potential mediators of CAA-related brain injury: impaired cerebrovascular reactivity and reduced transvascular water exchange.
Specific Aim 3 is a prospective, longitudinal analysis aimed at determining the causal relationship between location and severity of vascular abnormalities at baseline and appearance of new structural lesions on follow-up MRI or incident neurologic decline, defined as dementia, loss of functional independence, or death. This proposal brings together a productive multidisciplinary team with recognized expertise in patient-oriented investigation and multimodal neuroimaging. Successful achievement of these aims will establish a strong foundation for anticipated clinical drug trials for CAA, in which candidate agents will be selected by their ability to target key vascular mechanisms and screened for their ability to slow progression of key biomarkers.

Public Health Relevance

We propose a study of how cerebral amyloid angiopathy (or CAA), an age-related degenerative condition of the blood vessels in the brain, causes loss of cognitive skills. Severe CAA occurs in up to 31% of older people and up to 43% of older people with dementia and is both unpreventable and untreatable. We propose to use innovative imaging tools to identify the steps that lead from CAA to brain injury and problems with cognition. These studies will create a strong foundation for starting treatment trials aimed at preventing this major threat to our aging population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026484-07
Application #
8149866
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Hsiao, John
Project Start
2005-09-15
Project End
2015-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2011
Total Cost
$566,186
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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 :
Marquié, Marta; Verwer, Eline E; Meltzer, Avery C et al. (2017) Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case. Acta Neuropathol Commun 5:75
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
LaPoint, Molly R; Chhatwal, Jasmeer P; Sepulcre, Jorge et al. (2017) The association between tau PET and retrospective cortical thinning in clinically normal elderly. Neuroimage 157:612-622
Dekhtyar, Maria; Papp, Kathryn V; Buckley, Rachel et al. (2017) Neuroimaging markers associated with maintenance of optimal memory performance in late-life. Neuropsychologia 100:164-170
Marini, Sandro; Morotti, Andrea; Ayres, Alison M et al. (2017) Sex differences in intracerebral hemorrhage expansion and mortality. J Neurol Sci 379:112-116
Schultz, Aaron P; Chhatwal, Jasmeer P; Hedden, Trey et al. (2017) Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals. J Neurosci 37:4323-4331
Greenberg, Steven M (2017) William M. Feinberg Award for Excellence in Clinical Stroke: Big Pictures and Small Vessels. Stroke 48:2628-2631
Marini, Sandro; Morotti, Andrea; Lena, Umme K et al. (2017) Men Experience Higher Risk of Pneumonia and Death After Intracerebral Hemorrhage. Neurocrit Care :
van Veluw, Susanne J; Kuijf, Hugo J; Charidimou, Andreas et al. (2017) Reduced vascular amyloid burden at microhemorrhage sites in cerebral amyloid angiopathy. Acta Neuropathol 133:409-415

Showing the most recent 10 out of 92 publications