Research within the Brickman Laboratory is fundamentally concerned with understanding how vascular factors promote cognitive aging and Alzheimer's disease (AD). Using a combination of multiple neuroimaging modalities and epidemiological, basic neuroscience, and neuropsychological approaches, our work focuses primarily on small vessel cerebrovascular disease, how its severity predicts clinical outcomes, and how it interacts with pathological and physiological markers of AD.

Adam M. Brickman, PhD

White matter hyperintensities (WMH) are magnetic resonance imaging (MRI) markers of small vessel cerebrovascular disease and have been a central focus over the past several years. Our laboratory developed methods to quantify the severity of these lesions and their distribution throughout the brain. We have shown that WMH are increased among those at risk for development of AD; are more severe among patients with amnestic mild cognitive impairment than controls; predict future incident AD, when distributed in the parietal lobes; predict the rate of cognitive decline among those with prevalent AD; are related to in vivo markers of neurodegeneration; increase risk of future development of AD above-and-beyond in vivo markers of beta amyloid deposition; and progress specifically in the parietal lobes among individuals destined to develop AD. We further showed that APOE-ε4, the strongest genetic risk factor for AD, may confer risk through its effect on parietal lobe WMH. Our work establishes at least an additive contribution of small vessel cerebrovascular disease to the clinical presentation and progression of AD.

Members of the Brickman Laboratory, from left to right, Atul Narkhede, Edgar Busovaca, Jamie Hamilton, Vanessa Guzman, Erica Griffith, Robert Vorburger, Briana Last, Randi Scott, Giuseppe Tosto, and Sara Ebrahimi Nasrabady. Not pictured: Irene Meier.

Moving forward, we are addressing several questions. We are interested in understanding how WMH interact with Alzheimer's pathology, regional hippocampal dysfunction, and other markers of cerebrovascular disease, including cerebral microbleeds, enlarged perivascular spaces, and infarcts. We are also studying a group of individuals with autosomal dominant AD and testing the extent to which small vessel cerebrovascular disease emerges as a primary characteristic. We have preliminary data suggesting that cerebral autoregulation - - the brain's ability to maintain relatively constant blood flow with varying blood pressure - - may be involved with both Alzheimer's pathology and small vessel cerebrovascular disease and hope to examine this possibility in large sample studies.

Upper Left: Raw T2-weighted FLAIR image showing white matter hyperintensities (WMH) unlabeled (left) and labeled (right) by our automatic software. Lower Left: 3D reconstruction of a single subject's WMH. Upper right: An example of how our automatic labeling software can determine WMH burden in different regions throughout the brain. Lower right: Probability map of the distribution of WMH across hundreds of subjects in our studies. "Hotter" colors represent areas in the brain more likely to have WMH in aging; "colder" colors represent areas where WMH are still common but less prevalent. Fewer than 10% of our subjects have WMH in areas that do not have any color labeling.

Because our work points to abnormalities in the brain's white matter associated with AD, we are applying novel neuroimaging techniques to understand white matter microstructural abnormalities and examining how regional individual differences in microstructure and blood flow among young adults increase risk for vascular and AD pathology in late life. It is also important to understand the histopathological nature of the abnormalities we detect radiologically, so we have begun a series of studies to examine systematically white matter tissue taken from collected brains of patients with AD. Our future goals involve development and implementation of animal models and exploration of novel intervention and prevention strategies.

Some of the other techniques we employ in our laboratory. On the left side (top and bottom) are individual subject images labeled with FreeSurfer, which we use to derive regional volumes and measures of cortical thickness. On the top right is an illustration of the cone of uncertainty applied to the analysis of diffusion tensor imaging data. The subject on left has more disrupted white matter in the fornix than the subject on the right. The lower right two panels show examples of some of the vascular lesions we are interested in: the left shows a cerebral microbleed on a gradient echo image and the right shows a frontal-subcortical infarct with complete hyperintense envelopment on T2-weighted imaging.

In addition to the primary work conducted in the laboratory, we enjoy collaborations with many Taub and CUMC colleagues, as well as investigators at other institutions all over the world. We are able to process in high throughput capacity structural MRI data, including quantification of regional volume, cortical thickness, diffusion tensor imaging, and markers of cerebrovascular pathology. We provide expertise in the design and implementation of studies that combine neuropsychological techniques with neuroimaging techniques.

Members of the Brickman Laboratory include:

Robert S. Vorburger, PhD is a postdoctoral research fellow who exploits the potential of diffusion tensor imaging (DTI) to investigate age-related and pathological changes in the human brain white matter. His current work includes study-specific optimization of existing DTI parameters, the development of new diffusion contrasts (e.g. cone of uncertainty), and the search for new insights by combining DTI data with other imaging modalities such as white matter hyperintensities.

Jamie Hamilton, PhD is a postdoctoral fellow who is interested in understanding the relationship between neuropsychiatric symptoms and cognition across racial and ethnic groups. Jamie also uses neuroimaging techniques to understand whether white matter abnormalities account for racial and ethnic differences in brain-behavior relationships.

Sara Ebrahimi Nasrabady, MD, PhD is a postdoctoral research fellow who focuses on studying the histopathological characteristics of white matter in Alzheimer's disease with a primary focus on examination of the lineage of oligodendrocyte cells.

Giuseppe Tosto, MD, PhD is a postdoctoral research scientist in the Laboratory for Genetic Epidemiology but a close collaborator with our lab.  Giuseppe is interested in the contribution of small vessel cerebrovascular disease to clinical progression in AD and to neuropsychiatric symptoms, in addition to his primary work in genetic epidemiology and neurology.

Irene Meier, MS is a PhD student focused on cerebral microbleeds. Microbleeds are punctate lesions on T2*-weighted gradient-echo MRI. They reflect the deposition of amyloid within the walls of blood vessels when occurring in lobar regions. For Irene's doctoral work she is conducting cross-sectional and longitudinal studies that relate microbleeds to cognition. She is also studying the spatial association between regional blood and amyloid deposition.

Vanessa Guzman, MS is a PhD student studying the interaction of various cerebrovascular markers. Her research interests are in examining the relationship between lacunar infarcts, small and large perivascular spaces with other markers of small vessel disease and in the context of cognitive aging.

Atul Narkhede, M.S., is a Research Assistant who spearheads the development of novel image processing algorithms for quantification of white matter hyperintensities and their regional distribution in the brain using T2-weighted MRI sequences. In addition to methods development, Atul's research interests include combining multi-modal neuroimaging data sets for spatial analysis.

Erica Griffith, BS is a Research Assistant who is involved with MRI image processing and analysis. She carries out semi-quantitative infarct and perivascular space analysis and has expertise in the implementation of FreeSurfer for derivation of regional volumes and cortical thickness. Her scientific interests include understanding the contribution of WMH to clinical presentation of AD across various populations.

Randi Scott, MS is a research assistant in the laboratory. She performs neuropsychological testing for several studies that examine lifestyle interventions for improvement of cognition in aging and across various clinical populations. Her scientific interest involves understanding lifestyle mediators of cognitive function in older adults.

Briana Last, BA is a research coordinator for multiple ongoing neuroimaging studies. Her current scientific interest is in the relationship between sleep and aging, particularly whether cognitive deficits due to poor sleep are characterized by white matter abnormalities.

Edgar Busovaca, BA is a research assistant working on a project that examines the relationship between the morphological features of the cerebral cortex and cognitive functioning in younger and older adults.