Researchers at Washington University School of Medicine in St. Louis have been awarded $7.5 million from the National Institutes of Health (NIH) to study a form of dementia caused by cerebral small vessel disease, the second leading cause of dementia after Alzheimer’s disease.
The grant funds the Vascular Contributions to Cognitive Impairment and Dementia (VCID) Center, a “Center Without Walls” initiative of the National Institute of Neurological Disorders and Stroke that will coordinate researchers at six sites across the US.
The WashU Medicine team will apply new magnetic resonance imaging tools and other advanced “multi-omic” technologies (a technique that looks at proteins, genes, metabolites and other complex systems together) to analyze cerebrospinal fluid and brain tissue from human brains. and animal models to precisely map mRNA in cells affected by cerebral small vessel disease (CSVD). The long-term goals are to identify biomarkers that can be used to identify the onset of CSVD-related conditions and to pinpoint targets for drugs that can mitigate or protect against the damage caused by the disease.
Three co-investigators are leading the effort at WashU Medicine: Jin-Moo Lee, MD, PhD, the Andrew B. & Gretchen P. Jones Professor of Neurology and chief of the Department of Neurology; Carlos Cruchaga, PhD, the Barbara Burton & Reuben M. Morriss Professor of Psychiatry; and Manu Goyal, MD, associate professor of radiology at WashU Medicine’s Mallinckrodt Institute of Radiology.
CSVD occurs when small blood vessels in the brain become damaged and lose their ability to change caliber to receive larger or smaller amounts of blood as the brain needs it. When the blood vessels lose this ability, it can lead to a lack of blood flow to parts of the brain, a condition known as ischemia.
Over a long period of time, this ischemia can lead to white matter injury and result in memory loss, difficulty walking, incontinence, depression; symptoms that define vascular dementia.”
Jin-Moo Lee, MD, PhD, the Andrew B. & Gretchen P. Jones Professor of Neurology and chief of the Department of Neurology
Several conditions can lead to CSVD. These include hypertension and diabetes, which can lead to arteriolosclerosis (thickening of the walls of small blood vessels) or the buildup of amyloid around blood vessels, leading to cerebral amyloid angiopathy (CAA). The latter condition is linked to the progression of Alzheimer’s disease. The damaged areas caused by CSVD appear as bright spots called white matter hyperintensities on MRI scans of the brain.
“When we look at older patients, we routinely see evidence of small vessel disease,” Goyal said. “It’s something striking that we’ve known about for decades, but we don’t really know how exactly it happens, and we don’t have very good treatments.”
Lee explained that white matter hyperintensities associated with CSVD will occur in five different patterns and locations in the brain, depending on the condition underlying the CSVD. The team mapped these patterns using advanced image analysis tools developed in collaboration with Chia-Ling Phuah, MD, a former faculty member in the Department of Neurology. Each pattern of white matter hyperintensity is in turn associated with a clear underlying CSVD (arteriolosclerosis or CAA).
“The goal of our grant is to understand the importance of the spatial location of hyperintensities in the white matter, to understand exactly what the cellular and molecular mechanisms were that led to them,” Lee said. The hope is to identify relevant proteins that could be targets for new drugs or serve as screening biomarkers for early diagnosis of these conditions.
Cruchaga explained that previous studies on this phenomenon had examined the brain as a whole. That approach misses cell-specific changes that are fundamental to the presentation of each type of white matter hyperintensity and the changes in brain function associated with it.
“With this proposal, we will dive very deeply into the molecular and protein profiles at the single-cell level of CSVD, allowing us to identify new causal and druggable targets, as well as novel biomarkers,” said Cruchaga. He will also analyze cerebrospinal fluid samples to identify significant proteins associated with damage patterns in the brain. To link these cell-specific changes in genetic activity to the precise location in the brain, such as within the white matter hyperintensities where the damage occurs, his team will apply a technique known as spatial transcriptomics.
“With spatial transcriptomics we can identify which genes change, but also which cell type and the specific location of these cells, and how these changes affect the surrounding cells,” says Cruchaga. “If we can determine that there are hyperintensities in the white matter that express specific genes, we can investigate whether those genes are later involved in the development of dementia or memory problems.”
To achieve these goals, WashU Medicine has robust resources through the Knight Alzheimer’s Disease Research Center (Knight-ADRC) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Patients from these programs will serve as the cohort whose tissue and cerebrospinal fluid will be analyzed.
The research reported in this press release was supported by the National Institutes of Health (NIH) under award number 1RF1NS139970-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.