Researchers at Washington University School of Medicine in St. Louis have been awarded $7.5 million from the National Institutes of Health (NIH) to investigate 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, which is a National Institute of Neurological Disorders and Stroke "Center Without Walls" initiative that will coordinate researchers at six sites across the U.S.
The WashU Medicine team will apply new magnetic resonance image-processing tools and other cutting-edge "multi-omic" technologies (a technique that looks at proteins, genes, metabolites and other complex systems together) to analyze cerebrospinal fluid and brain tissues from human and animal models to precisely map mRNA within cells affected by cerebral small vessel disease (CSVD). The long-term goals are to track biomarkers that can be used to identify the onset of CSVD-linked conditions and to locate targets for drugs that might 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 in Neurology and head of the Department of Neurology; Carlos Cruchaga, PhD, the Barbara Burton & Reuben M. Morriss Professor of Psychiatry; and Manu Goyal, MD, an associate professor of radiology in the Mallinckrodt Institute of Radiology at WashU Medicine.
CSVD occurs when small blood vessels in the brain are damaged and lose their ability to change caliber to accommodate greater or lesser amounts of blood as needed by the brain. When the vessels lose this ability, it can lead to a lack of blood flow to regions of the brain, a condition known as ischemia.
Over a long period of time, this ischemia can lead to injury to the white matter, 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 in Neurology and head 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 vessels) or the buildup of amyloid around vessels, leading to cerebral amyloid angiopathy (CAA). This 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 indications of small vessel disease," Goyal said. "It's a striking thing that we've known about for decades, but we don't really know how it happens precisely, and we don't have very good treatments."
Lee explained that white matter hyperintensities associated with CSVD will occur in five distinct patterns and locations within the brain, depending on the condition underlying the CSVD. The team mapped out these patterns using sophisticated image-analysis tools developed 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 distinct underlying CSVD (arteriolosclerosis or CAA).
"The purpose of our grant is to leverage understanding of the importance of the spatial location of white matter hyperintensities, in order 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 that looked at 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 linked to them.
"With this proposal we are going to perform very deep dives into the molecular and protein profiles at the single-cell level of CSVD, that will allow us to identify novel causal and druggable targets as well as novel biomarkers," said Cruchaga. He will also analyze cerebrospinal fluid samples to identify the 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 is occurring, his team will apply a technique known as spatial transcriptomics.
"With spatial transcriptomics, we will be able to identify which genes are changing, but also which cell type and the specific location of these cells, and how these changes affect surrounding cells," Cruchaga said. "If we can determine that there are white matter hyperintensities that are expressing specific genes, we can investigate whether those genes are later involved in the development of dementia or memory problems."
To accomplish these goals, WashU Medicine has robust resources through the Knight Alzheimer's Disease Research Center (Knight-ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Patients from those programs will serve as the cohort whose tissue and cerebrospinal fluid will be analyzed.
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.
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