While researchers know that cerebral small vessel disease, which damages the brain’s smallest blood vessels, is linked to dementia and cognitive impairment, the exact mechanisms are still poorly understood. To help rectify this, Keck School of Medicine of USC researchers have joined a nationwide consortium, Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia, or MarkVCID, which aims to identify and validate biological markers that predict the onset of dementia. On Jan. 22 and 23, the group welcomed nearly 100 contributors to the Health Sciences Campus for its second annual meeting.

The five-year investigation, funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), was launched in 2016 with more than $6 million in year-one funding. Seven separate projects at institutions that include USC, the University of California at San Francisco and Davis, Johns Hopkins Medical Center and the CHARGE consortium, have spent the first two years analyzing and optimizing vascular cognitive impairment and dementia biomarkers, which are measureable biological factors that reliably predict health outcomes. Researchers across the consortium are studying a range of datatypes, including brain scans, genetic profiles, clinical and neuropsychological evaluations and fluid samples such as blood and cerebrospinal fluid.

Later this year, researchers will enter the project’s second phase, during which promising biomarkers will be validated by other consortium members and prepared for use in clinical trials. Ultimately, the discoveries made by the MarkVCID consortium could spur the development of effective drugs and interventions to treat Alzheimer’s disease and vascular dementia.

“We all know that dementia is a tsunami waiting to happen — it’s going to be a true public health emergency,” said Steven Greenberg, MD, PhD, principal investigator for the MarkVCID coordinating center at Massachusetts General Hospital. “But we need to understand what role damage to small blood vessels plays in the bigger picture. We’re committed to finding biomarkers that don’t just look promising, but are really ready for primetime, ready to be immediately plugged into clinical trials.”

Innovative imaging

The USC-based project, led by Danny Wang, PhD, MSCE, professor of neurology and radiology at the Keck School, employs two innovative imaging methods to examine small blood vessels in the brain. Wang’s group is using MRI to measure the vascular compliance, or stiffness, of blood vessels, which is an indicator of hypertension and other vascular diseases. The team at the USC Mark and Mary Stevens Neuroimaging and Informatics Institute (INI) also is examining the permeability of the blood-brain barrier, which increases with age and is believed to be closely linked to dementia.

John Ringman, MD, MS, professor of clinical neurology, and Amir Kashani, MD, PhD, assistant professor of clinical ophthalmology, are co-principal investigators on the USC project. While Ringman oversees the genetic and clinical analyses, Kashani is using another type of imaging — Optical Coherence Tomography Angiography (OCTA) — to look directly at capillaries and small arteries in the brain via the retina. OCTA enables researchers to obtain high-resolution images on the order of 10 microns, about one-tenth the diameter of a strand of hair.

“Typically, it’s difficult to look directly at small vessels in the brain, but OCTA is a relatively cheap and accessible way to see arterials and capillaries in great detail,” Wang said. “As a result, there has been growing interest in using this technology to find early markers of dementia.”

The USC researchers are drawing from a pool of 6,200 subjects, all of whom are Latino, a population traditionally underrepresented in aging research.

Sharing insights

Closely following the MarkVCID annual meeting, the consortium was featured in a panel discussion at the American Heart Association’s International Stroke Conferences in Los Angeles. The group’s leaders shared insights they have gained regarding multi-site collaboration on identifying, testing and validating biomarkers of small vessel disease.

MarkVCID also is actively seeking collaborations, both with researchers interested in contributing data they’ve collected and with those hoping to obtain data for their own studies. Greenberg said the group’s open sharing policy is intended to amplify the consortium’s impact as much as possible.

As the group enters the second phase of its investigation, “we have a very clear goal,” Greenberg said. “By the end of year five, we hope to have a suite of biomarkers ready for clinical trials so that the various candidate treatments for vascular cognitive impairment can be tested and hopefully shown to be effective.”

— Zara Abrams