New neuroimaging marker may identify persons at risk of dementia in future clinical trials

A new neuroimaging marker of cerebral small vessel disease is related to general cognition and may serve to identify persons at risk of dementia in future clinical trials, a landmark study has found.

The study led by researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) is especially relevant to the Hispanic population, which has a higher dementia risk from vascular injury compared to non-Hispanic white persons.

Specifically, it found that the cerebral small vessel disease marker known as peak-width of skeletonized mean diffusivity (PSMD) could be used to efficiently process numerous brain images in multi-site dementia studies.

Our biological validation work supports the pursuit of larger clinical validation studies positioning PSMD as a susceptibility/risk biomarker of small vessel disease contributing to cognitive impairment and dementia for use in clinical trials.”

Claudia Satizábal, PhD, associate professor at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases at UT Health San Antonio

She is senior author of the study, titled, “Biological validation of peak-width of skeletonized mean diffusivity as a VCID biomarker: The MarkVCID Consortium,” published Nov. 21 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“This study is a direct result of a committed partnership between research participants from the community, patients, clinicians and researchers right here at the Glenn Biggs Institute, and the South Texas Alzheimer’s Disease Research Center, over the past seven years,” said Sudha Seshadri, MD, director of the Biggs Institute and another study author.

“Even during the COVID pandemic, study participants and researchers worked together, safely doing brain MRI scans and cognitive tests,” she said. “I congratulate Dr. Satizábal and the team of doctors, participants and scientists who worked with her on the validation of this important biomarker.”

Global burden of cognitive impairment

Increasingly, literature suggests that cerebrovascular pathology is present to varying degrees in most adults suffering from cognitive impairment, the study notes. Although the vascular contributions to cognitive impairment and dementia (VCID) are significant, it is difficult to determine the number of people impacted due to the frequent occurrence of VCID with other etiologies and comorbidities.

Advances in neuroimaging have identified a high prevalence of brain white matter damage in persons with VCID, leading to consensus that slow progressive changes in the brain related to cerebral small vessel disease (SVD) are a major mechanism involved in VCID.

Additionally, as life expectancy increases worldwide, the global burden of age-related cognitive impairment, including presumed vascular etiology, will rise. Therefore, the study authors believe that any intervention that alleviates the burden of VCID should be investigated.

“Despite the pressing need to develop VCID biomarkers, only a few can reliably detect and track SVD changes leading to VCID, and these have yet to be approved by regulatory agencies to be used in clinical trials,” said Alison Luckey, PhD, postdoctoral research fellow with the Biggs Institute and first author of the study.

Currently, the most used neuroimaging marker of SVD is white matter hyperintensities (WMH). However, the etiology of WMH remains undetermined and is further suggested to not only represent vascular lesions but also neurodegeneration.

Enter, PSMD

The new study notes that PSMD had shown excellent instrumental properties as a marker, meaning it showed reliability across users, sites and time points. So, the scientists set out to extend their work to perform a biological validation, defined as the association with clinically meaningful aspects of VCID, such as cognitive performance.

The UT Health San Antonio-led team studied a group of 396 participants from the MarkVCID consortium (https://markvcid.partners.org), founded from an initiative of the National Institute on Neurological Disorders and Stroke (NINDS) to identify, develop and validate fluid- and imaging-based biomarkers for the SVDs associated with VCID.

For their study, the scientists derived PSMD from diffusion tensor imaging (DTI) using an automated algorithm, and related it to a composite measure of general cognitive function using linear regression models adjusting for confounders.

From that, they observed that higher PSMD was associated with lower general cognition in MarkVCID, independent of age, sex, education and intracranial volume. The findings were replicated in three independent samples. Further, PSMD explained cognitive status above and beyond WMH, the more common cerebrovascular marker.

The researchers concluded that PSMD has ideal biomarker qualities for the clinical trial pipeline across the most common form of dementias, as it is non-invasive, fully automated, fast and has excellent reliability, repeatability and reproducibility.

Additional longitudinal validation studies assessing the use of PSMD as a surrogate of cerebral small vessel diseases are underway.

Other authors of the study are with the Boston Chobanian & Avidisian University School of Medicine; Boston University School of Public Health; National Institute on Aging of the National Institutes of Health; Harvard Medical School; University of New Mexico School of Medicine; University of New Mexico; University of Kentucky; University of California at San Francisco; and Johns Hopkins University School of Medicine.

Also, the University of Mississippi Medical Center; Icelandic Heart Association; University of Iceland School of Health Sciences; University of California at Davis; Massachusetts General Hospital; University of Southern California; The Mind Research Network; The University of Texas Health Science Center at Houston; Illinois Institute of Technology; and Rush University Medical Center.

UT Health San Antonio is a world-class research university, ranking at the top 5% among institutions globally for clinical medicine according to U.S. News & World Report. It is No. 12 in the world among universities for the impact of its discoveries – in normalized citation impact, which compares the number of citations its research receives per paper to the average for similar published work, a recognized core measure of research impact.