A new neuroimaging marker for cerebral small vessel disease is linked to general cognition and may serve to identify individuals at risk for dementia in future clinical trials, a landmark study shows.
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 risk of dementia from vascular injury compared to non-Hispanic white persons.
Specifically, it showed that the marker for cerebral small vessel disease known as peak width of skeletonized mean diffusivity (PSMD) could be used to efficiently process numerous brain images in multisite dementia studies.
Our biological validation work supports the pursuit of larger clinical validation studies that position PSMD as a biomarker for the susceptibility/risk 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 dedicated collaboration between community research participants, patients, physicians and researchers 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 conducting brain MRI scans and cognitive tests,” she said. “I congratulate Dr. Satizábal and the team of physicians, participants and scientists who worked with her on the validation of this important biomarker.”
Global burden of cognitive impairment
The literature increasingly 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 affected 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 individuals with VCID, leading to consensus that slowly progressive changes in the brain related to cerebral small vessel disease (SVD) are an important mechanism that is involved in VCID.
Furthermore, as life expectancy increases worldwide, the global burden of age-related cognitive impairment, including presumed vascular etiology, will increase. Therefore, the study authors believe that any intervention that alleviates the burden of VCID should be explored.
“Despite the urgent 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 for use in clinical trials,” said Alison Luckey , PhD, postdoctoral research. fellow at the Biggs Institute and first author of the study.
Currently, the most commonly used neuroimaging marker for SVD is white matter hyperintensities (WMH). However, the etiology of WMH remains undetermined and it is further suggested that it represents not only vascular lesions but also neurodegeneration.
Come in, PSMD
The new study notes that PSMD demonstrated excellent instrumental properties as a marker, meaning it showed reliability across all users, locations and times. So the scientists wanted to extend their work to conduct 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), established 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 research, 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 that adjust for confounders.
From this, they concluded 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. Furthermore, PSMD further explained cognitive status than WMH, the most common cerebrovascular marker.
The researchers concluded that PSMD has ideal biomarker qualities for the clinical trial pipeline for the most common forms of dementia because it is non-invasive, fully automated, rapid, and has excellent reliability, repeatability and reproducibility.
Additional longitudinal validation studies assessing the use of PSMD as a surrogate for cerebral small vascular disease are underway.
Other study authors are affiliated with 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 the 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 and ranks in the top 5% of global clinical medicine institutions according to U.S. News & World Report. It ranks 12th 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 article to the average for similar published work, a recognized core measure of impact of research.
Source:
Magazine reference:
Happiness, AM, et al. (2024) Biological validation of the peak width of skeletonized mean diffusivity as a VCID biomarker: the MarkVCID Consortium. Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association. doi.org/10.1002/alz.14345.