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

A new neuroimaging marker of cerebral small vessel disease is associated with general cognitive function and may serve to identify people at risk of dementia in future clinical trials, according to a landmark study.

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

In particular, he found that the marker of cerebral small vessel disease known as peak amplitude of skeletal mean diffusion (PSMD) could be used to efficiently process multiple brain images in multisite dementia studies.

The biovalidation 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 and Neurodegenerative Diseases at UT Health San Antonio

She is the senior author of the study, titled, “Biological Validation of Skeletal Mean Diffusion Peak Width 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, clinicians and researchers here at the Glenn Biggs Institute and South Texas Alzheimer’s Disease Research Center over the past seven years,” he said. Sudha Seshadri. , MD, director of the Biggs Institute and another author of the study.

“Even during the COVID pandemic, study participants and researchers worked together, safely doing brain MRIs and cognitive tests,” he said. “I congratulate Dr. Satizábal and the team of physicians, participants, and scientists who worked with her to validate this important biomarker.”

Global burden of cognitive impairment

Increasingly, the literature suggests that cerebrovascular pathology is present to varying degrees in most adults with cognitive impairment, the study notes. Although the vascular contribution to cognitive impairment and dementia (VCID) is important, it is difficult to determine the number of individuals 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 a consensus that slowly progressive changes in the brain associated with cerebral small vessel disease (SVD) are a major mechanism involved in VCID.

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

“Despite the imperative to develop VCID biomarkers, only a few can reliably detect and monitor the SVD changes that lead to VCID, and these have not yet been approved by regulatory agencies for use in clinical trials,” said Alison Luckey, PhD, postdoc research. fellow of 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 undefined and it is further suggested that it not only represents vascular lesions but also neurodegeneration.

Enter, PSMD

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

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

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

From this, they observed that higher PSMD was associated with lower general cognitive ability on the MarkVCID, independent of age, sex, education and intracranial volume. Findings were replicated in three independent samples. Furthermore, PSMD explained cognitive status above and beyond WMH, the most common cerebrovascular index.

The researchers concluded that PSMD has ideal biomarker properties for the clinical trial line in the most common form of dementia, as it is non-invasive, fully automated, rapid and has excellent reliability, repeatability and reproducibility.

Additional longitudinal validation studies evaluating the use of PSMD as a surrogate for cerebral small vessel disease are ongoing.

Other study authors are with Boston University School of Medicine Chobanian & Avidisian. 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 San Francisco? and the Johns Hopkins University School of Medicine.

Also, the University of Mississippi Medical Center. Icelandic Heart Association; University of Iceland Faculty 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, ranked in the top 5% of clinical medicine institutions worldwide by US News & World Report. It is the 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 key measure of research impact.