New Diffusion Basis Spectrum Imaging and Brain PET Identify Neuroinflammation and AD In Overweight and Obese Persons

RSNA Research Scholar Grant recipient establishes NIH-funded laboratory during COVID-19 pandemic

Cyrus A. Raji, MD, PhD
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The risk of Alzheimer’s disease (AD) is increasingly recognized as modifiable by disorders arising from lifestyle, such as lack of exercise that can lead to unhealthy weight and obesity. Recently the Alzheimer’s Association and National Institute on Aging issued a new research framework for AD, focusing on biomarkers for amyloid (A), tau (T), and neurodegeneration (N).


Inclusion of obesity measures and metabolism into studies of AD based on the A-T-N framework allows for the expansion of the paradigm which could potentially lead to more personalized therapeutic interventions in the future.


Abnormally high body tissue adiposity is recognized as an attributable risk for dementia; in the U.S., midlife obesity increases the lifetime risk of dementia by 7.3%. Being overweight or obese in late life has been correlated with reduced brain volumes on MRI in regions important for memory and affected by AD pathology such as the hippocampus and posterior cingulate. However, evidence is emerging that differences exist between those who are overweight/obese and metabolically normal, and those who are metabolically abnormal.


In his 2019 RSNA Research Scholar Grant, “Diffusion Basis Spectrum Imaging for Quantifying Neuroinflammation in Metabolically Abnormal Overweight and Obese Persons at Risk for Alzheimer's Disease,” Cyrus A. Raji, MD, PhD, associate professor of radiology and director, Neuromagnetic Resonance Imaging at Mallinckrodt Institute of Radiology at Washington University School of Medicine, St. Louis, and his team hypothesized that metabolically abnormal overweight/obese individuals will have advanced A, T, and N pathology and increased neuroinflammation compared to metabolically normal overweight/obese and non-overweight individuals.


“The insulin resistance related to metabolically abnormal overweight and obese states can promote impaired clearance of amyloid, a key protein linked to the pathogenesis of Alzheimer's disease,” Dr. Raji said. “Additionally, metabolically abnormal overweight/obese states promote a pro-inflammatory state that can specifically increase neuroinflammation in the brain and consequently cerebral atrophy—a key feature of neurodegeneration in Alzheimer's disease.” 


Combined Imaging Focused on Brain Atrophy and Tau Deposition

Dr. Raji and his team evaluated brain atrophy on MR imaging to assess whether differences in neurodegeneration existed between metabolically abnormal and metabolically normal overweight and obese controls. All were cognitively normal. The cross-sectional study defined the metabolically abnormal overweight and obese categories using a combination of body mass index (BMI) greater than or equal to 25, which encompassed the overweight and obese groups, and a hemoglobin A1c of greater than or equal to 5.7.  They compared this group to metabolically normal overweight and obese participants and metabolically normal non-overweight participants.


They also evaluated neuroinflammation using a new type of diffusion MR imaging called diffusion basis spectrum imaging (DBSI), and AD pathology as characterized by amyloid and tau PET imaging.


“Diffusion basis spectrum imaging is a high-resolution diffusion MR imaging technique that can model the amount of extracellular water and cellular infiltration at the microstructural level in the white matter as imaging correlates of neuroinflammation. Neuroinflammation in turn has been linked to increased neurodegeneration as evidenced by increased brain atrophy,” Dr. Raji said.


The research compared the groups’ DBSI, atrophy, and amyloid and available tau imaging metrics. The preliminary data suggested a comparatively higher amount of brain atrophy and tau deposition in metabolically abnormal overweight and obese participants. 


Study Looked at Mid-Life and Younger Patients

A separate study in younger cognitively normal participants, 40-60 years old further refined the researchers’ understanding of obesity by going beyond BMI and measuring visceral and subcutaneous fat on abdominal MRI obtained at the same time as brain MRI with DBSI. The study correlated these measures along with cerebral volumetric analysis and the amyloid and tau PET markers for AD.


The researchers then statistically modeled the relationship between visceral fat and amyloid PET as well as brain atrophy metrics along with tau PET. They repeated the same analysis using subcutaneous fat as the predictor variable. They also performed these analyses evaluating these fat metrics against DBSI neuroinflammation imaging and MRI atrophy. 


“In our initial study of our midlife participants, we show that visceral fat is correlated with metabolically abnormal overweight and obese states, which makes sense given its tight link with insulin resistance. By contrast, subcutaneous fat was not found to have such a relationship, and this is important because 85% of BMI variance is due to subcutaneous fat and not visceral fat,” Dr. Raji said. “This is why visceral fat is called ‘hidden fat.’ It is considered to be a less healthy type of fat, related to its strong connection to metabolic abnormalities in pre-diabetes and diabetic states.”


The researchers found that in the midlife research participants, increased visceral fat predicts increased amyloid deposition on brain PET as well as a higher burden of entorhinal atrophy. By contrast, they did not find such a relationship between subcutaneous fat and the brain imaging metrics. This initial work was published in Aging and Disease with subsequent research on visceral fat predicting a higher burden of white matter neuroinflammation on DBSI being presented at RSNA 2023.


For patients who struggle with their weight, Dr. Raji and his team found that mid-life obesity, occurring primarily between age 40-60 years, is the strongest predictor of future AD.


“Weight management during this time is especially crucial for reducing the risk of Alzheimer's. While behavioral steps towards healthier diets, calorie restriction and physical activity can certainly help in controlling weight, there is also increased interest in using recently innovated drugs, such as semaglutide and tirzepatide, for weight loss as well,” Dr. Raji said. “However, a pharmacological approach that uses midlife weight control towards future Alzheimer's prevention requires additional and separate research investigations.”


R&E Foundation Grant Leads to NIH Funding

Dr. Raji’s research was challenged during the COVID-19 pandemic, particularly in obtaining preliminary data due to the shutdown of human participant research in the initial months of the crisis.


“However, with the progress I had already made from the RSNA R&E Research Scholar Grant, I was able to obtain preliminary data. That in combination with the RSNA Advanced Course in Grant Writing resulted in a successful grant application to the NIH in 2020 that was funded in the amount of $2.3 million in 2021,” Dr. Raji said.


As the pandemic abated and studies of research participants were permitted to resume, Dr. Raji and his team were able to move the study forward with NIH support.


“This success led to the creation of my independent laboratory, the Raji Brain Health Imaging Lab and I have since been promoted to associate professor with tenure in the Washington University in St. Louis Mallinckrodt Institute of Radiology with a secondary appointment in the Department of Neurology,” Dr. Raji said. “Such outcomes would not have been possible without the supportive resources of RSNA overall and the R&E Foundation in particular.”

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