A study headed by Johns Hopkins University researchers has shown how an MRI technique that detects iron levels in different regions of the brain can predict the onset of mild cognitive impairment (MCI) and cognitive decline in cognitively unimpaired older adults. The findings could potentially create a pathway to earlier interventions.
The team carried out a prospective study involving 158 cognitively unimpaired patients, and used a technique called quantitative susceptibility mapping (QSM) MRI to noninvasively measure brain iron at baseline. The researchers then followed the participants for up to 7.7 years. PET data was also available for 110 of the patients.
The findings suggested a link between higher baseline magnetic susceptibility on MRI in two brain regions that are important for memory and other cognitive functions, with a higher risk of mild cognitive impairment, which can precede Alzheimer’s disease (AD).
The link was especially notable for individuals with amyloid abnormalities. The researchers suggest that if their findings can be confirmed in larger studies, QSM MRI may become more widely used to identify individuals at risk of dementia, including Alzheimer’s disease. And in addition to its potential role as a biomarker, brain iron might also represent a therapeutic target, the researchers suggested.
Xu Li, PhD, associate professor of radiology at Johns Hopkins University and research associate at the F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute in Baltimore, is senior author of the team’s published paper in Radiology. In the paper titled “Susceptibility MRI Helps Predict Mild Cognitive Impairment Onset and Cognitive Decline in Cognitively Unimpaired Older Adults,” the team concluded, “Our study provides compelling evidence that brain iron levels, as measured with quantitative susceptibility mapping MRI, may serve as an important imaging marker for identifying individuals at greatest risk of developing cognitive impairment.”
As the leading cause of dementia worldwide, Alzheimer’s disease is a growing public health crisis. The disease is characterized by the accumulation of amyloid-β (Aβ) plaques and intracellular tau tangles, which manifest years before the appearance of clinical symptoms and can be detected with positron emission tomography (PET) scans. Treatments targeting these proteins are only modestly effective, indicating that other factors may contribute to cognitive impairment. “Consequently, the development of sensitive, noninvasive markers of early AD-related neurodegeneration is crucial for better understanding the disease, particularly in its preclinical phase, and for monitoring the effects of potential treatments.”
MCI is a transitional stage preceding AD-related dementia, the team further explained, and “… the early and accurate prediction of MCI in cognitively unimpaired individuals is crucial for timely intervention and prevention.”
Elevated levels of iron in the brain are one factor under investigation in recent years. Iron overload in the brain is known to drive neurodegeneration by inducing oxidative stress (an imbalance between two different types of molecules in your body: free radicals and antioxidants), exacerbating amyloid toxicity, disrupting tau protein function, and promoting nerve cell death. “Moreover, brain iron accumulation among older, cognitively unimpaired individuals has been reported to be associated with working memory, episodic memory, and motor performance,” the team stated. “Elevations in brain iron levels, which likely occur earlier than brain atrophy, have therefore been suggested as a potential marker for neurodegeneration in AD.”
However, the authors noted, the role of elevated iron in predicting the onset of mild cognitive impairment and prospective cognitive outcomes isn’t well understood.
Brain iron can be measured noninvasively through a special MRI technique called quantitative susceptibility mapping (QSM). “QSM is an advanced MRI technique developed over the last decade to measure tissue magnetic susceptibility with good precision,” said Li. “QSM can detect small differences in iron levels across different brain regions, providing a reliable and non-invasive way to map and quantify iron in patients, which is not possible with conventional MR approaches.”
For the newly reported study, 158 cognitively unimpaired participants drawn from the Johns Hopkins BIOCARD Study—a research project focused on the early stages of Alzheimer’s disease and related disorders—underwent baseline QSM MRI. Among the majority for whom PET data was available, cortical Aβ was also measured. The participants were then followed for up to seven and a half years.
The study results showed that higher baseline magnetic susceptibility on MRI in the entorhinal cortex and putamen—two brain regions important to memory and other cognitive functions—was associated with a higher risk of mild cognitive impairment, a transitional stage preceding Alzheimer’s disease-related dementia.
“Using QSM, we found higher brain iron in some memory-related regions that are linked to a higher risk of developing cognitive impairment and faster cognitive decline,” Li said. “This risk is even higher when the participants have higher levels of amyloid pathologies.”
Li suggested that even though amyloid burden and tissue susceptibility in the entorhinal cortex and putamen were independently associated with progression to mild cognitive impairment, they appeared to have synergistic effects, accelerating global cognitive decline over time.
Noting limitations of their research, the authors concluded, “The present study demonstrated that regional tissue susceptibility as assessed with quantitative susceptibility mapping MRI, especially in the entorhinal cortex and putamen among the tested regions of interest, could be a valuable prognostic marker for predicting mild cognitive impairment onset in cognitively unimpaired individuals.”
If confirmed in larger studies with more diverse patient populations, the findings could point to a role for QSM MRI in the workup of patients at risk of dementia. “We can use this kind of tool to help identify patients at higher risk of developing Alzheimer’s disease and potentially guide early interventions as new treatments become available,” Li said. “Also, besides serving as a biomarker, brain iron may become a future therapeutic target.”
Going forward, the researchers hope to gain a better understanding of how brain iron contributes to Alzheimer’s disease, including its interaction with other Alzheimer’s disease-related pathologies like amyloid and tau proteins. On the therapeutic side, clinical trials could test iron-targeted therapies. “At the same time, we hope to make the QSM technology more standardized, faster, and more widely accessible in clinical practice,” Li said.
In a related editorial, Carlota Andreu-Arasa, MD, PhD, assistant professor at Boston University, neuroradiologist, and investigator at the Translational Research Center for TBI and Stress Disorders and the Cognitive and Sensory Systems Laboratory at VA Boston Healthcare System, commented, “Biomarkers that can help identify individuals who have MCI are essential for early intervention, but biomarkers that can help predict MCI before onset have even greater promise for risk stratification and targeted early treatment. QSM MRI in particular could play a transformative role in the prediction of dementia because it is noninvasive, easy to perform, and affordable.”
Predicting increased risk of cognitive impairment would also allow expedited treatment. “The ability to identify individuals at risk for cognitive impairment before the onset of symptoms enables intervention within the critical window when disease-modifying therapies are believed to be most effective, representing a pivotal opportunity to alter the trajectory of the disease,” Andreu-Arasa added. “As radiology increasingly intersects with molecular diagnostics and cognitive assessment, QSM may offer a noninvasive tool for risk stratification to guide individualized therapeutic strategies and care planning before the onset of symptoms.”
