Disclosures: Mayblyum reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
May 13, 2021
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Entorhinal hypometabolism on PET scan predicts cognitive decline in preclinical AD

Disclosures: Mayblyum reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Entorhinal hypometabolism identified on fluorodeoxyglucose PET scans served as a “strong and independent predictor” of future cognitive decline in preclinical Alzheimer’s disease, according to findings from a prospective cohort study.

The results indicated that fluorodeoxyglucose PET scans represent “a potentially useful biomarker” for increasing power in clinical trials. Researchers published the findings in Neurology.

“Mounting evidence suggested that AD pathology starts accumulating before cognitive symptoms are evident, defining a preclinical stage,” Danielle V. Mayblyum, BS, and colleagues wrote. “Positron emission tomography (PET) studies investigating [amyloid beta] have shown that clinically normal (CN) older individuals with elevated [amyloid beta] are more likely to perform worse over time on cognitive tests than those with lower [amyloid beta]. However, not all CN individuals with high [amyloid beta] burden experience cognitive decline.”

Surrogate biomarkers for the characterization of preclinical, AD-related cognitive decline have been proposed, including structural MRI, fluorodeoxyglucose (FDG) PET and flortaucipir (FTP) PET imaging, according to Mayblyum, of the department of radiology at Massachusetts General Hospital and the Gordon Center for Medical Imaging and the Athinoula A. Martinos Center for Biomedical Imaging in Boston, and colleagues. The researchers conducted a prospective cohort study to determine how structural MRI, FDG PET and FTP PET predicted clinical decline among individuals with a high amyloid burden vs. a low amyloid burden, with the aim of identifying which biomarker combination provided the greatest increase in statistical power for prevention trials.

The researchers examined data from clinically normal adults in the Harvard Aging Brain Study with MRI, FDG, FTP and Pittsburgh Compound B obtained within 1 year and prospective cognitive exams over a mean follow-up period of 3 years. Mayblyum and colleagues concentrated their analyses on prespecified areas of interest in the brain, including the inferior temporal, the isthmus cingulate, the hippocampus and the entorhinal cortex. They analyzed cognition using the Preclinical Alzheimer’s Cognitive Composite and examined the relationship between biomarkers and cognitive decline using linear mixed-effect models adjusted for demographics. The researchers also generated power curves simulating prevention trials, according to the study results.

The analysis included data from 131 participants (women, n = 52; mean age, 73.98±8.29 years).

Across separate models, Mayblyum and colleagues observed closer correlations with cognitive decline for most biomarkers in participants with high Pittsburgh Compound B compared with participants with low Pittsburgh Compound B. A backward, stepwise regression that included all biomarkers showed that only neocortical Pittsburgh Compound B, entorhinal FTP and entorhinal FDG were independent predictors of subsequent cognitive decline, according to the study results. Power analyses demonstrated that using both high Pittsburgh Compound B and low entorhinal FDG as inclusion criteria decreased by threefold the number of participants that would be needed in a hypothetical trial, compared with using only participants with high Pittsburgh Compound B.

The results provide Class II evidence that entorhinal hypometabolism identified by FDG-PET predicts subsequent cognitive decline in individuals with preclinical AD, according to Mayblyum and colleagues.

“Entorhinal hypometabolism is associated with subsequent cognitive decline in preclinical AD, above and beyond the association with amyloid and tau pathology,” the researchers wrote. “Adding low entorhinal FDG as inclusion criterion in preclinical AD trials would significantly increase the power of the trials.”