Entorhinal Hypometabolism Levels on FDG-PET Predicts Subsequent Cognitive Decline

Both high PiB and low entorhinal fluorodeoxyglucose as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB.

Results from a prospective study comparing PET and MRI biomarkers showed that entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making fluorodeoxyglucose (FDG) a potentially useful biomarker to increase power in clinical trials.1

Senior author Bernard J. Hanseeuw, MD, PhD, professor of radiology, Massachusetts General Hospital, and colleagues analyzed data from 131 clinically normal adults from the Harvard Aging Brain Study (HABS) with MRI, FDG, flortaucipir (FTP), and Pittsburgh compound B (PiB)-PET over a mean 3-year follow-up. Linear mixed-effect models with random intercepts and slopes, while adjusting for demographics, were used to evaluate the association between biomarkers and cognitive decline. Prospective cognitive decline was determined by annual assessments of the Preclinical Alzheimer’s Cognitive Composite (PACC5).

All patients included in the HABS had structural MRI, FDG, FTP, and PiB-PET collected within a year of one another. Inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex were the 4 predefined regions of interest focused on in this study. In the low-PiB sample, FTP, FDG, and MRI measures were not associated with change in cognitive decline, whereas regional entorhinal cortex (EC), inferior temporal (IT), and hippocampal FTP predicted cognitive decline.

Hanseew et al wrote, "overall, our results indicate that FDG captures information that is relevant to cognition and can reflect a measure of downstream-related AD [Alzheimer disease] and non-AD processes that are not currently measurable in vivo. In combination with Aß [amyloid-beta] and tau-PET, FDG would allow enriched clinical trials in individuals with AD pathology and high risk of fast cognitive decline and minimize the possibility of coexisting pathologies."

Backward stepwise regressions in which age, sex, education, neocortical PiB, and all FTB, FDB, and MRI regions of interest (ROI) were used to evaluate which biomarkers independently predicted cognitive decline. In the entire sample, neocortical PiB (–0.047 [±0.033]; P = .005), EC FTP (–0.060 [±0.035]; P <.001), EC FDG (0.025 [±0.029]; P = .097, nonsignificant after Bonferroni correction), and age (–0.059 [±0.035]; P = .001) were independently predictive of subsequent cognitive decline. Age was the only significant predictor in the low-PiB sample (–0.060 [±0.031]; P <.001).

In high-PiB individuals, hippocampal volume (HV; 0.107 [±0.060]; P <.001), EC FTP (–0.073 [±0.047]; P = .003), and EC FDG (0.091 [±0.052]; P <.001) independently predicted prospective cognitive decline. The other predictors were excluded from the final backward regressions because of lack of significance.

A separate analysis using the high-PiB sample (n = 41) was conducted to estimate the number of participants needed for a clinical trial to detect a slowing of cognitive decline of 30%. Inclusion criteria that used high-EC FTP (FTP-SUVr threshold, 1.52) reduced the required sample size 2-fold, while using low-EC FDG (FDG-SUVr threshold, 0.81) reduced the required sample size 3-fold.

The investigators also concluded that to reach the 30% slope reduction threshold on PACC5 score, a clinical trial would need to include 285 high-PiB (95% CI, 118-1195), 139 high-PiB high-FTB (95% CI, 48-434), or 94 high-PiB low-FDG (95% CI, 41-193) participants in each arm.

The additive benefits these types of scans bring to the AD space have been increasingly identified in recent years. Using the FDA-approved FTP F18 injection (Tauvid; Eli Lilly), research published earlier this year showed that patients with an advanced AD are at a higher risk of clinically meaningful deterioration. At 18-month follow-up, 70% of those included in the data with an advanced AD pattern had 1 point or more increase in clinical dementia rating sum of box score.2

REFERENCES
1. Mayblyum DV, Becker A, Jacobs HI. Comparing PET and MRI biomarkers predicting cognitive decline in preclinical Alzheimer disease. Neurology. Published online June 15, 2021. doi: 10.1212/WNL.0000000000012108
2. Lu M, Pontecorvo MJ, Devous MD, et al. Aggregated tau measured by visual interpretation of flortaucipir positron emission tomography and the associated risk of clinical progression of mild cognitive impairment and Alzheimer disease. JAMA Neurol. Published online February 15, 2021. doi: 10.1001/jamaneurol.2020.5505