Predicting cognitive change using functional, structural, and neuropsychological predictors

Abstract

To effectively address Alzheimer's disease, it is crucial to understand its earliest manifestations, underlying mechanisms and early markers of progression. Recent findings of very early brain activation anomalies highlight their potential for early disease characterization and predicting future cognitive decline. Our objective was to evaluate the value of brain activation-both individually and in combination with structural and neuropsychological measures-for predicting cognitive change. The study included 105 individuals from the Consortium for the Early Identification of Alzheimer's Disease-Quebec cohort who exhibited subjective cognitive decline or mild cognitive impairment. Cognitive decline was assessed by calculating the slope of Montreal Cognitive Assessment scores using regression models across successive assessments, and individuals were characterized as either decliners or stable based on clinically reliable change. We evaluated cognitive decline predictions using unimodal models for each class of predictors and multimodal models that combined these predictors. Functional activation emerged as a strong predictor of cognitive change (R²=52.5%), with 87.6% accuracy and 98.7% specificity, performing comparably to structural and neuropsychological measures. Although the unimodal functional model exhibited high specificity, indicating that functional abnormalities frequently predict future decline, it had low sensitivity (60%), meaning that the absence of abnormalities does not rule out future decline. Multimodal models provided greater explanatory power than unimodal models and greater sensitivity than the functional model. These findings highlight the potential role of early brain activation anomalies in the early detection of future cognitive changes, offering valuable insights for clinicians and researchers in assessing cognitive decline risk and refining clinical trial criteria.

Keywords: brain structure; functional magnetic resonance imaging; mild cognitive impairment; neuropsychological measures; subjective cognitive decline.

Graphical Abstract

Figure 1

Regions of interest in functional and structural prediction models. Recall scores: sum of free and cued recall scores. Thickness: average cortical thickness, calculated across left and right hemispheres, based on cortical regions defined in the DKT labeling protocol. A positive relationship indicates a relationship between cognitive decline and volumetry/activation in the direction of a greater decline associated with a higher volume/activation; a negative relationship indicates a relationship between cognitive decline and volumetry/activation in the direction of a greater decline associated with a lower volume/activation. EC, entorhinal cortex; Hip, hippocampus; IFG, inferior frontal gyrus; lateral OFG, lateral orbitofrontal gyrus; medial OFG, medial orbitofrontal gyrus; MTG, middle temporal gyrus.

Figure 2

ROC curves. The dashed gray line represents the reference line. Unimodal models: (A) functional model, (B) structural model and (C) neuropsychological model. Multimodal models: (D) functional and structural model, (E) functional and neuropsychological model, (F) structural and neuropsychological model and (G) functional, structural and neuropsychological model. AUC, area under the curve; ROC, receiver operating characteristic.