Predicting progression from subjective cognitive decline to mild cognitive impairment or dementia based on brain atrophy patterns

Abstract

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder where pathophysiological changes begin decades before the onset of clinical symptoms. Analysis of brain atrophy patterns using structural MRI and multivariate data analysis are an effective tool in identifying patients with subjective cognitive decline (SCD) at higher risk of progression to AD dementia. Atrophy patterns obtained from models trained to classify advanced AD versus normal subjects, may not be optimal for subjects at an early stage, like SCD. In this study, we compared the accuracy of the SCD progression prediction using the 'severity index' generated using a standard classification model trained on patients with AD dementia versus a new model trained on β-amyloid (Aβ) positive patients with amnestic mild cognitive impairment (aMCI).

Methods: We used structural MRI data of 504 patients from the Swedish BioFINDER-1 study cohort (cognitively normal (CN), Aβ-negative = 220; SCD, Aβ positive and negative = 139; aMCI, Aβ-positive = 106; AD dementia = 39). We applied multivariate data analysis to create two predictive models trained to discriminate CN individuals from either individuals with Aβ positive aMCI or AD dementia. Models were applied to individuals with SCD to classify their atrophy patterns as either high-risk "disease-like" or low-risk "CN-like". Clinical trajectory and model accuracy were evaluated using 8 years of longitudinal data.

Results: In predicting progression from SCD to MCI or dementia, the standard, dementia-based model, reached 100% specificity but only 10.6% sensitivity, while the new, aMCI-based model, reached 72.3% sensitivity and 60.9% specificity. The aMCI-based model was superior in predicting progression from SCD to MCI or dementia, reaching a higher receiver operating characteristic area under curve (AUC = 0.72; P = 0.037) in comparison with the dementia-based model (AUC = 0.57).

Conclusion: When predicting conversion from SCD to MCI or dementia using structural MRI data, prediction models based on individuals with milder levels of atrophy (i.e. aMCI) may offer superior clinical value compared to standard dementia-based models.

Keywords: Alzheimer’s disease; Atrophy patterns; Multivariate analysis; Structural MRI; Subjective cognitive decline.

Fig. 1

Variable loadings. p1 = Contribution of individual variables to the predictive component in the model (A) trained on the Alzheimer’s disease dementia patients (B) trained on the aMCI patients

Fig. 2

Simplified overview of data-processing steps. Processing preceding computation of the “disease severity index” and prediction of progression; aMCI = β-amyloid positive amnestic mild cognitive impairment; CN = β-amyloid negative cognitively normal participants; DEM = dementia due to Alzheimer’s disease; OPLS = Orthogonal Projection to Latent Structures; SCD = subjective cognitive decline; Individual steps are described in detail in the manuscript

Fig. 3

Characteristics of the model. (A) trained on the Alzheimer’s disease dementia patients (B) trained on the aMCI patients ; R² = explained variance; Q² = predicted variance; (1) Permutation plot: Comparison of R² and Q² values of the model with other models, where random permutations of Y (diagnostic information) have been performed while X-data (input data) stayed intact; (2) Q² and R² values of individual components: p1 = predictive component; o1 = first orthogonal component (3) Score plot: individual scores of participants used in training; t1 = predictive component score; to1 = first orthogonal component score; (4) Loading plot: loadings of individual variables; p1 = predictive component; o1 = first orthogonal component

Fig. 4

Receiver operating characteristic curves. Curves of the ‘disease severity index’ generated using aMCI-based (green) and dementia-based (blue) models; AUC = area under curve

Fig. 5

Longitudinal progression of SCD groups. (A) using the model based on Alzheimer’s disease dementia patients (B) using the model based on aMCI patients; The survival event was defined by either progressing to MCI or dementia at the time of annual follow-up. The log rank test was used to test the difference between the curves