Single-Value Brain Activity Scores Reflect Both Severity and Risk Across the Alzheimer’s Continuum

Neurology Medical Imaging Medicine
Single-value scores Brain activity Alzheimer's disease Memory impairment Imaging biomarkers Mild cognitive impairment Diagnostic markers

Report on the Association Between Single Value Brain Activity Scores and the Progression of Alzheimer’s Disease

Introduction

Among the elderly population, cognitive decline and brain structural changes are widespread, even among healthy individuals1-3. Episodic memory, crucial for storing, maintaining, and retrieving single-event memories4, is especially susceptible to aging-related decline, which is more pronounced in individuals at risk for Alzheimer’s disease (AD)5-8. However, due to the high heterogeneity among individuals9, distinguishing accelerated yet normal cognitive decline from preclinical AD is a challenge.

Mild cognitive impairment (MCI), often defined as quantifiable cognitive decline while maintaining normal daily function10,11, is a clear risk factor for AD. Recently, subjective cognitive decline (SCD) has been defined as a pre-AD risk state12,13. Although the risks of AD dementia increase among those with SCD and MCI compared with the general population, not all people with MCI and even fewer with SCD will progress to dementia, making it urgent to identify biomarkers reflecting individual AD dementia risk14-17.

Background and Rationale

Currently, several neuroimaging biomarkers have been discovered regarding specific brain structures in AD, including reduced gray matter volume18,19, decreased hippocampal volume20, white matter lesion burden21,17, and functional magnetic resonance imaging (fMRI), which are potentially useful to differentiate between normal and abnormal neurocognitive aging22-25. Single scores derived from follow-up memory fMRI, such as Fault Activity Deviation (FADE) or Similarity to Activation Mode Exemplars (SAME), can serve as imaging biomarkers for healthy neurocognitive aging.

This paper aims to test the diagnostic and predictive capabilities of these single value scores in AD and its risk states (such as MCI and SCD).

Paper Information

The results of this research were published in 2024 by Oxford University Press on behalf of Brain. This research is open-access following the Creative Commons Attribution-NonCommercial License, which allows for non-commercial sharing, dissemination, and reproduction, provided proper attribution is given.

The authors of this paper mostly come from various research institutions in Germany, including the German Center for Neurodegenerative Diseases (DZNE), the Bernstein Center for Computational Neuroscience, the Max Planck Institute for Human Cognitive and Brain Sciences, etc.

Research Content

Methods

The study analyzed follow-up memory fMRI data from 468 individuals participating in the multicenter DELCode study, including healthy controls (HC), SCD, MCI and AD dementia patients, and first-degree relatives of AD patients (AD-Rel). FADE and SAME scores were calculated based on the participants’ whole-brain fMRI novelty and memory responses, and their associations with AD risk stages, neuropsychological test scores, CSF amyloid positivity, and APOE genotypes were evaluated.

Similar to previous studies, participants performed a previously described memory encoding task22 to study differences in the different stages of cross-sectional and longitudinal cognitive decline.

Specific Procedures and Technical Details:

  • fMRI data were collected using distributed multicenter data collection.
  • Offset data were obtained using two single-value scoring methods, FADE and SAME.
  • The fMRI data was preprocessed to ensure the scientific validity of the analysis results, including consistent MRI acquisition parameters, as detailed in the table attached to this paper.

Results

  1. fMRI Results:

Novelty and Memory Contrasts were significantly affected, primarily involving brain regions critical in visual episodic memory formation, including the hippocampus, precuneus, and temporo-parietal junction (TPJ).

  1. Score Differences:

    • FADE and SAME scores showed certain regular differences across different participant groups.
    • Comparing young, healthy elderly, and AD subjects, FADE scores showed a progressively increasing trend, while SAME scores gradually decreased. This trend is closely related to the disease progression stage.

  2. Correlation with Cognitive-Related Indicators:

After controlling for diagnostic status, FADE and SAME scores correlated with these indicators. For example, memory performance during fMRI tasks was significantly correlated with both scores.

  1. Impact of APOE Genotypes:

In AD relatives, significant differences were observed in FADE and SAME scores between APOE ε4 carriers.

  1. Amyloid Positivity Correlation with FADE and SAME:

A significant association was seen between increased FADE scores and decreased values in first-degree relatives of AD patients and SCD subjects (compared to the control group).

Conclusion

The study found that FADE and SAME scores could reflect disease severity to some extent and may serve as potential diagnostic and predictive biomarkers. Especially among those with SCD or first-degree relatives of AD patients, the association of FADE and SAME with amyloid positivity and the APOE genotype provides comprehensive references for predicting AD risk.