Abstract
Mapping the spatiotemporal dynamics of brain atrophy in the Alzheimer’s disease (AD) aids in discovering vulnerable brain networks. Various MRI-derived measures including hippocampal volume sloss are commonly used as imaging biomarkers of AD progression. Multivariate methods such as independent component analysis (ICA) have recently shown promise in revealing more complex patterns of brain atrophy.
Here, we aimed to extract a data-driven signature of brain atrophy in AD and its heralding risk factor, the mild cognitive impairment (MCI) state. Structural brain changes were quantified in 1,892 MRI scans from 1,100 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) by Tensor-Based Morphometry (TBM). Brain morphometry maps of this population were fed into an ICA-based feature extraction algorithm which revealed that AD is associated with a characteristic signature of brain degeneration spanning several areas of the limbic system. The highest probability of brain atrophy in AD was localized to amygdalae (pICA z-score>22), followed by hippocampus (pICA z-score>14), and the mammillary bodies (pICA z-score>9) together with their white-matter connections including fimbrial and fornical tracts as a unified MRI endophenotype. This endophenotype performed better than the hippocampal volume measure in discriminating both AD and MCI subjects from the cognitively normal group, and we evaluated the potential for this feature set to serve as a disease-related endophenotype in a whole-genome association study. A protein-altering polymorphism in the synaptic scaffold gene, SHARPIN, affected loss of volume in this endophenotype among 8,852,807 whole-genome sequencing-based variants (rs34173062; p =2.1×10-10). Other suggestive but subgenome-wide signals mapped to EPHA7 and FRMD4A, two known AD risk loci.
In conclusion, by unsupervised decomposition of brain morphometry maps, we have provided a unified imaging endophenotype of AD that closely maps to the brain’s memory center. Observation of bilateral amygdalae as the most vulnerable limbic structures spotlights impairment of emotional and memory processing integration in early AD.
Footnotes
1 Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
- Abbreviations
- AD
- Alzheimer’s disease
- GWAS
- Genome-wide association study
- ICA
- Independent component analysis
- MCI
- Mild cognitive impairment
- MTC
- Medial temporal circuit
- SNP
- Single-nucleotide polymorphism
- TBM
- Tensor-based morphometry