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Biological substrates of cortical atrophy in prodromal AD: A CSF proteomic study
Author(s) -
Ekblad Laura L.,
Visser Pieter Jelle,
Tijms Betty M.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.042894
Subject(s) - atrophy , neuroscience , cerebrospinal fluid , pathology , amyloid (mycology) , psychology , biology , medicine
Background Brain atrophy is a characteristic feature of Alzheimer´s disease (AD). Atrophy typically begins in the medial temporal regions and is closely related to cognitive decline. The biological processes that associate with or possibly lead to regional cerebral atrophy are largely unexplored. We used a cerebrospinal fluid (CSF) proteomic approach to study which biological processes are associated with cortical atrophy in prodromal AD. Method Prodromal AD individuals based on abnormal CSF beta‐amyloid were selected from ADNI when they had structural MRI and CSF proteomic data (measured with MRM and RBM). Correlations between 217 CSF proteins and cortical thickness of 34 cortical regions (averaged over the left and right hemispheres) were analyzed with linear models. We used hierarchical clustering to identify clusters of brain regions that showed similar CSF protein correlations. ClueGO enrichment analysis was used to identify biological processes associated with proteins that correlated with atrophy. Result We included 104 individuals (37.5% female; mean age 74.5±7.2 years). In total 150 proteins showed associations with cortical thickness in at least one brain region (p<0.05). We identified 4 clusters of brain regions that showed similar proteomic correlations with atrophy (Figure 1). Cluster 1 included the medial temporal, medial orbitofrontal and superior temporal regions. In these regions thinner cortex was associated with lower levels of proteins involved in the beta‐amyloid metabolic process and synaptic plasticity. Cluster 2 included dorsolateral frontal regions and the isthmus cingulate, and lower cortical thickness was associated with higher levels of proteins that reflect inflammatory processes and blood‐brain barrier disruption (Dayon et al. J Proteome Res. 2019;18:1162‐1174). Cluster 3 included the precuneus, superior and caudal middle frontal and superior parietal regions and the paracentral and postcentral gyri. Cortical thinning in Cluster 3 was associated with higher levels of proteins that associated with embryogenic hemopoiesis. Cluster 4 included regions in which thinning was not associated with CSF proteins. Conclusion In prodromal AD, regional cortical atrophy is associated with disruptions in distinct biological processes depending on the region involved. This suggests that treatment may need to consider a combination of targets in order to prevent atrophy, and eventually cognitive decline.