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P2‐383: Gene expression correlates of hippocampal atrophy across in cognitively normal elderly and MCI
Author(s) -
Apostolova Liana G.,
Hwang Kristy S.,
Lee Jason J.,
Gao Fuying,
Thompson Paul M.,
Ringman John,
Cummings Jeffrey L.
Publication year - 2010
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 - 10.1016/j.jalz.2010.05.1435
Subject(s) - amyotrophic lateral sclerosis , atrophy , tardbp , hippocampal formation , gene expression , refseq , bioconductor , hippocampal sclerosis , dementia , gene , genome wide association study , biology , neuroscience , genetics , medicine , disease , pathology , frontotemporal dementia , single nucleotide polymorphism , genome , genotype , temporal lobe , epilepsy
Background: Human genome-wide gene expression studies have generated important knowledge about the unique influences of multiple genes in health and disease. The complex interactions between gene expression and structural changes observed in Alzheimer’s disease (AD) and the at-risk state of mild cognitive impairment (MCI) may yield important insights about genetic influences on the pathogenesis of AD. Methods: We collected peripheral blood and 3D MPRAGE T1-weighted MRI data in 40 cognitively normal (NC), 19 nonamnestic and 22 amnestic MCI subjects. Peripheral blood RNA was extracted using Paxgene tubes, amplified, labeled, and hybridized onto Illumina Human RefSeq-8 BeadChip arrays, querying the expression of w22,000 RefSeq curated transcripts followed by quality control, and quantile normalization with R and Bioconductor packages. Hippocampi were segmented with novel automated segmentation technique and further analyzed with the radial distance approach. We applied linear regression models to study the relationship between log2-transformed absolute gene expression levels and hippocampal radial distance while adjusting for age and sex. For multiple comparison correction we used permutation tests with a threshold of p < 0.01. Results: We found significant associations between hippocampal atrophy and higher expression levels for two genes that are known to play a role in degradation of misfolded proteins including Abeta PARK2 and DNAJC12. Elevated expression of IL1RAPL2 a gene associated with inflammatory response, as well as ALS2CR11 and HAP1 that have been linked with two other neurodegenerative disorders amyotrophic lateral sclerosis and Huntington’s disease, respectively likewise showed significant correlation with hippocampal atrophy. Several genes known for their role in neuronal survival, axonoand synaptogenesis GH1, SYN1 and CNTN2 were significantly upregulated in subjects with hippocampal atrophy. Conclusions: Our data suggests that neurodegenerative neuronal and synaptic loss leads to over-expression of genes associated with neuronal and synaptic survival in MCI. The presence of toxic misfolded proteins such as Abeta likely triggers over-expression of genes involved in the degradation of misfolded proteins through the ubiquitin-proteasome and the chaperone-endoplasmic reticulum pathways. Over-expression of genes associated with other neurodegenerative disorders suggests that some pathophysiologic events may be shared across the neurodegenerative spectrum. Peripheral blood gene expression shows promise as a biomarker for neurodegenerative disorders. P2-384 DIFFUSION TENSOR IMAGING CAN DIFFERENTIATE HUMAN ALZHEIMER BRAIN FROM NORMAL BRAIN