Abstract
The extracellular RNAs (exRNAs) from human biofluid have recently been systematically characterized. However, the correlations of biofluid exRNA levels and human diseases remain largely untested. Here, considering the unmet need for presymptomatic biomarkers of sporadic Alzheimer's disease (AD), we leveraged the recently developed SILVER-seq (small-input liquid volume extracellular RNA sequencing) technology to generate exRNA profiles from a longitudinal collection of human plasma samples. These 164 plasma samples were collected from research subjects 70 years or older with up to 15 years of clinical follow-up prior to death and whose clinical diagnoses were confirmed by pathological analysis of their post mortem brains. The exRNAs of AD-activated genes and transposons in the brain exhibited a concordant trend of increase in AD plasma in comparison with age-matched control plasma. However, when we required statistical significance with multiple testing adjustments, phosphoglycerate dehydrogenase (PHGDH) was the only gene that exhibited consistent upregulation in AD brain transcriptomes from 3 independent cohorts and an increase in AD plasma as compared to controls. We validated PHGDH's serum exRNA and brain protein expression increases in AD by using 5 additional published cohorts. Finally, we compared the time-course exRNA trajectories between "converters" and controls. Plasma PHGDH exRNA exhibited presymptomatic increases in each of the 11 converters during their transitions from normal to cognitive impairment but remained stable over the entire follow-up period in 8 out of the 9 control elderly subjects. These data suggest the potential utilities of plasma exRNA levels for screening and longitudinal exRNA changes as a presymptomatic indication of sporadic AD.
Highlights
A 15-Year Follow-Up Study of Sporadic Alzheimer’s disease (AD) In order to generate longitudinal data on sporadic AD, we selected archived plasma samples from research subjects being followed at the University of California, San Diego (UCSD) ShileyMarcos Alzheimer’s Disease Research Center during a 15-year period from 2000 to 2014
The criteria were subjects older than 70 years of age who were examined post mortem to confirm the clinical diagnosis of AD; had multiple longitudinal blood samples spanning at least 5 years; and, in cases who transitioned from normal cognitive status to mild cognitive impairment (MCI) or dementia during the course of the study, provided samples prior to the change in cognitive status
There were 15 subjects who were clinically diagnosed as probable AD when they first enrolled, and their post mortem examinations were consistent with a pathological diagnosis of AD with Braak stages 4–6
Summary
METHOD DETAILSSILVER-seq analysis of human plasma samples Thawed plasma was aliquoted into 5 ml per sample and was subjected to SILVER-seq [11]. Retrieving the summary of tissue-specific expression from GTEx We retrieved the GTEx consortium’s summary table of tissue specific expression [52] This summary table was based on GTEx consortium’s definition of tissue-specific score (TS_Score), recommended threshold (TS_Score > 3), and GTEx V6p data release that included 8,527 samples from 13 brain regions and 36 other tissues [52]. Based on this summary table, we retrieved 1,514 brain-specific genes with TS_Score > 3 in at least one brain region and TS_Score % 3 in all peripheral tissues. Our stronger criteria for defining brain specific expression are: TS_Score > 3 in at least one brain region, and TS_Score % 3 in all peripheral tissues, and the average TPM of the 13 brain regions > 0.1, and the maximum TPM of the 41 peripheral tissues < 0.1
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