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DIA analysis from a large scale patient cohort for Cerebrospinal Fluid Biomarker Discovery in Alzheimer Disease

ABSTRACT: Diagnosis of Alzheimer disease (AD) primarily relies on cognitive assessments combined with imaging and cerebrospinal fluid (CSF) biomarkers of amyloid and tau proteins. These biomarkers correlate well with levels of neuropathology, but may be inadequate predictors of cognitive trajectory or treatment response to novel therapeutics. Analysis of larger sets of biomarkers together could improve the diagnosis and prognosis of AD, examine the interaction with and differentiate between comorbid pathophysiologies, and measure treatment efficacy. Here, we report data from a Data-independent Acquisition (DIA) analysis used to simultaneously quantify hundreds of proteins in a large-scale patient cohort from a neurology clinic, all of whom had clinical indication for diagnostic lumbar puncture. We aim to define markers that can stratify and diagnose AD in this clinically-complex cohort. Samples from 408 patients were collected from the clinic according to standardized collection and processing protocols. Samples were prepared in 21 different batches of 24 (23 samples plus one common pool) and analyzed by LC-MS/MS on an Orbitrap Fusion using a DIA method with non-overlapping 25m/z windows from 400-1000 m/z, with a resolution of 120K for MS1 and 60K for MS2. Each sample was injected in duplicate with 4 column washes between each sample. All samples from each batch were run sequentially, with multiples days separating each batch.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven Arnold Becky Carlyle

PROVIDER: MSV000092241 | MassIVE | Thu Jun 22 14:18:00 BST 2023

SECONDARY ACCESSION(S): PXD043216

REPOSITORIES: MassIVE

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Project description:Unravel the mechanisms underlying brain aging and Alzheimer´s disease (AD) has been difficult because of complexity of the networks that drive these aging-related changes. Analysis of the gene expression in the brain is a valuable tool to study the function of the brain under normal and pathological conditions. Gene microarray technology allows massively parallel analysis of most genes expressed in a tissue, and therefore is an important research tool that potentially can provide the investigative power needed to address the complexity of brain aging and neurodegenerative processes. One of the reasons that account for the resistance of AD pathogenesis to analysis is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging or AD. Here, we analyzed hippocampal and cortex frontal gene expression from 32 subjects separated in individuals presenting, 1) both pathologic and clinical AD (definitive AD); 2) AD pathology and normal clinic (pathologic AD); 3) cognitive impairment, without AD pathology (others dementias); and 4) no cognitive impairment, without AD pathology (normal individuals). Our results show that based on gene expression profile these individuals we could verify similarity between the definitive AD group and the group that only had AD-type pathology (pathologic AD). Specimens of hippocampus and cortex frontal used in this study were obtained at autopsy from 32 subjects. Neuropathology, specifically NFT and NP, was assessed in accordance to the Braak staging and CERAD scores, respectively. Based on pathologic and clinic criteria, subjects were categorized into four groups: 1) nine subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) presenting cognitive impairment (CDR ≥ 1), termed “definitive AD” (dAD); 2) five subjects with AD neuropathologic (Braak = IV / V / VI and CERAD ≠ 0) and without cognitive impairment (CDR = 0), termed “pathologic AD” (pAD); 3) nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) presenting cognitive impairment (CDR ≥ 1), termed “other dementias” (OD); 4) - nine subjects without AD neuropathologic (Braak = 0 / I / II and CERAD ≠ C) and without cognitive impairment (CDR = 0), termed “normal” (N). RNA isolation and Amplification. From total RNA, a two-round linear amplification procedure (T7-based protocol) was carried out for all samples and for a pool of RNAs obtained from 15 distinct human cell lines used as reference. Labeled cDNA was generated in a reverse transcriptase reaction using amplified RNA (aRNA). Equal amounts of test and reference cDNA reverse color Cy-labeled aRNA targets were competitively hybridized against the cDNA probes in a customized cDNA platform with 4,608 ORESTES representing human genes. Dye-swap was performed for each sample as control for dye bias and used as replicate.

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DIA analysis from a large scale patient cohort for Cerebrospinal Fluid Biomarker Discovery in Alzheimer Disease

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