Identification of a Simple and Novel Cut-Point Based Cerebrospinal Fluid and MRI Signature for Predicting Alzheimer's Disease Progression that Reinforces the 2018 NIA-AA Research Framework

Priya Devanarayan, Viswanath Devanarayan, Daniel Adolfo Llano

Research output: Contribution to journalArticle

Abstract

The 2018 NIA-AA research framework proposes a classification system with Amyloid-β deposition, pathologic Tau, and Neurodegeneration (ATN) for diagnosis and staging of Alzheimer's disease (AD). Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI), and AD subjects followed over a 3-10-year period were measured via multiple reaction monitoring mass spectrometry. CSF Aβ 42, total-Tau (tTau), phosphorylated-Tau (pTau-181), and hippocampal volume were also measured. From these candidate markers, optimal signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ 42 ratio, MRI hippocampal volume, and low CSF levels of a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting these signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used markers, and is easier to use in practice than recently published complex signatures. This signature also reinforces the ATN construct from the 2018 NIA-AA research framework.

Original languageEnglish (US)
Pages (from-to)537-550
Number of pages14
JournalJournal of Alzheimer's Disease
Volume68
Issue number2
DOIs
StatePublished - Jan 1 2019

Fingerprint

Cerebrospinal Fluid
Disease Progression
Alzheimer Disease
Research
Peptides
Amyloid
Neuroimaging
Mass Spectrometry
Multivariate Analysis
Databases
Cognitive Dysfunction

Keywords

  • Biomarker
  • PTPRN
  • mild cognitive impairment
  • receptor-type tyrosine-phosphatase-like N

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

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title = "Identification of a Simple and Novel Cut-Point Based Cerebrospinal Fluid and MRI Signature for Predicting Alzheimer's Disease Progression that Reinforces the 2018 NIA-AA Research Framework",
abstract = "The 2018 NIA-AA research framework proposes a classification system with Amyloid-β deposition, pathologic Tau, and Neurodegeneration (ATN) for diagnosis and staging of Alzheimer's disease (AD). Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI), and AD subjects followed over a 3-10-year period were measured via multiple reaction monitoring mass spectrometry. CSF Aβ 42, total-Tau (tTau), phosphorylated-Tau (pTau-181), and hippocampal volume were also measured. From these candidate markers, optimal signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ 42 ratio, MRI hippocampal volume, and low CSF levels of a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting these signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used markers, and is easier to use in practice than recently published complex signatures. This signature also reinforces the ATN construct from the 2018 NIA-AA research framework.",
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