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Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases.

ABSTRACT: INTRODUCTION:Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways. METHODS:We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects. RESULTS:We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples. DISCUSSION:Downregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these networks.

SUBMITTER: Allen M

PROVIDER: S-EPMC5866744 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases.

Allen Mariet M Wang Xue X Burgess Jeremy D JD Watzlawik Jens J Serie Daniel J DJ Younkin Curtis S CS Nguyen Thuy T Malphrus Kimberly G KG Lincoln Sarah S Carrasquillo Minerva M MM Ho Charlotte C Chakrabarty Paramita P Strickland Samantha S Murray Melissa E ME Swarup Vivek V Geschwind Daniel H DH Seyfried Nicholas T NT Dammer Eric B EB Lah James J JJ Levey Allan I AI Golde Todd E TE Funk Cory C Li Hongdong H Price Nathan D ND Petersen Ronald C RC Graff-Radford Neill R NR Younkin Steven G SG Dickson Dennis W DW Crook Julia R JR Asmann Yan W YW Ertekin-Taner Nilüfer N

Alzheimer's & dementia : the journal of the Alzheimer's Association 20171031 3

<h4>Introduction</h4>Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways.<h4>Methods</h4>We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects.<h4>Results</h4>We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD ...[more]

PMID: 29107053

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Project description:BackgroundAlzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions.PurposeTo evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow).Study typeProspective cross-sectional.PopulationSixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects.Field strength/sequence3T T2 -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR).AssessmentOEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed.Statistical testsMultiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology.ResultsWhen evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (β = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (β = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (β = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (β = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (β = 2.19 ± 0.71, T = 3.08, P = 0.004).Data conclusionThese findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment.Level of evidence1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.

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Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases.

Publications

Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases.

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