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Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associated brain alterations in TDP-43 proteinopathies. Cortical thickness (CT) and perfusion measurements were obtained in ALS (N = 18), pathologically and/or genetically confirmed bvFTD-TDP (N = 12), and healthy controls (N = 33). bvFTD showed reduced frontotemporal CT, hypoperfusion encompassing orbitofrontal and temporal cortices, and hyperperfusion in motor and occipital regions. ALS did not show reduced CT, but exhibited hypoperfusion in motor and temporal regions, and hyperperfusion in frontal and occipital cortices. Frontotemporal hypoperfusion and reduced CT correlated with cognitive and behavioral impairments as investigated using Mini-Mental State Examination and Philadelphia Brief Assessment of Cognition in bvFTD, and hypoperfusion in motor regions correlated with motor disability as measured by the ALS Functional Rating Scale-Revised in ALS. Hypoperfusion marked early pathologically involved regions, while hyperperfusion characterized regions of late pathological involvement. Distinct perfusion patterns may provide early markers of pathology distribution in TDP-43 proteinopathies.

SUBMITTER: Ferraro PM

PROVIDER: S-EPMC5993674 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

Ferraro Pilar M PM Jester Charles C Olm Christopher A CA Placek Katerina K Agosta Federica F Elman Lauren L McCluskey Leo L Irwin David J DJ Detre John A JA Filippi Massimo M Grossman Murray M McMillan Corey T CT

Neurobiology of aging 20180417

Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associa ...[more]

PMID: 29751289

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Project description:Importance:Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ?4 allele is strongly associated with ?-amyloid (A?) aggregation and risk of AD, but its association with TDP-43 is unknown. Objective:To determine whether the APOE ?4 allele is a risk factor for TDP-43. Design, Setting, Participants:This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), A? status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage???V). We fit structural equation models to map the association between APOE and TDP-43, A?, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed A?, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Main Outcomes and Measures:Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ?4 allele would be significantly directly and indirectly associated with TDP-43. Results:The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ?4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, A?, and tau, APOE ?4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P?=?.01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n?=?604 [81.8%]; estimate [SE], 0.51 [0.11]; P?<?.001), with a similar trend for those with a low likelihood of having AD (B1; n?=?134 [18.2%]; estimate [SE], 0.54 [0.32]; P?=?.10). We also found an indirect association of APOE ?4 with TDP-43 via A? and tau (estimate [SE], 0.34 [0.06]; P?<?.001), which was similar in magnitude to the direct association and an indirect association of APOE ?4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P?=?.01). Conclusions and Relevance:The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ?4 allele appears to be a risk factor for TDP-43 independently of A? in patients with AD.

Dataset Information

Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

Publications

Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

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