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Volumetric GWAS of medial temporal lobe structures identifies an ERC1 locus using ADNI high-resolution T2-weighted MRI data.

ABSTRACT: Medial temporal lobe (MTL) consists of hippocampal subfields and neighboring cortices. These heterogeneous structures are differentially involved in memory, cognitive and emotional functions, and present nonuniformly distributed atrophy contributing to cognitive disorders. This study aims to examine how genetics influences Alzheimer's disease (AD) pathogenesis via MTL substructures by analyzing high-resolution magnetic resonance imaging (MRI) data. We performed genome-wide association study to examine the associations between 565,373 single nucleotide polymorphisms (SNPs) and 14 MTL substructure volumes. A novel association with right Brodmann area 36 volume was discovered in an ERC1 SNP (i.e., rs2968869). Further analyses on larger samples found rs2968869 to be associated with gray matter density and glucose metabolism measures in the right hippocampus, and disease status. Tissue-specific transcriptomic analysis identified the minor allele of rs2968869 (rs2968869-C) to be associated with reduced ERC1 expression in the hippocampus. All the findings indicated a protective role of rs2968869-C in AD. We demonstrated the power of high-resolution MRI and the promise of fine-grained MTL substructures for revealing the genetic basis of AD biomarkers.

SUBMITTER: Cong S

PROVIDER: S-EPMC7609616 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Volumetric GWAS of medial temporal lobe structures identifies an ERC1 locus using ADNI high-resolution T2-weighted MRI data.

Cong Shan S Yao Xiaohui X Huang Zhi Z Risacher Shannon L SL Nho Kwangsik K Saykin Andrew J AJ Shen Li L

Neurobiology of aging 20200714

Medial temporal lobe (MTL) consists of hippocampal subfields and neighboring cortices. These heterogeneous structures are differentially involved in memory, cognitive and emotional functions, and present nonuniformly distributed atrophy contributing to cognitive disorders. This study aims to examine how genetics influences Alzheimer's disease (AD) pathogenesis via MTL substructures by analyzing high-resolution magnetic resonance imaging (MRI) data. We performed genome-wide association study to e ...[more]

PMID: 32768867

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Project description:This paper for the 20th anniversary of the Alzheimer's Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high-resolution T2-weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface-based tools to characterize MTL neurodegeneration across biomarker-defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high-resolution imaging of the MTL in ADNI Phase 4. HIGHLIGHTS: As of Phase 3, the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) protocol includes a high-resolution T2-weighted MRI scan optimized for imaging hippocampal subfields and medial temporal lobe (MTL) subregions. These scans are processed by the ADNI core to obtain automatic segmentations of MTL subregions and to derive morphologic measurements. More detailed granular examination of MTL neurodegeneration in response to disease progression is achieved by applying surface-based modeling techniques. Surface-based analysis of gray matter loss in MTL subregions reveals increasing and spatially expanding patterns of neurodegeneration with advancing stages of Alzheimer's disease (AD), as defined based on amyloid and tau positron emission tomography biomarkers in accordance with recently proposed criteria. These patterns closely align with post mortem literature on spread of pathological tau in AD, supporting the role of tau pathology in the presence of elevated levels of amyloid beta as the driver of neurodegeneration.

Project description:ObjectivesA published tumour regression grade (TRG) score for squamous anal carcinoma treated with definitive chemoradiotherapy based on T2-weighted MRI yields a high proportion of indeterminate responses (TRG-3). We investigate whether the addition of diffusion-weighted imaging (DWI) improves tumour response assessment in the early post treatment period.Materials and methodsThis retrospective observational study included squamous anal carcinoma patients undergoing MRI before and within 3 months of completing chemoradiotherapy from 2009 to 2020. Four independent radiologists (1-20 years' experience) scored MRI studies using a 5-point TRG system (1 = complete response; 5 = no response) based on T2-weighted sequences alone, and then after a 12-week washout period, using a 5-point DWI-TRG system based on T2-weighted and DWI. Scoring confidence was recorded on a 5-point scale (1 = low; 5 = high) for each reading and compared using the Wilcoxon test. Indeterminate scores (TRG-3) from each reading session were compared using the McNemar test. Interobserver agreement was assessed using kappa statistics.ResultsEighty-five patients were included (mean age, 59 years ± 12 [SD]; 55 women). T2-weighted TRG-3 scores from all readers combined halved from 24% (82/340) to 12% (41/340) with DWI (p < 0.001). TRG-3 scores changed most frequently (41%, 34/82) to DWI-TRG-2 (excellent response). Complete tumour response was recorded clinically in 77/85 patients (91%). Scoring confidence increased using DWI (p < 0.001), with scores of 4 or 5 in 84% (287/340). Interobserver agreement remained fair to moderate (kappa range, 0.28-0.58).ConclusionDWI complements T2-weighted MRI by reducing the number of indeterminate tumour responses (TRG-3). DWI increases radiologist's scoring confidence.Clinical relevance statementDiffusion-weighted imaging improves T2-weighted tumour response assessment in squamous anal cancer, halving the number of indeterminate responses in the early post treatment period, and increases radiologists' confidence.Key pointsTumour response based on T2-weighted MRI is often indeterminate in squamous anal carcinoma. Diffusion-weighted imaging alongside T2-weighted MRI halved indeterminate tumour regression grade scores assigned by four radiologists from 24 to 12%. Scoring confidence of expert and non-expert radiologists increased with the inclusion of diffusion-weighted imaging.

Dataset Information

Volumetric GWAS of medial temporal lobe structures identifies an ERC1 locus using ADNI high-resolution T2-weighted MRI data.

Publications

Volumetric GWAS of medial temporal lobe structures identifies an ERC1 locus using ADNI high-resolution T2-weighted MRI data.

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