Ex Vivo Imaging of the Aging Brain to Discover Morphology/Pathology Associations
衰老大脑的离体成像以发现形态学/病理学关联
基本信息
- 批准号:10608603
- 负责人:
- 金额:$ 207.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-Dimensional3D PrintAddressAlgorithmsAlzheimer associated neurodegenerationAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAmyloidAmyloid beta-ProteinAtlasesAtrophicAutopsyBenefits and RisksBiological MarkersBloodBlood VesselsBrainBrain imagingBrain regionCardiovascular DiseasesCerebral hemisphereCerebral small vessel diseaseChemicalsClinicalClinical TrialsCognitiveDataData SetDementiaDepositionDetectionDevelopmentDiagnosisDiseaseDisease MarkerDisease ProgressionFutureGrantHeterogeneityHistologicHistologyHistopathologyHumanImageImage AnalysisImpaired cognitionIndividualInfarctionKnowledgeLesionLinkLiteratureLocationMagnetic Resonance ImagingMapsMeasuresMedialMethodsMicrovascular DysfunctionMoldsMolecular AbnormalityMorphologyNerve DegenerationNeurofibrillary TanglesNeurologistNeuronsParticipantPathologicPathologyPatternPennsylvaniaPositron-Emission TomographyResearchResolutionScanningSlideSpecimenStructureSurfaceTauopathiesTechniquesTemporal LobeTestingTherapeuticThickThinnessTimeTracerTranslatingUniversitiesWhite Matter HyperintensityWorkaging brainalpha synucleinautomated segmentationbrain cellbrain magnetic resonance imagingcerebral atrophyclinical practicecohortdeep learningdensityex vivo imaginggray matterhippocampal atrophyhistological imagehuman imagingimaging biomarkerimprovedin vivoin vivo imagingindividual patientmagnetic resonance imaging biomarkermorphometrymultimodalityneuron lossneuropathologynovelopen source toolprospectiveprotein TDP-43successtau Proteinstau aggregationtooltreatment responsetwo-dimensionalvascular risk factorwhite matter
项目摘要
Alzheimer's disease (AD) is associated with surprisingly high degree of pathologic heterogeneity. In most
individuals diagnosed with AD at autopsy, the brain not only harbors the β-amyloid and tau pathologies that are
the hallmarks of AD, but also one or more co-pathologies, including TDP-43, α-synuclein, non-AD tauopathy,
and cerebral small vessel disease (SVD). The primary AD pathologies and co-pathologies all contribute to
neurodegeneration in AD, but their relative contribution in different brain regions and the degree in which co-
pathologies modulate the progression of primary pathologies is not well understood. It is widely recognized that
it is important for clinical trials in AD to account for these additional drivers of neurodegeneration, but there is a
lack of in vivo biomarkers that can reliably detect and quantify co-pathology. Pathologic heterogeneity may help
explain why AD treatments targeting a single pathological mechanism have been largely ineffective.
This project seeks to address this limitation by using ex vivo human brain MRI to characterize the contributions
of primary AD pathologies and co-pathologies to neuronal loss and cortical thinning in AD. The project leverages
a prospective dataset from 100-120 autopsies conducted at the University of Pennsylvania AD Research Center
that will include high-resolution 7 Tesla MRI of intact brain hemispheres with co-registered histology at selected
gray matter locations and around white matter lesions. Moreover, the temporal lobe, part of the brain where
earliest and most severe AD-related neurodegeneration occurs, will be scanned at 9.4 Tesla, and undergo serial
histological imaging, allowing three-dimensional mapping of tau pathology (tangles, threads, etc.) and neuronal
density across the entire temporal lobe. This unique ex vivo imaging dataset will represent a convergence of
structural and pathological imaging data in the same 3D space, allowing a broad range of studies analyzing
trajectories of pathology deposition and pathology-neurodegeneration relationships. The specific aims of the
proposal are as follows. Aim 1 is to develop deep learning-based image analysis techniques for 7 Tesla whole-
hemisphere MRI, which are currently lacking, including segmentation of cortical gray matter, white matter lesions,
normal-appearing white matter, and subcortical structures; groupwise registration to both ex vivo and in vivo MRI
templates; and extraction of both MRI-based and histological features to characterize white matter lesions
associated with SVD. Aim 2 is to analyze the complete 100-120 specimen dataset to characterize the distribution
of tau pathology, neuronal loss, and cortical thinning both in the temporal lobe and in the whole brain and to
describe the impact of co-pathologies on these distributions and on the relationships between them. Aim 3 is to
leverage pathology-specific “signatures” extracted from analyzing this ex vivo dataset to improve the sensitivity
of in vivo biomarkers for inferring the presence of co-pathology and tracking disease progression.
阿尔茨海默氏病(AD)与令人惊讶的高度病理异质性相关。在大多数
在尸检中被诊断患有 AD 的个体中,大脑不仅存在 β-淀粉样蛋白和 tau 蛋白病变,
AD 的标志,还有一种或多种共同病理,包括 TDP-43、α-突触核蛋白、非 AD tau 蛋白病、
和脑小血管疾病(SVD)。主要 AD 病理学和共病理学均有助于
AD 中的神经退行性变,但它们在不同大脑区域的相对贡献以及共同作用的程度
病理学调节原发性病理学的进展尚不清楚。人们普遍认为
对于 AD 的临床试验来说,解释这些神经退行性变的额外驱动因素非常重要,但有一个因素
缺乏能够可靠地检测和量化共病理的体内生物标志物。病理异质性可能有所帮助
解释为什么针对单一病理机制的 AD 治疗基本上无效。
该项目旨在通过使用离体人脑 MRI 来表征贡献来解决这一限制
AD 中的原发性 AD 病理学和神经元损失和皮质变薄的共病理学。该项目利用
宾夕法尼亚大学 AD 研究中心进行的 100-120 例尸检的前瞻性数据集
其中将包括完整大脑半球的高分辨率 7 特斯拉 MRI,并在选定的地点共同注册组织学
灰质位置和白质病变周围。此外,颞叶是大脑的一部分
最早和最严重的 AD 相关神经变性发生,将以 9.4 特斯拉进行扫描,并进行系列治疗
组织学成像,可对 tau 病理学(缠结、线状等)和神经元进行三维绘图
整个颞叶的密度。这个独特的离体成像数据集将代表
同一 3D 空间中的结构和病理成像数据,允许进行广泛的研究分析
病理沉积轨迹和病理-神经变性关系。该计划的具体目标
建议如下。目标 1 是开发基于深度学习的图像分析技术,用于 7 特斯拉整车
目前缺乏的半球MRI,包括皮质灰质、白质病变的分割,
正常的白质和皮层下结构;离体和体内 MRI 的分组配准
模板;提取基于 MRI 和组织学的特征来表征白质病变
与 SVD 相关。目标 2 是分析完整的 100-120 个样本数据集以表征分布
颞叶和整个大脑中的 tau 蛋白病理学、神经元损失和皮质变薄
描述共同病理对这些分布及其之间关系的影响。目标 3 是
利用从分析该离体数据集中提取的病理特异性“特征”来提高灵敏度
用于推断共同病理的存在和跟踪疾病进展的体内生物标志物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul A. Yushkevich其他文献
Posterior hippocampal sparing in Lewy body disorders with Alzheimer’s copathology: An <em>in vivo</em> MRI study
- DOI:
10.1016/j.nicl.2024.103714 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:
- 作者:
Jesse S. Cohen;Jeffrey Phillips;Sandhitsu R. Das;Christopher A. Olm;Hamsanandini Radhakrishnan;Emma Rhodes;Katheryn A.Q. Cousins;Sharon X. Xie;Ilya M. Nasrallah;Paul A. Yushkevich;David A. Wolk;Edward B. Lee;Daniel Weintraub;David J. Irwin;Corey T. McMillan - 通讯作者:
Corey T. McMillan
Operationalizing postmortem pathology-MRI association studies in Alzheimer’s disease and related disorders with MRI-guided histology sampling
- DOI:
10.1186/s40478-025-02030-y - 发表时间:
2025-05-28 - 期刊:
- 影响因子:5.700
- 作者:
Chinmayee Athalye;Alejandra Bahena;Pulkit Khandelwal;Sheina Emrani;Winifred Trotman;Lisa M. Levorse;Zahra Khodakarami;Daniel T. Ohm;Eric Teunissen-Bermeo;Noah Capp;Shokufeh Sadaghiani;Sanaz Arezoumandan;Sydney A. Lim;Karthik Prabhakaran;Ranjit Ittyerah;John L. Robinson;Theresa Schuck;Edward B. Lee;M. Dylan Tisdall;Sandhitsu R. Das;David A. Wolk;David J. Irwin;Paul A. Yushkevich - 通讯作者:
Paul A. Yushkevich
Correction: Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early Alzheimer’s disease
- DOI:
10.1186/s13195-023-01374-8 - 发表时间:
2024-01-12 - 期刊:
- 影响因子:7.600
- 作者:
Long Xie;Sandhitsu R. Das;Laura E. M. Wisse;Ranjit Ittyerah;Robin de Flores;Leslie M. Shaw;Paul A. Yushkevich;David A. Wolk - 通讯作者:
David A. Wolk
213: Novel 3D morphologic analysis of the early placenta using deformable medial modeling
- DOI:
10.1016/j.ajog.2016.11.118 - 发表时间:
2017-01-01 - 期刊:
- 影响因子:
- 作者:
Alison M. Pouch;Ipek Oguz;Natalie Yushkevich;James C. Gee;Paul A. Yushkevich;Nadav Schwartz - 通讯作者:
Nadav Schwartz
Paul A. Yushkevich的其他文献
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{{ truncateString('Paul A. Yushkevich', 18)}}的其他基金
AD-specific changes in the MTL: Novel biomarkers using in vivo / ex vivo imaging
MTL 中的 AD 特异性变化:使用体内/离体成像的新型生物标志物
- 批准号:
9301869 - 财政年份:2017
- 资助金额:
$ 207.77万 - 项目类别:
AD-specific changes in the MTL: Novel biomarkers using in vivo / ex vivo imaging
MTL 中的 AD 特异性变化:使用体内/离体成像的新型生物标志物
- 批准号:
9927957 - 财政年份:2017
- 资助金额:
$ 207.77万 - 项目类别:
Adaptive Large-Scale Framework for Automatic Biomedical Image Segmentation
自动生物医学图像分割的自适应大规模框架
- 批准号:
9350173 - 财政年份:2014
- 资助金额:
$ 207.77万 - 项目类别:
Adaptive Large-Scale Framework for Automatic Biomedical Image Segmentation
自动生物医学图像分割的自适应大规模框架
- 批准号:
8761531 - 财政年份:2014
- 资助金额:
$ 207.77万 - 项目类别:
Adaptive Large-Scale Framework for Automatic Biomedical Image Segmentation
自动生物医学图像分割的自适应大规模框架
- 批准号:
9119513 - 财政年份:2014
- 资助金额:
$ 207.77万 - 项目类别:
Continued Development and Maintenance of ITK-SNAP 3D Image Segmentation Software
ITK-SNAP 3D 图像分割软件的持续开发和维护
- 批准号:
8333255 - 财政年份:2011
- 资助金额:
$ 207.77万 - 项目类别:
Continued Development and Maintenance of ITK-SNAP 3D Image Segmentation Software
ITK-SNAP 3D 图像分割软件的持续开发和维护
- 批准号:
8531010 - 财政年份:2011
- 资助金额:
$ 207.77万 - 项目类别:
Continued Development and Maintenance of ITK-SNAP 3D Image Segmentation Software
ITK-SNAP 3D 图像分割软件的持续开发和维护
- 批准号:
8725972 - 财政年份:2011
- 资助金额:
$ 207.77万 - 项目类别:
Continued Development and Maintenance of ITK-SNAP 3D Image Segmentation Software
ITK-SNAP 3D 图像分割软件的持续开发和维护
- 批准号:
8222185 - 财政年份:2011
- 资助金额:
$ 207.77万 - 项目类别:
Novel Imaging Biomarkers for Treatment Evaluation in Neurodegenerative Disorders
用于神经退行性疾病治疗评估的新型成像生物标志物
- 批准号:
8454486 - 财政年份:2010
- 资助金额:
$ 207.77万 - 项目类别:
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