Imaging Iron-Rich Pathology to Monitor and Diagnose FLTD Subtypes

对富铁病理学进行成像以监测和诊断 FLTD 亚型

• 批准号: 10591031
• 负责人: Matthew Dylan Tisdall
• 金额: $ 36.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591031
• 关键词: Address; Advanced Development; Age; Alzheimer' s disease related dementia; Anatomy; Atrophic; Autopsy; Behavior; Biological; Biological Markers; Blood; Brain; Cerebral cortex; Clinical; Collaborations; Dedications; Dementia; Deposition; Detection; Development; Diagnosis; Diagnostic Specificity; Disease; Disease Progression; Exhibits; FDA approved; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Future; Genotype; Gliosis; Goals; Grain; Histology; Histopathology; Human; Image; Individual; Iron; Joints; Laboratories; Language; Language Disorders; Magnetic Resonance Imaging; Maps; Measures; Methods; Monitor; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiologic pulse; Process; Protocols documentation; Recommendation; Research; Resources; Sampling; Severities; Social Impacts; Spatial Distribution; Symptoms; Syndrome; Work; clinical care; diagnostic value; digital; disease diagnosis; disorder subtype; economic impact; gray matter; imaging biomarker; imaging modality; in vivo; motor deficit; motor symptom; mutation carrier; neuroimaging; neuropathology; non-invasive monitor; noninvasive diagnosis; novel; recruit; symposium; targeted imaging; targeted therapy trials; tau Proteins; tool; treatment trial; ultra high resolution; volunteer; white matter

PROJECT SUMMARY Frontotemporal lobar degeneration (FTLD) is a debilitating neurodegenerative disease that in almost all cases has one of two underlying proteinopathies – FTLD-tau and FTLD-TDP. To date MRI-based measures have not been able to reliably distinguish clinical syndromes or their underlying proteinopathies. A key feature of FTLD is the localized pattern of degeneration associated with various disease subtypes. These spatial patterns have been associated with clinical syndromes, as well as the underlying proteinopathies that are most-relevant for treatment studies. However, to date these patterns alone are not sufficiently specific to fully predict syndromes or separate FTLD-tau from FTLD-TDP in a single patient. We have recently shown that, in addition to atrophy, FTLD is associated with iron-rich cortical pathology. Moreover, our findings indicate that the specific cortical layers impacted by this pathology are distinct in FTLD-tau and FTLD-TDP, offering a potential target for the development of imaging biomarkers. We propose to use iron-sensitive MRI as the basis for the development of novel imaging biomarkers, with the aim of both monitoring disease progression and diagnosing underlying pathologic subtypes, addressing a highest priority recommendation of the 2019 ADRD Summit. We propose a two-pronged approach to this goal: First, we will use joint ex vivo MRI and histopathology in 50 human hemispheres, donated by patients with FTLD and typical age-matched controls, to quantify the distributions of iron-rich pathology. In particular, we will quantify both the laminar distribution and its relation to the patients’ underlying proteinopathies. In addition, we will evaluate the distribution of disease across the cortex, and associate this with clinical information collected during the patients’ lifetimes, including clinical syndrome and more fine-grained measures of symptoms. Second, we will use in vivo MRI at 3T and 7T with 100 FTLD patients an typical volunteers to develop and validate imaging protocols sensitive to the pathologic iron. At 3T, we will focus on quantifying the distribution of iron across the cortex. We will correlate these cortical findings with MRI-based measures of atrophy, and clinical measures including both symptoms and blood and CSF-based measures of degeneration and pathology. At 7T, we will develop and validate focal laminar imaging methods, with the aim of recapitulating our ex vivo findings in living patients and age-matched controls. The overall goal of this study is to develop and validate novel, iron-sensitive imaging biomarkers for FTLD to both monitor and diagnose underlying syndromes and pathologies. The ability to disciminate underlying proteinopathies is a key need in treatment trials which focus on either FTLD-tau or FTLD-TDP. Moreover, measuring the quantity and distribution of iron in the brain will also be valuable for monitoring disease progression, both in treatment trials, and more generally for FTLD patients in clinical care.

项目总结 额颞叶变性(FTLD)是一种衰弱的神经退行性疾病，几乎在所有病例中 有两种潜在的蛋白质病之一-FTLD-tau和FTLD-TDP。到目前为止，基于MRI的措施还没有 能够可靠地区分临床症状或其潜在的蛋白质病。FTLD的一个关键特征 是与各种疾病亚型相关的局部退行性变模式。这些空间模式有 与临床症状以及与以下方面最相关的潜在蛋白病变有关 治疗研究。然而，到目前为止，仅靠这些模式还不足以完全预测症状 或在单个患者中分离FTLD-tau和FTLD-TDP。我们最近的研究表明，除了萎缩， FTLD与富含铁的皮质病理有关。此外，我们的发现表明，特定的大脑皮层 受这种病理影响的层在FTLD-tau和FTLD-TDP中是不同的，为 成像生物标记物的发展。 我们建议使用铁敏感的磁共振成像作为开发新的成像生物标记物的基础， 监测疾病进展和诊断潜在病理亚型的目标，解决 2019年亚洲复兴开发银行首脑会议的最优先建议。我们提出了一种双管齐下的方法来实现这一目标： 首先，我们将使用联合体外核磁共振成像和组织病理学在50个人类大脑半球，由患者捐赠 FTLD和典型年龄匹配的对照组，量化富铁病理的分布。特别是，我们将 量化板层分布及其与患者潜在蛋白病变的关系。此外，我们 将评估疾病在大脑皮层的分布，并将其与收集的临床信息联系起来 在患者的一生中，包括临床症状和更细粒度的症状衡量。 其次，我们将使用体内MRI在3T和7T与100名典型的FTLD患者志愿者一起开发和 验证对病理性铁敏感的成像方案。在3T，我们将专注于量化 铁质穿过大脑皮层。我们将把这些皮质发现与基于MRI的萎缩测量相关联，并且 临床措施包括症状和血液两方面，以脑脊液为基础的退行性变和 病理学。在7T，我们将开发和验证焦点层流成像方法，目的是概括我们的 活着的患者和年龄匹配的对照组的体外研究结果。 这项研究的总体目标是开发和验证FTLD的新型铁敏感成像生物标记物 两者都监测和诊断潜在的症状和病理。辨别潜在因素的能力 蛋白质病是关注FTLD-tau或FTLD-TDP的治疗试验中的关键需求。此外， 测量大脑中铁的数量和分布也将对监测疾病有价值。 无论是在治疗试验中，还是在临床护理中，FTLD患者的进展都是如此。