Leveraging myelin-sensitive imaging to predict early lesion pathogenesis in cerebral adrenoleukodystrophy
利用髓磷脂敏感成像预测脑肾上腺脑白质营养不良的早期病变发病机制
基本信息
- 批准号:10301855
- 负责人:
- 金额:$ 19.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:18 year oldAddressAdolescentAdrenoleukodystrophyAffectAgeAnisotropyAppearanceArchitectureAutopsyBiologyBiometryBrainCerebrumCessation of lifeChildChildhoodConsensusCorpus CallosumDataDemyelinating DiseasesDemyelinationsDevelopmentDiffuseDiffusionDiseaseDisease ProgressionEarly DiagnosisEarly InterventionEarly identificationEncephalitisFiberFunctional disorderGeneral HospitalsGenesGeneticGoalsGrowthHematopoietic Stem Cell TransplantationHistologicHistopathologyImageImage AnalysisImaging TechniquesIncidenceIndividualInflammatoryInjuryInstitutionInvestigationLeadLesionLipidsLiteratureMagnetic Resonance ImagingMassachusettsMeasurementMeasuresMentorsMentorshipMinorityModalityModelingMonitorMorbidity - disease rateMutationMyelinNeonatal ScreeningNerve DegenerationNeurocognitive DeficitNeurologicNeurologic SymptomsNeurological outcomePathogenesisPathologicPatient CarePatientsPrevention strategyProceduresProcessPublishingResearch PersonnelSiteStructural defectStructureTechniquesTestingTimeTrainingTranslatingVegetative StatesVery Long Chain Fatty AcidWaterWhite Matter DiseaseWorkbasebiomarker developmentboyscareer developmentclinical applicationextracellularimaging biomarkerin vivoinfancyinter-institutionalleukodystrophylongitudinal analysismedical schoolsnervous system disorderneurogeneticsneuroimagingpediatric patientspost-transplantskillswhite matter
项目摘要
ABSTRACT
X-linked Adrenoleukodystrophy (ALD) is a devastating neurological disorder caused by mutations in the
ABCD1 gene. The estimated incidence of disease is 1/17,000, however the recent institution of newborn
screening has revealed significantly higher rates. The majority of patients will develop cerebral ALD (CALD),
with the highest incidence occurring in childhood. Most patients undergo inflammatory demyelination followed
by neurodegeneration and death in 2 to 3 years. Hematopoietic Stem Cell Transplant (HSCT) is most effective
when initiated in the narrow window prior to the onset of neurological symptoms. There is an explicitly stated
need for more sensitive measures to detect lesion onset and progression. Early diagnosis of CALD will widen
the treatment window, provide lead-time for possible preventative strategies, and thereby help maximize
neurological outcomes. Decreased overall lipid content, increase in myelin very long chain fatty acid lipid
fractions, and decrease in myelin water content are the earliest pathological changes in CALD, prior to
demyelination. Diffusion Tensor (DTI) and Myelin Water Fraction (MWF) Imaging are advanced, in vivo
modalities specific to local fiber architecture and myelin water content. Dr. Mallack hypothesizes that
abnormal microstructural changes in early CALD during myelin development can be detected by DTI
and MWF prior to the onset and/or progression of demyelination. Dr. Mallack will test this hypothesis by
investigating individual white matter tract development (Aim 1), and lesion onset and progression (Aim 2), in
pediatric patients who developed CALD, asymptomatic hemizygotes, and controls. If his hypotheses are
validated by this study, the approach will (1) confirm normal myelin development in patients with CALD, (2)
reframe early CALD as a regional, tract-specific, divergence from the expected white matter tract maturational
curve, (3) provide a sensitive modality for early disease monitoring, and (4) aid in prediction of patients
appropriate for therapy.
By achieving these aims, Dr. Mallack will undergo rich inter-institutional mentorship by Dr. Florian Eichler, a
world expert in the leukodystrophies, at Massachusetts General Hospital and Dr. Sumit Niogi, a leader in
advanced neuroimaging, at Weill Cornell Medical College. Additionally, Dr. Mallack will be guided by a team
with complementary expertise in neurogenetic disorders, advanced imaging biomarker development and
investigation, and biostatistics. In addition to his career development activities, Dr. Mallack's committee of
mentors, collaborators, and advisors will promote his development and transition to an independent
investigator. This will address his goals of (1) using advanced imaging techniques to probe the underlying
biology of genetic white matter disease, and (2) translate cutting-edge image analyses into clinical applications,
thereby advancing the care of patients affected by these devastating disorders.
摘要
X-连锁肾上腺脑白质营养不良(ALD)是一种破坏性的神经系统疾病,
ABCD 1基因。估计发病率为1/17,000,但最近新生儿
筛查显示发病率明显较高。大多数患者会发展为脑ALD(CALD),
儿童期发病率最高。大多数患者发生炎性脱髓鞘,
神经退化和死亡。造血干细胞移植(HSCT)最有效
当在神经症状发作之前的窄窗口内开始时。有一个明确的规定,
需要更敏感的措施来检测病变的发作和进展。CALD的早期诊断将扩大
治疗窗口为可能的预防策略提供了准备时间,从而有助于最大化
神经学结果。总体脂质含量降低,髓鞘极长链脂肪酸脂质增加
髓鞘水含量的减少是CALD最早的病理变化,
脱髓鞘扩散张量(DTI)和髓鞘水分数(MWF)成像是先进的,在体内
局部纤维结构和髓鞘水含量的特定模式。Mallack博士假设
DTI可以检测到早期CALD在髓鞘发育过程中的异常显微结构变化
以及在脱髓鞘发生和/或进展之前的MWF。Mallack博士将测试这个假设,
研究个体白色物质束发育(目标1)和病变发作和进展(目标2),
发生CALD的儿科患者、无症状半合子和对照。如果他的假设是
经本研究验证,该方法将(1)证实CALD患者的髓鞘发育正常,(2)
将早期CALD重新定义为与预期的白色物质道成熟的区域性、特定道的分歧
曲线,(3)为早期疾病监测提供灵敏的模式,(4)有助于预测患者
适合治疗。
通过实现这些目标,Mallack博士将接受Florian Eichler博士的丰富的机构间指导,
马萨诸塞州总医院的世界脑白质营养不良专家Sumit Niogi博士和
高级神经影像学,在威尔康奈尔医学院。此外,马拉克博士将由一个团队
在神经遗传性疾病、先进的成像生物标志物开发和
调查和生物统计学。除了他的职业发展活动,Mallack博士的委员会
导师,合作者和顾问将促进他的发展和过渡到独立的
调查员这将解决他的目标(1)使用先进的成像技术来探测潜在的
遗传性白色疾病的生物学,以及(2)将尖端图像分析转化为临床应用,
从而促进对受这些破坏性疾病影响的患者的护理。
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)
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Eric Mallack的其他文献
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{{ truncateString('Eric Mallack', 18)}}的其他基金
Leveraging myelin-sensitive imaging to predict early lesion pathogenesis in cerebral adrenoleukodystrophy
利用髓磷脂敏感成像预测脑肾上腺脑白质营养不良的早期病变发病机制
- 批准号:
10649537 - 财政年份:2021
- 资助金额:
$ 19.6万 - 项目类别:
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