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Advanced MRI biomarkers in HD mouse models translatable to humans: nature history and response to therapeutics

HD 小鼠模型中的先进 MRI 生物标志物可转化为人类：自然史和对治疗的反应

基本信息

批准号：
10665777
负责人：
Wenzhen Duan
金额：
$ 65万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665777
关键词：
Acceleration Affect Age Atrophic Basal Ganglia Behavior assessment Behavioral Biological Markers Biology Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Brain region CRISPR/Cas technology Cerebrum Clinical Clinical Trials Code Corpus striatum structure Coupled Data Disease Disease Progression Early identification Elements Event Functional Magnetic Resonance Imaging Genes Goals Human Huntington Disease Huntington gene Impairment Inherited Knock-in Mouse Length Lymphatic Magnetic Resonance Imaging Measures Mediating Metabolic Metabolism Monitor Motor Movement Disorders Mus Nature Neurodegenerative Disorders Outcome Outcome Measure Oxygen Pathogenicity Patients Phase Photic Stimulation Recording of previous events Relaxation Reporting Signal Transduction Symptoms System Techniques Testing Therapeutic Time Treatment Efficacy Treatment Protocols biomarker identification blood-brain barrier permeabilization brain metabolism brain volume cerebral atrophy cerebral blood volume cerebrovascular clinical diagnosis detection method early detection biomarkers effectiveness evaluation gain of function gene therapy glymphatic dysfunction glymphatic function glymphatic system indexing lymph flow lymphatic drainage lymphatic vessel magnetic resonance imaging biomarker metabolic rate motor symptom mouse model multimodality mutant neuropathology neurovascular neurovascular unit novel preclinical study prevent protein aggregation response treatment effect treatment response wasting

项目摘要

Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. HD preferentially involves the basal ganglia- especially the striatum- but also affects other brain regions and has no cure or disease-modifying treatment yet. Because of its gain-of- function mechanism, strategies to lower mutant HTT are promising as first-ever disease-modifying therapies. Most approaches are currently targeted at manifest HD when clinical outcomes can be used to evaluate the effectiveness. However, as almost 50% of striatal volume has been lost at the time of onset, it would be preferable to begin treatment in the premanifest period before massive loss of striatal volumes. An unmet challenge is how to reliably evaluate therapeutic efficacy in the absence of clinical symptoms as outcome measures. The clinical diagnosis of HD is based on the presence of movement disorders. However, functional changes in the brain can precede motor onset by many years. Neurovascular abnormalities have been reported in premanifest and early HD by us and others. We have reported significantly altered arteriolar CBV (CBVa) in premanifest HD brains, when striatal atrophy was undetectable. We recently found that altered CBVa occurred prior to striatal atrophy in an HD mouse model and that CRISPR/Cas9-mediated mHTT lowering restored CBVa in premanifest HD mice. Collectively, these data suggest reliable measures of neurovascular changes might be valuable biomarkers in premanifest HD. CBV is strongly coupled with brain metabolism, and cerebral metabolic abnormalities are increasingly considered as early neuropathological events in HD. We found impaired response of cerebral metabolism to visual stimulation in premanifest HD patients, correlating with the CAG-Age product (CAP) score, supporting that metabolic disturbances occur at early pathogenic stage and may be another early biomarker for HD. In addition, the recent (re)discovery of brain lymphatic vessels and CSF-lymphatic drainage system illustrates an important brain waste clearance system. Our preliminary data implicate that impairment of elements of this system precedes striatal atrophy and mHTT aggregation in HD mice. The objective of this project is to identify early brain functional changes that rapidly respond to treatment in HD preclinical study by incorporating multimodal advanced MRI measures and to develop sensitive biomarkers translatable to HD clinical trials, particularly in the premanifest period. Aim 1. We will test the hypothesis that mutant HTT impairs cerebral metabolism and alters neurovascular responsivity prior to brain atrophy and behavioral deficits in HD mice. Aim 2. We will assess glymphatic function by measuring lymphatic flow dynamics and BBB permeability in HD mice. Aim 3. We will determine the extent to which metabolic, vascular, and lymphatic MRI measures can monitor the effects of premanifest and manifest treatment of HD mice with CRISPR/Cas9-mediated HTT lowering.

亨廷顿氏病（HD）是一种主要由CAG引起的遗传性致命神经退行性疾病