In-depth Analysis of Cholesterol Metabolism and Related Biomarkers in the Pathogenesis and Progression of the Disease in Neurodegenerative Dementias
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- Characterize differences in cholesterol precursors
研究概览
简要总结
The aim of the study is to evaluate the role of cholesterol in the pathogenesis of neurodegenerative dementias. Hypercholesterolemia is a known risk factor for Alzheimer disease (AD), and oxysterols, the principal cholesterol metabolites, are involved in neuroinflammation, amyloid aggregation, and tau accumulation.
Oxysterols will be measured in different biological samples (post-mortem brain tissue, CSF, and plasma) from patients with different neurodegenerative dementias, including AD, frontotemporal dementia (FTD), and primary tauopathies. This approach will allow determination of whether their modifications correlate primarily with Aß deposition, tauopathy, or neuronal loss, with the goal of identifying correlations with disease severity and progression.
Since preliminary results suggest that the levels of most oxysterols in the brain significantly increase in parallel with the levels of the enzyme PCSK9, the investigators will explore the role of cholesterol metabolism and PCSK9 in AD and other dementias to evaluate whether cholesterol dysregulation represents a common alteration across these neurodegenerative disorders or is specific to AD
详细描述
The project is a monocentric retrospective and prospective low-intervention clinical study. All samples collected will be sent for analysis to the Laboratory of General Pathology and Pathophysiology, Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga Hospital, Orbassano (TO), Italy.
- Selection and characterization of post-mortem brains Twenty brains from patients with AD (ranging from Braak stage II to VI of neurofibrillary pathology severity), ten brains from patients with FTD/tauopathies, and six brains from FTD/TDP43 patients will be included in the study. These samples are already available for the project and have been neuropathologically characterized by Neurology 5 - Neuropathology Unit.
- Recruitment and follow-up of patients with neurodegenerative dementias
Retrospective study Samples (CSF and plasma) previously collected from patients at Neurology 5 - Neuropathology Unit over the years will be used. The study will include 40 AD patients, 40 FTD patients, and 20 age-matched non-demented controls. Clinical and MRI data will be retrospectively collected, as well as levels of markers of neurodegeneration (tau, Abeta42, and phospho-tau) in CSF.
Longitudinal study During the first 18 months of the project, 30 AD patients, 20 FTD patients, and 10 patients with primary tauopathies (PSP/CBD) will be recruited. A group of 20 age-matched healthy subjects will serve as controls. All patients and controls will undergo a comprehensive neurologic assessment, a neuropsychological evaluation, and a brain MRI with a standard protocol at baseline (T0) and after 1 year (T1). CSF collection will be performed at baseline in patients. DNA and plasma will be collected from controls and patients at baseline and follow-up. Measurements of BMI, total cholesterol, LDL and HDL cholesterol, and triglycerides will be performed at baseline and follow-up in all subjects. ApoE genotype will be analyzed for all subjects to determine E2, E3, and E4 polymorphisms. MRI will be performed on a 3T scanner, including volumetric T1, FLAIR, T2, DWI, and DTI sequences at baseline and follow-up. 3. Study of the role of the enzyme PCSK9 in the brain (performed by University of Turin) SK-N-BE cells and mouse-derived primary cortical neurons and astrocytes will be treated with PCSK9 or with an oxysterol mixture obtained from brain dosages.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 40 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age 40-85
- •Diagnosis based on the current diagnostic criteria for AD (McKhann et al., 2011), FTD (Gorno-Tempini et al., 2011; Rascovsky et al., 2011), PSP and CBD (Amstrong et al., 2013; Höglinger et al., 2017)
- •Mini Mental State Examination MMSE > 10.
排除标准
- •Other neurological or psychiatric disorders Severe chronic metabolic diseases
研究组 & 干预措施
AD
Patient with Alzheimer's disease
FTD
Patient wirh Frontotemporal dementia
PSP/CBD
Patient with tauopathy
CN
Controll subjects
结局指标
主要结局
Characterize differences in cholesterol precursors
时间窗: 12 months
To identify and characterize differences in cholesterol precursors and metabolites between patients with neurodegenerative dementias vs controls and between patients with different types of neurodegenerative dementia.
次要结局
- different brain areas(12 months)
- cerebral oxysterol changes in AD(12 months)
- different cholesterol precursors in neurodegenerative diseases examined in CSF and plasma(12 months)
- cortical atrophy(12 months)
- PCSK9(12 months)
- PCSK9 in neurons(12 months)
- potential neurotoxic action of PCSK9(12 months)