In-depth Analysis of Cholesterol Metabolism and Related Biomarkers in the Pathogenesis and Progression of the Disease in Neurodegenerative Dementias

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

80 participants

Study Classification

OBSERVATIONAL

Study Start Date

2023-06-05

Study Completion Date

2027-04-29

Brief Summary

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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) in patients with different neurodegenerative dementias, AD, frontotemporal dementia (FTD) and primary tauopathies. This will allow establishing whether their modifications correlate primarily with Aß deposition, tauopathy or neuronal loss with the aim of finding a correlation with the severity and progression of the disease.

Since preliminary results suggest that the levels of most oxysterols in the brain significantly increase in parallel with the levels of the enzyme PCSK9, we will explore the role of cholesterol metabolism and PCSK9 in AD and other dementias to evaluate if cholesterol dysregulation represents a common alteration in these neurodegenerative disorders or is specific for AD.

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Detailed Description

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The project is a monocentric retrospective and prospective low-intervention clinical study. All the samples collected will be sent for all 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.

1. Selection and characterization of post-mortem brains 20 brains from AD (ranging from Braak stage II to VI of neurofibrillary pathology severity), 10 brains from FTD/tauopathies patients as well as 6 brains from FTD/TDP43 patients will be included in the study and are already available for the project and neuropathologically characterized by Neurology 5 - Neuropathology Unit.
2. Recruitment and follow-up of patients with neurodegenerative dementias Retrospective study We will use samples (CSF and plasma) already collected from patients from Neurology 5-Neuropathology Unit over years. We will include 40 AD, 40 FTD and 20 age-matched non demented controls. Clinical and MRI data will be retrospectively collected as well as the levels of markers of neurodegeneration (tau, Abeta42 and phospho-tau) on CSF.

Longitudinal study During the first 18 months of the project, we will recruit 30 AD patients, 20 FTD patients and 10 patients with primary tauopathies (PSP/CBD). A group of 20 age-matched healthy subjects will be enrolled 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 in controls and patients at baseline and follow-up. The measurement of BMI, total cholesterol, LDL and HDL-cholesterol and triglycerides will be performed at baseline and at follow-up in all subjects. ApoE genotype will be analysed for all subjects to determine E2, E3, E4 polymorphisms. MRI will be performed on a 3T MRI, with volumetric T1, FLAIR, T2 and DWI and DTI sequences at baseline and follow-up.
3. Study of the role of the enzyme PCSK9 in the brain (this part will be 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.

Conditions

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Dementias Neurodegenerative Dementia

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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AD

Patient with Alzheimer's disease

No interventions assigned to this group

FTD

Patient wirh Frontotemporal dementia

No interventions assigned to this group

PSP/CBD

Patient with tauopathy

No interventions assigned to this group

CN

Controll subjects

No interventions assigned to this group

Eligibility Criteria

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Inclusion Criteria

* 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.