Exploring Brain CSF-Mediated Clearance in Major Depressive Disorder using Neuroimaging

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Major Depression Disorder (MDD) is a significant neuropsychiatric disorder which leads to disabilities worldwide. Considerable evidence has shown links between peripheral inflammation and MDD pathophysiology, but how these peripheral inflammation changes are incorporated into the brain remains poorly understood. Peripheral and central immune interactions are discussed in the literature, which suggests a mechanism for developing neuroinflammation linked to the disruption of the brain solute clearance and fluid homeostasis in the brain. In this model, the dysregulation of the dynamic or the production of cerebrospinal fluid (CSF) may contribute to the dysfunction of the brain’s waste clearance pathways.

A few studies on neurological conditions have indirectly examined the CSF-mediated clearance alteration by assessing the CSF dynamic in the lateral ventricles using Positron Emission Tomography (PET). Other studies have used the Magnetic Resonance Imaging (MRI) to evaluate the alteration in the solute clearance. However, no previous studies have investigated CSF-mediated clearance and its relevance for neuroinflammation in MDD. This PhD thesis aims to examine indirect measurements of the brain CSF-mediated clearance using neuroimaging data to quantify their link to neuroinflammation in depression.

Study1:
This study aimed at testing the immune-mediated model of depression that proposes a direct effect of peripheral cytokines and immune cells on the brain to elicit a neuroinflammatory response via a leaky blood–brain barrier and ultimately depressive behaviour. The blood-to-brain and blood-to-CSF perfusion rates for two TSPO radiotracers collected in two separate studies and were estimated, in two datasets normal and depressed cohorts and 7 healthy controls where peripheral inflammation was induced via subcutaneous injection of interferon (IFN)-α. In both studies we observed a consistent negative association between peripheral inflammation, measured with C-reactive protein (CRP), and radio tracer perfusion into and from the brain parenchyma and CSF. These results suggest a different model of peripheral-to-central immunity interaction whereas peripheral inflammation may cause a reduction in BBB permeability.

Study 2: this study aimed to investigate choroid plexus (CP) volume alterations in depression and their associations with inflammation depressed participants and age- and sex-matched healthy controls using [11C]PK11195 PET/structural MRI imaging for measuring neuro- inflammation and CP volume respectively. A significantly greater CP volume in depressed subjects compared to HCs was found which positively correlated with [11C]PK11195 PET binding in the anterior cingulate cortex, prefrontal cortex, and insular cortex, but not with the peripheral inflammatory markers. The CP volume correlated with the [11C]PK11195 PET binding in CP. This result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression.

Study 3:
This paper aimed to explore the use of a free water (FW) measurement taken from the Neurite Orientation Dispersion and Density Imaging (NODDI) MRI process as an alternative to TSPO PET to quantify neuroinflammation in patients with depression. No significant associations were observed between the FW fraction and peripheral and central inflammation markers, nor between the FW fraction and the depression clinical scores. Although we found evidence of changes in the FW in depression, there is no clear link between the FW and the immune response or depression.

These overall results indicate that CSF-mediated clearance alterations can be assessed using neuroimaging and explore a modified model of the peripheral-to-central immune axis. The changes in the CSF clearance are associated with peripheral and central inflammation, but not necessarily with MDD.
Date of Award1 Aug 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMattia Veronese (Supervisor) & Danai Dima (Supervisor)

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