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The influence of Apolipoprotein E genotypes on pathways of neurotransmission measured in vivo. Implications for dementia research

Project Description

Monoaminergic midbrain nuclei are currently emerging as major players in the definition of the pathological changes of early Alzheimer’s disease (AD) stages. A number of recent studies have characterised the integrity and functionality of these structures in vivo using magnetic resonance imaging (MRI). It is still unclear, however, in what way the pathways of neurotransmission these nuclei provide input to are influenced by genetic susceptibility. A number of studies have demonstrated using functional MRI that the presence of the Apolipoprotein E ε4 allele (the best established genetic risk factor for the late-onset sporadic form of AD) influences pathways of cholinergic neurotransmission. It is still unknown, however, whether the ε4 allele has any impact on monoaminergic pathways of neurotransmission. The goal of this project is to test the effect of the ApoE ε4 allele on these neural systems in a large cohort (n = 212) of datasets acquired in healthy controls, patients with mild cognitive impairment, and patients with dementia of the AD type. These datasets include multimodality MRI images, ApoE genotype, and extensive clinical and cognitive profiles.

The student will familiarise themselves with the ApoE gene, the main principles of neurotransmission, and how MRI (especially functional MRI) allows the investigation of synaptic function on a large scale. The student will then process various types of MRI acquisition to analyse structure and function of the major subcortical and midbrain nuclei, (i.e., ventral tegmental area, raphe, locus coeruleus and nucleus basalis of Meynert) and separate the effects of AD from the effect of the ε4 allele. Moreover, the link between the properties of these nuclei and clinical traits will be investigated to define the consequences of these patterns of neural down-regulation, and how ApoE genotype modulates this effect.

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Funding Notes

This project is open to self-funded students only.

Candidates must have a MSc degree in psychology or neuroscience. Previous experience in MRI data processing and analysis is requested.


References (ctd)

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[15] De Marco M, Clough PJ, Dyer CE, Vince RV, Waby JS, Midgley AW, Venneri A. Apolipoprotein E ε4 allele modulates the immediate impact of acute exercise on prefrontal function. Behav Genet. 2015; 45(1): 106-16.

[16] De Marco M, Vallelunga A, Meneghello F, Varma S, Frangi AF, Venneri A. ApoE ε4 allele related alterations in hippocampal connectivity in early Alzheimer's disease support memory performance. Curr Alzheimer Res. 2017a; 14(7): 766-777.

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[20] De Marco M, Meneghello F, Pilosio C, Rigon J, Venneri A. Up-regulation of DMN connectivity in mild cognitive impairment via network-based cognitive training. Curr Alzheimer Res. 2018; 15(6): 578-589.

[21] Manca R, Sharrack B, Paling D, Wilkinson ID, Venneri A. Brain connectivity and cognitive processing speed in multiple sclerosis: A systematic review. J Neurol Sci. 2018; 388: 115-127.

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