Birkbeck, University of London Featured PhD Programmes
Norwich Research Park Featured PhD Programmes
Imperial College London Featured PhD Programmes
FindA University Ltd Featured PhD Programmes
The Hong Kong Polytechnic University Featured PhD Programmes

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.

For information, please feel free to write at:
Please visit also: https://www.sheffield.ac.uk/neuroscience/staff/demarco

References:
[1] Forner S, Baglietto-Vargas D, Martini AC, Trujillo-Estrada L, LaFerla FM. Synaptic impairment in Alzheimer’s disease: A dysregulated symphony. Trends Neurosci. 2017; 40(6): 347-357.

[2] Beliveau V, Svarer C, Frokjaer VG, Knudsen GM, Greve DN, Fisher PM. Functional connectivity of the dorsal and median raphe nuclei at rest. Neuroimage. 2015; 116: 187-95.

[3] Li H, Jia X, Qi Z, Fan X, Ma T, Ni H, Li CR, Li K. Altered functional connectivity of the Basal Nucleus of Meynert in mild cognitive impairment: A resting-state fMRI study. Front Aging Neurosci. 2017; 9: 127.

[4] Liu KY, Marijatta F, Hämmerer D, Acosta-Cabronero J, Düzel E, Howard RJ. Magnetic resonance imaging of the human locus coeruleus: A systematic review. Neurosci Biobehav Rev. 2017; 83: 325-355.

[5] Meng D, Li X, Bauer M, Taylor JP, Auer DP; Alzheimer’s Disease Neuroimaging Initiative. Altered Nucleus Basalis connectivity predicts treatment response in mild cognitive impairment. Radiology. 2018; 289(3): 775-785.

[6] Serra L, D’Amelio M, Di Domenico C, Dipasquale O, Marra C, Mercuri NB, Caltagirone C, Cercignani M, Bozzali M. In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer’s disease. Neurobiol Aging. 2018; 72: 72-82.

[7] Nobili A, Latagliata EC, Viscomi MT, Cavallucci V, Cutuli D, Giacovazzo G, Krashia P, Rizzo FR, Marino R, Federici M, De Bartolo P, Aversa D, Dell’Acqua MC, Cordella A, Sancandi M, Keller F, Petrosini L, Puglisi-Allegra S, Mercuri NB, Coccurello R, Berretta N, D’Amelio M. Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease. Nat Commun. 2017; 8: 14727.

[8] De Marco M, Venneri A. Volume and connectivity of the ventral tegmental area are linked to neurocognitive signatures of Alzheimer’s disease in humans. J Alzheimers Dis. 2018; 63(1): 167-180.

[9] Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM. Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging. 2007; 28(3): 327-35.

[10] Peterson AC, Li CR. Noradrenergic dysfunction in Alzheimer’s and Parkinson’s diseases-An overview of imaging studies. Front Aging Neurosci. 2018; 10: 127.

[11] Vakalopoulos C. Alzheimer’s disease: The alternative serotonergic hypothesis of cognitive decline. J Alzheimers Dis. 2017; 60(3): 859-866.

[12] Smith GS, Barrett FS, Joo JH, Nassery N, Savonenko A, Sodums DJ, Marano CM, Munro CA, Brandt J, Kraut MA, Zhou Y, Wong DF, Workman CI. Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis. 2017; 105: 33-41.

[13] Mahley RW, Weisgraber KH, Huang Y. Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006; 103(15): 5644-51.

Funding Notes

This project is open to self-funded students only.

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

References

References (ctd)

[14] Nicoll JA, Savva GM, Stewart J, Matthews FE, Brayne C, Ince P; Medical Research Council Cognitive Function and Ageing Study. Association between APOE genotype, neuropathology and dementia in the older population of England and Wales. Neuropathol Appl Neurobiol. 2011; 37(3): 285-94.

[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.

[17] Hersi M, Irvine B, Gupta P, Gomes J, Birkett N, Krewski D. Risk factors associated with the onset and progression of Alzheimer's disease: A systematic review of the evidence. Neurotoxicology. 2017; 61: 143-187.

[18] De Marco M, Manca R, Mitolo M, Venneri A. White matter hyperintensity load modulates brain morphometry and brain connectivity in healthy adults: A neuroplastic mechanism? Neural Plast. 2017; 2017b: 4050536.

[19] De Marco M, Duzzi D, Meneghello F, Venneri A. Cognitive efficiency in Alzheimer's disease is associated with increased occipital connectivity. J Alzheimers Dis. 2017c; 57(2): 541-556.

[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.

Email Now

Insert previous message below for editing? 
You haven’t included a message. Providing a specific message means universities will take your enquiry more seriously and helps them provide the information you need.
Why not add a message here
* required field
Send a copy to me for my own records.

Your enquiry has been emailed successfully





FindAPhD. Copyright 2005-2019
All rights reserved.