Date of Award

2012

Document type

Thesis

Degree Name

MD (Medical Doctor)

First Supervisor

Professor Kieran Murphy

Keywords

Dementia, Down's Syndrome, Alzheimer's Disease

Abstract

Introduction

Dementia is a progressive and largely irreversible clinical syndrome which is characterised by a disturbance of higher cortical functioning, occurring in clear consciousness. Alzheimer’s disease is the most common form of dementia. People with Down’s syndrome, the most common genetic cause for intellectual disability, have a significantly increased risk for developing Alzheimer’s disease in later life.

Neuroimaging is an important tool in the preclinical detection and monitoring of Alzheimer’s disease. Much attention has focused on volumetric manual Region of Interest MRI studies to investigate changes confined to a limited set of brain regions. Automatic techniques have been developed to study more widespread brain volume and thickness measures than Region of Interest MRI studies. Proton Magnetic Resonance Spectroscopy (HI-MRS) can be employed to investigate the concentrations of a number of brain metabolites including N-acetylaspartate [NAA], myo-inositol [ml], choline [cho] and creatine plus phosphocreatine [Cr+PCr], NAA is hypothesized to be a marker of the number of viable neurons. Elevation of ml is a marker for gliosis.

To my knowledge, no in vivo case-control study exists comparing the anatomy of dementia in Down’s syndrome to people with Alzheimer’s disease in the general population.

Methodology

Subjects were scanned using a 1.5 Tesla, GE NU/i Signa MR System at the Maudsley Hospital in London. The reformatted SPGR data set was analysed using Measure Software. Volumetric analysis of the hippocampi, temporal lobes, lateral ventricles, whole brain and total cranial volumes were performed by means of manually tracing regions of interest to compare subjects with Down’s syndrome to those with Alzheimer’s disease in the general population. In addition, an automated technique enabled the investigation of more widespread brain volume and thickness measures in subjects with Down’s syndrome, Alzheimer’s disease and age-matched healthy controls. Additional volumetric analysis was undertaken on MRI scans of subjects with Alzheimer’s disease, mild cognitive impairment and Alzheimer’s disease healthy controls at baseline and on subjects who were re-scanned after 12 months. Magnetic resonance spectroscopy was used to investigate differences in hippocampal metabolite concentrations between subjects with Down’s syndrome, Alzheimer’s disease and age-matched healthy controls.

Results

Subjects with dementia had a significant reduction in the volume of the hippocampus, temporal lobe and whole brain and an increase in the volume of the lateral ventricles, compared to their non-demented controls. There was a significant correlation between atrophy of the hippocampus and temporal lobe, and cognitive decline. Significant differences were demonstrated for more global cortical volume and thickness measures between demented and non-demented subjects, and between subjects with Alzheimer’s disease and demented subjects with Down’s syndrome.

In the longitudinal study, when compared to age matched healthy controls, subjects with Alzheimer’s disease had a significant reduction in the volume of the hippocampus and temporal lobe, and an increase in the volume of the lateral ventricles at baseline and when re-scanned at 12 months, and subjects with mild cognitive impairment had findings intermediate between those of Alzheimer’s disease and age matched healthy controls. The Alzheimer’s disease group had a significant reduction in [NAA] compared to its age matched healthy control group but not when compared to demented subjects with Down’s syndrome or younger Down’s syndrome healthy control groups. Demented subjects with Down’s syndrome had a significantly higher [ml] than the other groups.

Conclusion

MRI and HI-MRS are useful tools to compare the anatomy of dementia in Down’s syndrome to subjects with Alzheimer’s disease in the general population. Significant differences between demented and non-demented subjects can enable the distinction between subjects with and without dementia, and may distinguish between individuals with Alzheimer’s disease and demented subjects with Down’s syndrome.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

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Comments

A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Medicine from the National University of Ireland in 2012.

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