Brain Iron Toxicity and Neurodegeneration - MRI study at 7T

Alzheimer's disease is a devastating condition that initially causes a gradual decline in memory, thinking and reasoning skills, resulting in disruption of daily life and the onset of dementia.

The early diagnosis of Alzheimer's disease is possible by identification of traces of Amyloid protein, either in the brain or from the fluid around the brain, called cerebrospinal fluid. However, so far, treatments based on reducing Amyloid have not been shown to be effective in treating Alzheimer's disease. Excessive iron has been found to contribute to the deposition of Amyloid, thus promoting the development of Alzheimer's disease and therefore, iron-targeted treatments have become an important new direction in Alzheimer's disease.


Magnetic resonance imaging (MRI) is a relatively cheap, widely used medical imaging technique, and it can be repeated safely to monitor changes in the brain with time. Ultra-High Field MRI uses a very strong magnetic field to produce very high resolution images that can depict brain shrinkage of less than a millimeter. It can also be used to produce novel images that are very sensitive to the amount of iron in the brain.

This research will build on strong local expertise in neuroimaging and the availability of powerful and modern MRI scanners at the Sir Peter Mansfield Imaging Centre at the University of Nottingham.

We aim to use Ultra-High Field MRI at 7 Tesla (7T) to study the way that changes in brain iron with time relate to brain shrinkage in the brains of patients with Alzheimer's disease. We will invite people from our Memory Clinics, who have mild Alzheimer's disease and evidence of abnormal amyloid/tau protein in their cerebrospinal fluid to take part in this study. Once the participants have consented to join the trial, they will undergo an Ultra-High Field MRI scan, have a small blood sample taken and undergo a series of memory and thinking tests. If samples of their cerebrospinal fluid have already been stored, we will test this sample rather than asking people to undergo a further lumbar puncture. After 12 months, we will ask the participants to come back into the research clinic and to repeat the series of tests. We will recruit healthy volunteers of the same age. With permission, anonymous data and MRI images will be added to a Europe-wide database to enable other researchers to use these data.

We plan to use the results of this 3-year study to:

- Improve our understanding of the trajectory of iron accumulation in the brain and its relation to memory and thinking (cognition), amyloid markers in the cerebrospinal fluid, and the presence of a gene that increases the risk of developing Alzheimer's (called Apolipoprotein E).
- Identify specific features on brain scans that may improve the diagnosis of early Alzheimer's disease.
- To use the above features to monitor minor changes in the brain and possibly predict the speed of progression of Alzheimer's disease to help people manage their condition.
- Potentially form the basis for future studies into the role of iron in early Alzheimer's disease including new treatment targets and a faster way of monitoring drug trials.
- Form a resource for future research.

We are working closely with a group of patients (the dementia PPI group at the Institute of Mental Health), who have helped us develop this application; and they, and patients and their families from the Memory clinic at the Queen's Medical Centre, will be invited to work with us throughout the project. This will ensure that the patient voice is embedded in the project in a meaningful way, and will be key to the success of the project, from design to dissemination.

Ultra-High Field MRI can be used to study variation in sub-structural markers of neurodegeneration with time and has the potential to identify and possibly quantify another pathological element in Alzheimer's disease, by using a non-invasive and cheaper method than Amyloid/tau examination. Changes in brain volume can be monitored with great sensitivity, even in very small regions such as the hippocampal subfields. The recently developed MRI technique of quantitative susceptibility mapping (QSM) can quantify the concentration of paramagnetic materials including iron, with greatly increased sensitivity at 7T. The use of QSM will allow the iron content in substructures and strategically important areas of the brain to be characterised over time in patients with Alzheimer's disease.
Knowledge of the distribution of iron deposition in brain tissue of patients with Alzheimer's disease can, characterise the heterogeneity of Alzheimer's pathology, and help us to understand the relevance of iron in neurodegeneration and its clinical and cognitive implications. Characterisation of the trajectory of brain tissue iron content in the Alzheimer's group will improve our knowledge of the relationship between iron accumulation and local neurodegeneration/hippocampal volume loss, in relation to Amyloid/tau-pathology and APO status. This project may potentially identify an imaging-based biomarker which can either provide a disease-specific pathological marker (i.e. presence of iron in hippocampal subfields) or a pre-neurodegeneration indicator in patients with Alzheimer's disease. In follow-on work, we would test whether any imaging biomarker found in 7T MRI could also be exploited at 3T.

The key driver behind this study is the patients that I see in my clinics who strive for early diagnostic and prognostic markers to inform their future before dementia occurs. Many of them consistently state that they would be willing to take part in imaging studies as well as future clinical trials.

It would be of enormous benefit to patients if we could identify imaging biomarkers to allow the diagnosis of Alzheimer's disease at an early stage, and indicate prognosis, as it would help patients to plan their futures.

There are numerous molecular and animal studies on the role of iron toxicity in neurodegeneration while clinical studies on patients will be most informative particularly for a condition with growing incidence, catastrophic outcome and lack of modifiable treatment. This study will utilise existing knowledge and innovative imaging sequences in patients with Alzheimer's disease and help researchers to better understand the characteristic pattern of paramagnetic signals in the brain in relation to cognitive performance, Amyloid/tau pathology, CSF ferritin, APOE status, and atrophy.

If this study identifies primary or epiphenomenonal presence of iron accumulation during the early stage of Alzheimer's disease, there may be a period of opportunity to detoxify the brain from iron to delay neurodegeneration. The concept of tracking iron accumulation in the brain prior to neuron loss would invite pharmaceutical companies to invest in iron targeting therapy for Alzheimer's disease.

The study could provide a surrogate marker for clinical trials of iron therapy for neurodegenerative disorders. The use of such a biomarker would potentially shorten clinical trials if short-term imaging biomarker outcomes predict long-term clinical outcome. This would significantly reduce the cost of clinical trials and allow more rapid evaluation of new drugs and therapies.

The imaging sequences used here at 7T will be shared through the UK7T Network and EUFIND consortium to enhance impact.

The identification of a surrogate marker of iron toxicity at ultrahigh resolution can be explored at 3T through the BRC link, and collaborations with the Cambridge Dementia Platform (DPUK) for the wider community of researchers, scientists and trialists.