Current research

Genetics

Background

Dr Russell McLaughlin
Dr Russell McLaughlin

The entire set of instructions for how to make a human is contained in a small number of molecules in almost every cell in the body.  These molecules are collectively called a person’s genome, and the substance from which this is made is called DNA.  Sometimes the instructions can contain errors, known as genetic mutations, and it is likely that certain genetic mutations play a key role in the cause of ALS.  Although many of the responsible mutations have already been discovered, we have recently found that only around 10% of cases of ALS in Ireland can be explained by known mutations.  Many unknown genetic risk factors therefore remain to be discovered.  A better understanding of the genetic causes underlying ALS is vital for the development of effective therapies.

Aims

Recent technological advances in DNA sequencing mean that we can search for mutations in large portions of the genome in a large number of patients simultaneously.  This makes us more likely to discover the cause of ALS in these patients.  A vital resource for this research is our DNA bank which now contains nearly 1,000 samples from patients collected over the past three decades.  We also use DNA collected from people unaffected by ALS, known as controls, against which we compare our findings from patients.  This bank of DNA samples from patients and controls is a tremendous resource for all kinds of projects researching the genetic cause of ALS.

One of the ways we are investigating the genetics of ALS in Ireland is by harnessing a principle called identity-by-descent.  Using enormous datasets already generated in previous projects, we are able to tell which portions of the genome have been inherited from the same ancestor in any given pair of patients.  We have observed that, interestingly, there is some level of hidden relatedness for many pairs of patients previously thought to be unrelated, and it is possible that this shared ancestry has led to increased ALS risk.  Ireland is the ideal place for such studies, with a small population and large family sizes.  These findings help us to reconstruct the family structures of ALS patients which is immensly useful in the design of our genome sequencing projects.  The ultimate goal is to determine the genetic cause of ALS in every case in Ireland. This is necessary if effective therapies are to be developed, tested and ultimately administered to patients.

Participation

Patients (and unaffected individuals) can contribute to this research by simply donating a blood sample, from which DNA is then extracted. For the most part, this is carried out during a routine visit to the MND outpatients’ clinic at Beaumont Hospital, Dublin.

Researchers: Dr Russell McLaughlin

Principal Investigators: Professor Orla Hardiman, Professor Dan Bradley (Smurfit Institute of Genetics, TCD)

Funders: Thierry Latran Foundation, ALS Association of America, Health Research Board, Research Motor Neurone

 

Neuropsychology

Marta Pinto Grau, Dr Marwa Elamin, Prof. Orla Hardiman and Tom Burke.
Marta Pinto Grau, Dr Marwa Elamin, Prof. Orla Hardiman and Tom Burke.

Research in the area has now established that some people with motor neuron disease (MND) can develop difficulties with aspects of their thinking, learning and memory during the course of their illness. These difficulties may be accompanied by changes in behaviour or personality, and can present challenges for both the patients and carers. To date, the Irish research group has worked on examining the nature and extent of these cognitive and behavioural changes, and has succeeded in identifying the subgroups of patients for whom they are an issue. In the MND outpatients’ clinic at Beaumont Hospital we continue to explore this using a new, shorter test examining brain function. Administered during the routine clinic visit, the test takes about 15 minutes to complete and results can be used to inform medical care while also contributing to research. A family member or carer is invited to fill out a questionnaire reporting any changes they may have noticed. This screening test can be repeated every 3-6 months, examining patient’s progress over time.

A full neuropsychological assessment is completed with patients who consent to take part in research being conducted by the team. This assessment involves a battery of neuropsychological tests which are also designed to assess cognitive function but in greater detail. These assessments investigate areas such as language, memory and attention, are repeated every 6 months, and are approximately 90 minutes in duration. In these research projects, participants can withdraw from the study if they wish.

As part of Professor Hardiman’s team, and under the supervision of Dr. Niall Pender, research includes assessing cognitive and behavioral changes over time in MND, investigating the relationship between everyday impairment in thinking and how that relates to brain structure, and also what we can learn about information processing by measuring brain networks with the assistance of neurophysiology. If you are interested in research, as a patient or healthy volunteer, contact 01 809 2963 and ask for Tom or Marta.

Recently the Neuropsychology strand of the MND research team have been working on international research projects with centres within Europe with an aim to develop and validate standardized ways to assess brain function in people with MND. This will create a more consistent approach to testing, but also it will enhance the knowledge we can share with our colleagues in order to generate better care for people with MND on an international level.

Researchers: Tom Burke, Marta Pinto Grau

Principal Investigators: Professor Orla Hardiman,  Dr Niall Pender (Principal Clinical Neuropsychologist, Beaumont Hospital)

Health Services Research

The aim of our three year project is to develop a best practice framework/ care pathway for the management of motor neuron disease (MND), as well as other neurodegenerative disorders. In particular, the project will examine the palliative needs, services and outcomes for those living with MND in Ireland. The research programme is divided into a number of specific and interlinked areas of research which will inform the development of the best practice framework. The first work package is concerned with the epidemiology of MND.  Using data from the Irish MND register of patients, a number of research questions will be addressed, including an assessment of the factors influencing survival among those with MND.

The second work package will involve the recruitment and follow-up of approximately 100 patients currently living with MND, and their primary caregivers. The research will characterise the patient’s journey through MND, and examine factors around delay diagnosis and the economic and welfare implications of the condition on the family, caregiver and society.  Finally, using evidence generated from work packages one and two, in combination with other relevant research, the final work package will develop a structured framework for the management of MND.

In addition, our research project will contribute significantly to a European wide project – ALS-CarE – which is scheduled to start in 2014. The ALS-CarE project will bring together data from 8 centres across 6 European countries with the aim of developing a best practice programme for ALS that can be  subsequently modified for the management of other related degenerative diseases of the nervous system. Comprising six work packages, the European project will address a number of pertinent questions around disease staging, end of life decisions, quality of life, caregiver burden, as well as examining the cost effectiveness of various models of service delivery.

International best practice recommends early palliative care intervention from time of diagnosis of motor neurone disease. However in Ireland access to palliative care is limited and the clinical indications for specialist palliative intervention are not clearly defined. The aim of this project is to identify the deficits in current palliative management of motor neurone disease by comparing existing practice with best practice guidelines, and to develop a structured framework based on a multidisciplinary approach towards the palliative management of motor neurone disease. Prospective longitudinal clinical, health service, quality of life and burden of illness data relating to the patient journey of 100 patients in Ireland with motor neurone disease and their caregivers will be available for analysis.  Access to and utilisation of palliative care services will be assessed and comparison between current management and best practice will be evaluated. A multifaceted care framework will be developed and piloted with health care professional and users. Service providers’ perspective will be captured and the perceived ultility of the service evaluated for a patient and carer perspective.  On completion the project will provide a road map for palliative services intervention for MND, and will assist in the future development of palliative services in Ireland.

Chloe Heslin, Dr Katy Tobin and Dr Miriam Galvin
Chloe Heslin, Dr Katy Tobin and Dr Miriam Galvin

Researchers: Dr Miriam Galvin, Dr Katy Tobin, Dr Sinead Maguire, Síle Carney

Principal Investigators: Professor Orla Hardiman, Professor Charles Normand (Health Policy), Professor Virpi Timonen (Social Studies), Professor Ivan Perry (Epidemiology UCC), Professor Anthony Staines (Epidemiology & Health Services, DCU), and Dr. Regina McQuillan (St.Francis Hospice).

Funders: Health Research Board (HRB) interdisciplinary capacity enhancement (ICE) award

 

 

 

Spatial Epidemiology

In recent years, Ireland has developed a wealth of geographical information systems (GIS) allowing sophisticated spatial analysis to be performed in a variety of research fields. This technology allows us the opportunity to perform sophisticated mapping of ALS incidence risk in Ireland.

The aims of the ALS spatial epidemiology project are primarily to produce maps of localized ALS risk in Ireland using advanced computational methods such as spatial auto-regression and Bayesian smoothing. Secondarily, we aim to apply formal spatial clustering analysis to our geocoded case list to identify any statistically significant hotspots of ALS risk in the country.  Such clusters may prove very important in giving us clues to help identify local causative factors such as unknown genetic polymorphisms or possibly environmental effects. Thirdly, we aim to combine the ALS spatial analysis with data from other GIS resources such as social-deprivation maps, environmental data, weather data and others in an effort to identify significant risk factors for ALS.

Researchers: Dr James Rooney

Magnetic Resonance Imaging Study in MND

The diagnosis of MND does not require a brain scan. However, most patients with MND have a routine brain MRI (Magnetic Resonance Imaging) scan and sometimes a spinal cord MRI scan during their initial investigations. These scans are organised to explore and exclude possible alternative diagnoses. The majority of routine brain scans in MND are essentially normal as clinical MRI scans are optimised to identify other neurological conditions such as inflammation, old-strokes etc.

Novel sophisticated MRI techniques give us unique insights into subtle changes in the brain, and more importantly, changes in various parts of the brain can be measured with great accuracy. We use a dedicated research MRI scanner that generates very high resolution images thanks to its very strong magnet. (This is a bit similar to using a powerful digital camera with a lot of megapixels that reveals more details!).

By scanning patients with an established diagnosis of MND with these new techniques, in a dedicated research scanner we can find out which parts of the brain are affected and to what extent. We also gain a unique insight into the internal “wiring” of the brain, and map out which pathways (cables) are affected. (A bit like an electrician!)

Our work so far led to a number of interesting results. We found that subtle changes in part of the brain that controls voluntary movement correlate sensitively with the extent of physical disability. We also found that parts of the brain that were previously considered unaffected by the disease may play an important role in the disease process.Our intention is to develop sensitive diagnostic protocols and learn more about how MND affects various parts of the brain. Ultimately, the objective measurements of these scans could be also utilised in clinical trials.

I would like to sincerely thank the kindness and generosity of all of our patients who participated in this MRI study so far, and put up with the noise of the scanner (and my compilation CD)!

Researcher: Dr Peter Bede, Christina Schuster

Principal Investigator: Professor Orla Hardiman

Funding: Health Research Board (HRB) Research Training Fellowship for Healthcare Professionals and Research Motor Neurone

Developing EEG as a Biomarker in ALS/MND

Background

Motor Neurone Disease (MND) causes damage to specific nerves involved in muscle control, called motor neurones. These nerves carry messages from brain regions responsible for movement to the muscle controlling those gestures. MND can also result in changes in other regions, such as those responsible for behaviour and language.

The brain is a very well-organized and efficient network consisting of interconnected brain cells so damage in one part of a brain network results in a failure for the whole network to work efficiently. Such re-arrangements of the network can result into behavioural and cognitive deterioration such as fluency and mood problems.

One way to measure the activity of such networks is to use EEG (electroencephalography). It is a painless procedure using small flat metal discs, called electrodes, attached to a cap. Those electrodes detect electrical activity in the brain. The next step is to find what brain regions are activated, how efficient those are activated, and how well those regions are connected with each other.

Aims

Our aim is to explore whether we can detect any abnormalities within and between different brain networks in people with ALS/MND using this EEG technology. Different patterns of brain network disruption might reflect different subtypes of ALS/MND.  Correlating these pattern disruptions with changes on MRI scanning, psychological testing and genetic profiles can give us a powerful set of tools that will help us to identify groups of patients with different disease characteristics.

Abnormalities within and between different brain networks in ALS/MND patients can be used as a marker to make sure that when we  develop new drugs they are matched to  the needs of different subgroups of people with ALS/MND.

Researchers: Dr Bahman Nasseroleslami, Michael Broderick

Principal Investigators: Professor Orla Hardiman, Dr Edmund Lalor

Funders: Health Research Board (HRB), Research Motor Neuron (RMN) and Irish Institute of Clinical Neuroscience (IICN).

If you are interested in taking part in this research or have any questions about this project, please email Tom Burke (burket2@tcd.ie) or phone 01 8093262 (office) or 085 1624668 (mobile).

 

A study of Frontotemporal Dementia (FTD) and Motor Neurone Disease (MND) in Ireland

Frontotemporal Dementia (FTD) is a neurodegenerative disorder affecting the brain. Neurodegeneration is a process in which our brain cells fail, resulting in disorders of thinking and memory, as well as movement function. Other examples of neurodegeneration include Alzheimer’s disease, Parkinson’s and Motor Neurone Disease.

FTD is the second most common form of dementia after Alzheimer’s disease, with a younger age of onset and a more rapid progression. FTD sometimes develops in people with Motor Neurone Disease; a syndrome known as FTD-MND. At present, medical treatment is extremely limited and the causes of the condition are not fully understood. It is certain that there is a genetic component underlying FTD and the tendency for the condition to cluster in families is well recognized. As many as 40-50% of patients with FTD have an affected family member. It is important to measure the severity of the problem in our country so that we know what services are required for younger people with this disorder.

Dr Taha Omer, Neurologist
Dr Taha Omer, Neurologist

The purpose of this study is to identify patients with FTD, to examine them, collect blood samples for genetic studies, perform brain imaging using MRI and collect brain wave data using EEG.  Analysis of this data and the establishment of an FTD patient database will help us to better understand the condition with the ultimate goal of developing new and improved treatment strategies.

Researchers: Dr Taha Omer

Principal Investigators: Professor Orla Hardiman

Funders: The EU Joint Programme – Neurodegenerative Disease Research (JPND) project SOPHIA (Sampling and biomarker OPtimization and Harmonization In ALS and other motor neuron diseases)

Clinical Trials

We will be recruiting for a new study very soon.  This study does not involve any trial medication. It is called:  Methodology Study of Novel Electrophysiological, Physical, and Imaging Outcome Measures to Assess the Progression of Amytrophic Lateral Sclerosis.

In short, this means the study will assess a set of potential outcome measures to determine the relative utility for incorporation in future phase II studies for patients with MND. There will be 7 visits to the Clinical Research Centre and 11 phone calls over 2 years.

 


 

Neuropharmacology

The Neuropharmacology and New Drug Development Group within the Academic Unit of Neurology Trinity College Dublin (TCD) School of Medicine is located in the recently opened Trinity Biomedical Sciences Institute.  Here, the group is currently carrying out cutting edge research to develop a novel compound that has exciting potential to provide innovative treatment for MND.  This novel compound (LC) was discovered by Dr Julie Kelly, a Research Associate Professor of Neurology, through her Wellcome Trust-funded research at TCD and is protected by composition of matter patents.

New effective treatments for MND are urgently needed.  Since the pathology of MND is complex and involves multiple biological factors and processes, a drug with multifaceted neurotherapeutic effects holds greater prospects for achieving therapeutic benefit in MND compared to a drug targeting only a single disease factor.  LC has the potential to offer such an advantageous multifaceted approach and research supported by Enterprise Ireland, Research Motor Neuron and Fondation Thierry Latran is ongoing within the group to develop this promising compound.

Researchers: Dr Julie Kelly, Gillian Slator, Dr Alice Vajda

Funders: Enterprise Ireland, Research Motor Neuron and Fondation Thierry Latran

The goal of the Euro-MOTOR project is to further understand the causes of ALS to allow the development of new therapies. This is being carried out through efficient, standardised and harmonised collection of patient samples and life-style questionnaires across Europe.

The Irish ALS research group is coordinating one strand of this project, which aims to identify risk factors that may contribute to a

n individual’s chances of developing motor neurone disease. Information is being collected in Ireland, Italy and The Netherlands from a large number of patients and controls who are gender, age and geographically matched. Participation involves a questionnaire about lifestyle including questions on occupation, health and exercise. In addition, a blood and urine sample will be collected to allow research into genes and proteins associated with MND.

For further information see the Euro-MOTOR website.

Funding: European Union Seventh Framework Programme