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 more than 1,500 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.

We are currently engaged in several projects to better understand the genetic causes of ALS. Through Project MinE, the world’s largest ALS genome sequencing initiative, we are profiling all of the genetic sequence in the genomes of over 1,000 Irish people, two thirds of which have ALS. This will enable us to detect rare and unobvious genetic mutations that increase a person’s risk to get the disease. We are also actively engaged in seeking out the role of an unconventional class of mutation known as repeat expansion in increasing disease risk. Finally, through large international collaborations, we are determining the role of common genetic variants in ALS, and how these interact together and with environmental factors to cause disease.

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.

Our research can also be supported by making a financial donation to Project MinE.

Researchers: Assistant Professor Russell McLaughlin, Ross Byrne (PhD student), Mark Doherty (PhD student), Jenny Hengeveld (PhD student), Ciaran Kelly (PhD student)

Principal Investigators: Professor Orla Hardiman, Assistant Professor Russell McLaughlin (Smurfit Institute of Genetics, TCD)

Funders: MND Association, Science Foundation Ireland, Research Motor Neurone

 

Neuropsychology

Recent research has est

ablished that over 60% of people with ALS develop some changes in the way they think (cognition) or behave, with approximately 13% of people with ALS developing dementia. The type of dementia associated with ALS is called frontotemporal dementia. These changes 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.

Recently the Neuropsychology strand of the MND research team has 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. Neuropsychology has a very important part in some of our current Epidemiology and Health Services Research projects and also collaborates closely with our MRI and EEG work.

Researchers: Tom Burke, Marta Pinto Grau, Caoimhe Kavanagh, Emmet Costello

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

Funders: MND Association, ALS Association

Volunteering: If you are interested in taking part in this type of research, as a patient or healthy volunteer, contact Mark on 01 8964376.

Epidemiology

Epidemiology is the study of how often diseases occur in populations and what factors may alter an individual’s risk of developing a certain disease. Using data from the Irish ALS register, epidemiology studies have found that the incidence of ALS in Ireland is stable, with approximately 3 people per every 100,000 newly diagnosed with ALS every year.  However, due to the poor prognosis of the condition, only 300-400 people are living with ALS at any one time in Ireland. While it was originally thought to be a disease purely affecting the motor nerves, recent studies have identified that over 60% of people with ALS develop some changes in the way they think or behave, with 13% of people with ALS developing dementia. Research by our group has also shown that more neurological, psychological and psychiatric conditions occur in family members of those with MND compared to the general population. In particular, our research team has found evidence supporting a shared genetic origin between ALS and schizophrenia.

Genetic Pleiotropy study

Genetic pleiotropy occurs when one gene influences two or more seemingly unrelated disorders. By using neuropsychiatric, neuropsychological and behavioural profiling batteries in conjunction with genetic testing to compare family members of people with ALS with family members of people who don’t have ALS, we aim to identify differences across families that might provide clues as to why ALS affects some families and not others. By performing genetic analyses on informative families, we hope to identify new susceptibility genes and biological pathways in ALS and neuropsychiatric disorders which will allow for the discovery of potential novel therapeutic targets.

Participation

Participating first and second-degree relatives of people with MND are visited at home and asked to donate a blood sample and complete neuropsychological tests of memory, language and thinking. They are also asked to complete an online questionnaire on their thoughts and feelings.

Multicentre international epidemiological collaborations

To date, the vast majority of epidemiological studies of ALS have been performed in populations of European ancestry. Despite this, there is evidence to suggest that the incidence and clinical characteristics of ALS varies across populations which may be partially due to differences in the genetic composition of the population under study. In contrast to the Irish populations, some Latin American populations have more varied ethnic origins. By comparing the clinical features of people with ALS across South America (Cuba, Uruguay and Chile) with those from European populations , the LAENALS consortium (Latin American Epidemiological Network for ALS), aims to further our understanding of how differences in population genetics impact  ALS risk and clinical manifestations. This work is being led by the Irish ALS Research Group and builds on the previous research by the EuroMOTOR consortium of which Ireland is a part. The ultimate goal is to combine the European and South American data for comparison. More information on the original work and findings of the EuroMOTOR consortium can be found here

Prof. Hardiman and collaborators at the launch of the LAENALS Consortium in Santiago, Chile in 2016
Prof. Hardiman and collaborators at the launch of the LAENALS Consortium in Santiago, Chile in 2016

 

Researchers: Dr. Marie Ryan, Mr. Emmet Costello, Ms. Caoimhe Kavanagh

Principal Investigators: Professor Orla Hardiman, Dr. Niall Pender

Collaborators: Dr. Russell McLaughlin, Professor Sharon Abrahams (University of Edinburgh), Dr. Patricia Lillo (Chile), Dr. Carlos Ketzoian, Dr. Abayubá Perna and Dr. Jochen Hachembruch (Uruguay), Dr. Tatiana Zaldivar, Dr. Joel Gutierrez and Dr Gloria Lara (Cuba), Prof. Giancarlo Logroscino (Italy)

Funders: Research Motor Neuron (RMN), Science Foundation Ireland (SFI), the Irish Motor Neurone Disease Association “Ice Bucket Challenge”, Center for Disease Control and Prevention

Volunteering: If you are interested in taking part in this research or have any questions about this project, please email Marie Ryan (ryanm65@tcd.ie) or Emmet Costello (ecostel2@tcd.ie) or phone 01 896 4376 (office) or 089 2018386 (mobile)

 

Magnetic Resonance Imaging Study in MND

The diagnosis of MND does not require a brain scan. However, most patients with MND have a routine MRI (Magnetic Resonance Imaging) scan during their initial investigations to exclude possible alternative diagnoses.

Prof. Orla Hardiman and Prof. Peter Bede
Prof. Orla Hardiman and Prof. Peter Bede

Contrary to routine clinical scans, dedicated research MRI techniques provide unique insights into subtle brain changes, and it is now possible to visualise the internal “wiring” of the brain. We use a dedicated research MRI scanner that generates very high-resolution images. This is similar to using a top-of-the-line digital camera with many “megapixels” that reveal much more detail.

By scanning patients with an established diagnosis of MND we can not only identify which brain regions are affected, but also measure how much these areas are involved and detect progressive change over time. Our work has already led to a number of interesting results. We identified subtle changes in brain regions that control voluntary movement and showed that these focal changes contribute to physical disability. We also identified pathology in non-motor brain regions which explain the considerable individual differences between MND patients. We have published our findings in peer-reviewed journals, shared our observations with our European and North-American collaborators and presented our results at international conferences. In addition to our academic research studies, we are in the process of developing novel diagnostic and monitoring protocols to aid individualised patient care and improve pharmacological trial designs.

We would like to thank the kindness and generosity of all of our patients who have already participated in our MRI study, and we would be delighted to provide further information for patients who may be interested to participate in this research study. Contact email: chipikar@tcd.ie

Researchers: Dr. Ranga Chipika, Dr. Eoin Finegan, Dr. Stacey Li Hi Shing

Principal Investigators: Prof. Peter Bede, Prof Orla Hardiman

Funding: Health Research Board (HRB – Ireland; HRB EIA-2017-019), the Andrew Lydon scholarship, the Iris O’Brien Foundation, and the Research Motor Neuron (RMN-Ireland) Foundation.

 

Developing Biomarkers for MND/ALS using Neuro-Electric Signals (EEG)

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 cognition.

The brain is organized to work as networks consisting of interconnected brain cells. Therefore, damage in specific parts of the brain in MND/ALS, disrupts the brain networks more broadly. The degeneration of brain cells (neurons) and the dysfunctional networks are manifested as symptoms affecting movement, breathing, behaviour and cognition.

One way to measure the activity of such networks is to use neuroelectric signals such as EEG (electroencephalography, also referred to as brain waves). It is a painless inexpensive procedure using small flat metal discs, called electrodes, attached to a cap worn over scalp. Those electrodes detect electrical activity and oscillations in the brain. The next step is to find what brain regions are activated, and how those regions are connected with each other. The measurements of neural signals including EEG and muscle activity (EMG) take place when individuals are at rest (resting-state), when they perform movement tasks or cognitive tasks.

 

Aims

Our aim is to develop novel tools using EEG for the diagnosis of disease categories and measuring the efficacy of new drugs for ALS/MND.

We explore whether we can detect the abnormalities within and between different brain networks in people with ALS/MND using this EEG technology. Changes in the activity and neural communication in specific brain networks can identify different subtypes of ALS/MND that is not yet known to clinicians. Correlating these network 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, its efficacy is accurately measured, and they are matched to the needs of different subgroups of people with ALS/MND.

 

Researchers: Ms Roisin McMackin, Dr Amina Coffey, Mr Stefan Dukic, Dr Antonio Fasano, Mr Matthew Fenech

Principal Investigators: Professor Orla Hardiman, Dr Bahman Nasseroleslami

Collaborators: Dr Edmund Lalor, Professor Madeleine Lowery, Professor Richard Carson, Professor Muthuraman Muthuraman (Germany).

Funders: Health Research Board (HRB), Research Motor Neuron (RMN), Science Foundation Ireland (SFI) and Irish Research Council (IRC).

Volunteering: If you are interested in taking part in this research or have any questions about this project, please email Roisin McMackin (mcmackr@tcd.ie) or Amina Coffey (coffeya1@tcd.ie) or phone 01 896 4376 (office) or 089 488 7098 (mobile).

 

Health Services Research

The interactions between the patient/caregiver and these services are a large part of the focus of this research
The interactions between the patient/caregiver and these services are a large part of the focus of this research

Health services research (HSR) is a broad multidisciplinary field, at the interface of clinical medicine and human sciences. The research domains for HSR are individuals, families, organisations, institutions, communities and populations. It looks at how people get access to health care professionals (HCPs) and services, financial cost, what happens to patients and caregivers/families as a result of this care; and the effects of individual behaviour, social factors, financing systems, organizational structures and processes on health and well-being.

There are currently no effective disease modifying therapies for ALS/MND, clinical intervention is focused on enhancing the quality of life for patients and relatives by relieving symptoms, providing emotional, psychological and spiritual support as needed, and supporting the family in bereavement. As is the case for all neurodegenerative diseases, the generation of management protocols for ALS are more complex than for monophasic illnesses. This complexity relates to the multi-dimensionality and interdependence of required service provision. By extension, outcomes measurements must also be recognized as being multidimensional and interdependent.

The use of multiple research methods is best suited to understand complex problems in health/healthcare experiences, provision, delivery and utilization. In the Academic Unit of Neurology, the patient-oriented and Health Services Research theme incorporates multidisciplinary and interdisciplinary enquiry, and qualitative/mixed methods approaches complement traditional biomedical research.

Ongoing research and future objectives

Through a number of interlinked research projects we are developing a best practice framework/ care pathway for the management of ALS/MND as well as other neurodegenerative disorders. In particular, we examine the palliative needs, services and outcomes for those living with ALS/MND in Ireland –patients, caregivers and families.

We document the patient’s journey through MND, and examine factors around diagnosis, multidisciplinary care and the economic and welfare implications of the condition on the family, caregiver and society (Living and dying with Amyotrophic Lateral Sclerosis: A Population based Analysis of Palliative Needs, Services and Outcomes in non-malignant terminal illness). As part of a European wide project – ALS-CarE (A Programme for ALS Care in Europe), patient and caregiver journeys are being assessed with data from 8 centres across 6 European countries, developing a best practice programme for ALS that can be subsequently modified for the management of other related degenerative diseases. This project addresses a number of 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.

We want to develop an educational programme for families of those with ALS/MND, and health care professionals, and provide information about the cognitive, behavioural and personality changes that can occur in ALS/MND. This helps health care professionals to recognize the increased burden associated with thinking, behaviour and personality changes (Behavioural Changes in ALS: What Families Need to Know). By understanding the intricate relationship between cognitive decline, behaviour change, and caregiver needs, a clear pathway can be enunciated for health services to alleviate burden. Addressing the needs of caregivers will contribute to the better clinical management of patients both in a service setting, and at home.

The overall purpose of the study Defining and Addressing the Complex Needs of ALS Caregivers is to systematically investigate the consequences of cognitive and behavioural effects on caregiver burden. Investigation of the consequences of burden, and the identification of needs, will allow for the better management of needs and greater caregiver empowerment. A greater understanding of the dimensions and components of burden and experiences of caring for someone with ALS will facilitate tailored interventions to better support the caregiver.

The latest study in this area entitled A Randomised Controlled Study of Psychological intervention in ALS to Address the Significant and Complex Mental Health Needs of Caregivers aims to evaluate the effectiveness and efficacy of psychological interventions with this group; to inform best practice regarding the identification and management of caregiver burden in ALS; and to create a formal psychological intervention tailored specifically to the needs and wants of ALS caregivers. This is building directly on the research that has come before it (described above).

Researchers: Ms. Sile Carney, Dr. Sinead Maguire, Mr. Tommy Gavin, Ms Caoimhe Kavanagh, Ms. Caroline Wheeler, Dr. Katy Tobin, Dr. Ger Foley

Principal Investigators: Professor Orla Hardiman, Dr. Miriam Galvin, Dr. Niall Pender

Collaborators: Professor Anthony Staines (Health Systems, DCU); Professor Charles Normand (Health Policy and Management, TCD); Dr. Regina McQuillan (Palliative Care, St. Francis Hospice, and Beaumont Hospital); Ms. Bernie Corr (National MND Clinic, Beaumont Hospital); Professor Christopher McDermott (Sheffield Institute for Translational Neuroscience); Professor Zachary Simmons (Penn State Hershey Medical Center, Pennsylvania); IMNDA; ALSCarE consortium partners

Funders: HRB (Health Research Board), JPND (EU Joint Programme – Neurodegenerative Disease Research), ALSA (ALS Association)

 

Clinical Trials

CLINICAL TRIALS
It is time to be optimistic for future clinical trials. There are at least 15 new compounds in development for ALS/MND

Our clinical trial centre is actively involved in developing new drugs in early and phase trials.

Currently we are enrolling for the REFALS study, sponsored by Orion.

https://clinicaltrials.gov/ct2/results?cond=ALS&term=REFALS&cntry=&state=&city=&dist

=&Search=Search

We are participating in the FORTITUDE study , sponsored by Cytokinetics (enrolment
close)

https://clinicaltrials.gov/ct2/results?cond=ALS&term=FORTITUDE&cntry=&state=&city=

&dist=&Search=Search

FUTURE TRIALS = plans to enrol in the early new year (more details to follow)

TUDCA study funded by the European Commission, sponsored by Humanitas University,
Italy.

LIGHTHOUSE II: Investigator funded. Protocol under development

Details of a previous trial of this drug can be found here:https://clinicaltrials.gov/ct2/show/NCT02868580?term=Lighthouse&cond=ALS&rank=1)

ADORE: Oral Edaravone : Protocol under development

PRELUDE : Lithium trial in those with a specific genetic variant: Protocol nder
development

 


 

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 (JAK4D) 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.  JAK4D 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, Ms Roisin McMackin

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

Treatment and Research Initiative to Cure ALS  (PROJECT TRICALS) involves centres of ALS research in Ireland, Holland, the UK, France, Belgium and Italy joining together. The aim of the project is to develop a precision medicine-based approach towards new treatments for ALS/MND.

THE CHALLENGE 

There is no effective treatment for ALS. Despite huge investment over the years in animal models of ALS, we have not yet succeeded in translating successful treatments to humans. In the past 15 years, over 45 clinical trials of new treatments in human have failed, costing hundreds of millions of euro. This is because human ALS is more than one condition, but our clinical trials have not reflected this.

THE GOAL 

It is time to move to a new precision-medicine based approach towards treatment

To achieve this we need a radical change in how we engage in research. ALS is a human disease. We must shift the focus from animal research to human research. We will not find new treatments without working together and investing in the study of people with the disease.

European ALS Centres must join forces to capitalize on our individual strengths, and to build on new and creative approaches that enhance our collective scientific expertise. It is also imperative that we include those who are experiencing the disease first hand.

More on the structure and specific research goals of the project can be found here.