Report from the Irish Institute of Clinical Neuroscience

16th Annual Neurology Update Meeting

Advancing research and outcomes in neurology

There is no database which defines how much brain atrophy a person should have at a certain age and which could be used to aid assessment samples of brain tissue for cognitive impairment by neuropathologists.

That is according to Dr Francesca Brett, Consultant Neuropathologist, Beaumont Hospital, Dublin, who gave a talk entitled ‘An approach to cognitive impairment in a clinical void’ at the Irish Institute of Clinical Neuroscience (IICN) 16th Annual Neurology Update Meeting, held in the Davenport Hotel, Dublin, on 13 October 2017.

Alzheimer’s disease (AD) and dementia are the commonest cause of death due to neurological disease and there has been a doubling of the numbers that die, or are disabled due to AD in the last 25 years.

Dr Brett said that she often receives brain samples from the brain bank and pathologists around Ireland and is asked to analyse the tissue.

This analysis seeks signs of atrophy or cerebrovascular disease in the brain and then applies a rating of none, moderate, mild or severe to that sample.

The big question to be determined from the sample is how did the patient end up with cognitive decline, when that was present in life.

One key is the pattern of protein deposition and whether there is extra cellular or intra-cellular deposition present.

The Tau protein, TDP-43, FUS and alpha-synuclein are the key intracellular proteins to look out for and it is crucial to see where they accumulate.

Are there proteins in the neurons or the glial cells, for example? These are the questions, said Dr Brett, that a sample analysis should seek to answer.

Tau is present in normal neurons, but Tau is also associated with abnormalities called the primary and secondary tauopathies, which result in AD.

The primary tauopathies are things like piD, PSP, CBD and AGD disease and abnormal neuronal inclusions and glial inclusions can identify each of these.

The hippocampus is routinely examined for signs of AD, said Dr Brett and it is also routine to check for the presence of amyloid in the vessels.

Most people with AD have memory impairment, but rapidly progressive cases can sometimes be confused with sporadic CJD.

It is worth examining the Lewy bodies (abnormal aggregates of alpha-synuclein protein) and if some way could be found for preventing them forming there would be no Parkinson’s disease (PD).

Dr Brett said that most of the older population of patients that she sees at St James’s Hospital are carrying a burden of cerebrovascular disease.

An examination of the proteins in a patient’s sample, their distribution and a correlation with the clinical history – such as any evidence of AD changes – can help to address questions about what might be normal age-related atrophy for a 60-year-old brain, versus a 90-year-old brain.

However, there is no database in existence which says at 50 years of age people should have this amount of brain atrophy, while at 70 years they should have this amount, she noted.

Changes in dementia clinical practice outlined

Many advances in dementia research and diagnostic strategies will have implications for clinical practice in coming years, according to Prof Nick Fox, Consultant Neurologist, University College London, UK, the guest speaker for the meeting.

A child born in Dublin today has a one-in-three chance of spending the latter part of their life with dementia, said Prof Fox.

The number of people with dementia is increasing. This is due to improved diagnosis and changes in how death is recorded, he said.

One million people in the UK will have dementia in a decade or so and research is finding that there is a strong genetic component to the disease, Prof Fox commented.

The Decode project in Iceland found that in people 85 years and older there is a rare mutation in a gene that is protective for dementia.

People are having their genome tested now, said Prof Fox, and it does not cost a lot of money. About 20 per cent of people have APO e4, he said, which means a three-fold increased risk of dementia, while two copies of APO e4 means a 10-fold increased risk of dementia.

There are now dementia tests, ‘chips’, which can test for 17 genes, and cost about £100. Looking at frontotemporal dementia, there is a familial link. The genetic risk is highest in families with early onset dementia, but one-in-six late-onset cases are also probably genetic, said Prof Fox.

While there is now the availability of rapid multi-gene testing, the question is whether a family will have a test if they know they are at risk, he commented,

The next big advance is in biomarkers and everyone that is at risk from dementia should have structural imaging, with MRI preferable to CT, he stated.

The technology has developed to the point where it is possible to move to a predictive approach to dementia rather than an exclusionary one, said Prof Fox.

For Alzheimer’s disease, MRI scans are useful, but for dementia with Lewy bodies, it is not very useful, while for semantic dementia MRI is almost definitive.

The use of good imaging technology, with the new era of biomarkers is going to change clinical practice, said Prof Fox.

It is known that the hippocampus is already 10 to 20 per cent smaller than in controls at the time dementia is diagnosed.

Innovative technology will mean that a result will be produced, which will say that the patient is in the ‘x’ percentile for hippocampal size and that will change practice.

It will also change how dementia is monitored, because precise scans can see how the brain structure is changing over a year, for example.

There are other technologies, such as amyloid imaging, said Prof Fox, which is already a decade old and was developed in Pittsburgh.

An amyloid negative test can predict semantic dementia, while an amyloid-positive test can predict AD.

F18 amyloid PET tracers are being widely used for scans in the private health system in the US, said Prof Fox, and they are appropriate technologies for use in young-onset, or primary psychiatric dementia.

The combination of memory deficit, a biomarker and a hippocampal deficit can indicate a patient’s problems are due to AD. This means that patients do not have to wait to learn their diagnosis like they used to, said Prof Fox.

There are a couple of biomarkers that will enable blood tests to be developed for AD in the future, which will be of value, Prof Fox noted.

For example, plasma neurofilament lights up clearly in cases of neurodegeneration and it will be up for AD and not depression.

There are plenty of targets now for disease modification and Prof Fox said he is himself doing work on gene silencing.

This work could prove to be “miraculous” he said, and he is looking for patients that have autosomal dominant AD to take part in clinical trials.

There is work too now on prevention of AD through the Dominantly Inherited Alzheimer Network Trials Unit. This unit is offering people therapies that would have developed AD inevitably aged 40 or 50 years and decided not to have families, said Prof Fox.

Raising dementia awareness in Ireland

The question of how best to raise awareness of the growing dementia problem in Ireland was addressed by Prof Brian Lawlor, Consultant Psychiatrist, St James’s Hospital, Dublin, and Director of the Memory Clinic at the same hospital.

‘Can we address modifiable risk factors for dementia and, if yes, how?’ was the question Prof Lawlor began his talk with.

Education about dementia can help to delay onset of dementia or slow its trajectory, he said, but what is the best way to motivate people now, to prevent something happening in 20, 30 or 40 years?

Prof Lawlor listed the modifiable dementia risk factors as education levels in early life, hypertension, obesity and hearing loss in midlife, and in later life, smoking, depression, physical inactivity, social isolation and diabetes.

There has been a decline in dementia in high-income countries, but is this due to better education, or better control of cardio risk factors? It is not known for sure, he said.

We need to be careful in a public health campaign, to suggest that reducing risk factors for dementia will reduce dementia, as the evidence is not there for that yet, cautioned Prof Lawlor.

People over 50 years of age are more in fear of a dementia diagnosis than cancer, he said, but only about one-in-four people in Ireland have a reasonable understanding of dementia.

Over 50 per cent of people have been found to be unaware that there are modifiable risk factors for dementia. There is a poor knowledge of risk and protective factors for dementia, right across the board, not just the lower socio-economic groups, so the correct messages must be gotten across, he said.

Trying to motivate people in middle life is hard when the threat is remote, but there will be adverts on television about dementia over the next few weeks as part of a new HSE awareness campaign, concluded Prof Lawlor.

Organ transplantation and brain death

Ireland must do more to encourage the donation of organs in cases of brain death, Prof Jim Egan, Consultant in Respiratory Medicine at the Mater Hospital, Dublin, and Director of the HSE National Organ and Transplant Service, told the meeting.

There are currently 550 people awaiting kidney transplants alone in Ireland, with the number of people on kidney dialysis growing exponentially, he revealed.

Ireland is below the European average for deceased organ donation, so it is very rare here, said Prof Egan, while in other EU countries such as Croatia and Spain there is a strong culture of organ donation.

To try and increase the numbers of deceased organ donations here, the Government is seeking to introduce legislation based on presumed consent (opt-out) in line with the law that exists in Spain, said Prof Egan.

Organ Donation and Transplant Ireland was set up in 2013 and since then they have been growing the Irish version of the Spanish system here.

“We have about 20 donors per million of population. Whereas Spain has about 40 per million. They have a better system…

“But we are not good at considering organ donation in an older population, because surgeons are judged on the outcomes if it fails and it is more complex, due to presence of disease and so on.

“In Madrid if you drop dead in street, you are brought to accident and emergency and sustained until the organ donation option is explored. We are not at that level in Ireland.

Epilepsy treatment and diagnosis is changing

The diagnosis and treatment of epilepsy is changing and it is an exciting time for young doctors to get involved in the field, according to Dr Danny Costello, Consultant Neurologist at Cork University Hospital, who gave a talk entitled ’10 reasons to like epilepsy’.

There is a much deeper understanding of epilepsy today thanks to brain imaging, genetics and neurophysiology, he told the meeting.

Dr Costello said that epilepsy is a family of conditions that affect the grey matter and cerebral cortex and that there are a lot of hidden epilepsies.

The condition remains challenging as one-third of patients are drug-resistant and 40 per cent of patients have an unknown epilepsy mechanism.

It is a common disorder, with epilepsy clinics full and overbooked, he said. It is also frequently misdiagnosed, but there are prospects to help those affected.

There is a greater push to find out why the disorder occurs, and the advance of imaging and MRI has helped this, Dr Costello reported.

It is a field that is advancing fast with image-guided surgery, computer technology, and intra-operative imaging making a difference, he continued.

There have been advances in therapeutics with three new medicines coming online: Lacosamide, perampanel and brivaracetam.

There is potential for cures in epilepsy and there is a lot of work being done in the RCSI and elsewhere on epilepsy genetics, which is an emerging area, Dr Costello noted. 

There are common, familial forms of epilepsy where there is an increased likelihood of finding genes in those patients.

There is a greater drive to find the epileptogenic area of the brain, whether on the brain surface, or deep in the brain, using depth electrodes if required.

There is also exciting research happening on auto-immune conditions associated with epilepsy, said Dr Costello.

He showed the meeting videos of people having seizures, which showed the impact on individuals from epilepsy and how it can even be life-threatening.

Helping patients with epilepsy can make a difference by preventing social drift in a cohort of people that would really struggle without such help, said Dr Costello.

See www.iicn.ie for more photographs and details of the meeting.