The study highlights the potential of new technologies to help diagnose and monitor conditions such as Alzheimer’s disease, which affects more than 525,000 people in the UK.

In 2014, Professor John O’Keefe of UCL was jointly awarded the Nobel Prize in Physiology or Medicine for ‘discoveries of cells that constitute a positioning system in the brain’. Essentially, this means that the brain contains a mental ‘satnav’ of where we are, where we have been, and how to find our way around.

A key component of this internal satnav is a region of the brain known as the entorhinal cortex. This is one of the first regions to be damaged in Alzheimer’s disease, which may explain why ‘getting lost’ is one of the first symptoms of the disease. However, the pen-and-paper cognitive tests used in clinic to diagnose the condition are unable to test for navigation difficulties.

In collaboration with Professor Neil Burgess at UCL, a team of scientists at the Department of Clinical Neurosciences at the University of Cambridge led by Dr Dennis Chan, previously Professor O’Keefe’s PhD student, developed and trialled a VR navigation test in patients at risk of developing dementia. The results of their study are published today in the journal Brain.

In the test, a patient dons a VR headset and undertakes a test of navigation while walking within a simulated environment. Successful completion of the task requires intact functioning of the entorhinal cortex, so Dr Chan’s team hypothesised that patients with early Alzheimer’s disease would be disproportionately affected on the test.

The team recruited 45 patients with mild cognitive impairment (MCI) from the Cambridge University Hospitals NHS Trust Mild Cognitive Impairment and Memory Clinics. Patients with MCI typically exhibit memory impairment, but while MCI can indicate early Alzheimer’s, it can also be caused by other conditions such as anxiety and even normal aging. As such, establishing the cause of MCI is crucial for determining whether affected individuals are at risk of developing dementia in the future.

The researchers took samples of cerebrospinal fluid (CSF) to look for biomarkers of underlying Alzheimer’s disease in their MCI patients, with 12 testing positive. The researchers also recruited 41 age-matched healthy controls for comparison.

All of the patients with MCI performed worse on the navigation task than the healthy controls. However, the study yielded two crucial additional observations. First, MCI patients with positive CSF markers — indicating the presence of Alzheimer’s disease, thus placing them at risk of developing dementia — performed worse than those with negative CSF markers at low risk of future dementia.

Secondly, the VR navigation task was better at differentiating between these low and high risk MCI patients than a battery of currently-used tests considered to be gold standard for the diagnosis of early Alzheimer’s.

“These results suggest a VR test of navigation may be better at identifying early Alzheimer’s disease than tests we use at present in clinic and in research studies,” says Dr Chan.

VR could also help clinical trials of future drugs aimed at slowing down, or even halting, progression of Alzheimer’s disease. Currently, the first stage of drug trials involves testing in animals, typically mouse models of the disease. To determine whether treatments are effective, scientists study their effect on navigation using tests such as a water maze, where mice have to learn the location of hidden platforms beneath the surface of opaque pools of water. If new drugs are found to improve memory on this task, they proceed to trials in human subjects, but using word and picture memory tests. This lack of comparability of memory tests between animal models and human participants represents a major problem for current clinical trials.

“The brain cells underpinning navigation are similar in rodents and humans, so testing navigation may allow us to overcome this roadblock in Alzheimer’s drug trials and help translate basic science discoveries into clinical use,” says Dr Chan. “We’ve wanted to do this for years, but it’s only now that VR technology has evolved to the point that we can readily undertake this research in patients.”

In fact, Dr Chan believes technology could play a crucial role in diagnosing and monitoring Alzheimer’s disease. He is working with Professor Cecilia Mascolo at Cambridge’s Centre for Mobile, Wearable Systems and Augmented Intelligence to develop apps for detecting the disease and monitoring its progression. These apps would run on smartphones and smartwatches. As well as looking for changes in how we navigate, the apps will track changes in other everyday activities such as sleep and communication.

“We know that Alzheimer’s affects the brain long before symptoms become apparent,” says Dr Chan. “We’re getting to the point where everyday tech can be used to spot the warning signs of the disease well before we become aware of them.

“We live in a world where mobile devices are almost ubiquitous, and so app-based approaches have the potential to diagnose Alzheimer’s disease at minimal extra cost and at a scale way beyond that of brain scanning and other current diagnostic approaches.”

The VR research was funded by the Medical Research Council and the Cambridge NIHR Biomedical Research Centre. The app-based research is funded by the Wellcome, the European Research Council and the Alan Turing Institute.

In an article in the journal Brain, Professor Catani lays out the evidence supporting his hypothesis, drawing on historical accounts of Leonardo’s work practices and behaviour. As well as explaining his chronic procrastination, ADHD could have been a factor in Leonardo’s extraordinary creativity and achievements across the arts and sciences.

Professor Catani, from the Institute of Psychiatry, Psychology & Neuroscience at King’s, says: ‘While impossible to make a post-mortem diagnosis for someone who lived 500 years ago, I am confident that ADHD is the most convincing and scientifically plausible hypothesis to explain Leonardo’s difficulty in finishing his works. Historical records show Leonardo spent excessive time planning projects but lacked perseverance. ADHD could explain aspects of Leonardo’s temperament and his strange mercurial genius.’

ADHD is a behavioural disorder characterised by continuous procrastination, the inability to complete tasks, mind-wandering and a restlessness of the body and mind. While most commonly recognised in childhood, ADHD is increasingly being diagnosed among adults including university students and people with successful careers.

Leonardo’s difficulties with sticking to tasks were pervasive from childhood. Accounts from biographers and contemporaries show Leonardo was constantly on the go, often jumping from task to task. Like many of those suffering with ADHD, he slept very little and worked continuously night and day by alternating rapid cycles of short naps and time awake.

Alongside reports of erratic behaviour and incomplete projects from fellow artists and patrons, including Pope Leone X, there is indirect evidence to suggest that Leonardo’s brain was organised differently compared to average. He was left-handed and likely to be both dyslexic and have a dominance for language in the right-hand side of his brain, all of which are common among people with ADHD.

Perhaps the most distinctive and yet disruptive side of Leonardo’s mind was his voracious curiosity, which both propelled his creativity and also distracted him. Professor Catani suggests ADHD can have positive effects, for example mind-wandering can fuel creativity and originality. However, while beneficial in the initial stages of the creative process, the same traits can be a hindrance when interest shifts to something else.

Professor Catani, who specialises in treating neurodevelopmental conditions like Autism and ADHD, says: ‘There is a prevailing misconception that ADHD is typical of misbehaving children with low intelligence, destined for a troubled life. On the contrary, most of the adults I see in my clinic report having been bright, intuitive children but develop symptoms of anxiety and depression later in life for having failed to achieve their potential.’

‘It is incredible that Leonardo considered himself as someone who had failed in life. I hope that the case of Leonardo shows that ADHD is not linked to low IQ or lack of creativity but rather the difficulty of capitalising on natural talents. I hope that Leonardo’s legacy can help us to change some of the stigma around ADHD.’

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Materials provided by King’s College London. Note: Content may be edited for style and length.

It is believed that, if doctors had recognized that influenza was the cause of an illness which was killing soldiers in Etaples, France, and Aldershot, England, in 1916, scientists would then have had better grounds to embark on a two-year vaccination programme and some of the worst effects of the Spanish influenza could have been avoided. Such are the findings of a new paper, launched by Professor John S. Oxford, the UK’s top expert on influenza, and Douglas Gill, a military historian.

Published in Human Vaccines & Immunotherapeutics, the study uses modern day scientific technology and delves through literature published in The Lancet from the time, to not only track the origins of the virus, but to seek how we can use this information to learn from the past to prevent the spread of an influenza pandemic.

In their quest, Oxford and Gill trace the origins of the Spanish influenza as it emerged in 1915 and 1916 in the Etaples Administrative District in northern France. At the time, up to 30,000 soldiers were admitted each year to British army hospitals in France and England, suffering from typical influenza symptoms. In early 1917, however, a medical group in Etaples treated hundreds of patients infected with what they described as an “unusually fatal disease” presenting “complex” respiratory symptoms.

In Aldershot, in the south of England, three senior physicians were also tackling a problem whose hallmarks looked very much the same. In both instances, the disease was characterized by a ‘dusky’ cyanosis, a rapid progression from quite minor symptoms to death — with death in any case usually resulting from a superinfection involving staphylococcus, streptococcus, etc.

Both medical groups were encountering a case fatality in the order of 50%, and they were learning from colleagues in England and France (who were publishing in The Lancet in 1917) that the malady was occurring elsewhere.

It is this information which has helped Oxford and Gill to track what was then believed to be a minor respiratory infection as the very origins of the biggest killing pandemic of the 20th century.

“We have identified long-neglected outbreaks of infection: outbreaks which, judged as minor at the time, can now be seen as increasingly important, and a portent of the disaster to come,” explains Professor Oxford, of Queen Mary University, London.

“The research undertaken in the production of the Etaples paper was particularly exhaustive in its scope and depth. Not only were the usual examinations undertaken, of tissue and sputum, but a postmortem examination was conducted of every single soldier dying of disease, throughout a period of seven weeks in early 1917.”

The findings of the literature as to the origins of the Spanish influenza are further supported in modern papers analysed by Oxford and Gill, wherein scientific methods, namely phylogenetic (the study of evolutionary relationships among biological entities — often species, individuals or genes) and molecular clock analysis, point to all eight genes of the H1N1 family of influenza A viruses as emerging in 1915-1916.

These modern studies have also shown that the ’emerging virus’ began with aquatic geese, ducks, and swans as a reservoir. It is likely that this disease was then passed on to the soldiers through the faeces of migrating water birds.

So what happened between 1915-1916 and 1918-1919 to make this pre-pandemic virus to become pandemic?

Professor Oxford explains.

“In essence, the virus must have mutated. It lost a great deal of its virulence, but gained a marked ability to spread. Recent experiments with a pre-pandemic ‘bird flu’ called H5N1, deliberately mutated in the laboratory, have shown that as few as five mutations could have permitted this change to take place.”

“We appreciate today that a unique characteristic of a pre-pandemic virus lies in its inability to spread from person to person,” Professor Oxford added. “The teams at Etaples and Aldershot, although strong in clinical diagnosis, were misled by the lack of spread of this infection. Accordingly, they failed to pinpoint influenza as the underlying cause.”

There was, however, a silver lining to a very dark cloud.

“Pathologists in the United States and in France strove to construct the first universal vaccines against influenza. Their efforts were not misdirected, because the ultimate cause of death in nearly all cases flowed from superinfections with respiratory bacteria.”

Oxford and Gill conclude: “We remain impressed by the care and initiative shown by our predecessors 100 years ago. Their efforts did have an impact on the level of fatalities, but — not unexpectedly — had no effect upon spread: the result, of course, of everyone’s misunderstanding of the nature of the pathogen involved.

“Once the virus is able to spread from human to human, disaster strikes. With a generation time of two to three days, from just three patients who were infected originally, a million infections can be caused in around 40 days. And this is probably exactly what happened in 1918-1919.”

Today, the World Health Organisationis on full alert; and every nation in the world has been asked to plan for a pandemic of bird influenza A (H5N1) or (H7N9).

By understanding the origins of the Spanish influenza via analyzing modern day research and papers written in 1917, it is hoped this study could help us prevent a new influenza pandemic.

Professor Oxford thinks that existing vaccines have a role to play.

“Something similar to what happened at the beginning of the twentieth century could easily be repeated. As a precaution, governments everywhere are stockpiling vaccines against the pneumococcus that usually develops as a secondary infection after the flu, and which causes fatalities on a very large scale.”