Cognitive Reserve      by Lisa Melton

The threat hung in the air. Ian Deary, one of the UK’s top researchers into intelligence and ageing, had become disgruntled at the lack of original ideas and could not contain himself any longer. “Please say something else or I'll catch an early train back to Edinburgh,” he snapped. Several of his peers laughed awkwardly. Deary, professor of differential psychology at Edinburgh University and organiser of the remarkable meeting, had hit a nerve amid an already charged atmosphere.

The respected clinicians, epidemiologists, geneticists, and psychologists were leaders in their fields, gathered in London at the Novartis Foundation to discuss the contentious concept of cerebral reserve. But now the very person who had summoned them all to share their thoughts seemed to be angling to walk out.

The focus of their attentions was undeniably challenging. Cerebral reserve, a notional quality that gives individuals differing levels of mental resilience, is a proposal that has all the ingredients needed to stoke a controversy - intelligence, genes, social status, education and health. Behind it all is a set of widely accepted scientific results that suggest that people with high intelligence and superior education cope better with the progress of Alzheimer’s disease and other forms of dementia and recover more rapidly from stroke, head injuries, depression and even intoxication than the average. And while mental faculties always decline with age, there are marked differences in the rate at which the years dull the mind. Cerebral reserve was dreamt up to explain such anomalies.

Sir Michael Marmot, the epidemiologist whose ground-breaking Whitehall studies of civil servants showed how social standing affects life expectancy, was in the chair at the meeting back in November 2004. In typically understated manner, he had opened proceedings by acknowledging the depressing truth that age brings about cognitive degeneration. But he wondered about the growing body of evidence that education might soften the blow of advanced years. “Is that what we mean by cognitive reserve?” Marmot prodded his audience. “Does it relate to something basic in the brain structure, something crude about brain size or is it something to do with the software?” And so it started.

The group had been hand-picked. Meetings held at the Novartis Foundation’s 18th century London headquarters are generally invitation only and numbers are deliberately limited to between 20 and 30 experts to encourage interaction. Participants sit in comfortable chairs in a plain room, with no distractions other than a projector. And, in a complete departure from the usual format for scientific meetings, equal time is dedicated to discussion as to presentations. Delegates are there to comment, critique and collude. Exchanges can become heated, yet scientists relish the opportunity to exchange ideas with their scientific peers. The Foundation is renowned for generating scientific ruckus of the highest calibre and always attracts scientific luminaries to take part in the intellectual free-for-all.

Cognitive reserve is an ideal subject for such a meeting. To some, Deary included, the concept is nothing but a chimera conjured up simply to explain a puzzling observation. So it was no surprise that Yaakov Stern, a neuroscientist at the Sergievsky Centre at Columbia University, New York, was clearly on his guard as he presented his latest data. He believes that brain networks are the biological underpinning to cognitive reserve and is using brain imaging to probe them. “What are people with high reserve doing differently?" he asked. He went on to explain that his research suggests that they are using alternative brain networks to compensate for those that have lost their function. Meanwhile those with low reserve fail are unable to do this and so run into difficulties.

An elegant approach, but had Stern uncovered the smoking gun? His contribution sparked some enthusiastic speculation among several participants that, finally, here was something that might be of practical help for patients. If cognitive reserve be measured, people could be tested for it, like measuring blood pressure or cholesterol levels. Then clinicians could then see whether a patient had strayed across some sort of threshold into the danger zone when mental decline was imminent and maybe even take action to prevent the onset of debilitating symptoms.

The brain’s plasticity makes a strong case for measuring reserve. Cognition can be modified, even in the adult years, and neurons can be rearranged, by physical and mental exercises, be it crossword puzzles, juggling, or taking night classes. If the dwindling reserve is spotted early, it opens a biological window in which to boost cognition and slow the rate of decline. 

But others felt distinctly uncomfortable with the one-size-fits-all idea. From the back of the room, Nick Fox, a clinician scientist at the Institute of Neurology, London, who heads the dementia group and specializes in Alzheimer's disease, took the opportunity to throw a spanner into the enthusiasts' works.

He told the meeting of a former university lecturer who had arrived at his clinic complaining of failing memory. The man’s family insisted that nothing was wrong with him, and indeed, psychometric tests showed no problem. But the academic was clearly troubled. He complained that while he used to think nine moves ahead in a chess game. Now he could only think five moves ahead. Some weeks later, the former lecturer died of an unrelated illness. The autopsy revealed something remarkable - the man’s brain was riddled with the plaques and tangles typical of Alzheimer's disease. For some people, such physical damage would have reduced them to a state of confusion. For the academic it meant an impairment in his ability to play chess. "In his case, measuring cognitive reserve would not have predicted disease outcome," Fox insisted.

Deary enthusiastically agreed. Would nuclear physicists care about a universal safety level that was set a long way below the level at which they worked, he asked. “They've got their internal threshold which is far higher than average and dropping to that threshold is what matters to them,” he noted. The only way to really know how an individual was doing was to track, say, how their hippocampus, the area of the brain dedicated to storing information, shrank over time.

Is reserve merely down to brain anatomy? Neither brain volume, neuron density nor number of synapses hold up. Education, however, does. According to Marcus Richards an epidemiologist at University College London who has tracked people over their lifecourse by sifting through data from the British 1946 cohort study, education at age 26 can predict cognitive ability at age 53. As he succinctly put it: “Education works.” Intellectual challenges make a difference to cognition in old age, yet Richards points out that the biggest influence is adolescent cognitive ability, itself a cocktail of biology, behavioural and societal influences

Deary’s sceptical take on reserve seemed to infect the meeting as he pressed on. "Are we talking about anything other than the biology of intelligence?" he mused. "In people's talks I tried to replace reserve with ability or intelligence and it didn't do too much violence to what they were saying." Deary then systematically took apart every publication that claimed reserve as the explanation for a particular set of observations, demolishing their arguments. "Cognitive reserve could just be the continuity of cognitive ability in youth to old age, and this could influence disease expression,” he said. “Is it just the case that people who peak higher have further to drop? That's not terribly profound - if you drop something from the first floor window then it reaches the floor sooner than if you drop it from the fourth floor." 

Eventually he came clean, admitting his belief in a signature for brain reserve that can be detected with a precise formulation. “Where you end up, if you have a lot of reserve, should be greater than you would predict given the accumulated brain insults and where you started out from.” Yet Deary acknowledged that, as yet, the biology of reserve remains elusive. 

"If reserve is really getting at the biology of intelligence then that's the terra incognito - we have really very little handle on it."

The meeting was losing momentum. Then Jonathan Seckl, an endocrinologist at Edinburgh University, observed: "The brain is just another organ. It may be a terribly complicated one, but you can work it out." 

Taking an all-encompassing physiological bent, he delivered an impassioned exhortation. There was a time, he said, when heart disease was not understood - it was a black box. As a succession of risk factors like smoking, obesity, lack of exercise, stress and hypertension were uncovered, that black box faded away. Ninety per cent of heart attacks can now be explained. "I wonder whether reserve stops us thinking about what fills the black box of the brain, and actually what we really need to be doing is understanding all those factors that have come up today like genes, early life events and the adult risk factors that tell us where we are going to get with our intelligence and the rate at which it will decline." 

It was the meeting's epiphanies argument. One person clapped. Others mumbled in admiration, and an incredulous voice interjected: "But that is what we interested in!" "Then stop calling it reserve and call it risk factors," Seckl retorted. 

Sir Michael Rutter, the single most influential figure in child and adolescent psychopathology over the last 35 years, had listened attentively but kept silent throughout. As the proceedings were drawing to a close, the professor of developmental psychopathology at the Institute of Psychiatry, London, delivered a crushing verdict on cognitive reserve. "I wouldn't advise students to spend their lives measuring it," he said. "I'd pay a lot of attention to the phenomena but I'd get rid of the concept. The research should be focused on individual differences because that's what it's about - not on some hypothetical construct of reserve."

Society is faced with ageing population that will slip into dementia and Alzheimer’s. Any way in which such a fate can be avoided will clearly have enormous implications. So even as Deary regards cognitive reserve as "superfluous wrapping-paper" for intelligence, it is certain to remain high on the public health agenda. As Stern pointed out "This is as powerful as any drug we will ever have to prevent progression of Alzheimer's disease." At least the discussion had been gripping enough to keep Deary until the very end.

Based on a Novartis Foundation Discussion meeting in London on Cognitive Reserve, held on 12 November 2004

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