Cellular
and animal studies suggest that hypercholesterolemia contributes to
Alzheimer disease (AD). However, the relationship between cholesterol
and dementia at the population level is less clear and may vary over the
lifespan.
Methods:
The
Prospective Population Study of Women, consisting of 1,462 women
without dementia aged 38–60 years, was initiated in 1968–1969 in
Gothenburg, Sweden. Follow-ups were conducted in 1974–1975, 1980–1981,
1992–1993, and 2000–2001. All-cause dementia was diagnosed according to DSM-III-R
criteria and AD according to National Institute of Neurological and
Communicative Disorders and Stroke–Alzheimer's Disease and Related
Disorders Association criteria. Cox proportional hazards regression
examined baseline, time-dependent, and change in cholesterol levels in
relation to incident dementia and AD among all participants. Analyses
were repeated among participants who survived to the age of 70 years or
older and participated in the 2000–2001 examination.
Results:
Higher
cholesterol level in 1968 was not associated with an increased risk of
AD (highest vs lowest quartile: hazard ratio [HR] 2.82, 95% confidence
interval [CI] 0.94–8.43) among those who survived to and participated in
the 2000–2001 examination. While there was no association between
cholesterol level and dementia when considering all participants over 32
years, a time-dependent decrease in cholesterol over the follow-up was
associated with an increased risk of dementia (HR 2.35, 95% CI
1.22–4.58).
Conclusion:
These
data suggest that midlife cholesterol level is not associated with an
increased risk of AD. However, there may be a slight risk among those
surviving to an age at risk for dementia. Declining cholesterol levels
from midlife to late life may better predict AD risk than levels
obtained at one timepoint prior to dementia onset. Analytic strategies
examining this and other risk factors across the lifespan may affect
interpretation of results.
GLOSSARY
AD
= Alzheimer disease;
BMI
= body mass index;
CI
= confidence interval;
DBP
= diastolic blood pressure;
DSM-III-R
= Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised;
It’s not headline news that our brains are the seat of our
thoughts and feelings. The brain is a body’s decision-maker, the pilot
of its actions and the engineer that keeps all systems going. The brain
suits the body’s actions to its surroundings, taking in sensory details
and sending out appropriate and timely responses. We’ve long attributed
the marvelous workings of the brain to the intricate structures formed
by its highly specialized cells, neurons. These structures constitute
the hardware of the brain.
But new genomic research reveals that, at an even deeper level,
emotions and behavior are also shaped by a second layer of organization
in the brain, one that we only recently created the tools to see. This
one relies on genes.
We are beginning to appreciate how genes and neurons work together,
like software and hardware, to make brain function possible. Learning to
understand this two-layer system can help us understand how the
environment affects behavior, and how to hack the system to improve
mental health.
It is time to fully recognize gene activity not as the background
utility of the brain, but as an integral part of its operation.
Neurons in the driver’s seat
A cat’s neuron stained with Golgi’s technique as drawn by Santiago Ramón y Cajal. Santiago Ramón y Cajal
The sheer complexity of the human brain became apparent in the late 19th century, when two skilled anatomists, Camillo Golgi of Italy and Santiago Ramón y Cajal of Spain, invented tissue-staining techniques that revealed intricate microscopic networks of neural cells.
We now know that about 100 billion neurons connect with each other in a human brain to form complex circuits that carry electrical and chemical messages to make memories and govern behavior. This physical structure, the one that yielded itself to the scientific tools of the time, constitutes the hardware of our neural control system, which is uniquely rewireable by experience.
Throughout the 20th century, scores of scientists characterized the sugars, lipids, proteins and myriad other molecules that build, run and repair our brains. These molecules seemed to stay out of the limelight; they appeared to play a supporting role to the neurons that ostensibly controlled our behavior.
But the 21st-century science of genomics delivered a new surprise about the brain. Genomics examines the entire set of genetic information contained within cells, the activities of genes and the interactions between them. Genomics revealed that the brain’s genes are considerably more involved in regulating behavior than ever imagined.
Genes direct the production of the above-mentioned brain molecules via intermediaries made of RNA. RNA molecules tell the machinery of the cell when and how to make the proteins it needs to grow and function. Technologies developed over the last 20 years have allowed researchers to monitor the ebbs and flows of RNA produced by every gene in the brain with increasing precision. These studies have unveiled a surprisingly close relationship between behavior and gene activity in the brain.
Some of the earliest insights into the close relationship between behavior and brain gene activity came from an unlikely source: the brain of the honeybee. Honeybees, like humans, live in a complex society, and they too are strongly influenced by what others around them are doing.
My laboratory discovered that changes in behavior are orchestrated by altered activity of thousands of genes in the bee brain. In some cases, the relationship between behavior and brain gene activity is so close that a computer program can accurately predict, from patterns of brain gene activity alone, the bee’s behavior. It turns out that similar genomic responses are found in many other species, including human beings, a finding that reinforces the idea of genes within neurons as a driving force underlying behavior.
This discovery was surprising because neurons are known to adjust how they communicate with each other to cause changes in behavior via mechanisms that do not require immediate changes in gene activity. Although we knew the molecules of the brain must be continually manufactured to enable neuronal circuits to rewire as a result of age and accumulated experience, neuroscientists didn’t anticipate that the relationship between brain gene activity and behavior would be so tightly coupled.
Why is there such a close coupling of brain gene activity and behavior? One hint comes from another bee study. Honeybees respond aggressively and immediately to a threat to their hive; in nature any prolonged delay could prove fatal. This behavioral response is much faster than the time it takes to produce new molecules of RNA, suggesting the initial response is more dependent on the neural system than the genomic one. Nevertheless, my laboratory found changes in the activity of hundreds of genes in the brains of individual bees in response to an intruder in the hive, hours after the threat was neutralized. The threatening experience changed them, in both molecular and behavioral terms.
Coincident with the persistent changes in brain gene activity, which we could see via changes in amounts of each individual type of RNA molecule, was a persistent increase in the vigilance of the once-agitated bees. This makes good sense; while past performance does not necessarily predict future results on Wall Street, it is a safe bet in nature to remain vigilant after experiencing a threat. Experimental manipulations that simulated the gene activity profile of the post-intruder brain made naïve bees more aggressive, demonstrating a causal relationship between brain gene activity and behavior. The bee brain, confronted with a threat that might be recurring, has genomic apps that help it respond more effectively.
My colleagues and I also showed that the same kinds of changes occur after stickleback fish and mice are threatened, suggesting that this slow, persistent, genomic response to experience is a universal property of brains.
The brain’s neurons and the genomes within them, the hardware and the software, together orchestrate one’s response to a new situation, which can vary from person to person. The same dramatic event – a challenge at school or work, a new person in one’s social circle – might cause a great deal of stress in one person, and very little in another. We now think that the neural systems of two such people are likely tuned differently by their genomic systems, perhaps as a consequence of differentially stressful past experiences. In the living brain, unlike a computer, the software can help modify the hardware, and as new situations are encountered, the functioning of the neural hardware continues to modify the genomic software. Nature has come up with a “smart” system in which hardware and software are adaptable and interact dynamically!
This reciprocity between genes and neurons continually builds on an interwoven history that stretches all the way back to inherited individual differences in temperament, which also influence gene activity. And while an acute stress might cause genomic changes that provoke fear and anger for a few hours, chronic stress due to deprivation or violence can cause debilitating health effects because it activates genomic changes in the brain that do not dissipate. In some cases, it induces long-lasting changes to the chemical structure of DNA; these changes, referred to as epigenetic, might even be passed down from one generation to the next.
We need to learn how to better read the genomic record of changes left by experience in order to predict future outcomes. Not only would this deepen our fundamental understanding of the brain, but it would also help us understand how socioeconomic stresses “get under the skin” to negatively affect health and well-being.
Research efforts, including the exciting new federal Brain Initiative, must focus on developing new technologies – both to measure neuronal activity with greater precision and to explore how the neuronal and genomic systems communicate with each other.
Brains do more than direct our behavior. They build our experiences into a coherent perception of the world. This world will be as unique for each of us as our personal history, with the potential to be sunny, or cloudy, or filled with shadows. If we can become proficient in the code our brains run on, perhaps we can learn to give these narratives a nudge in the right direction, and flood every person’s world with light.
Todd Sampson is standing on the precipice of a Sydney
office tower, 21 floors off the ground, preparing to step onto a thin
wire cable.
The advertising executive, television personality and
company director is a novice tightrope walker but is attempting
a skywalk across an eight-metre line to an office tower on the other
side.
Sampson hasn't lost his mind. In fact, he's never felt smarter.
The chief executive of ad agency Leo Burnett Australia, who was recently appointed to the boards of Qantas and Fairfax – publisher of The Australian Financial Review – has
been undergoing a radical brain makeover using leading scientists in
brain plasticity to prove that people can be made smarter.
Todd Sampson: training your brain is as important as physical exercise.
Chris Hopkins
For decades, the
prevailing dogma in neuroscience was that the adult human brain is
essentially immutable and hardwired so that by the time we reach
adulthood, we are stuck with what we have.
But Sampson's brain training has already helped him escape from underwater chains, climb a 150-metre rock face blindfolded and compete in a global safe-cracking competition.
"I
got up there and looked at the wire and I tell you what, I thought, I
don't think this is possible, it looked so exposed, it looked so … out
there," the Canadian-born Sampson tells AFR Weekend about the skywalk that didn't exactly go to plan.
"I
meditated, I calmed myself down, I used the training, I tried to
visualise myself crossing it. I put one foot forward and I remember
thinking, just go for it, don't think too much – I've been trained to do
this."
Todd Sampson puts his prowess to the test while trying to crack open a safe on ABC TV's Redesign My Brain 2.
ABC
Power of visualisation
The dramatic skywalk is the climax of the latest season of Redesign My Brain,
which begins screening on ABC this coming week and takes Sampson "on a
quest to train my mind to better cope with the challenges of modern
life".
In the show, the T-shirt-wearing father of two offers
himself as a scientific guinea pig to improve his hearing, sight,
memory, touch and decision-making skills.
The self-described "science nerd" rose to fame after co-creating the Earth Hour initiative and appearing on ABC's The Gruen Transfer. He is now a regular on Channel Ten's The Project.
Todd Sampson on the cover of Fitness First's magazine.
None
But the polymath says
his true passion is the emerging science of brain plasticity – and it so
happens that another major proponent of this discipline, best-selling
author of The Brain that Changes Itself, psychiatrist Norman Doidge, arrives in Australia for the Sydney Writers' Festival on the weekend.
Neuroplasticians
won the Nobel prize for medicine in 2000 by showing that the brain
changes as it works and that as learning occurs, connections among nerve
cells increase. Doidge's latest book, The Brain's Way of Healing,
proposes that the brain's ability for self-repair may even help treat
conditions such as Parkinson's disease and autism or help to heal stroke
damage and head trauma.
To tackle the skywalk, Sampson first had
to conquer his fear of heights, which meant working with psychologist
Dr Todd Farchione at Boston University. Farchione engaged Sampson in
immersion therapy, including spending time at 3D virtual-reality
providers WorldViz to simulate the walk.
"The longer you stay in the situation, the easier it gets," Farchione says.
The theory goes that if
we can train the thinking region of our brain to be less reactive to
the amygdala, the brain structure that triggers our fear alarm system,
we can conquer our fears.
"The key to visualisation is, your brain
doesn't really know the difference between what is real and fake," the
fast-talking Sampson says.
American skywalker Nik Wallenda, the first person to high-wire walk across the Grand Canyon, also emphasises the power of visualisation.
"I
spent time on the edge of the Grand Canyon before I walked, I would sit
there for hours at a time just visualising myself … I encourage you to
do the same."
Sampson was also tested by the Massachusetts
Institute of Technology's decision-making department, which revealed an
"extreme optimism bias", meaning the advertising executive too easily
dismisses bad news. He is not alone – experts claim up to 80 per cent of
us suffer from an optimism bias.
"When I made the decision to
climb Mount Everest, I remember the stat that one in six [people] die
and I remember thinking, those are brilliant odds," he recalls.
Sampson
says he tackled his decision-making skills by training with Fire Rescue
NSW, where he led a team of firefighters into a burning building to
rescue six dummies.
And he spent time walking barefoot each week
to improve his sensation of touch. "Humans have been on the earth for
about 200,000 years but shoes have only shown up in about the last
8000," neuroscientist Dr David Blake says.
Lastly, Sampson learnt
mindfulness meditation to tackle his anxiety,
with neuroscientists Dr Fadel Zeidan and Dr David Vago – including
remaining Zen while having the back of his calf scalded by a hot iron
and being struck on the back of his neck with a bamboo stick.
Pay attention
The neuroscientists say
that meditation strengthens the regions of the brain that regulate our
feelings – the insula, anterior cingulate cortex and limbic system – to
calm our emotional responses and reduce the sensation of stress.
"You
have to continually practise to develop and strengthen your mind, just
like you would go to the gym to strengthen your muscles," Zeidan says.
The skywalk taught Sampson that we can train our brains to manage fear, rather than suppress it.
"Whether
you're scared of heights, public speaking or failure, you can face that
and overcome it. It never goes away. The clarification is that brave
people are not without fear, they just deal with it differently – it's
the fear that makes them brave," Sampson tells AFR Weekend.
The
intense and determined family man, who left his Canadian home at 16 and
worked in advertising in South Africa before immigrating to Sydney with
"nothing", thinks about his brain training in the same way as physical
fitness.
"You just have to continuously practise. You don't need
super experts or technology to do it, just in your life practise things
like memorising the names of people in the room. Learn to juggle, or
play table tennis," Sampson says.
"I trained every day, I woke up
in the morning at 6am in my backyard, one foot off the ground, and
trained at night after work. I would go to the six-metre high wire ... I
had a lot on during that filming period in addition to my other
responsibilities in life," he smiles wryly.
Meditation and
visualisation were the two most useful techniques he learnt but he lists
focused attention, active listening and practising memory as the most
important skills he gained.
"The biggest gift you can give is
attention," Sampson says. "The major issue with learning and memory is
attention. The last stat I heard is, we only pay attention to a third of
the things around us. If we were to pay more attention, we would
improve across the board. You think the brain is recording everything,
but you only remember the things that you pay attention to."
Our
lack of attention is being exacerbated by smartphones – a trend he
sees with his two young daughters – or as Sampson calls the devices,
"our substitute brains".
"The numbers are saying that with
technology our IQs have gone up but our EQs [emotional intelligence]
have gone down, so we are doing better on these tests because we have
more information at our fingertips but our ability to relate is dropping
because we have more virtual friends than real friends," he says. "If
someone asked me which I would focus on as a predictor for success,
hands down it's EQ."
Stand and deliver
Sampson's practical tip to exercise your brain is to learn to juggle.
"Multi-object
tracking is very good for your brain – for focus, for attention, for
calming yourself down. It's good to do before presentations. If you want
to focus your mind and eliminate distractions, when you've got three
balls flying in front of you, you're not thinking about other things. I
do it before [ABC television show] Gruen Transfer," he says.
The
45-year-old also recommends standing in the office and says he stands
during meetings, a practice that must raise a few eyebrows around the
Fairfax and Qantas boardrooms.
"Standing is good because it
creates a sense of energy and urgency because people get tired standing
and also a lot of people think better on their feet," he says. "I stand
in my meetings, even if other people are sitting."
The perennially busy advertising executive likes to limit his meetings to 20 minutes.
"They
say brainstorming time is roughly 20 minutes, so it makes sense to use a
technique called 'chunking': chunking or hitting problems in 20-minute
intervals," Sampson says.
One of his favourite problem-solving techniques is to "rent-a-head" – borrow other people's perspectives.
"Ask
yourself, how would someone like Richard Branson solve this problem?
Once you've done that, you look at the problem through the eyes of
someone at Apple – how would they solve it?" Sampson says.
"One of
the defining factors of creative people is the ability to switch
perspectives. As we age, we become functionally fixed, we narrow our
perspectives and actions. Really good creative people have the ability
to switch. If you follow the same people on Twitter and subscribe to the
same magazines, then your perspective stays the same because you're
pretty much getting self-selected information."
The brain training
is paying dividends for Sampson – both Fairfax and Qantas sought his
unique perspective for their boards, despite his unusual credentials.
"Both
Roger Corbett and Leigh Clifford see their boards not just as
governance boards but as strategy, advisory boards," he says. "They want
diverse, eclectic minds across all disciplines. Obviously they saw in
me someone who understands marketing and communication, digital
transformation, but I think the skill they wanted most was strategy."
Sampson's
"extreme optimism bias" and confidence tend to polarise opinions – such
as his recent decision to pose with his shirt off for the house
magazine of gym chain Fitness First, a publicity stunt that could be
seen as surprising by the conservative company director community.
He
says that because people know him "from television and not from
business, you expose yourself to criticism. There's a lot of people who
have no idea that I actually run a company with 200 people across four
businesses".
Redesign My Brain 2 with Todd Sampson will premiere on Thursday, May 28, at 8.30pm on ABC TV.
THE BRAIN CAN CHANGE ITSELF. It is a plastic, living organ that can
actually change its own structure and function, even into old age.
Arguably the most important breakthrough in neuroscience since
scientists first sketched out the brain’s basic anatomy, this
revolutionary discovery, called neuroplasticity, promises to overthrow
the centuries-old notion that the brain is fixed and unchanging. The
brain is not, as was thought, like a machine, or “hardwired” like a
computer. Neuroplasticity not only gives hope to those with mental
limitations, or what was thought to be incurable brain damage, but
expands our understanding of the healthy brain and the resilience of
human nature. Norman Doidge, MD, a psychiatrist and researcher, set out
to investigate neuroplasticity and met both the brilliant scientists
championing it and the people whose lives they’ve transformed. The
result is this book, a riveting collection of case histories detailing
the astonishing progress of people whose conditions had long been
dismissed as hopeless. We see a woman born with half a brain that
rewired itself to work as a whole, a woman labeled retarded who cured
her deficits with brain exercises and now cures those of others, blind
people learning to see, learning disorders cured, IQs raised, aging
brains rejuvenated, painful phantom limbs erased, stroke patients
recovering their faculties, children with cerebral palsy learning to
move more gracefully, entrenched depression and anxiety disappearing,
and lifelong character traits altered. Doidge takes us into terrain that
might seem fantastic. We learn that our thoughts can switch our genes
on and off, altering our brain anatomy. Scientists have developed
machines that can follow these physical changes in order to read
people’s thoughts, allowing the paralyzed to control computers and
electronics just by thinking. We learn how people of average
intelligence can, with brain exercises, improve their cognition and
perception in order to become savant calculators, develop muscle
strength, or learn to play a musical instrument, simply by imagining
doing so. Using personal stories from the heart of this neuroplasticity
revolution, Dr. Doidge explores the profound implications of the
changing brain for understanding the mysteries of love, sexual
attraction, taste, culture and education in an immensely moving,
inspiring book that will permanently alter the way we look at human
possibility and human nature.
