When it comes to diseases of the brain and nervous system, two UC Davis neurology pioneers have a simple way to sum up a lifetime of complex and cutting-edge research: White matter matters.
"White matter is that part of the brain made of cells called ‘axons' that connect one to the other so that nerves can communicate," says UC Davis Alzheimer's Disease Center director Charles DeCarli. "White matter enables the brain to operate intact."
Full of myelin – a fatty insulation that speeds up nerve impulses – white matter is, of course, white in color, says neurology professor David Pleasure, who directs the Institute for Pediatric Regenerative Medicine, a joint research effort between UC Davis and Shriners Hospitals for Children – Northern California.
Studying Alzheimer's, multiple sclerosis, cerebral palsy and other neurological impairments, DeCarli and Pleasure have made several profound discoveries that seem to hinge on a simple idea.
High blood pressure, atherosclerosis, inflammation and other basic disease processes may travel the brain on a superhighway of white matter, causing some of neurology's most mysterious and troubling disorders.
If the nervous system were a computer network, gray matter – a non-myelinated portion that contains nerve cells and capillaries – would be the computers and white matter the cables.
Although diseased white matter impairs the nervous system much like broken, frayed or poorly operating cables impair a computer network, research was mostly focused on gray matter until Charles DeCarli came along.
One of the world's foremost experts in neurological dementia, DeCarli jokingly refers to himself as "the king of white matter."
"I have a humorous side, but the moniker reflects that I have been doing research in this area since 1990," DeCarli says. "Initially, white matter was not too interesting to the scientific community. But they are slowly coming around."
DeCarli has zeroed in on white matter hyperintensity and its role in dementia.
Seen on brain magnetic resonance images as ultra-white patches, "white matter hyperintensity indicates injury to the axons," DeCarli explains, "possibly representing loss of blood flow."
Also called "brain rust," DeCarli says that when he began his research in 1990, "everyone thought these hyperintensities were just innocent changes associated with aging."
He has since focused his attention on an emerging connection between white matter and neurological maladies and their less-mysterious counterparts in other parts of the body: stroke, heart attack, diabetes, hypertension and atherosclerosis.
Stroke and white matter hyperintensities, for instance, share the same risk factors, DeCarli says. "Having these hyperintensities on your brain scan indicates that you are at risk for stroke."
Referring to it as "the million-dollar question of my research," DeCarli has sought links between Alzheimer's disease and white matter hyperintensities.
"We found that hyperintensities injure the frontal lobes of the brain and impair the brain's ability to manipulate and store information," he explains. DeCarli's research team also discovered that white matter hyperintensity-causing vascular disorders add insult to Alzheimer's injury and might accelerate the disease by damaging axons and weakening neurons.
Using a novel mapping technique, DeCarli has observed that Alzheimer's patients share large amounts of white matter hyperintensity with a common distribution.
"This is important as it helps us understand what brain connections are impaired," he explains.
"Once we know which connections are impaired, we can do something to improve those connections." Obesity, diabetes, high blood pressure and coronary artery disease are well-known menaces to 21st century heart health, but what about their effects on the brain?
"Our current research suggests that some of the changes in memory and thinking associated with aging are actually the consequence of under-treated vascular disease," DeCarli says.
"There is also some evidence that these diseases can create Alzheimer's pathology. Forming the plaques and tangles of Alzheimer's disease may be one way nerve cells in the brain react to injuries of any type."
He also suspects that an MRI study of obese children and young adults would show increased white matter hyperintensity.
The good news: DeCarli says research indicates that "vascular risk factors are treatable and much of vascular disease is preventable through healthy lifestyle choices."
Where DeCarli is studying how reduced blood flow harms white matter, David Pleasure wants to know the impact of inflammation.
Inflamed white matter is implicated in multiple sclerosis, cerebral palsy and several inherited childhood diseases such as adrenoleukodystrophy.
Decoding the pathways that inflammation opens is a puzzle Pleasure is solving with genetic, immune and vascular pieces.
For instance, inflammation causes the normally immunoprivileged central nervous system to become immunocompromised.
Pediatric neurologist David Pleasure is studying how inflammation of white matter contributes to certain autoimmune diseases like multiple sclerosis.
"The blood-brain barrier becomes partially ineffective, and peripheral immune cells and antibodies can enter the central nervous system," Pleasure says.
Once that happens, complications such as multiple sclerosis can result. Using what he calls "the most commonly used model for MS" – experimental autoimmune encephalomyelitis – Pleasure says his team can duplicate "many of the pathological features of MS, trying out new treatment regimens before applying them to patients."
Pleasure also is focusing on periventricular leukomalacia (PVL) – a disorder of developing white matter in premature infants – that frequently results in cerebral palsy.
Pleasure's studies on immature oligodendroglia – cells that make myelin – contributed significantly to the understanding of both disorders.
"A common complication of pregnancy – intrauterine infection – increases the incidence of PVL and cerebral palsy by raising levels of inflammatory cytokines, such as interferon-gamma, in the brain of the fetus," Pleasure says.
Cytokines are signaling proteins that help cells communicate with one another.
Historian of medicine
With a history degree from Yale University, David Pleasure explains medicine like a historian.
"Experimental autoimmune encephalomyelitis was first discovered in the late 19th century, when Louis Pasteur developed an anti-rabies vaccine by growing rabies virus in monkeys," he says.
And although most people think of MS as a disease of the spinal cord, it has a historical connection with white matter "first described by the French neurologist Jean-Martin Charcot, who named multiple sclerosis back in the late 19th century," Pleasure explains.
History's important, and having an historical background gives some perspective to medicine, he says. White matter inflammation causes the brain-blood barrier to become partially ineffective.
"For instance, without Charcot's discovery that MS affected axons – white matter – as well as myelin, for instance – we would not have the important discovery that followed: that the permanent disability that eventually develops in patients with progressive MS is chiefly due to axonal loss, rather than to demyelination."
White matter matters
In "The Mysterious Affair at Styles," Agatha Christie's quirky Belgian detective Hercule Poirot introduced gray matter into the popular lexicon by tapping his forehead.
"This affair must be unraveled from within," Poirot said. "These little gray cells. It is up to them."
Eighty-seven years later, David Pleasure and Charles DeCarli have tapped their own gray cells – and those of the UC Davis research community – to find that it may be up to white matter to unravel the brain's unique mysteries.