Dr. Alois Alzheimer first described the disease that bears his name more than 100 years ago. Yet the causes of this devastating breakdown of memory and mind are just coming into view. What took so long?
Until the last couple of decades, when brain imaging became effective and widespread, neurologists could only observe the consequences of Alzheimer's disease (AD)—the inability to form new memories, loss of judgment, changes in gait—and then examine the brain at autopsy. It was like trying to understand how a clock works by watching the movement of the hands or examining the parts after it stops ticking.
Today, in contrast, a variety of brain-imaging techniques are providing scientists and doctors with vivid pictures of the brain at work. In turn, these images are opening up new ways to diagnose, interpret, and treat AD and many other neurologic conditions.
ADVANCES IN BRAIN IMAGING
“I've been practicing neurology for about 20 years. But when I was in medical school, a lot of students—myself included—hesitated to go into the field because we didn't have much in the way of treatment,” says Michael Hutchinson, M.D., associate professor of neurology at New York University's Langone Medical Center and member of the American Academy of Neurology (AAN). “Now, neurology has grown so much. We have good treatments for multiple sclerosis (MS), stroke, Parkinson's disease (PD), epilepsy, and many other conditions.”
Advances in brain imaging have helped make this possible—without the invasive requirements of earlier techniques such as pneumoencephalography. The procedure involved removing cerebrospinal fluid from a patient and replacing it with air. Then, strapped into a chair, the patient would be rotated face down, face up, and upside down to make the air move and provide better contrast for X-rays. Patients were left with intense headaches and nausea.
“These were barbaric procedures, at least by our standards,” says Joseph C. Masdeu, M.D., Ph.D., a physician and scientist with the National Institutes of Health. “Most of the things we now do with brain imaging couldn't be done at all.” (See box, “Types of Brain Imaging.”)
The brain and spinal cord are surrounded by bone, which absorbs most X-rays. But in the mid-1970s, CT scans combined X-rays with computer technology to convert the faint X-rays that penetrate bone into clear brain images.
“With CT scanning, we could see brain tumors directly, rather than from the displacement of arteries they cause,” says Dr. Masdeu, who coauthored one of the first books on brain and spinal cord imaging, in 1985. “We also began to see brain bleeds and tissue that had been damaged by a stroke.”
Brain imaging can involve some risk, which is one of the reasons neurologists recommend it only when necessary. CT scans expose patients to a small amount of radiation, and PET scans read traces from a radioactive chemical injected into the body. But MRI uses radio waves, in a process that involves no radioactive substances at all.
MRI FOR MULTIPLE SCLEROSIS
MRI and fMRI have enabled neurologists to see subtle brain changes that contribute to MS. The disease involves the breakdown of myelin—the fatty white coating that insulates axons, which carry signals between brain cells. Areas of myelin loss appear as white spots on MRI. MS can affect any part of the brain, and it produces an array of symptoms. MRI, which can help distinguish MS from other disorders.
“When you're not sure, imaging can be extremely helpful,” says Istvan Pirko, M.D., a neurologist at the Mayo Clinic in Rochester, MN, and a Fellow of the AAN. “In our research projects, we can measure brain and spinal cord volumes, monitor brain atrophy, and examine areas of gray and white matter (the bodies of brain cells and the long fibers that connect them to other cells). In clinical practice, we also use it to monitor treatment.”
In addition, MRI helps Dr. Pirko distinguish the lesions produced by MS from damage caused by infection, aging, chemotherapy, radiation treatments, and other problems. For example, MRI helps him to recognize the “pseudo-attacks” produced by Uhthoff's phenomenon, which causes MS symptoms to worsen when the body heats up from exercise, a fever, immersion in a hot tub, or hot weather. MRI reveals the breakdown of myelin in MS, but the widespread use of brain imaging has even revealed that myelin breaks down in healthy adults, especially beyond the age of 60. These white spots that show up on MRI scans are now regarded as signs of leukoaraiosis, a condition caused by damaged small blood vessels in the brain. The condition has been associated with high blood pressure and perhaps diabetes.
Last year, researchers at Mayo Clinic in Rochester, MN, determined that leukoaraiosis can be harmful, decreasing activation in brain regions involved in processing language. “The white matter is damaged, but it doesn't look the same as in MS, where there's inflammation,” says Kirk M. Welker, M.D., assistant professor of radiology at Mayo Clinic College of Medicine, who led the study. (Go to http://bit.ly/NbvqJU for video interviews with MS experts.)
A NEW VIEW OF DEMENTIA
Advances in brain imaging have also improved diagnosis and research into dementia. MRI can reveal the brain shrinkage characteristic of AD, while fMRI combined with PET can show regions of the brain that are no longer utilizing normal amounts of oxygen and glucose.
A new form of PET can reveal the presence of beta-amyloid, a protein believed to play an important role in AD. Patients receive an injection of a compound that binds to beta-amyloid and causes it to show up vividly on the PET scan, revealing a possible risk factor for the disease years before symptoms appear. Currently, in the absence of effective treatments, such information is not very useful. But PET scans can be used to determine the effectiveness of existing drugs when prescribed before symptoms appear, or to test new drugs designed to slow the production of beta-amyloid or remove it from the brain.
With MRI, neurologists are starting to be able to distinguish AD from other forms of dementia such as Lewy body dementia (LBD), frontotemporal dementia, and vascular dementia. For example, although damage from AD and LBD can look very similar, MRI can help distinguish the two, in part by measuring the size of the hippocampus (a part of the brain that is involved in the formation and storing of memory) which tends to shrink more in AD.
IMAGING OTHER NEUROLOGIC CONDITIONS
Epilepsy has long been a particularly difficult problem to treat because the cause often remains unknown. Brain imaging is helping to change that, according to Ruben Kuzniecky, M.D., professor of neurology at New York University's Epilepsy Center and Fellow of the AAN.
“Once MRI became available, about 20 to 25 years ago, we became able to see lesions and other causes of epilepsy,” Dr. Kuzniecky says. “We've been able to identify malformations of the brain associated with seizures, which has led to genetic studies about how this happens.” (Go to http://bit.ly/NbvqJU for video interviews with epilepsy experts.)
The most common use of brain imaging involves looking for a brain tumor, stroke, or other damage that would explain the seizures.
TBI is a common problem among soldiers who have survived explosions in Iraq and Afghanistan, and MRI has been very helpful in revealing the damage. DTI techniques have revealed a more subtle problem known as chronic traumatic encephalopathy, which has been found in professional athletes. The damage, primarily to delicate axon tracts that tear as a result of a blow to the head, is believed to set the stage for long-term neurodegeneration, making it particularly threatening to teenage athletes.
Brain imaging can even reveal the loss of dopamine-producing neurons that give rise to the muscle rigidity, tremors, and slowness of movement characteristic of PD.
“MRI is sensitive to pathological changes in the substantia nigra (the location of dopamine-producing cells that fail in PD)—even early in the progression of PD,” Dr. Hutchinson says.
The hope is that as imaging techniques continue to improve, treatments will come into better focus as well.
Types of Brain Imaging
Computed Tomography (CT) and Computerized Axial Tomography (CAT) combine multiple X-rays into an image of the brain and spinal cord. Dye injected into blood vessels can reveal evidence of tumors, inflammation, and other problems. Although still used, CT and CAT scans have largely been replaced by magnetic resonance imaging.
Magnetic Resonance Imaging (MRI) uses powerful magnets and radio waves—not X-rays—to create pictures of the body. MRI produces remarkably detailed images of the brain, including “slices” of brain viewed from various angles.
Functional MRI (fMRI) reveals which parts of the brain are most active when the patient is at rest or performing a specific task, based on the fact that oxygen-rich blood responds to the magnetic field of MRI differently than oxygen-depleted blood. fMRI can reveal areas where the brain is not working properly due to AD, infection, traumatic brain injury (TBI), and other conditions.
Diffusion Tensor Imaging (DTI) can reveal damage due to disease or injury (such as TBI) that hinders the transmission of signals among brain cells. It works because water molecules in the brain disperse randomly unless they bump into cell membranes and fibers. By recording the amount of diffusion in various brain regions, DTI can produce an image of those fibers.
Positron Emission Tomography (PET) can help reveal how organs and tissues in the body are functioning. A small amount of radioactive material is injected into a person's body. More radioactive material accumulates in areas that have higher levels of chemical activity or metabolism. In some cases, higher levels of chemical activity correspond to areas of disease. For example, certain kinds of radioactive material acan bind to and reveal beta-amyloid, a protein thought to be an important risk factor for AD.
Single-Photon Emission Computed Tomography (SPECT) uses a radioactive tracer to assemble three-dimensional image of the brain, which can be helpful in detecting the location of tumors and other disorders. SPECT is also used to examine the substantia nigra, an area of the brain that loses dopamine-producing neurons in people with PD.