Alzheimer's Disease: Unraveling the Mystery - 3 Basics ...

Alzheimer's Disease: Unraveling the Mystery - 3 Basics of the healthy brain

To understand AD, it is important to know a bit about the brain. This part of Unraveling the Mystery gives an inside view of the normal brain, how it works, and what happens during aging.

The brain is a remarkable organ. Seemingly without effort, it allows us to carry out every element of our daily lives. It manages many body functions, such as breathing, blood circulation, and digestion, without our knowledge or direction. It also directs all the functions we carry out consciously. We can speak, hear, see, move, remember, feel emotions, and make decisions because of the complicated mix of chemical and electrical processes that take place in our brains.

The brain is made of nerve cells and several other cell types. Nerve cells also are called neurons. The neurons of all animals function in basically the same way, even though animals can be very different from each other. Neurons survive and function with the help and support of glial cells, the other main type of cell in the brain. Glial cells hold neurons in place, provide them with nutrients, rid the brain of damaged cells and other cellular debris, and provide insulation to neurons in the brain and spinal cord. In fact, the brain has many more glial cells than neurons—some scientists estimate even 10 times as many.

Another essential feature of the brain is its enormous network of blood vessels. Even though the brain is only about 2 percent of the body’s weight, it receives 20 percent of the body’s blood supply. Billions of tiny blood vessels, or capillaries, carry oxygen, glucose (the brain’s principal source of energy), nutrients, and hormones to brain cells so they can do their work. Capillaries also carry away waste products.


The Brain’s Vital Statistics

Adult weight
about 3 pounds

Adult size
a medium cauliflower

Number of neurons
about 100,000,000,000 (100 billion)

Number of synapses
(the gaps between neurons)
about 100,000,000,000,000 (100 trillion)

Number of capillaries
(tiny blood vessels)
about 400,000,000,000 (400 billion)


INSIDE THE HUMAN BRAIN

The brain has many parts, each of which is responsible for particular functions. The following section describes a few key structures and what they do.

The main players

Two cerebral hemispheres account for 85 percent of the brain’s weight. The billions of neurons in the two hemispheres are connected by thick bundles of nerve cell fibers called the corpus callosum. Scientists now think that the two hemispheres differ not so much in what they do (the “logical versus artistic” notion), but in how they process information. The left hemisphere appears to focus on details (such as recognizing a particular face in a crowd). The right hemisphere focuses on broad background (such as understanding the relative position of objects in a space). The cerebral hemispheres have an outer layer called the cerebral cortex. This is where the brain processes sensory information received from the outside world, controls voluntary movement, and regulates cognitive functions, such as thinking, learning, speaking, remembering, and making decisions. The hemispheres have four lobes, each of which has different roles:

* The frontal lobe, which is in the front of the brain, controls “executive function” activities like thinking, organizing, planning, and problem solving, as well as memory, attention, and movement.
* The parietal lobe, which sits behind the frontal lobe, deals with the perception and integration of stimuli from the senses.
* The occipital lobe, which is at the back of the brain, is concerned with vision.
* The temporal lobe, which runs along the side of the brain under the frontal and parietal lobes, deals with the senses of smell, taste, and sound, and the formation and storage of memories.

The cerebellum sits above the brain stem and beneath the occipital lobe. It takes up a little more than 10 percent of the brain. This part of the brain plays roles in balance and coordination. The cerebellum has two hemispheres, which receive information from the eyes, ears, and muscles and joints about the body’s movements and position. Once the cerebellum processes that information, it sends instructions to the body through the rest of the brain and spinal cord. The cerebellum’s work allows us to move smoothly, maintain our balance, and turn around without even thinking about it. It also is involved with motor learning and remembering how to do things like drive a car or write your name.

The brain stem sits at the base of the brain. It connects the spinal cord with the rest of the brain. Even though it is the smallest of the three main players, its functions are crucial to survival. The brain stem controls the functions that happen automatically to keep us alive—our heart rate, blood pressure, and breathing. It also relays information between the brain and the spinal cord, which then sends out messages to the muscles, skin, and other organs. Sleep and dreaming are also controlled by the brain stem.


Other crucial parts

Several other essential parts of the brain lie deep inside the cerebral hemispheres in a network of structures called the limbic system. The limbic system links the brain stem with the higher reasoning elements of the cerebral cortex. It plays a key role in developing and carrying out instinctive behaviors and emotions and also is important in perceiving smells and linking them with memory, emotion, and instinctive behaviors. The limbic system includes:

* The amygdala, an almond-shaped structure involved in processing and remembering strong emotions such as fear. It is located in the temporal lobe just in front of the hippocampus.
* The hippocampus, which is buried in the temporal lobe, is important for learning and short-term memory. This part of the brain is thought to be the site where short-term memories are converted into long-term memories for storage in other brain areas.
* The thalamus, located at the top of the brain stem, receives sensory and limbic information, processes it, and then sends it to the cerebral cortex.
* The hypothalamus, a structure under the thalamus, monitors activities such as body temperature and food intake. It issues instructions to correct any imbalances. The hypothalamus also controls the body’s internal clock.


The brain in action

Sophisticated brain-imaging techniques allow scientists to monitor brain function in living people and to see how various parts of the brain are used for different kinds of tasks. This is opening up worlds of knowledge about brain function and how it changes with age or disease.

One of these imaging techniques is called positron emission tomography, or PET scanning. Some PET scans measure blood flow and glucose metabolism throughout the brain. (For more on metabolism, see "Metabolism".) During a PET scan, a small amount of a radioactive substance is attached to a compound, such as glucose, and injected into the bloodstream. This tracer substance eventually goes to the brain. When nerve cells in a region of the brain become active, blood flow and glucose metabolism in that region increase. When colored to reflect metabolic activity, increases usually look red and yellow. Shades of blue and black indicate decreased or no activity within a brain region. In essence, a PET scan produces a “map” of the active brain.

Scientists can use PET scans to see what hap-pens in the brain when a person is engaged in a physical or mental activity, at rest, or even while sleeping or dreaming. Certain tracers can track the activity of brain chemicals, for example neurotransmitters such as dopamine and serotonin. (To learn about exciting developments using one new tracer, see "PiB and PET".) Some of these neurotransmitters are changed with age, disease, and drug therapies.


NEURONS AND THEIR JOBS

The human brain is made up of billions of neurons. Each has a cell body, an axon, and many dendrites. The cell body contains a nucleus, which controls much of the cell’s activities. The cell body also contains other structures, called organelles, that perform specific tasks.

The axon, which is much narrower than the width of a human hair, extends out from the cell body. Axons transmit messages from neuron to neuron. Sometimes, signal transmissions—like those from head to toe—have to travel over very long distances. Axons are covered with an insulating layer called myelin (also called white matter because of its whitish color). Myelin, which is made by a particular kind of glial cell, increases the speed of nerve signal transmissions through the brain.

Dendrites also branch out from the cell body. They receive messages from the axons of other neurons. Each neuron is connected to thousands of other nerve cells through its axon and dendrites.

Groups of neurons in the brain have special jobs. For example, some are involved with thinking, learning, and memory. Others are responsible for receiving information from the sensory organs (such as the eyes and ears) or the skin. Still others communicate with muscles, stimulating them into action.

Several processes all have to work smoothly together for neurons, and the whole organism, to survive and stay healthy. These processes are communication, metabolism, and repair.

Communication

Imagine the many miles of fiber-optic cables that run under our streets. Day and night, millions of televised and telephonic messages flash at incredible speeds, letting people strike deals, give instructions, share a laugh, or learn some news. Miniaturize it, multiply it many-fold, make it much more complex, and you have the brain. Neurons are the great communicators, always in touch with their neighbors.

Neurons communicate with each other through their axons and dendrites. When a dendrite receives an incoming signal (electrical or chemical), an “action potential,” or nerve impulse, can be generated in the cell body. The action potential travels to the end of the axon and once there, the passage of either electrical current or, more typically, the release of chemical messengers, called neurotransmitters, can be triggered. The neurotransmitters are released from the axon terminal and move across a tiny gap, or synapse, to specific receptor sites on the receiving, or post-synaptic, end of dendrites of nearby neurons. A typical neuron has thousands of synaptic connections, mostly on its many dendrites, with other neurons. Cell bodies also have receptor sites for neurotransmitters.

Once the post-synaptic receptors are activated, they open channels through the cell membrane into the receiving nerve cell’s interior or start other processes that determine what the receiving nerve cell will do. Some neurotransmitters inhibit nerve cell function (that is, they make it less likely that the nerve cell will send an electrical signal down its axon). Other neurotransmitters stimulate nerve cells, priming the receiving cell to become active or send an electrical signal down the axon to more neurons in the pathway. A neuron receives signals from many other neurons simultaneously, and the sum of a neuron’s neurotransmitter inputs at any one instant will determine whether it sends a signal down its axon to activate or inhibit the action of other neighboring neurons.

Three scientists reviewing information on paper in front of a microscopeDuring any one moment, millions of these signals are speeding through pathways in the brain, allowing the brain to receive and process information, make adjustments, and send out instructions to various parts of the body.

Metabolism

All cells break down chemicals and nutrients to generate energy and form building blocks that make new cellular molecules such as proteins. This process is called metabolism. To maintain metabolism, the brain needs plenty of blood constantly circulating through its billions of capillaries to supply neurons and other brain cells with oxygen and glucose. Without oxygen and glucose, neurons will quickly die.

Repair

Nerve cells are formed during fetal life and for a short time after birth. Unlike most cells, which have a fairly short lifespan, neurons in the brain live a long time. These cells can live for up to 100 years or longer. To stay healthy, living neurons must constantly maintain and repair themselves. In an adult, when neurons die because of disease or injury, they are not usually replaced. Research, however, shows that in a few brain regions, new neurons can be generated, even in the old brain.


THE CHANGING BRAIN IN HEALTHY AGING

In the past several decades, investigators have learned much about what happens in the brain when people have a neurodegenerative disease such as Parkinson’s disease, AD, or other dementias. Their findings also have revealed much about what happens during healthy aging. Researchers are investigating a number of changes related to healthy aging in hopes of learning more about this process so they can fill gaps in our knowledge about the early stages of AD.

As a person gets older, changes occur in all parts of the body, including the brain:

* Certain parts of the brain shrink, especially the prefrontal cortex (an area at the front of the frontal lobe) and the hippocampus. Both areas are important to learning, memory, planning, and other complex mental activities.
* Changes in neurons and neurotransmitters affect communication between neurons. In certain brain regions, communication between neurons can be reduced because white matter (myelin-covered axons) is degraded or lost.
* Changes in the brain’s blood vessels occur. Blood flow can be reduced because arteries narrow and less growth of new capillaries occurs.
* In some people, structures called plaques and tangles develop outside of and inside neurons, respectively, although in much smaller amounts than in AD (see "The Hallmarks of AD" for more information on plaques and tangles).
* Damage by free radicals increases (free radicals are a kind of molecule that reacts easily with other molecules; see "The Aging Process" for more on these molecules).
* Inflammation increases (inflammation is the complex process that occurs when the body responds to an injury, disease, or abnormal situation).

What effects does aging have on mental function in healthy older people? Some people may notice a modest decline in their ability to learn new things and retrieve information, such as remembering names. They may perform worse on complex tasks of attention, learning, and memory than would a younger person. However, if given enough time to perform the task, the scores of healthy people in their 70s and 80s are often similar to those of young adults. In fact, as they age, adults often improve in other cognitive areas, such as vocabulary and other forms of verbal knowledge.

It also appears that additional brain regions can be activated in older adults during cognitive tasks, such as taking a memory test. Researchers do not fully understand why this happens, but one idea is that the brain engages mechanisms to compensate for difficulties that certain regions may be having. For example, the brain may recruit alternate brain networks in order to perform a task. These findings have led many scientists to believe that major declines in mental abilities are not inevitable as people age. Growing evidence of the adaptive (what scientists call “plastic”) capabilities of the older brain provide hope that people may be able to do things to sustain good brain function as they age. A variety of interacting factors, such as lifestyle, overall health, environment, and genetics also may play a role.

Another question that scientists are asking is why some people remain cognitively healthy as they get older while others develop cognitive impairment or dementia. The concept of “cognitive reserve” may provide some insights. Cognitive reserve refers to the brain’s ability to operate effectively even when some function is disrupted. It also refers to the amount of damage that the brain can sustain before changes in cognition are evident. People vary in the cognitive reserve they have, and this variability may be because of differences in genetics, education, occupation, lifestyle, leisure activities, or other life experiences. These factors could provide a certain amount of tolerance and ability to adapt to change and damage that occurs during aging. At some point, depending on a person’s cognitive reserve and unique mix of genetics, environment, and life experiences, the balance may tip in favor of a disease process that will ultimately lead to dementia. For another person, with a different reserve and a different mix of genetics, environment, and life experiences, the balance may result in no apparent decline in cognitive function with age.

Scientists are increasingly interested in the influence of all these factors on brain health, and studies are revealing some clues about actions people can take that may help preserve healthy brain aging. Fortunately, these actions also benefit a person’s overall health. They include:

* Controlling risk factors for chronic disease, such as heart disease and diabetes (for example, keeping blood cholesterol and blood pressure at healthy levels and maintaining a healthy weight)
* Enjoying regular exercise and physical activity
* Eating a healthy diet that includes plenty of vegetables and fruits
* Engaging in intellectually stimulating activities and maintaining close social ties with family, friends, and community
* "Vascular Disease" and "Lifestyle Factors" provide more information about these issues and how they may influence the risk of developing AD.

ACTIVE Study May Provide Clues to Help Older Adults Stay Mentally Sharp

The phrase “use it or lose it” may make you think of your muscles, but scientists who study brain health in older people have found that it may apply to cognitive skills as well. In 2006, scientists funded by NIA and the National Institute of Nursing Research completed a study of cognitive training in older adults. This study, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, was the first randomized controlled trial to demonstrate long-lasting, positive effects of brief cognitive training in older adults.

The ACTIVE study included 2,802 healthy adults age 65 and older who were living independently. Participants were randomly assigned to four groups. Three groups took part in up to 10 computer-based training sessions that targeted a specific cognitive ability—memory, reasoning, and speed of processing (in other words, how fast participants could respond to prompts on a computer screen). The fourth group (the control group) received no cognitive training. Sixty percent of those who completed the initial training also took part in 75-minute “booster” sessions 11 months later. These sessions were designed to maintain improvements gained from the initial training.

The investigators tested the participants at the beginning of the study, after the initial training and booster sessions, and once a year for 5 more years. They found that the improvements from the training roughly counteracted the degree of decline in cognitive performance that would be expected over a 7- to 14-year period among older people without dementia:

* Immediately after the initial training, 87 percent of the processing-speed group, 74 percent of the reasoning group, and 26 percent of the memory group showed improvement in the skills taught.
* After 5 years, people in each group performed better on tests in their respective areas of training than did people in the control group. The reasoning and processing-speed groups who received booster training had the greatest benefit.

The researchers also looked at the training’s effects on participants’ everyday lives. After 5 years, all three groups who recieved training reported less difficulty than the control group in tasks such as preparing meals, managing money, and doing housework. However, these results were statistically significant for only the group that had the reasoning training.

As they get older, many people worry about their mental skills getting “rusty.” The ACTIVE study offers hope that cognitive training may be useful because it showed that relatively brief and targeted cognitive exercises can produce lasting improvements in the skills taught. Next steps for researchers are to determine ways to generalize the training benefits beyond the specific skills taught in ACTIVE and to find out whether cognitive training programs could prevent, delay, or diminish the effects of AD.