The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Who hasn’t complained about loss of memory? With increasing frequency, I forget where I left my glasses, what’s her name? Where did I meet him? And for the hundredth time, what’s the name of this bird?

No, it is not incipient Alzheimer’s. I still write blogs, although that’s no proof of a sound mind. I manage a large drug development project, read the newspapers daily and am up on the latest political twist. So what’s going on?

Beware received wisdom

When I went to medical school (UCSF) I was struck by a paper I read claiming that 50% of what we were taught would be either obsolete, or plain wrong, within 5 years; amazing, but true, and not very reassuring to both physician and patient. One of the things I was taught with great certitude was that with age we progressively lose neurons, which make up the gray matter in the brain. True enough even today. It was then a no brainer to conclude that this loss of neurons is responsible for the creeping loss of cognitive function in the elderly. This tidbit of “information” turns out to be part of the 50% that is obsolete, and maybe even wrong.

The nerve cell

A neuron, like any other cell, has a “body”, enclosed by a membrane. It contains a nucleus, where DNA resides, mitochondria, the power plants that provide energy for the functions a neuron performs, and cytoplasm, where proteins are shuttled about and enzymes perform what they are supposed to. But then there is something unique to neurons: they have long projections, some of them inches long (which is enormous in the context of microscopically small cells). These long projections, called axons, serve two purposes: they serve as conduits for a traffic of neurotransmitters and other substances on their way out of the neuron. And, through tiny projections coming off their surface, called dendrites (small branches, in Latin), they make contact with other neurons around them. This is how information, in the form of electrical impulses, is passed around the brain along precisely demarcated circuits and over very long distances. The neuronal cell bodies, where the nucleus and the DNA reside, are the “brain” of the cell; they have a gray hue under the microscope—hence “gray matter”. The axons, on the other hand, are considered conduits only, very much like water or sewer pipes—no “brain” at all. They have a white hue, and are called the “white matter”.

Organization of the brain

The human brain can be divided into major functional regions, each responsible for different kinds of “applications,” such as memory, sensory input and processing, executive function or even one's own internal musing. The functional regions of the brain are linked by a network of white matter conduits. These communication channels help the brain coordinate and share information from the brain's different regions. White matter is the tissue through which messages pass from different regions of the brain.

Scientists have known that white matter degrades with age, but they did not understand how that decline contributes to the degradation of the large-scale systems that govern cognition.

So what’s new?

New research, published December 6, 2007, in the journal Neuron, begins to reveal how simply growing old can affect the higher-level brain systems that govern cognition. The research was conducted by Randy buckner’s group at the Harvard Medical School and the Howard Hughes Medical Institute. As Jessica Andrews-Hanna, a graduate student in Buckner's lab and the lead author of the study stated:
“The crosstalk between the different parts of the brain is like a conference call; we were eavesdropping on this crosstalk and we looked at how activity in one region of the brain correlates with another.”
Buckner, Andrews-Hanna, and their colleagues looked at crosstalk in the brains of 93 people aged 18 to 93, divided roughly into a young adult group (18-34 years old) and an old adult group (60-93 years old). The older participants were given a battery of tests to measure their cognitive abilities—including memory, executive function and processing speed. Each person was studied using functional magnetic resonance imaging (fMRI) exams to measure activity in different parts of the brain. fMRI can precisely map enhanced blood flow in specific regions of the brain. Increased blood flow reflects greater activity in regions of the brain that are utilized during mental tasks.
For the task used in the Neuron study, subjects were presented words and were asked to decide whether each word represented a living (e.g., dog) or nonliving (e.g., house) object. Such a task requires the participants to meaningfully process the words.
Buckner's group explored whether aging in the older group caused a loss of correlation between the regions of the brain that — at least in young adults — engage in robust neural crosstalk.
They focused on the links within two critical networks, one responsible for processing information from the outside world and one, known as the default network, which is more internal and kicks in when we muse to ourselves. For example, the default network is presumed to depend on two regions of the brain linked by long-range white matter pathways. The new study revealed a dramatic difference in these regions between young and old subjects. “We found that in young adults, the front of the brain was pretty well in sync with the back of the brain,” said Andrews-Hanna. “In older adults this was not the case. The regions became out of sync and they were less correlated with each other.” Interestingly, the older adults with normal, high correlations performed better on cognitive tests.
According to the authors, it is inferred that in a young, healthy brain, signals are readily transmitted by white-matter conduits. As we age, those conduits are compromised. Depending on the networks at play, the result may be impaired memory, reasoning or other important cognitive functions. Buckner and Andrews-Hanna emphasized that other changes in the aging brain may contribute to cognitive decline. For example, cells' ability to express chemical neurotransmitters may also be compromised.

My take

1. Extremely important work. The dogma that “dropped neurons” is solely responsible for the cognitive deficits of normal aging simply did not make sense. First, the billions of neurons in the brain have plenty of capacity to make up for losses; we have a tremendous reserve. Second, the brain has the capacity to reroute specific information through alternative circuits if the original ones are compromised in any way. This is what underlies the phenomenon called “brain plasticity”, which is the basis for rehabilitation of stroke victims, or the educational strategies for dyslectic children.

2. This finding, like any in science, raises new questions. What is the nature of the disruption in the default network? Is it reduced number of axons due to neuronal death? Is it a functional defect in the conductive properties of the axons? Is the dysfunction generalized or restricted to specific pathways? What is the root cause of the changes? How can they be avoided?

What can we do about it now?

No doubt you have encountered claims of “brain rejuvenation”. Just work on your daily crossword puzzle, learn a new language, solve sudoku puzzles, stand on your head. The trouble with all these is that they work—but very specifically. If you do your daily crossword puzzles or sudoku you’d be good at them, but you will still forget names and misplace your car keys.

So far, the most convincing global change in the aging brain is reduced blood supply. Blood vessels either get occluded (atherosclerosis) or degenerate because of death of tissue they had supplied. Not surprisingly, the only strategy that proved effective in maintaining the overall integrity of cognitive function is, you guessed it, increase blood supply through aerobic exercise.

So throw away your sudoku puzzle or crossword puzzle and go out for a brisk walk or run. And don’t forget the keys to the house.

Dov Michaeli MD, Ph.D is in the biotech industry.