The doctor is in

More on brains. This is submitted by Dr. Rowe and is of interest to you, especially if you have a birthday.

Losing your mind? It's your white matter, stupid
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of the 50% that is obsolete, and maybe even wrong.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.