| Vol 6 n° 4 - Mild Cognitive Impairment |
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I n t h i s i s s u e . . .
The aging brain,
and specifically the subject of the
dementias, has been the
focus of three theme issues of
Dialogues in Clinical Neuroscience. In 2000, we addressed
issues in Alzheimer’s
disease (Vol 2, No. 2), in 2001 cere-
bral aging (Vol 3, No. 3),
and in 2003 (Vol 5, No. 1)
dementia; all these issues
are freely available on our web-
site (www.dialogues-cns.org).
In the present issue, a dis-
tinguished international
group of investigators explores
the territory between normal
aging and Alzheimer’s dis-
ease and deals comprehensively
with the subject of mild
cognitive impairment (MCI).
Consideration of MCI has
important conceptual and clin-
ical dimensions, and raises
the issue of interventions as
being developed for purposes
of both therapeutics and
prophylaxis. These are
not only concerns for investigators
and clinicians, but also
for regulators. In background
material prepared for a
2001 meeting of its Peripheral and
Central Nervous System
Advisory Committee on drug
development for MCI, the
US Food and Drug Administra-
tion (FDA) identified five
questions for committee discus-
• Can MCI be
clearly defined in a clinical setting?
• Are there valid
criteria for the diagnosis of MCI?
• Can MCI be
distinguished from Alzheimer’s disease and
other causes of dementia?
• What outcome
measures are appropriate to use in clin-
ical drug trials conducted
in MCI?
• Should clinical
drug trials in MCI incorporate any special
features in their design?
As is evident from the
papers in this issue, we are well posi-
tioned to provide definitive
answers to most of these ques-
tions. But first, why should
we care about the answers, or
even about MCI? Some would
hold that MCI is simply nor-
mal aging (referred to
as “age-related cognitive decline”
in the Diagnostic
and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision [DSM-IV-TR]2)
and
that intervening would
amount to “human engineering”
or “tinkering with
nature.” Of course, we “tinker with
nature” all the time—many
of us use corrective lenses to
restore vision to a near-normal
state after experiencing the
result of age-related change
in sensory function. There is
no dispute that eyeglasses
or contact lenses are useful and
necessary.
Some would hold that MCI
is simply Alzheimer’s disease
that has been recognized
early. That too would lead us to
the justifiable use of
interventions. There are few, if any,
conditions in all medicine
in which outcome is enhanced
by delay in the initiation
of treatment. We do not delay
diabetes treatment until
someone is in coma nor do we
delay arthritis treatment
until someone is totally immobi-
lized. Earlier is almost
always better.
Others would assert that
MCI is a nonspecific prodrome
that could possibly result
in Alzheimer disease. If that were
the case then we would
have a pressing need for inter-
vention as well. In this
case, the intervention would be
directed toward prophylaxis
or risk reduction. Such an
approach would necessarily
be built upon a much more
complete understanding
of etiology and pathophysiology
of brain diseases than
we currently have. The develop-
ment of mechanism-based
approaches to intervention3 is
a major need in our field.
It is important to note
that therapeutics and prophylaxis
almost always require
different approaches. For example,
we use fluorides to prevent
dental caries, but not to treat
them. On the other hand,
we use insulin to treat diabetes,
but not to prevent its
onset (indeed, insulin could be dan-
gerous if given to reduce
risk of developing diabetes).
Though this is almost
always the case, there are notable
exceptions, specifically
in the area of infectious diseases.
Even if MCI were totally
epiphenomenal or arbitrary, how-
ever—and the papers
in this issue clearly demonstrate
that this is not the case—we
would still have to care
about it because of the
strong relationship between MCI
and overall health. One
such demonstration comes from
a large community study
of older people in Stockholm,
4
in which they show a clear
relationship between MCI and
three health indicators:
self-rated health, number of
chronic conditions, and
3-year mortality. Data from the
(US) Cardiovascular Health
Study show that the associa-
tion between MCI and symptomatology,
both physical
and mental, is robust
and clinically important.
5,6
For all these reasons,
MCI has become a subject of inter-
est to the worldwide community
of clinicians and scien-
tists. Anyone approaching
the area cannot avoid certain
realities: substantial
variability in definitions, standards,
assessment protocols,
and diagnostic criteria; great het-
erogeneity in presentation,
course, and outcome; a num-
ber of speculative hypotheses
with respect to risk factors
and etiology; absence
of validated biomarkers; and equiv-
ocal evidence for the
efficacy or durability of interven-
tions. One attempt at
forging consensus was carried out
in 2003 and published
recently.7 This valuable addition to
the literature identifies
an agenda for future research that
will move the field forward
enormously.
