AGE-RELATED CHANGES IN COGNITION AND THE BRAIN OF THE RHESUS MONKEY:
EVIDENCE FOR INFLAMMATORY PROCESSES IN WHITE MATTER
Douglas L. Rosene
Departments of Anatomy & Neurobiology and Biochemistry, Boston
University School of Medicine, Boston, MA 02118 and Yerkes Regional
Primate Research Center, Emory University, Atlanta GA 30322
Studies of the neurobiological basis of age-related cognitive decline
conducted in the rhesus monkey allow changes due to normal aging to be
assessed without the potential confounding by the presence of
undetected early stages of Alzheimer's disease. For these studies young
(5 to 10) and elderly (20 to 30+ years of age) rhesus monkeys were
carefully selected from the population at the Yerkes Regional Primate
Research Center. They were then tested on an extensive battery of
cognitive tasks assessing learning, recognition memory and executive
system function. Using this model we have demonstrated that neuron
numbers in the cortex do not decline with age and that overall brain
volume and volume of forebrain gray matter is stable over the life span
of the monkey. Neurophysiological studies of neurons in the hippocampus
and prefrontal cortex have demonstrated that membrane properties are
unchanged with age. Studies of amyloid have demonstrated the presence
of amyloid plaques as well as diff use amyloid in the gray matter of
the cerebral cortex but revealed that this amyloid is highly variable
between aged monkeys and is unrelated to cognitive impairments, a
finding that is congruent with the absence of Alzheimer's disease in
the rhesus monkey. Additional studies of the brain have shown that
some neurotransmitter receptors are lost in the cerebral cortex while
others are unchanged or may even be upregulated but have also failed to
demonstrate any strong relationships with cognitive decline. In
contrast, studies of forebrain white matter have revealed profound
changes. MRI scans show that ventricular volume increases with age but
that only forebrain white matter volume decreases. Electron microscopic
studies of white matter have identified a variety of different forms of
abnormal myelin suggesting myelin degeneration while biochemical
studies have found evidence of myelin regeneration. And in vivo
neurophysiological studies of conduction velocity suggests that this is
slowed in normal aging. In an effort to identify makers of pathological
changes that may reflect potential causal factors we have processed
tissue sections with the antibody LN-3, an antibody that binds to MHC
surface markers that are highly expressed on activate d microglia.
These microglia are the immune cells of the brain and activation
suggests that active phagocytosis as well as production of
pro-inflammatory compounds is occurring. Quantitative analysis of
LN-3. positive microglia in young and old monkeys demonstrated the
presence of scattered LN-3+ glial cells in the gray matter of both
young and old monkeys. In contrast large numbers of LN-3+ microglia
were found in the white matter of only the aged monkeys. While some
regional differences in density of microglia were observed, the most
striking thing was that almost every identifiable white matter tract
expressed this pathological marker. Together these data suggest that
age-related cognitive decline reflects damage to the white matter and
that activation of microglia in white matter may actually contribute to
or exacerbate the problem through the production of inflammatory
mediators and reactive oxygen species. Identification of the first
expression of this in late middle aged monkeys suggests that
anti-oxidant and/or anti-inflammatory drugs may have salutatory
effects.
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