There are many causes of dementia,
a term used by the medical community to describe patients with
impaired cognition. Alzheimer’s disease (AD) and cerebrovascular
disease (CVD) are widely regarded as major causes of dementia
in older persons, but there are many unanswered questions about
these important disease processes. There is a need for better
understanding of how these diseases cause cognitive impairment
and dementia, and of the effects of having both diseases versus
having just one. There are related clinical questions about
how to diagnose these diseases, and about clinical treatment
and management. These types of questions are being explored
by a collaborative project involving UC Davis, the University
of Southern California, UC San Francisco, and UCLA. This project,
titled ‘The Aging Brain” has been ongoing since 1994
and is funded by the National Institute on Aging. Many patients
of the UC Davis Alzheimer’s Disease Center and healthy
volunteers have participated in this study. Through multiple
visits to our clinics, they have made an important contribution
to understanding how AD and CVD cause dementia.
AD had been more widely studied than CVD, and consequently,
the basic mechanisms that underlie the development of AD are
better understood. The complexity of dementia associated with
CVD is not well understood, and astonishingly little progress
has been made in understanding when dementia will develop in
persons who have had small strokes, or what cognitive changes
define the dementia. How these changes differ from AD and interact
with AD in cases of mixed AD/CVD are particularly elusive. There
are a number of key findings from this grant that are providing
answers to some of these questions.
It has generally been presumed that the location and volume
of strokes (infarcts), is critical for causing dementia. While
multiple or large strokes result in dementia in certain cases,
the link of strokes to dementia is weak. This is particularly
true when the strokes are small and are not in the cerebral
cortex, the part of the brain where information is processed
and maintained. The significance of subcortical ischemic vascular
disease (SIVD) is of special interest. These SIVD changes are
common in older persons, but are poorly understood. An important
advance from this project is a finding that SIVD is associated
with shrinkage or atrophy of the cortex, and that cognitive
and functional changes are more strongly associated with the
cortical atrophy than with the SIVD.
Sophisticated magnetic resonance imaging (MRI) methods are used
in this project to measure volume of the cerebral cortex, of
subcortical structures, and of SIVD. It has been well known
that cortical atrophy occurs in AD, but results of this project
have consistently shown that SIVD is associated with cortical
atrophy equal to that in AD. Further, magnetic resonance spectroscopy
(MRS) imaging has shown that there is a distinct loss of cortical
neurons, or nerve cells, in patients with SIVD.
Studies using positron emission tomography (PET) imaging have
provided evidence that the frontal lobes of the brain are particularly
affected by SIVD. Finally, studies correlating MRI changes with
tests of cognitive abilities like memory, attention, and language
have shown that cortical atrophy is much more strongly associated
with test performance than is SIVD.
It has also been widely known that the hippocampus, a small
structure on the interior surface of the temporal lobe, is an
area of major pathological changes early in the course of Alzheimer’s
disease. The hippocampus is critical for memory, and atrophy
of this structure explains the profound memory loss that occurs
in AD. Hippocampal atrophy also has been associated with progression
of cognitive impairment and dementia in a number of studies.
Based upon these studies, hippocampal atrophy has been widely
regarded as a marker of AD. Results from this project have shown
that hippocampal atrophy may also occur in cases with CVD, though
it is much more common and generally more severe in AD. Progressive
hippocampal atrophy may be a particularly effective marker for
AD. This is being evaluated in studies associated with this
project that compare change in repeated MRI scans with change
in cognitive tests scores, and ultimately with structural changes
in the brains of participants who have volunteered for brain
autopsy after their death.
Metabolic markers offer hope for diagnosing independent contributions
of SIVD and AD to dementia. PET scans monitor brain function
by measuring how well the brain breaks down a substance to yield
energy. In AD, there is decreased activity on both sides of
the brain in the temporal and parietal lobes. The pattern in
SIVD is very much different. Metabolism is most slowed in the
frontal lobes, and the rate of slowing can predict how the disease
progresses. It’s promising that clinicians may use metabolic
markers such as these to diagnosis and predict the course of
SIVD.
Imaging and brain changes aside, how do SIVD and AD patients
differ on Neuropsychological tests? Patients with AD demonstrate
fast rates of forgetting as well as more complete loss of information.
Patients with SIVD subjects show a slower rate of forgetting
and better retention of information. Executive function; which
involves ability to maintain information in “working memory”,
perform complex operations on that information, and to formulate
effective strategies for problem solving; is affected by SIVD.
This is consistent with other findings about effects of SIVD
on the frontal lobes, since the frontal lobes are important
for executive function.
Accurate diagnosis leads to more reliable prediction of the
disease course and treatment options. Unfortunately, the only
way to make a definite conclusion about the presence of AD or
SIVD or both is through an autopsy. AD has diagnostic gold standards
and several scoring systems for rating severity, but this is
not so for SIVD. It is important for researchers to quantify
this disease in order understand its prevalence and incidence
rate, and conduct valid clinical research and drug trials. Project
investigators comparing the pathology data with the imaging
data are creating a novel classification system for rating SIVD
that will improve neuropathology methods for diagnosing SIVD.
In addition there are very promising preliminary results that
suggest that MRI methods developed in this project may be of
considerable use for measuring the extent of AD and CVD pathology
in living persons.
Many gains have been made with regard to causes, diagnosis and
prognosis in SIVD and AD. Ongoing efforts associated with this
project are teasing apart the differences between these diseases.
But the gains we make also generate questions. “The Aging
Brain” study will continue to probe what cognitive changes
occur, how the brain changes structurally and metabolically,
why these changes occur, and how these changes predict the course
of AD and SIVD.
We gratefully acknowledge the commitment and contributions made
to this important study by those who have volunteered to participate.
