Magnetic Resonance
Team approach sheds new light on cognitive
disorders of the elderly
Form follows function as neuroradiologists
chase disease process and explore treatment physiology
By Karen
Sandrick
A decade from now, neuroradiologists will routinely merge data from MR
spectroscopy, activation and resting state functional studies, diffusion tensor
techniques, and tractography to evaluate pathologies of the elderly they
haven’t previously been able to visualize. These specialists will interpret
clinical and imaging data to establish pathologic diagnosis, distinguish
Alzheimer’s disease from vascular dementias, and detect dementia before
plaques have stolen too many precious memories.
Understanding the brain’s ability to alter the distributive process in
large-scale neurocognitive networks is the starting point for teams of
neuroradiologists, psychologists, neurologists, and neuroscientists. These teams
will then target treatments to specific forms of dementia and guide the
rehabilitation and maintenance of cognitive function. In the process,
radiologists will open the door to a new patient population, develop new
relationships with other specialists and basic scientists, and take a new
approach to disease—following function, not just form.
With the aging of the population, the overwhelming neurological problem faced
by patients, families, clinicians, and imagers will be diminished cognitive
function, said Dr. Allen Elster, chair of radiology and director of radiological
sciences at Bowman Gray Medical School in Winston-Salem, NC. Around 18 million
people in the world have dementia, and this number is expected to nearly double
in the next 20 to 25 years.
By 2010, we will have a better genetic, anatomic, and even microscopic
understanding of cognitive diseases, according to Dr. Jonathan Burdette, an
assistant professor of neuroradiology at Bowman Gray. Sophisticated MRI
techniques will illuminate the cognitive problems patients suffer and the areas
of the brain from which they arise. Burdette envisions a standard battery of
imaging tests that predict whether mild memory loss will lead to dementia so
cognitive disease specialists can start patients on therapy and forestall
further memory erosion.
Assessing cognitive function is not an area familiar to imaging, however.
Standard MRI can do little more than count simple white matter dots and evaluate
hippocampal atrophy in the normal population, Elster said. In patients with
dementia, standard MRI can spot white matter infarcts related to vascular
dementia and measure changes in volume in the medial temporal lobe and
hippocampus. Because most patients with cognitive disorders have white matter
infarcts as well as hippocampal atrophy, however, it is difficult to
differentiate vascular dementia from Alzheimer’s disease on a single
clinical image.
There are inherent problems with conventional 1.5-tesla scanners as well.
Images captured at 1.5 tesla reveal only small-scale changes in signal size, on
the order of 1%. As a result, functional imagers must pool data from many
patients and perform signal averaging to detect an effect, making diagnostic and
treatment decisions about individual patients impossible, said Dr. Keith
Thulborn, director of MR research at the University of Illinois at Chicago.
Three-tesla scanners, which snare signal changes of 5%, produce robust
functional imaging data that may be able to direct therapy for a single patient.
Stronger gradient sets available on 3-tesla magnets increase b-value diffusions
and permit a look at intracellular brain biochemistry and function. Emerging
techniques that assess brain metabolites, brain function, and molecular motion
are moving MRI away from strict morphological determinations of the shape and
traits of signals in the brain and into the province of physiologic imaging,
according to Dr. John Ulmer, associate professor of radiology at the Medical
College of Wisconsin (MCW) in Milwaukee.
No single MR technique will garner all the information needed to evaluate
cognitive function, however. Like the shards of memories that form snapshots of
time in a person’s life, each physiologic MR technique will provide
glimpses into the cognitive whole.
Spectroscopy is probably the most developed technique for assessing
Alzheimer’s disease, according to Ulmer. With a mid-field-strength magnet,
such as the 0.5-tesla scanner at MCW, spectroscopy can isolate peaks that are
invisible on higher field instruments and reveal changes in glutamate levels
against background noise. Using a mid-field magnet may seem counterintuitive,
but it allows neuroradiologists to examine glutamate excitotoxicity, which is
thought to be the common mechanism underlying neuronal injury in many
neurodegenerative diseases as well as trauma, stroke, and seizure.
Functional MRI paradigms can produce specific and reliable diagnostic
findings in patients with Alzheimer’s disease. A paradigm that asks
patients to follow a dot as it changes position across a screen triggers an
abnormal activation pattern in the parietal lobe, which reflects the loss of
attention associated with the known pathology of Alzheimer’s disease.
Another paradigm that tracks brain activity while patients follow a dot moving
randomly along a horizontal meridian in the field-of-view results in a normal
activation pattern. Investigators at UIC consequently have two
paradigms—one acting as a control and another serving as a test for
pathology—that can identify patients with probable Alzheimer’s disease
in minutes. [Fig. 1]
Resting state fMRI is a powerful and practical passive measurement of brain
performance that maps functional connectivity within the hippocampus of patients
with Alzheimer’s disease. The technique was pioneered by Dr. Bharat Biswal,
an assistant professor in the Biophysics Research Institute at MCW. While
patients sit still, examiners take only three to six minutes to observe changes
in signal oscillations from functionally connected regions of the brain.
Diffusion tensor imaging gives neuroradiologists a chance to evaluate
morphological connectivity by looking at the integrity of structural white
matter. Some laboratories employ average diffusion tensor imaging of the whole
brain to examine global processes, such as Alzheimer’s disease, and plot
the direction of white matter tracts or the physical barriers that cause water
to move in a particular direction.
Others are adopting tractography to navigate the fiber connections between
portions of the brain. Neuroradiologists at New York-Presbyterian Hospital are
conducting tractography experiments in young healthy adults to delineate normal
connections. In five to 10 years, neuroradiologists will know what happens to
these connections during the natural aging process and what kinds of changes
will likely lead to dementia. Neuroradiologists will also be able to view water
molecules that are moving a couple hundred microns a second, chart the history
of these molecules as they traverse cells, and study intracellular organelles by
increasing b-value diffusions from 1000 to 6000 or 7000 with high-field magnets
and stronger gradients.
Combination Is Key
While each of these techniques is valuable, MR imaging of cognitive disorders
will take off when techniques are combined and when neuroradiologists team with
clinicians and scientists who are interested in the underlying disease process
and with physicists who understand MRI and can refine its applications. Each of
the tests gives slightly different information. For example, with standard
anatomic imaging, Thulborn can detect brain lesions. When he adds spectroscopy,
he can demonstrate that metabolic abnormalities are more extensive than anatomic
ones. Diffusion studies show changes in physiology that can be interpreted in
light of fMRI findings.
In the next few years, cognitive disease teams will fling everything they
have at patients. Large batteries of imaging tests will drive hypotheses about
the origin and manifestations of specific disorders and how they interrelate.
Tests for discovering the precise cause of symptoms, the distinctive profiles of
individual dementias, and the paths of physiological parameters will emerge.
When an effective preventive therapy emerges, cognitive disease teams will
want to identify suitable patients well before symptoms occur. Since
neurodegenerative pathology occurs as much as 20 years before symptoms appear,
imaging ideally will begin in 40-year-olds who are at high risk. As research
gets closer to pathology-specific treatment approaches, cognitive disease teams
will target prevention to individuals who have hallmark pathology and
differentiate patients with vascular dementia from those with Alzheimer’s
disease.
Neuroradiologists expect to use MRI to find patients with cognitive disorders
before they experience severe deficits. They could triage patients into
appropriate diagnostic categories, develop models for following cognitive
performance over time, unveil potential plasticity in large-scale cognitive
networks, and guide and monitor treatment on a daily basis.
“We’re talking about a transition where we not only will be
analyzing morphology and signal characteristics of brain disease, we also will
be looking at physiology,” Ulmer said. And we will explore not only the
changes in physiology caused by disease but changes that occur with
treatment.”
