UCLA: After six years of painstaking research, a UCLA-led team has validated the first standardized protocol for measuring one of the earliest signs of Alzheimer’s disease — the atrophy of the part of the brain known as the hippocampus.
Using brain tissue of deceased Alzheimer’s disease patients, a group
headed by Dr. Liana Apostolova, director of the neuroimaging laboratory
at the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA,
confirmed that the newly agreed-upon method for measuring hippocampal
atrophy in structural MRI tests correlates with the pathologic changes
that are known to be hallmarks of the disease — the progressive
development of amyloid plaques and neurofibrillary tangles in the brain.
“This hippocampal protocol will now become the gold standard in the
field, adopted by many if not all research groups across the globe in
their study of Alzheimer’s disease,” said Apostolova, who was invited to
play a key role in the consortium because of her reputation as one of
the world’s leading experts in hippocampal structural anatomy and
atrophy. “It will serve as a powerful tool in clinical trials for
measuring the efficacy of new drugs in slowing or halting disease
The brain is the least accessible and most challenging organ to study
in the human body; as a result, Alzheimer’s disease can be diagnosed
definitively only by examining brain tissue after death. In living
patients, physicians diagnose Alzheimer’s by evaluating other health
factors, known as biomarkers, in combination with memory loss and other
The hippocampus is a small region of the brain that is associated
with memory formation, and memory loss is the earliest clinical feature
of Alzheimer’s disease. Its shrinkage or atrophy, as determined by a
structural MRI exam, is a well-established biomarker for the disease and
is commonly used in both clinical and research settings to diagnose the
disease and monitor its progression.
But until now, the effectiveness of structural MRI has been limited
because of the widely different approaches being used to identify the
hippocampus and measure its volume — which has called into question the
validity of this approach. A typical hippocampus is about 3,000 to 4,000
cubic millimeters in volume. But, Apostolova notes, two scientists
analyzing the same structure can come up with a difference of as much as
2,000 cubic millimeters.
In addition, no previous study had verified whether estimates for the
volume of the hippocampus using MRI corresponded to actual tissue loss.
To address these deficiencies, the European Alzheimer’s Disease
Consortium–Alzheimer’s Disease Neuroimaging Initiative was established
to develop a Harmonized Protocol for Hippocampal Segmentation, or HarP —
an effort to establish a definitive method for measuring hippocampal
shrinkage through structural MRI in a way that best corresponds to the
Alzheimer’s disease process.
Once the HarP was established, Apostolova and four other experts were
invited to develop the gold standard for measuring the hippocampus to
be used by anyone employing the HarP protocol. The UCLA-led team then
validated the technique and ensured the changes in the hippocampus
corresponded to the hallmark pathologic changes associated with
“The technique is meant to be used on scans of living human subjects,
so it’s important that we are absolutely certain that this methodology
measures what it is supposed to and captures disease presence
accurately,” Apostolova said.
To do that, her group used a powerful 7 Tesla MRI scanner to take
images of the brain specimens of 16 deceased individuals — nine who had
Alzheimer’s disease and seven who were cognitively normal — each for 60
hours. This provided unprecedented visualization of the hippocampal
tissue, Apostolova said.
After applying the protocol to measure the hippocampal structures,
the researchers analyzed the tissues for two changes that signify the
disease: a buildup of amyloid tau protein and loss of neurons. The team
found a significant correlation between hippocampal volume and the
Alzheimer’s disease indicators.
“As a result of the years of scientifically rigorous work of this
consortium, hippocampal atrophy can finally be reliably and reproducibly
established from structural MRI scans,” Apostolova said.
Although the technique can be used immediately in research settings
such as clinical trials, the next step, Apostolova noted, will be to use
the standardized protocol to validate automated techniques available
for measuring the hippocampus so the approach could be used more widely —
including for the diagnosis of the disease in doctor’s offices and
other patient care settings.
Funding for the study was provided by the National Institute on Aging
(P50 AG16570), the Jim Easton Consortium for Alzheimer’s Drug Discovery
and Biomarker Development, the National Institutes of Health (R01
AG040770), and the Alzheimer’s Association (IIRG 10-174022). Please see
the paper for a complete list of the study’s authors.