March 3, 2016--New
research led by scientists at UC Berkeley shows for the first time that PET
scans can track the progressive stages of Alzheimer’s disease in cognitively
normal adults, a key advance in the early diagnosis and staging of the
neurodegenerative disorder.
In the process, the scientists also obtained important clues
about two Alzheimer’s-linked proteins – tau and beta-amyloid – and how they
relate to each other.
The findings, published March 2 in the journal Neuron, come
from positron emission tomography (PET) of 53 adults. Five were young adults
aged 20-26, 33 were cognitively healthy adults aged 64-90 and 15 were patients
aged 53-77 who had been diagnosed with probable Alzheimer’s dementia.
The stages of tau deposition were established by German
researchers Heiko and Eva Braak through post-mortem analysis of the brains of
suspected Alzheimer’s patients.
“Braak staging was developed through data obtained from autopsies,
but our study is the first to show the staging in people who are not only
alive, but who have no signs of cognitive impairment,” said study principal
investigator Dr. William Jagust, a professor at UC Berkeley’s School of Public
Health and at the Helen Wills Neuroscience Institute and a faculty scientist at
the Lawrence Berkeley National Laboratory. “This opens the door to the use of
PET scans as a diagnostic and staging tool.”
PET scans are used to detect early signs of disease by looking
at cellular-level changes in organs and tissue. The results of the scans in
this study paralleled Braak neuropathological stages, which range from one to
six, describing the degree of tau protein accumulation in the brain.
Jagust worked with study co-lead authors Michael Schöll, a
visiting scholar, and Samuel Lockhart, a postdoctoral fellow, both at UC
Berkeley’s Helen Wills Neuroscience Institute.
Tau vs. amyloid
Their findings also shed light on the nature of tau and
amyloid protein deposits in the aging brain. For many years, the accumulation
of beta amyloid plaques was considered the primary culprit in Alzheimer’s
disease. Over the past decade, however, tau, a microtubule protein important in
maintaining the structure of neurons, has emerged as a major player. When the
tau protein gets tangled and twisted, its ability to support synaptic
connections becomes impaired.
While a number of symptoms exist that signal Alzheimer’s
disease, a definitive diagnosis has been possible only through an examination
of the brain after the patient has died. The availability of amyloid imaging
for the past decade has improved this situation, but how Alzheimer’s developed
as a result of amyloid remains a mystery. Studies done in autopsies linked the
development of symptoms to the deposition of the tau protein.
Through the PET scans, the researchers confirmed that with
advancing age, tau protein accumulated in the medial temporal lobe — home to
the hippocampus and the memory center of the brain.
“Tau is basically present in almost every aging brain,” said
Schöll, who holds an appointment at Sweden’s University of Gothenburg. “Very
few old people have no tau. In our case, it seems like the accumulation of tau
in the medial temporal lobe was independent of amyloid and driven by age.”
The study revealed that higher levels of tau in the medial
temporal lobe was associated with greater declines in episodic memory, the type
of memory used to code new information. The researchers tested episodic memory
by asking subjects to recall a list of words viewed 20 minutes earlier.
Both proteins involved in dementia
One question yet to be answered is why so many people have tau
in their medial temporal lobe yet never go on to develop Alzheimer’s. Likewise,
adults may have beta amyloid in their brains and yet be cognitively healthy.
“It’s not that one is more important than the other,” said
Lockhart. “Our study suggests that they may work together in the progression of
Alzheimer’s.”
.
While higher levels of tau in the medial temporal lobe was
linked to more problems with episodic memory, it was when tau spread outside
this region to other parts of the brain, such as the neocortex, that
researchers saw more serious declines in global cognitive function.
Significantly, they found that tau’s spread outside the medial temporal lobe
was connected to the presence of amyloid plaques in the brain.
“Amyloid may somehow facilitate the spread of tau, or tau may
initiate the deposition of amyloid. We don’t know. We can’t answer that at this
point,” said Jagust. “All I can say is that when amyloid starts to show up, we
start to see tau in other parts of the brain, and that is when real problems
begin. We think that may be the beginning of symptomatic Alzheimer’s disease.”
What the study does indicate is that tau imaging could become
an important tool in helping to develop therapeutic approaches that target the
correct protein — either amyloid or tau — depending on the disease stage, the
researchers said.
Funding from the National Institutes of Health helped support
this research.
