ARTICLE IN BRIEF
Investigators were able to use a novel PET tracer to track the progression of tau protein pathology in people with Alzheimer's disease and normal controls. They found that higher quantities of tau in the medial temporal lobes of the brain were associated with greater decline in episodic memory.
Using an experimental radiotherapeutic tracing compound and positron emission tomography (PET), researchers were able to evaluate tau protein pathology in living adults with Alzheimer's disease (AD), age-matched older adults, and younger persons with normal cognition. Until now, tau deposits, called neurofibrillary tangles, could only be observed after brain autopsy.
Investigators at the University of California, Berkeley Helen Wills Neuroscience Institute used the investigative tracer florbetapir 18F-AV-1451, which has not yet been approved by the US Food and Drug Administration (FDA), to conduct the study.
STUDY METHODS, FINDINGS
In the new study, published in the March 2 issue of Neuron, the investigators studied tau pathology in 53 adults, including five young adults (ages 20-26), 33 cognitively healthy adults (ages 64-90), and 15 patients (ages 53-77) with probable AD.
They found that higher quantities of tau in the medial temporal lobes of the brain were associated with greater decline in episodic memory, which processes and stores new information for later recall. The changes were also consistent with Braak staging, a six-stage system developed by German researchers Heiko and Eva Braak through autopsies of brains of suspected AD patients.
According to Samuel N. Lockhart, PhD, a post-doctoral scholar at the Helen Wills Neuroscience Institute and one of the paper's co-lead authors, the PET tracer demonstrated that it can track stages of tau in AD progression. Ifconfirmed in larger and longer studies, it might represent a major advance in the early diagnosis and staging of the disease, he said.
“We've made advances in understanding AD because we can see how amyloid accumulates in the brain, however amyloid is only part of the story,” Dr. Lockhart told Neurology Today. “For example, unlike tau, amyloid accumulation correlates poorly with cognitive symptoms.”
Theories and models of how AD develops, together with this and other studies suggest some interaction between amyloid and tau is necessary for cognitive problems, he noted. “When you have a lot of amyloid with tau in the brain, the problem of cognitive loss becomes more severe. Our study suggests that they may work together in AD.”
ABETA AND TAU ‘SYNERGY’
Normal tau serves as a form of scaffolding in neurons, but as people age it begins to aggregate as microfilaments. As these grow out of control, they form neurofibrillary tangles, which eventually cause neurons to burst. One question that has remained unclear, however, is why many older individuals have tau in their medial temporal lobes, yet never develop AD.
“We know that tau occurs in almost every aging brain. In fact, very few older persons are tau-free,” Dr. Lockhart said. “What we found suggests that tau accumulation in the medial temporal lobes is independent of amyloid and driven by age alone, but together they result in progressive cognitive decline.”
Interactions between Abeta and tau are very complex and exist at multiple levels — both amyloid and tau, in many forms, can affect the structure and function of the brain at molecular, cellular, and systems levels, he explained.
In the study, when tau had spread outside of the medial temporal lobes to other parts of the brain, such as the neocortex, there was significantly greater decline in cognitive function. Tau's spread outside the area was also associated with the presence of Abeta plaques.
“Having both pathologies seems to be critical to diseases like AD. Tau and beta-amyloid have synergistic toxic effects, with Abeta seeming to drive tau pathology. But tau can also mediate the toxic effects of amyloid-beta on neurons,” noted Dr. Lockhart.
“It was interesting to see, and it has been validated in previous research from many other labs, that tau pathology seems to be related to increased age in some regions of the brain like the medial temporal lobes, and to increased amyloid in other areas, such as the inferior and lateral temporal lobes. These data suggest some complex interaction between the two that could be critical to successful memory function late in life.”
In Braak staging, the degree of tau is ranked from one to six. Stages I and II are given when tau in primarily found in the transentorhinal region, III and IV if found in the limbic areas like the hippocampus, and stages V and VI where there is extensive neocortical involvement.
The new study is the first to confirm the staging system in people who are not only alive, but in older adults without cognitive impairment, according to the researchers.
Tau imaging could become an important tool in helping develop therapeutic approaches that target the correct protein — either amyloid or tau — depending on the disease stage, the researchers said.
Dr. Lockhart said the researchers are already planning baseline and longitudinal analyses of larger samples of young, middle-aged, and cognitively normal older adults using tau PET in conjunction with other more established methods like amyloid PET, fluorodeoxyglucose (FDG-PET), cognitive testing, and magnetic resonance imaging (MRI).
The research was funded in part by the National Institutes of Health and conducted at the William Jagust Lab, a joint research program involving the Helen Wills Neuroscience Institute, UC Berkeley School of Public Health, and the Lawrence Berkeley National Laboratory.
TOWARD AN INTERVENTION
The study demonstrates, in principle, that tau can be studied harmlessly in living adults said Steven T. DeKosky, MD, FAAN, the Rene Aerts/Virginia J. Cosper professor of Alzheimer's Research at the McKnight Brain Institute at the University of Florida College of Medicine in Gainesville, who was not involved with the study.
“This is a terrific group of researchers and their findings are both very interesting and informative,” he told Neurology Today.
Dr. DeKosky, who is also associate director of the Florida Alzheimer's Disease Research Center and deputy director of the McKnight Brain Institute, noted that while some of the AD cases in the study appear to have been atypical, whether or not this affected the findings in any way is unclear.
“What it does do is support that tau is a normal part of aging that does not necessarily lead to AD. It has always been proposed — like love and marriage — first comes Abeta and then comes tau. It may be Abeta somehow stimulates some mechanism in tau that causes it to spread from the transentorhinal region, where AD is believed to start, into the neocortex.”
“Stopping Abeta before it begins stimulating tau might be one way to test potential therapeutic interventions. This is a really fascinating concept and seems to confirm the observation from autopsies that if you see tangles in the cortex you will see dementia,” he noted.
Ronald Petersen, MD, PhD, FAAN, a professor of neurology and director of the Mayo Clinic Alzheimer's Disease Research Center in Rochester, MN, said the study corroborates the suspicion that the effect of tau in certain individuals is progressive and lifelong, something indicated in the Braak staging model.
Intervention strategies to try to block either tau or Abeta will happen “sooner rather than later,” he told Neurology Today, noting that researchers are already testing possible strategies to limit the spread of tau not just in AD, but also in frontotemporal dementia and related tauopathies, and a few are already under development.
“This imaging seems to be more specific for AD tauopathies than for other brain problems, and it could play an important role in testing any possible interventions. If an intervention strategy for tau is developed, it will have huge clinical implications.”
EXPERTS: ON AN IMAGING AGENT THAT TRACES TAU PROGRESSION