In the past few years, tau imaging tracers have given researchers their first live look at the neurofibrillary tangles inside people’s brains, visualizing where tau builds up in people who age normally or who develop a neurodegenerative disorder. How do tau patterns fit with more established markers of Alzheimer’s disease (AD)? To find out, researchers led by Beau Ances and Tammie Benzinger at Washington University in St. Louis correlated tau imaging with amyloid PET, cerebrospinal fluid (CSF) measures of both amyloid and tau pathology, cognitive status, and neuropsychological measures among people with mild AD and age-matched normal controls. As reported in the May 11 Science Translational Medicine, distinct patterns of tau deposition in the brain best predict each one. The data help position tau positron emission tomography (tau-PET) data with more established AD biomarkers, and add to prior evidence that regional tau PET predicts cognitive decline better than amyloid-β. Spoiler alert: Even here, the relationship between amyloid and tau pathology is not simple or straightforward.
“This study represents a thoughtful advance in our understanding of the relations between early stage Alzheimer’s disease pathology and both clinical and cognitive measures,” wrote Samuel Lockhart, University of California, Berkeley, to Alzforum. “It confirms and extends other recent tau PET findings to start to break down the specific topographies of pathology that are critical to cognitive differences in late life.” Lockhart was not involved in this work.
A few recent studies have taken Aβ and tau PET images from the same people. They so far support the old idea that of the two, tau is better at predicting cognitive decline (Johnson et al., 2016; Ossenkoppele et al., 2016). In addition, those studies suggest that in normal aging, tau builds up in the medial temporal lobe and episodic memory declines slightly, but when amyloid enters the picture, tau spreads out into the cerebral cortex and widespread cognitive impairment ensues (Mar 2016 news on Scholl et al., 2016). However, no paper had explored the region-to-region Aβ-to-tau PET associations. Nor had anyone matched up tau PET with Aβ imaging, CSF measures, and performance on neuropsychiatric tests all in the same people.
First author Matthew Brier and colleagues aimed to place neurofibrillary tangle deposition as per PET into staging diagrams. “There has been a lot of work starting to put these markers in a temporal order,” said Ances. “We were interested in trying to figure out where tau PET fits in this progression, and how it relates to other biomarkers we have.”
The researchers recruited 46 people from the Knight Alzheimer’s Disease Research Center at Washington University in St. Louis, average age 75. All were cognitively assessed using the clinical dementia rating scale (CDR). Thirty-six were cognitively healthy, 10 had been clinically diagnosed with either mild cognitive impairment (MCI) or mild AD. Each underwent PET scanning with T807 to image neurofibrillary tangles and florbetapir to visualize amyloid-β. Most participants also gave a CSF sample and took a series of neuropsychological tests, including those of semantic, episodic, visuospatial, and working memory.
As has been reported before, florbetapir uptake was already elevated in many of the healthy controls (see, for example, Crystal et al., 1988; Nov 2011 news). Brain amyloid deposition was lowest in those with normal CSF Aβ and tau, intermediate in those with abnormally low CSF Aβ, and highest in people with abnormal CSF Aβ and elevated CSF tau. This suggests amyloid deposition helps pick out patients who have CSF evidence of AD pathology from those who are still cognitively normal, Ances said.
By contrast, T807 scans revealed that cognitively normal people had little fibrillar tau in the brain, except some in the basal ganglia. In those who were slightly cognitive impaired, however, insoluble tau appeared to have risen and spread. In people diagnosed with MCI or mild AD, tau had accumulated in the temporal lobes and throughout the cerebral cortex. This tangle burden associated more strongly with cognitive status than did amyloid load (see image above).
What’s more, where tau was deposited in the brain tau tracked better with declining neuropsychological test scores. Tau deposits in temporal and basal frontal regions coincided with declining semantic, visuospatial, and global memory. The predictive value of florbetapir uptake was much weaker. “The results fit with the idea that amyloid is among the earliest changes going on in AD; it goes up and stays elevated before cognitive impairment,” Ances told Alzforum. “Later on, in the transition to MCI or symptomatic AD, that’s where tau fits in.”
Using multivariate analysis, Brier and colleagues identified a disease-related regional distribution pattern, aka topography, for Aβ, and one for tau. These patterns of covariance tracked with disease, being found only in people with MCI or AD. For Aβ, this topography included primarily frontal and parietal regions; for tau, the temporal lobe including the hippocampus.
Given that these Aβ and tau topographies differed, the authors wondered if there was any relationship between the accumulation of Aβ in one area, and tau in another. They found that in people with mild AD, frontal and parietal Aβ highly correlated with tau in the medial temporal lobe, parietal cortex, and precuneus (see image above). “This is telling us that both of these pathologies contribute to disease progression and are related to each other, but [as seen above] tau tracks cognitive symptoms more closely,” wrote Brier to Alzforum.
How are these correlated distributions of Aβ and tau tied together? “That’s the million-dollar question,” said Ances. “It may be that Aβ-affected regions are physically connected to tau-affected regions, or maybe they are connected in a different way.” The results reveal intermediate stages of tau progression rarely seen in neuropathology studies. In some people, tau has spread into lateral, temporal, parietal, and even occipital areas while the person was still cognitively normal, Ances said. The scientists still don’t know what causes tau to spread, and how the relationships between tau, Aβ imaging, CSF, and cognition change over time.
Historically, researchers have had no luck correlating amyloid plaque burden to cognitive decline. This new data suggest that amyloid can give some information about cognitive status, but less than tau. “At the extremes, it’s very useful; if someone has no Aβ, they don’t have AD, and if they have a lot of Aβ, they likely have severe AD,” noted Brier. “But tau gives a better prediction of cognition using a smaller number of brain regions,” he wrote.
The researchers also used a type of regression analyses to examine which regions of Aβ and tau deposition best predicted CSF measures of AD pathology. Aβ deposits in the frontal and parietal regions predicted lower CSF Aβ42. Tau tangles in the entorhinal and temporal cortices, as well as the cuneus, best predicted higher CSF tau. Interestingly, florbetapir uptake in the frontal and temporal regions also predicted elevated CSF tau. This suggested to the authors that tau pathology depends initially on the presence of Aβ.
The data fit with the idea that amyloid accumulation precedes tau pathology, and that large amounts of amyloid plus the spread of tau outside of the medial temporal lobe trigger the progression of disease, said Ances. He said the study largely confirms the temporal order of Alzheimer’s biomarkers proposed by Cliff Jack from the Mayo Clinic, Rochester, Minnesota (Jack et al., 2010; Feb 2013 news). In other words, amyloid accumulates first, followed by tau, and the resulting assault on synaptic communication leads to cognitive decline.
“This study found that while amyloid and tau are clearly related to each other, they are separated in space, with different brain regions showing an early proclivity for each pathology,” wrote Gil Rabinovici, University of California, San Francisco, to Alzforum. “Though we have known about this paradox for some time from neuropathology studies, the imaging findings highlight the need to integrate these findings into unifying models of AD that will better explain how amyloid and tau interact with each other and synergize to drive disease,” he wrote. Rabinovici said he would have liked to see a measure of neurodegeneration included, such as MRI, as it may mediate the relationship between tau deposition and cognitive decline. He also pointed out that the data are heavily weighted toward normal older people. Since the relationships between tau PET and other imaging, cognitive, and CSF variables probably vary across disease stages, it will be interesting to sample a larger number of patients with MCI and AD dementia, he said.—Gwyneth Dickey Zakaib
- Tau PET Aligns Spread of Pathology with Alzheimer’s Staging
- In Healthy Brains, Does Aβ Really Matter?
- HAI—Sharper Curves: Revamping a Biomarker Staging Model
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