Aβ nudges tau out of the hippocampus and into the cortex, where the previously benign microtubule-associated protein turns into a neuronal killer. At least, this is the hypothesis that gains support from the use of brain imaging to estimate tau accumulation and neurodegeneration in people with or without Aβ deposits in the brain. Published July 25 in JAMA Neurology, the findings are the latest of several recent reports using the tau tracer [18F]-AV-1451. While some of those linked tau deposition to abnormal cerebrospinal fluid (CSF) tau and Aβ, dips in brain glucose metabolism, and AD progression, the new analysis is the first published to correlate AV-1451 uptake with loss of brain volume. The researchers, led by Beau Ances at Washington University in St. Louis, report that in people who have Aβ accumulation in the brain, tau deposition correlates tightly with brain atrophy. Even among some cognitively normal people harboring Aβ deposits, tau accumulated in the cortex, casting cortical tau as a potentially useful disease staging tool.
Until recently, anything scientists knew about tau filaments in the human brain came from postmortem analyses. Those suggested that neurofibrillary tangles arose in the entorhinal cortex, then spread into the hippocampus and the rest of the cerebral cortex as AD progressed (see Braak and Braak, 1991; Delacourte et al., 1999). PET tracers have since allowed researchers to monitor the distribution of tau aggregates in living people. Thus far, cross-sectional analyses indicate that tau filaments build up in the brain in much the same order as reported from neuropathology studies, only appearing in the cortex if Aβ plaques are present (see Mar 2016 news). Tangles also seem to accumulate in metabolically sluggish areas of the brain, and in functionally impaired regions; for example, AD patients who struggle finding words tend to amass more tau in the left hemisphere of the cortex, which processes language (see Ossenkoppele et al., 2016). Other reports have linked cortical tau deposition to cognitive decline and AD progression, and also to characteristic changes in CSF biomarkers (see Johnson et al., 2016; May 2016 news; and Gordon et al., 2016).
“What was still missing after all of this research is how tau deposition directly relates to neurodegeneration,” Ances told Alzforum.
First author Liang Wang and colleagues sought to fill in that gap by investigating the relationship between tau deposition, Aβ, and brain atrophy. First, they wanted to confirm that tau imaging can track disease progression. The researchers conducted AV-1451 PET scans of 59 participants, 42 of whom had undergone lumbar puncture and been designated as Aβ-positive or -negative based on the concentration of Aβ42 in their CSF. Of these 42 patients, 35 were cognitively normal, including 14 people positive for Aβ. The remaining seven were diagnosed with AD, although one of them tested negative for Aβ. People with AD had higher levels of tau deposition in the hippocampus and in several “AD cortical signature regions.” Originally identified as areas of the cortex where thinning correlated with disease progression, atrophy in these signature regions also correlated with tau accumulation in both autopsy and CSF biomarker studies (see Dickerson et al., 2009; Vemuri et al., 2008; and Wang et al., 2015).
Using a cutoff of 1.19 in the standardized uptake value ratio (SUVR) for AV-1451 in the AD cortical signature regions, the researchers could distinguish healthy controls who had normal CSF Aβ from people with AD. A fraction of cognitively normal people who tested positive for Aβ had SUVRs above the cutoff, suggesting they might be on the verge of conversion to AD, Ances said. This indicated that tau imaging could be used as a staging tool to determine who among cognitively normal people will soon develop AD, he said.
After confirming that the tracer seemed to track with disease progression, the researchers next teased apart the relationships between Aβ plaques, tau deposition, and brain volume. They found that unlike in the AD cortical signature regions—where tau was higher in Aβ-positive people than in Aβ-negatives—in the hippocampus, tau deposition did not vary with Aβ status (though it trended higher in people with Aβ).
What about brain volume? Compared with cognitively normal people, those with AD had smaller hippocampi and thinning in cortical regions associated with the disease. Tau levels in the hippocampus and cortex inversely correlated with hippocampal volume and cortical thickness, respectively. In the hippocampus, the relationship only held in people who had abnormal CSF Aβ. However, in the cortex, the tau deposition coupled tightly with atrophy regardless of Aβ status. The strength of this relationship between tau and neurodegeneration maxed out in the medial temporal lobe, and waned moving outward into the inferior and lateral temporal, and ultimately parietal areas. This pattern tracked closely with the hypothetical path of neurofibrillary tangle propagation proposed previously based on neuropathology (see Braak and Braak, 1991). Together, the findings suggested to the researchers that in the absence of Aβ, hippocampal tau seems insufficient for neurodegeneration. They propose that the accumulation of Aβ somehow transforms this benign hippocampal tau into a toxic entity, which then proceeds to kill neurons in the hippocampus and in the cortical regions to which it then spreads, an idea that has gained momentum (see Aug 2015 conference news; Jan 2016 conference news).
Christopher Rowe of the University of Melbourne in Australia found this suggestion intriguing, but said that the study may have been too small to determine whether neurodegeneration depended upon the conversion of tau into a more toxic form, or simply on there being more of the protein present. That hippocampal neurodegeneration among people with similar levels of hippocampal tau only occurs when Aβ enters the picture supports the idea of conversion to some toxic form of tau. However, Rowe pointed out that the level of tau in the hippocampus of Aβ-positive people did trend higher than that in Aβ-negative people, suggesting tau concentration may still be germane. “A larger study is needed to clarify this potentially very important issue,” he wrote.
Mark Mintun of Avid Radiopharmaceuticals in Philadelphia agreed. “Maybe Aβ does transform tau into a malignant form, but we can’t conclude that with this data alone,” he said. However, he pointed out that the correlations between tau and neurodegeneration were impressive, and called the study icing on the cake of previous studies linking cortical tau to the transition to clinical AD.
“The findings support the idea that this tau tracer will be a powerful way to monitor neurodegeneration during clinical trials,” Mintun added. He is currently heading a clinical trial aimed at validating [18F]-AV-1451 as a bona fide imaging agent for tau, in which researchers will compare tau imaging in patients close to death to postmortem neuropathology afterwards (see clinicaltrials.gov).
“Mapping brain tau in relation to measures of neurodegeneration is the beginning of more precisely staging the disease,” wrote William Jagust of the University of California, Berkeley, in an editorial that accompanied the paper. “Preclinical AD may ultimately be staged by relating tau to these neurodegenerative biomarkers, and the neocortical localization of tau may be a harbinger of incipient neurodegeneration and cognitive symptoms. This staging may be crucial in selecting people for participation in clinical trials of drugs that are directed at either Aβ or tau,” he added.—Jessica Shugart
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No Available Further Reading
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