PET imaging studies of aging brains revealed uptake of a radiolabeled tau tracer that correlated with the Braak stages of tau pathology in Alzheimer’s disease, according to two studies published online in Neuron and Brain.
The findings show that PET can be used to track tau deposition in living humans, “with results that confirm and extend information obtained from neuropathological studies,” wrote Michael Schöll, Ph.D., of the Helen Wills Neuroscience Institute at the University of California, Berkeley. Age and beta-amyloid deposition on PET imaging with Pittsburgh compound B also were associated with distinct patterns of tau deposition, which in the medial temporal lobe was tied to episodic age-related memory decline, he and his associates reported in Neuron. “The relationship between tau and cognition, even in cognitively normal older people, suggests a crucial role for this protein in aging, supporting the use of tau imaging in naturalistic studies and therapeutic trials,” they added.
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Tau pathology occurs in Alzheimer’s disease, but also characterizes normal cognitive aging. Previously, the relationships between age, beta-amyloid, and tau protein accumulation had only been studied in cerebrospinal fluid, postmortem brain tissue, and animals, Dr. Schöll and his coinvestigators said. Using open source software (Freesurfer), they delineated brain regions that correlated anatomically with the histopathologically defined Braak stages of Alzheimer’s disease. Then they used PET to characterize uptake of 18F-AV-1451, a radioligand for tau, in 53 adults. A total of 5 participants were 20-26 years old, 33 were cognitively healthy older adults aged 64-90 years, and 15 were 53-77 years old and had suspected Alzheimer’s disease (Neuron. 2016;89[5]:971-82).
Older age predicted tau deposition in the medial temporal lobe and in the basal forebrain and insula, the investigators found. In cognitively healthy older adults, worse performance on a word recall test of episodic memory was associated with tau deposition in regions of the medial temporal lobe regions that are affected in Braak stages I and II. Age-related tau deposition in the medial temporal lobe seemed to be independent of beta-amyloid accumulation, but tau deposition in other isocortical regions required the presence of cortical beta-amyloid, and was associated with lower global cognition. “Our results suggest that tau deposition, especially in the medial temporal lobe, is an important aspect of cognitive aging that may have behavioral consequences. They also suggest a relationship between tau and beta-amyloid, with implications for Alzheimer’s disease pathogenesis,” said the investigators.
Patients with Alzheimer’s disease had increased tau deposition in early and middle Braak stage regions, which often involved larger areas of the medial and lateral parietal and, to a lesser extent, frontal lobes, the investigators also reported. “This was consistent with Braak stage V/VI, which was confirmed by our in vivo Braak staging,” they added.
In the second study, Adam Schwarz, Ph.D., of Eli Lilly and Company, Indianapolis, and his associates performed 18F-AV-1451 PET scans of 14 controls aged 21-39 years and 173 adults aged 50-95 years, of which 42 were cognitively normal, 87 had mild cognitive impairment, and 44 had Alzheimer’s disease. As in the first study, the investigators defined brain regions that closely approximated those traditionally associated with Braak stages 0 through VI. Then they estimated the Braak stage for each subject based on individual PET results (Brain. 2016 Mar 2. doi: 10.1093/brain/aww023).
The researchers estimated Braak stages corresponding to stereotypical progression patterns in 149 (86%) of the 173 test subjects, while another 12 (7%) had relative sparing of the hippocampus, occipital lobe, or both, but fit predefined variants (2 with atypical Braak stage IV and 10 with atypical Braak stage V profiles). The remaining 12 (7%) did not fit any of the stereotypical or variant profiles in either brain hemisphere. Estimated Braak stage was significantly associated with amyloid status, diagnostic category, and measures of global cognition. “We demonstrated the presence of anatomical profiles of increased 18F-AV-1451 binding that strongly mirrored the stereotypical spread and progression of tau pathology that is encapsulated in the Braak staging scheme,” the researchers concluded.
The work by Dr. Schöll and associates was supported by the National Institutes of Health, the Swedish Medical Association, Tau Consortium, Blanceflor Foundation, John Douglas French Alzheimer’s Foundation, Marie Curie FP7 International Outgoing Fellowship, and BrightFocus Foundation. The tracer was used with the permission of Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. Dr. Schöll had no disclosures, and two coinvestigators reported relationships with Avid, Bioclinica, Genentech, and Novartis.
Dr. Schwarz and his coauthors all reported current employment with either Eli Lilly or Avid Radiopharmaceuticals.