Tau Imaging Takes the Stage

Tao is making headlines. The journal Neuron recently published a clinical study heralding a viable tau PET agent. Co-author Makoto Higuchi from the Molecular Imaging Center of the National Institute of Radiological Sciences in Chiba, Japan, provided us with an exclusive look into this game-changer that will no doubt inform new formulas for dementia imaging.

A consistently binding tau agent has been a critical and elusive piece in the puzzle of Alzheimer’s disease imaging because it is as much a part of its pathology as beta-amyloid, now practically a household name. Pathological tau fibrils comprise intraneuronal neurofibrillary tangles and other tau lesions that are key to not only Alzheimer’s disease but other neurodegenerative disorders including corticobasal degeneration and progressive supranuclear palsy, otherwise known as taupathies. These are linked to Parkinson’s and frontotemporal dementia.

One of the reasons imaging tau fibrils is so important is due to its pattern of development over time, which is very different than amyloid burden in the brain.

“As revealed by PIB-PET, amyloid deposition in the brain occurs 10 to 20 years before the clinical onset of Alzheimer’s disease, and the intensity and distribution of PIB-PET signals are nearly unaltered in the progression from mild cognitive impairment to severe Alzheimer’s disease,” notes Higuchi. “By contrast, our findings indicate that tau lesions continuously spread from the hippocampal formation to the entire limbic system and thereafter to extensive neocortical areas in transition from normal aging to advanced Alzheimer’s disease. Hence, Tau PET images can be more useful than amyloid PET data as objective indices for the severity and progression of the disease.”

With this research, tau is now on top. Higuchi says an increasing number of radiopharmaceutical companies and research scientists are narrowing in on anti-tau therapies following this pivotal understanding. The novel tau ligands described in the research are phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs)—united in this study with radionuclide carbon-11. The Neuron study included both optical fluorescence preclinical and PET clinical research with one pyridinated PBB, C-11 PBB3, which showed powerful signal in the hippocampus of a patient diagnosed with Alzheimer’s disease. Another reason this particular ligand is gaining attention is due to its ability to image a range of tau aggregates.

During this study, researchers made a head-to-head comparison of C-11 PBB3 tau imaging and C-11 PiB beta-amyloid imaging. The results showed very clearly contrasting areas of pathology. C-11 PBB3 also was able to pick up corticobasal syndrome in contrast to beta amyloid imaging with C-11 PiB.

The next step is to expand the research beyond a small-population, single-center study to a wide-ranging longitudinal clinical trial involving several institutions. Neuropathological exams of autopsied patients also will be necessary to confirm the results of PET imaging. 

“It will be of critical importance to conduct a more extensive evaluation of a tau PET ligand on a multi-center basis to validate the reproducibility of image data, analytical methods to quantify the specific radioligand binding and assessment of the dynamic range of PET signals at each stage of the disease,” remarks Higuchi.

Researchers are not yet out of the woods. There are challenges inherent in tau imaging that include weak binding stemming from the inherent anatomy of tau in the brain. Tau could potentially lack assembly formation with the kinds of binding sites that ligands can really latch onto, unlike amyloid, which has been easier so far to image, showing stronger binding and image contrast. Another issue is making sure binding is tau-exclusive and not binding to both tau aggregates and beta amyloid plaque.

“As currently available tau and amyloid tracers are basically beta-sheet ligands, it is difficult to generate tau ligands without affinity for amyloid,” Higuchi explains. “Moreover, the selectivity of a PET ligand for tau vs. amyloid may not be readily assessed in living brains of Alzheimer’s disease patients enriched with both pathologies.”

In the future, a hybrid dementia-imaging agent might include both biomarkers for amyloid and tau, for more comprehensive imaging of neuropathology, but extensive studies will likely continue for both imaging mechanisms before any hybridization could occur. Higuchi notes that PET radioligands highly reactive with both tau and amyloid could eventually be useful for initial screening of elderly subjects, since these tracers could provide an alert that Alzheimer’s disease-associated fibrillar pathologies, either amyloid or tau aggregations, come into being. “Our data and previous postmortem observations suggest that tau deposition in the hippocampal formation may appear in a considerable subset of normal elderly subjects probably in a manner independent of amyloid accumulation,” he says. “This may imply that amyloid imaging alone is not sufficient for assessing brain aging leading to the onset of Alzheimer’s disease and related disorders, and it would be more sensitive for detecting age-related abnormalities in the brain if a single scan is capable of capturing both tau and amyloid.” Stay tuned.

Don’t miss our pictorial review in this issue to see the head-to-head comparison of tau and amyloid agents in an Alzheimer’s brain.