The particular type of tangle found in Alzheimer’s is unique to this disease, making tau PET a highly specific marker. In the May 11 JAMA Neurology, researchers led by Oskar Hansson at Skåne University Hospital in Malmö, Sweden, reinforce this point. In a large observational cohort, the second-generation tau tracer RO-948 outperformed both cerebrospinal fluid markers and MRI at telling AD dementia apart from other neurodegenerative disorders and from healthy aging. “You get higher specificity with tau PET than with amyloid markers,” Hansson told Alzforum. Because every person with a positive tau PET scan also had amyloid plaques, tau scans may eventually obviate the need to check amyloid status to diagnose AD, he suggested.
- Tau tracer RO-948 uptake is highly specific for Alzheimer’s dementia.
- Tau PET could supplant amyloid PET and CSF as an AD diagnostic.
- At the prodromal stage, however, CSF picks up more cases than tau PET.
However, this is not the case at earlier, prodromal stages. Because tangles form late in the disease course, CSF biomarkers performed better than tau PET at that stage.
"This is a milestone paper in establishing tau PET, and specifically RO-498 PET, as a clinically useful biomarker for patients attending Memory clinics," Bernard Hanseeuw of Massachusetts General Hospital wrote to Alzforum (full comment below).
Tobey Betthauser at the University of Wisconsin-Madison School of Medicine noted that this is one of the largest studies to date to examine differential diagnosis with tau PET. “This study presents a tremendous step forward for understanding the clinical and research utility of RO-948 and tau PET imaging,” he wrote to Alzforum (full comment below).
Only in Alzheimer’s. Tau tracer RO-948 lights up symptomatic AD brain (top right), and shows a smaller signal in prodromal AD (bottom middle). Even amyloid-positive but cognitively normal people show a hint of signal (bottom left), but amyloid-negative controls and other disorders do not. [Courtesy of Leuzy et al., JAMA Neurology.]
Most current tau tracers recognize the paired helical filaments of 3/4R tau found in AD brain, but not other types of tau aggregate (Feb 2020 conference news). In keeping with this, Hansson and colleagues had previously reported that flortaucipir distinguished AD from other disorders with about 90 percent sensitivity and specificity (Sep 2018 news). However, flortaucipir has off-target binding in the basal ganglia, choroid plexus, and temporal lobe, which sometimes muddies results. Next-generation tau tracers such as RO-948 are reputed to be cleaner.
The authors evaluated RO-948 scans from 613 participants in the Swedish BioFINDER2 observational cohort, whose average age was 69. First author Antoine Leuzy at Lund University, Sweden, analyzed cross-sectional data from 257 cognitively healthy controls, 154 people with mild cognitive impairment, 100 with AD dementia, and 102 with another neurodegenerative disorder. About 40 percent of controls and non-AD patients had amyloid plaques, as did about 60 percent of the MCI group, making amyloidosis a poor discriminator of these groups.
The tau tracer RO-948, on the other hand, was highly specific for AD dementia. Its uptake in Braak regions I-IV distinguished AD from non-AD disorders with an area under the curve of 0.97. The AUC measure estimates the accuracy of a diagnostic test by taking into account the test’s rate of both false negatives and false positives. Broken out, the tracer’s sensitivity and specificity were 92 and 91 percent, respectively, similar to the previous findings with flortaucipir. Tau PET was equally effective at picking out AD patients from healthy controls, with an AUC of 0.98 and sensitivity and specificity of 91 and 95 percent, respectively (see image above).
Compared with these tau PET findings, CSF Aβ42/40 topped out slightly lower, posting an AUC of 0.93 for distinguishing AD from other disorders, and 0.91 versus healthy controls. While CSF biomarkers were highly sensitive, they lacked specificity for AD, leading to many false positives.
MRI measures fared worse. Temporal lobe thickness achieved an AUC of 0.80 for discriminating AD from other disorders, while whole-brain cortical thickness reached 0.91 for separating AD dementia from healthy controls.
Tangles in DLB. RO-948 binds to some DLB brains (top middle), reflecting Alzheimer’s-type tangles there. The tracer has very low off-target binding to the temporal lobe in svPPA (bottom left). [Courtesy of Leuzy et al., JAMA Neurology.]
How about other neurodegenerative diseases? Twelve participants with behavioral variant frontotemporal dementia, 16 with progressive supranuclear palsy, 26 with Parkinson’s disease, six with multiple system atrophy, and 10 people with vascular dementia did not bind this tracer in their brains. On the other hand, 25 people with dementia with Lewy bodies did retain some tracer in their temporal and lateral parietal cortices (see image above). AD proteopathy is common in DLB, and indeed, 15 of the 25 had amyloid plaques, as well. Only those DLB participants with plaques took up the tracer, suggesting this was an on-target signal. Unsurprisingly, RO-948’s specificity for distinguishing DLB from AD was low, at 70 percent.
For another disorder, off-target binding was a problem. Seven people with semantic-variant primary progressive aphasia had some RO-948 uptake in the temporal pole. Because people with this disorder do not develop tau tangles, this was likely nonspecific binding. It is unclear what the tracer binds to, although binding was associated with white matter and could reflect astrocytosis, Hansson suggested. All svPPA participants fell below the cutoff for positivity with RO-948, which was set at 2.5 standard deviations above the average value in healthy young controls. Curiously, for temporal regions, this cutoff ended up at about 1.36 SUVR for RO-948 as well as for flortaucipir and MK-6240. “The cutoff seems to be surprisingly stable between different cohorts and tracers. That’s a very good thing for clinical implementation,” Hansson said.
Flortaucipir lights up svPPA brain as well, with uptake in the temporal lobe and cortex. In this study, the researchers directly compared RO-948 and flortaucipir in three participants who underwent scans with both tracers, and found RO-948 to be much cleaner. Even though the overall diagnostic accuracy with both tracers is similar, the lower off-target binding with RO-948 would be an advantage in specific cases such as svPPA patients, Hansson noted. Flortaucipir also binds off-target to choroid plexus, and this signal can spill over into the hippocampus, a key location for tangle pathology, he added. “There might be fewer false positives with RO-948,” Hansson speculated.
Notably, across the whole cohort, RO-948 retention indicated the presence of amyloid plaques with almost perfect accuracy. Only two people without plaques had high tau tracer uptake in Braak regions I and II. Both carried the MAPT R406W mutation, which gives rise to tangles. Two other amyloid-negative participants were barely over the threshold for tau positivity in Braak regions I and II. This could reflect primary age-related tauopathy, or noise in the data, the authors noted.
Because plaques and tangles were so highly concordant, and because tangles more closely track cognitive decline, tau PET scans could become the primary diagnostic tool for AD dementia, the authors proposed. If the tau PET scan is negative, clinicians could then use other tools such as FDG PET, dopamine imaging, and MRI to evaluate the likelihood of FTD, DLB, and vascular dementia, respectively.
So far, no tau tracers have been approved by the U.S. Food and Drug Administration, though a decision for flortaucipir is pending (May 2020 news). RO-948 is currently only available for research studies. Edilio Borroni at Roche told Alzforum that the company has not yet decided whether to develop RO-948 or the similar second-generation tracer, Genentech’s GTP1, for clinical use.
Although tau PET seems well-suited to detect AD dementia, the MCI stage of the disease is a different story. Here, it is not sharp enough. In the BioFINDER2 cohort, RO-948 identified MCI with an AUC of 0.80, sensitivity of 38 percent, and specificity of 95 percent. At this stage, CSF Aβ42/40 did well, posting an AUC of 0.89, with 100 percent sensitivity and 64 percent specificity. This fits with prior findings suggesting that CSF picks up Alzheimer’s pathology sooner than PET scans do (Aug 2016 conference news).
“More sensitive tau imaging agents, capable of capturing small increments of tau tangles, are still desirable,” noted Tharick Pascoal at McGill University, Montreal (full comment below).
Hansson suggested that longitudinal tau imaging might improve the ability of these scans to pick up early AD cases, since researchers could look for accumulation in early Braak regions, rather than using a brain-wide cutoff for tau positivity. In future work, Hansson and colleagues are investigating whether they can predict the best brain regions to monitor for future tangle accumulation based on a person’s baseline tau PET scan. This would also improve sensitivity.—Madolyn Bowman Rogers
- Leuzy A, Smith R, Ossenkoppele R, Santillo A, Borroni E, Klein G, Ohlsson T, Jögi J, Palmqvist S, Mattsson-Carlgren N, Strandberg O, Stomrud E, Hansson O. Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders. JAMA Neurol. 2020 May 11; PubMed.