Visual Interpretation of Tau PET Predicts Cognitive Decline | Nutrition Fit



A relatively simple and accessible Food and Drug Administration (FDA) approved method of visually classifying flortaucipir PET accurately predicts cognitive deterioration, new research shows.

The results from two independent studies consistently showed that patients with a flortaucipir advanced tau pattern had greater mean deterioration across several clinical endpoints within 18 months.

Dr Ming Lu

“We believe tau PET scans provide additional information to predict a patient’s outcome within a short follow-up time frame, on top of other indicators of baseline clinical status,” study investigator Ming Lu, MD, MPH, director of statistics, Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Co, Philadelphia, Pennsylvania, told Medscape Medical News.

The study was published online February 15 in JAMA Neurology.

Two Prospective Studies

The analysis included data on 364 cognitively impaired participants enrolled in two similarly designed prospective, longitudinal clinical studies.

The first study, conducted at sites in the US, evaluated the association between flortaucipir uptake at baseline and the rate of cognitive decline over the next 18 months.

The second study was an international trial that evaluated the β-secretase 1 (BACE) inhibitor lanabecestat; this study was terminated early due to futility. Participants in the second study were included in the analysis if they had a flortaucipir scan at baseline and completed a clinical dementia rating (CDR) assessment at 18 months.

Pooled baseline information from the two studies showed the mean age of participants was 71.8 years, 47.8% were female, and 89.6% were White. About 57.5% of pooled subjects were APOE ε4 carriers and 55.8% were diagnosed with Alzheimer’s disease. All participants in the second study were Aβ positive vs 63.5% in the first study.

Mean pooled numbers from cognitive and functional assessments were 16.4 for the 11-item version of the Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-Cog11), 3.6 for the CDR-sum of box (CDR-SB), 9.1 for the Functional Activities Questionnaire (FAQ) and 24.3 for the Mini-Mental State Examination (MMSE).

In both studies, flortaucipir scans were independently evaluated by radiologists blinded to clinical information. Researchers rated scans according to the amount and location of tau in the brain based on PET imaging.

Investigators classified patients into one of three AD tau patterns — advanced, moderate and negative. An advanced AD tau pattern was characterized by increased neocortical activity in the parietal/precuneus regions or frontal regions, with increased uptake in the posterolateral temporal (PLT), parietal, or occipital regions.

Moderate tau patterns showed increased neocortical activity in the PLT or occipital regions, while a negative pattern showed no increased neocortical activity or increased neocortical activity isolated to the mesial temporal, anterolateral temporal, and/or frontal regions.

About 49% of participants in the first study had an advanced AD pattern, 7% had a moderate pattern, and 44% had a negative pattern. In the second study, 79% had an advanced, 7.3% had a moderate, and 13.7% had a negative AD pattern.

Researchers then compared advanced AD tau pattern with negative or moderate AD tau pattern.

Faster Decline

In both studies, investigators measured clinical progression using the CDR scale, the MMSE, ADAS-Cog11, and FAQ. The CDR-SB was the primary endpoint for determining success in both studies.

Pooled data showed that 240 participants had an advanced pattern whereas 124 participants had a nonadvanced AD flortaucipir scan pattern. Participants with an advanced AD scan pattern experienced more clinical meaningful deterioration vs those with a nonadvanced pattern.

For example, in the pooled analysis, 70% of advanced compared to 45.7% of nonadvanced pattern participants had a CDR-SB increase of 1 point or more (risk ratio [RR] 1.40; 95% CI, 1.11 – 1.76; P = .005). Results showed similar statistically significant RRs for CDR-Global, MMSE, ADAS-Cog11, and FAQ.

The pooled adjusted mean CDR-SB changes over 18 months were 2.28 for advanced and 0.98 for nonadvanced AD pattern groups (P < .001). Again, results showed similar significant differences for the other study assessments.

“We showed that subjects who carried the advanced AD pattern progressed faster compared to those with the nonadvanced pattern,” said Lu.

Previous studies have examined association between tau and cognitive progression, but they generally focused on a specialized and complicated quantitative method of determining presence of tau in the brain.

“It’s not easy to apply that method in a clinical setting. For general clinicians, like radiologists, it’s difficult to run that kind of analysis,” said Lu.

“The uniqueness of our study is that it’s generalized to clinical practice, so radiologists can reliably quantify those scans to those patterns and using those patterns, they can inform patients about their future outlook, their prognosis,” he added.

This simplified and more accessible method of assessing tau in the brain has been “very rigorously validated” through an autopsy study and was approved last May by the FDA, said Lu.

However, he cautioned that that while it “could be a major contributor” to predicting a patient’s progression, “it’s not necessarily the sole contributor.”

Clinically Useful

Commenting on the analysis for Medscape Medical News, David Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, Minnesota, said its dataset was “very unique” in that it included such a large number of subjects with symptomatic cognitive impairment.

The results provide “important further validation” of the relevance of tau PET for cognition, and “suggest that a visual read, as opposed to a quantitative analysis, could work in clinical settings,” said Knopman, who was not associated with the current research.

“Overall, the results provide a great demonstration of role of tauopathy in the AD spectrum.”

However, the magnitude of the effect was not as large as would be expected if the tau accumulation pattern alone were driving prognosis, said Knopman.

He cited possible reasons for what he called “less than dramatic” effects of tau on decline. One is that tau is dynamic and so some advanced cases could have been on a very slow accumulation trajectory while moderate cases were on a rapid trajectory.

In addition, pathologies other than tau, such as TAR DNA binding protein-43 (TDP-43), synucleinopathy, or cerebrovascular disease, may be contributing to decline. As Knopman noted, at least one of these pathologies is likely to be co-occurring in participants over age 70 years.

Another potential reason for a less than expected effect size is that some subjects with a larger brain or higher premorbid intellect may be more resilient to tau pathology, said Knopman.    

Lu is an employee of Eli Lilly and Company and/or Avid Radiopharmaceuticals and is a minor shareholder of Eli Lilly and Company.

Knopman served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He is a site investigator in the Biogen aducanumab trials discussed here. He is an investigator in a clinical trial sponsored by Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock, Roche and Alzeca Biosciences but receives no personal compensation. He receives research support from the NIH. In addition, in our own work at Mayo Clinic with flortaucipir, we received precursor and other radiochemistry assistance from Lilly-Avid.

JAMA Neurology. Published online February 15, 2021. Full text

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