PiB PET Uncovers Hidden ATTR-CM

Transthyretin amyloidosis (ATTR) is increasingly recognized as a multisystem disease with both cardiac and neurologic manifestations, particularly in hereditary forms driven by pathogenic transthyretin (TTR) variants. Bone scintigraphy can be used for noninvasive diagnosis and even screening of transthyretin amyloid cardiomyopathy (ATTR-CM), especially after exclusion of light-chain amyloidosis. However, certain TTR variants—including early-onset p.(Val50Met), p.(Tyr134Cys), and p.(Phe84Leu)—have reduced sensitivity with bone scintigraphy.

These variants are associated with type B amyloid fibrils, which differ structurally from the type A fibrils more commonly detected by conventional bone scintigraphy. The distinction matters because bone-seeking tracers, including technetium-labeled hydroxydiphosphonate scans, appear to bind less effectively to type B fibrils, potentially delaying diagnosis in patients who may already have evolving cardiomyopathy.

In a pilot study published in Frontiers in Nuclear Medicine, investigators explored whether the PET tracer [¹¹C]-Pittsburgh Compound B ([¹¹C]PiB) could help address this limitation by detecting cardiac amyloid deposition in patients with these low-sensitivity variants, while also assessing potential brain involvement in hereditary ATTR (ATTRv) amyloidosis.

Study Design

Investigators at the Groningen Amyloidosis Centre of Expertise prospectively evaluated six patients between April 2024 and March 2025. Four patients had ATTRv mutations linked to reduced bone scintigraphy sensitivity, while two comparator patients had positive bone scintigraphy findings—one with ATTRv and one with wild-type ATTR amyloidosis (ATTRwt).

All participants underwent long-axial field-of-view PET/CT imaging with [¹¹C]PiB, a radiotracer originally developed for amyloid imaging in Alzheimer’s disease. The technology enabled simultaneous cardiac and brain assessment in a single acquisition. Dynamic PET imaging was performed for 50 minutes after tracer injection, and uptake was evaluated visually and quantitatively using target-to-background ratios (TBRs) for the heart and standardized uptake value ratios (SUVRs) for the brain.

[¹¹C]PiB Reveals Hidden Cardiac Amyloid

Among the four ATTRv patients with negative bone scintigraphy, three demonstrated clear cardiac [¹¹C]PiB uptake with elevated TBRs. One additional patient showed equivocal visual uptake but still met quantitative thresholds for ATTR-CM based on elevated lateral and posterior wall TBRs.

By contrast, the two patients with positive bone scintigraphy findings—including one ATTRwt patient with Perugini grade 3 uptake—had negative or inconclusive [¹¹C]PiB PET scans. This inverse relationship reinforces a growing hypothesis: different amyloid fibril subtypes may exhibit different affinities for PET versus bone scintigraphy tracers.

Notably, the ATTRv patients with positive [¹¹C]PiB findings did not yet exhibit overt heart failure symptoms. Cardiac biomarkers were relatively modest, despite evidence of conduction abnormalities, ventricular wall thickening, and/or rhythm disturbances. Two patients required device implantation. These observations suggest that [¹¹C]PiB PET may identify cardiac amyloid deposition at an earlier stage than conventional imaging in select genetic subtypes.

The findings also highlight a clinically relevant phenotype: patients with type B fibrils may present with relatively subtle cardiac symptoms despite progressive myocardial infiltration. In practice, that phenotype can easily be overlooked if clinicians rely heavily on negative bone scintigraphy.

Cerebral Amyloid Signals Remain Uncertain

The study also explored cerebral amyloid detection, an area of increasing interest in ATTRv disease. Two asymptomatic patients demonstrated elevated cortical SUVRs suggestive of early amyloid deposition. However, the interpretation remains uncertain, particularly because one of these patients had ATTRwt amyloidosis, where cerebral involvement is not typically expected. The authors note that age-related beta-amyloid pathology, including cerebral amyloid angiopathy or changes related to Alzheimer’s, may explain these findings.

Equally intriguing was what the scans did not show. Two symptomatic ATTRv patients with transient focal neurologic episodes—including one with MRI-confirmed leptomeningeal amyloid deposits—had no significant cortical [¹¹C]PiB uptake. The investigators propose that PET resolution may be insufficient to detect leptomeningeal-restricted amyloid deposition, even with advanced long-axial field-of-view systems.

Clinical Takeaways

This report does not establish [¹¹C]PiB PET as a replacement for bone scintigraphy, and the authors appropriately emphasize the investigational nature of the approach. The study lacked histologic confirmation, only included six patients, and used static rather than fully quantitative dynamic imaging protocols.

Still, the study offers a compelling proof of concept. For patients carrying TTR variants associated with low bone scintigraphy sensitivity, [¹¹C]PiB PET may provide a meaningful noninvasive alternative for earlier detection of ATTR-CM.

Reference:
Tingen HSA, Stormezand GN, van Snick P, et al. Pittsburgh compound B positron emission tomography detects cardiomyopathy in hereditary transthyretin amyloidosis patients with negative bone scintigraphy: a pilot study. Front Nucl Med. 2026;6:1747625. doi:10.3389/fnume.2026.1747625