Quantification of 99mTc-DPD uptake in patients with

transthyretin-related cardiac amyloidosis

James C. Ross1,2, David F. Hutt1, Maria Burniston1,3, Joanne Page1,4, and Marianna Fontana1.

1National Amyloidosis Centre, UCL Medical School (Royal Free Campus), London, UK.

2Institute of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, London, UK. 3Nuclear Medicine, Barts Health NHS Trust, London, UK.

4Nuclear Medicine Department, Royal Free London NHS Foundation Trust, London, UK.

Transthyretin amyloidosis (ATTR)

• Transthyretin (TTR) is a normal blood protein that transports thyroid hormone and retinol (vitamin A).

• There can be significant cardiac involvement, resulting in heart muscle stiffening and wall thickening

• Problems are often overlooked due to heart-related problems with age.

• One autopsy study demonstrated ATTR amyloid deposits in 25% of people > 85 years old.2

• Cardiac amyloid fibril deposits may also be due to AL.

[1] Mysorekar VV, Rao SG, Satish NT, Kamath SM. Cardiac amyloidosis: Report of an autopsy case with review of the literature. Indian J Pathol Microbiol 2010;53:842–843.

[2] Tanskanen M, Peuralinna T, Polvikoski T, Notkola I-L, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008;40:232–239.

99mTc-DPD scintigraphy

• Binding of bone-seeking phosphate derivatives (DPD, MDP, PYP) to amyloid was first

observed over 40 years ago.3

• Uptake of a 99mTc-labelled bisphosphonate in cardiac amyloid was first reported in

1981.4

• 99mTc-DPD WB + SPECT forms part of non-invasive diagnostic algorithm at the NAC,

given its remarkable sensitivity and specificity.5

[3] VanAntwerp JD, O'Mara RE, Pitt MJ, Walsh S. Technetium-99m-diphosphonate accumulation in amyloid. J Nucl Med 1975;16:238–240.

[4] Ali A, Turner DA, Rosenbush SW, Fordham EW. Bone scintigram in cardiac amyloidosis: a case report. Clin Nucl Med 1981;6:105–108.

[5] Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, Wechalekar AD, Berk JL, Quarta CC, Grogan M, Lachmann HJ, Bokhari S, Castaño A, Dorbala S,

Johnson GB, Glaudemans AWJM, Rezk T, Fontana M, Palladini G, Milani P, Guidalotti PL, Flatman K, Lane T, Vonberg FW, Whelan CJ, Moon JC, Ruberg FL, Miller EJ, Hutt

DF, Hazenberg BP, Rapezzi C, Hawkins PN. Non-biopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404–2412.

The Perugini grading system6

0: Absent cardiac

uptake; normal bone

uptake.

1: Mild cardiac uptake

inferior to bone uptake.

2: Moderate cardiac

uptake; ‘attenuated’

bone uptake.

3: Strong cardiac

uptake; mild/absent

bone uptake.

[6] Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic

diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–1084.

Rationale for quantification 2010 2012 2013

• Can we monitor disease burden?

• Most studies have reported data from

whole-body images. However: – AC is not available.

– It can be difficult to outline heart.

– There are contributions from bone and soft tissue.

• Do results relate to Perugini grades?

• How do 99mTc-DPD uptake patterns relate to

results from other modalities?

• Is uptake related to morbidity and mortality?

Unpublished data

Our study

• SPECT quantitation was retrospectively carried out on 74 patients who underwent 99mTc-DPD studies (WB + SPECT at 3 h).

• We quantified 99mTc-DPD uptake with three different software applications:

1. Myovation™ (Xeleris, GE): left ventricle.

2. OsiriX (for MacOS, Apple): left ventricle.

3. Q.Metrix (Xeleris, GE): whole heart.

• Correlated results with each other and assessed agreement.

• Correlated results with an independent parameter: extracellular volume fraction (ECV) according to cardiac magnetic resonance (CMR) imaging.

• Expressed results by Perugini grade.

Myovation™ and OsiriX

• Both methods assess left ventricular uptake at the myocardial centre in counts (bottom-left).

• Myovation™: semi-automated, quick, and produces polar maps. However, it struggles to

identify scanty uptake (bottom-right).

• OsiriX: manual and versatile.

Myovation segments

Osirix segments

1

7

13

17

15

10

4

16 14

8 2

12 6

11 5 3

9

1 Base

1 Mid

1 Apex

3

4

4

4 2

2 2

6 6

5 5 3

3

Myovation™ OsiriX Unpublished data

Q.Metrix

• Whole heart is manually outlined according to CT image data.

• Each result is expressed as the percentage of the injected dose.

Unpublished data

Processing

• Two different cameras are used but both are GE with the same software.

• Initially started with L-mode acquisitions but changed to H-mode.

• OSEM iterative reconstruction (6i10s).

• TEW scatter correction.

• Matrices were all resized to 128 × 128.

• We validated percentage uptake by analysing data from phantoms.

• Counts were corrected for:

Administered activity.

Acquisition duration.

Delay between administration and start of acquisition.

Results: Q.Metrix vs. CMR data

Unpublished data

Results: Q.Metrix data by grade

• NM quantification results all

correlated strongly with each

other (p < 0.001). Left ventricle is appropriate

surrogate?

Unpublished data

Results: CMR data by grade

• Significant differences between

groups.

Unpublished data

Conclusions

• Three methods of SPECT quantification of 99mTc-DPD uptake were developed.

• NM results correlated strongly each other.

LV is a good surrogate of whole heart.

• NM results correlated strongly with an independent parameter.

Quantification has at least some value.

• However, uptake was not greater in Grade 3 patients than in Grade 2 patients, contradicting

Perugini’s assumptions and CMR results. Survival outcomes are the same…7

Should Grade 2 and Grade 3 patients be one group or is 99mTc-DPD unable to differentiate them?

[7] Hutt DF, Fontana M, Burniston M, Quigley A-M, Petrie A, Ross JC, Page J, Martinez-Naharro A, Wechalekar AD, Lachmann HJ, Quarta CC, Rezk T, Mahmood S,

Sachchithanantham S, Youngstein T, Whelan CJ, Lane T, Gilbertson JA, Rowczenio D, Hawkins PN, Gillmore JD. Prognostic utility of the Perugini grading of 99mTc-DPD

scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid. Eur Heart J Cardiovasc Imaging 2017;0:1–7.

Future

• Investigate clinical value of repeat scanning.

• ECV is not a gold standard; assess uptake in terms of clinically meaningful variables.

• Molecular basis of binding mechanism of phosphate derivatives to cardiac amyloid unknown.

• Uptake occurs in a third compartment (soft tissue), which further complicates quantification.

Continue to investigate in labs.

Compare to other tracers and imaging.

Undertake kinetic studies.

Thank you for your attention.

Any questions?

James C. Ross1,2, David F. Hutt1, Maria Burniston1,3, Joanne Page1,4, and Marianna Fontana1.

1National Amyloidosis Centre, UCL Medical School (Royal Free Campus), London, UK.

2Institute of Nuclear Medicine, University College London Hospitals NHS Foundation Trust, London, UK. 3Nuclear Medicine, Barts Health NHS Trust, London, UK.

4Nuclear Medicine Department, Royal Free London NHS Foundation Trust, London, UK.

Supplementary slides

Amyloidosis

• Copies of misfolded protein can clump together to form insoluble fibrils.

• These are deposited in extracellular space, disrupting architecture and function.

• Can be localised (certain organs or tissues) or systemic (throughout body).

• Symptoms occur with sufficient amyloid accumulation.

National Amyloidosis Centre (NAC) at the UCL Medical School (Royal Free Campus), London, UK.

Planar methods: Radiotracer retention6

Regions of Interest Whole image, Background, Heart, Kidneys, Bladder.

𝐻𝑒𝑎𝑟𝑡 𝑟𝑒𝑡𝑒𝑛𝑡𝑖𝑜𝑛, H (%) = 100 × 𝐻𝑒𝑎𝑟𝑡𝑙𝑎𝑡𝑒

𝐻𝑒𝑎𝑟𝑡𝑒𝑎𝑟𝑙𝑦

𝑊𝐵 𝑟𝑒𝑡𝑒𝑛𝑡𝑖𝑜𝑛, WB (%) = 100 × (𝑊ℎ𝑜𝑙𝑒 − 𝑘𝑖𝑑𝑛𝑒𝑦𝑠 − 𝑏𝑙𝑎𝑑𝑑𝑒𝑟)𝑙𝑎𝑡𝑒

𝑊ℎ𝑜𝑙𝑒𝑒𝑎𝑟𝑙𝑦

Heart-to-whole-body retention, H/WB (%) = 100 × 𝐻/𝑊𝐵

[6] Perugini E, Guidalotti PL, Salvi F, Cooke RM, Pettinato C, Riva L, Leone O, Farsad M, Ciliberti P, Bacchi-Reggiani L, Fallani F, Branzi A, Rapezzi C. Noninvasive etiologic

diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol 2005;46:1076–1084.

Planar methods: Heart-to-contralateral ratio8

[8] Bokhari S, Casta ño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. 99mTc-Pyrophosphate Scintigraphy for Differentiating Light-Chain Cardiac Amyloidosis From the

Transthyretin-Related Familial and Senile Cardiac Amyloidoses. Circ Cardiovasc Imaging 2013;6:195–201.

.

• Attenuation correction not available.

• Can be difficult to determine cardiac boundaries (see right).

• Counts include bone and soft tissue contributions (e.g. sternum).

Limitations of planar quantitation