1. Ivan M. DeQuesada, M.D. David C. Brandon, M.D. Emory University Department of Nuclear Medicine & Molecular Imaging Amyvid (Florbetapir- 18 F): A review of the concept, protocol and imaging.

2. DEMENTIA More than 16 million people in the U.S. are living with cognitive impairment 1. Alzheimer’s Disease (AD) is the most common irreversible cause of dementia in the elderly 2. More than 5 million Americans have been diagnosed with AD.

3. PATHOPHYSIOLOGY The formation of β-amyloid fibrils into amyloid plaques in the brain is the standard for neuropathologic diagnosis 3. However, the underlying cause of AD has not yet been determined. The coexistence of clinically overlapping forms of dementia—which are treatable or less debilitating—creates a clinical dilemma. Post-mortem studies have shown a high rate of false-positive and false- negative AD diagnoses 4. AD remains a diagnosis of exclusion due to the lack of a non-invasive, specific test for AD.

4. IMAGING Initial discovery and study of Pittsburgh compound B, which bound in-vivo to amyloid. Ill-suited to clinical application due to its use of 11 C (half-life of 20 minutes). Florbetapir- 18 F is a PET ligand with high affinity and specificity for b-amyloid in the brain. Longer half-life 18 F (110 minutes) obviates the need for an on-site cyclotron.

5. RADIOTRACER Florbetapir- 18 F is a PET radiopharmaceutical approved by the FDA in January, 2011 Marketed by Eli Lilly & Co. under the trade name AMYViD™ <5% injected radioactivity remains in the blood after 20 minutes.

6. CLINICAL DATA A prospective cohort study of patients with cognitive impairment who underwent post-mortem autopsy confirmed the high sensitivity and specificity of Florbetapir PET imaging in the diagnosis of AD 5. Longitudinal study of these patients with positive scans showed significant decline in cognitive function compared with those with negative scans 3. A review of cases published in Oct, 2013 has also shown that positive and negative scans significantly influenced clinical decision-making 4.

7. APPROPRIATE USE Indicated in adult patients with cognitive impairment, who are being evaluated for AD for exclusion of other causes of cognitive decline. There are no contraindications to its use.

8. LIMITATIONS A positive scan alone does not establish a diagnosis of AD or other disorder. Must be correlated with the clinical findings The results cannot be used to monitor a response to therapy or predict future development of any condition.

9. PROTOCOL

10. ADMINISTRATION Recommended dose is 10 mCi (370 MBq) 6 Administered in a single bolus of 10 ml or less of normal saline Follow with a normal saline flush. Sensitivity profile No serious adverse reactions Side effects included headache (2%), pain (1%) and nausea (1%).

11. IMAGING A 10 minute PET acquisition should begin 30-50 minutes after drug administration Patient positioning Optimally there is no movement with the brain centered in the PET scanner field of view Images are displayed in transaxial for interpretation with access to coronal and sagittal reconstructions

12. INTERPRETATION

13. FINDINGS Scans are either positive or negative [prescribing info]: Positive scans show loss of grey-white differentiation with increased uptake in: Two or more brain areas larger than a single gyrus One or more brain areas in which grey matter uptake is greater than the adjacent white matter Negative scans show a clear differentiation of grey and white matter Co-registration with CT data can be used to match the radioactivity to the anatomy

14. FINDINGS Image interpretation can only be performed by readers who have completed a free training program offered online or in- person by the manufacturer. http://www.amyvidhcp.com/Pages/reader-training.aspx Interpretation should be rendered in isolation of the clinical history.

15. NEGATIVE SCAN Negative scans demonstrate a definite contrast of grey and white matter in uptake Mirrors the expected anatomic grey- white distribution Indicates sparse to no amyloid plaques Inconsistent with a diagnosis of AD at the time of imaging

16. POSITIVE SCAN Positive scans demonstrate areas of diminished contrast between expected grey-white differentiation Indicates moderate to frequent amyloid plaques May be observed in elderly with normal cognition or in AD Different patterns can be seen: Two or more areas of obscured grey- white differentiation—as in this example

17. POSITIVE SCAN Another pattern of positive scan is one or more areas of increased grey matter radioactivity compared to the adjacent white matter–as in one paper’s example 4

18. UNKNOWNS

19. NO HISTORY GIVEN Press any key to see the answer. Normal

20. NO HISTORY GIVEN Press any key to see the answer. Abnormal Diffuse loss of grey-white contrast

21. NO HISTORY GIVEN Press any key to see the answer. Abnormal Diffuse loss of grey-white contrast

22. THANK YOU

23. REFERENCES 1.Yang L, Rieves D, Ganley C. Brain amyloid imaging--FDA approval of florbetapir F18 injection. The New England journal of medicine. 2012;367(10):885-7. Epub 2012/08/31. doi: 10.1056/NEJMp1208061. PubMed PMID: 22931256. 2.Lister-James J, Pontecorvo MJ, Clark C, Joshi AD, Mintun MA, Zhang W, et al. Florbetapir f-18: a histopathologically validated Beta-amyloid positron emission tomography imaging agent. Seminars in nuclear medicine. 2011;41(4):300-4. Epub 2011/06/01. doi: 10.1053/j.semnuclmed.2011.03.001. PubMed PMID: 21624563. 3.Doraiswamy PM, Sperling RA, Coleman RE, Johnson KA, Reiman EM, Davis MD, et al. Amyloid- beta assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology. 2012;79(16):1636-44. Epub 2012/07/13. doi: 10.1212/WNL.0b013e3182661f74. PubMed PMID: 22786606; PubMed Central PMCID: PMC3468774. 4.Zannas AS, Doraiswamy PM, Shpanskaya KS, Murphy KR, Petrella JR, Burke JR, et al. Impact of F-florbetapir PET imaging of beta-amyloid neuritic plaque density on clinical decision-making. Neurocase. 2013. Epub 2013/05/16. doi: 10.1080/13554794.2013.791867. PubMed PMID: 23672654. 5.Clark CM, Pontecorvo MJ, Beach TG, Bedell BJ, Coleman RE, Doraiswamy PM, et al. Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-beta plaques: a prospective cohort study. Lancet neurology. 2012;11(8):669-78. Epub 2012/07/04. doi: 10.1016/S1474- 4422(12)70142-4. PubMed PMID: 22749065. 6.Highlights of prescribing information: Amyvid (florbetapir F18 injection). Silver Spring, MD: Food and Drug Administration (http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202008s000lbl.pdf).