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No evidently abnormal findings, such as brain atrophy, vascular change, or space-occupying lesion. Image source: QST-ANC original data.

Biomarker test results

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Hypertension and CKD

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Name: Mitsuharu Age: 70 years old Sex: Male

LEFT column Presenting reason Referred by her neurologist for an amyloid PET scan to confirm eligibility for an amyloid-targeting therapyMedical history Blood tests show controlled hyperlipidemia and no signs of vitamin deficiencies, thyroid dysfunction, or syphilis RIGHT column Neuropsychological testing Recent memory impairment and disorientationActivities of daily living are still preservedClassified as having mild cognitive impairmentCurrent symptoms Progressive memory loss and severe anxiety have been present for the past 2 yearsNo vivid visual hallucinations or unexplained symptom fluctuations have been reportedNeurological examination shows no signs of aphasia, apraxia, paralysis, ataxia, or parkinsonismImaging results MRI shows mild medial temporal lobe atrophy without other significant findingsNotes from referring physician Shared decision-making conversation was conducted; the purpose of biomarker testing and how amyloid PET imaging works was explainedConsent for biomarker testing was obtained from the patient and care partner

Moderately decreased cerebral glucose metabolism around the precuneus and posterior cingulate gyrus.This image was originally published in JNM. Taswell C, et al. J Nucl Med. 2015;56:1547-1553 https://doi.org/10.2967/jnumed. 115.161067. (c) SNMMI.

Clinical profile

How to use

Medical history

Markedly reduced

1. This room has multiple hotspots which will be presented one at a time. Select each hotspot to access more information and a question.

LEFT column Reasons for referral Referred to radiology; imaging workup required to help differentiate AD from other causes of dementia, including Lewy body dementia (LBD), in a patient with cognitive decline and atypical featuresSocial history Has worked as an accountant at a company for the past 25 yearsNon-smokerDrinks alcohol socially; no history of drug use RIGHT column Family history Mother diagnosed with ADMaternal uncle and grandmother diagnosed with dementiaMedical history No significant past illnesses or concurrent conditionsConstipation since her late 40sCurrent symptoms About 2 years ago, the patient began forgetting conversations at work; recently this has started to impact her ability to do her jobShe has been unable to remember the password for her home computer, which she has been using for a long timeShe has recently been experiencing mild dizziness when she stands upOccassionally, a blurry shadow appears in her field of visionNo obvious pareidolia or visual hallucinations are reportedNo obvious symptom fluctuations or symptoms of parkinsonism are reported

Focal but remarkable uptake in the right frontal cortex and precuneus. Centiloid is 17. Image reproduced under a Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/) from Collij LE, et al. Eur J Nucl Med Mol Imaging. 2021;48:2169-2182.

2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question.

Clue 3: Robert’s clinical profile and imaging results

Blood plasma Aẞ42:Aẞ40 ratio

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CLOSE CLUE PAGE

Social history Retired elementary school teacherEx-smokerNo history of alcohol or drug useFamily history Brother with postoperative colon cancerYounger sister with rheumatoid arthritisMedical history Appendicitis in his 20sCurrently taking medications for hypertension and hyperuricemiaCurrent symptoms This patient developed symptoms approximately 1 year agoInitial symptoms include forgetfulness, frequently asking about the date, and missing commitments with family and friendsHis wife also reports increased irritabilityEvaluation shows mild short-term memory impairment and disorientation to timeNeurological examination shows no deficits, including no aphasia, apraxia, palsy, ataxia, or parkinsonismAs his activities of daily living are still preserved, he was diagnosed with mild cognitive impairment

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You are reporting the results of a positive amyloid PET scan in a patient with early-stage cognitive impairment.

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Cognitive assessment score (MoCA)

Clue 1: Hana’s case profile

CONTINUE TO BIOMAKER TEST RESULTS

The referring clinician is considering an amyloid-targeted therapy.

May 10, 2025

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CONTINUE TO QUESTION

Date of test

BACK TO BACKGROUND

Layla and her daughter are visiting the imaging department for an amyloid PET scan. Before the procedure, Layla appears confused and says that she does not recall why she is having the scan. Here is her clinical information:

Markedly elevated

Amyloid PET

You have reached the end of Room 5: imaging physician office

100%

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 A- N-: findings not consistent with AD pathology 2 A- N+: neurodegeneration present but not consistent with AD 3 A+ N-: consistent with early-stage AD pathology without clear evidence of neurodegeneration 4 A+ N+: consistent with AD pathology with evidence of amyloid deposition and neurodegeneration 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

BACK TO CLINICAL PROFILE

Welcome to the imaging physician escape room with Professor Hitoshi Shimada.

Blood p-tau217

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 “Strict control of your blood pressure may reduce the risk of ARIA during treatment with amyloid-targeting therapy” 2 “You can’t receive amyloid-targeting therapy because your MRI showed a small microbleed. This is a contraindication to treatment” 3 “Before starting amyloid-targeting therapy, we need to confirm amyloid pathology with a PET scan or spinal fluid test” 4 “If you undergo genetic testing, the results can help us estimate your individual risk of side effects from the treatment” 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

BEGIN

CONTINUE TO BIOMARKER TEST RESULTS

BACK TO ESCAPE QUESTION 2

4. Clues you collect will appear in the Clues panel. They will give you the information you need to answer the final questions to escape the clinic. You can also click on the Clues to review the clue pages.

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Tell the patient the scan is used to confirm AD pathology and that a positive result means she can start an amyloid-targeted therapy 2 Explain the purpose of the PET scan and clarify how the results may support diagnosis and treatment planning 3 Proceed with the scan and tell the patient the referring clinician will explain the rationale behind the test again at follow up 4 Defer all further discussion and refer the family back to the referring physician to re-explain the purpose and implications of the PET scan 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Brain MRI

A 72-year-old female patient has been referred to the imaging department with a 1-year history of cognitive impairment, including progressive memory loss and confusion.

The patient also has symptoms of urinary incontinence.

Chouliaras L, O'Brien JT.Mol Psychiatry. 2023;28:4084-4097. Dickerson BC, et al. Alzheimers Dement. 2025;21:e14337. Rabinovici GD, et al. J Nucl Med. 2025;66(Suppl 2):S5-S31.

FDG PET

CONTINUE TO ESCAPE QUESTION 1

BACK TO CLUE 1

No evidently abnormal finding except for a single microbleeding (<2 mm).Image source: Kim KJ, et al. J Korean Med Sci. 2018;33:e289.

CONTINUE TO CLUE 2

THE CLUES YOU COLLECT WILL APPEAR IN THIS AREA

Mildly decreased cerebral glucose metabolism in frontoparietal cortices.Image source: QST-ANC original data.

CONTINUE TO ESCAPE QUESTION 2

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CONTINUE TO CLUE 3

Retired accountant

Has a daughter, who lives across the country and does not accompany her to appointments

3. Hotspots will be a mixture of questions and patient scenarios. Answer each by selecting the best choice and then 'Submit'. You must answer each question to proceed and obtain a clue.

Social history

5. Use the arrow buttons to navigate.

Clue 4: Layla’s clinical profile and biomarker test results

Bousiges O, Blanc F. Int J Mol Sci. 2022;23:6371. Diaz-Galvan P, et al. Neurology. 2023;101:e178-e188. Shimizu S, et al. Eur J Nucl Med Mol Imaging. 2016;43:184-192.

Blood pressure: 165/94 mmHgpressure: 165/94 mmHg

Presenting reason

Answer

Annual wellness examination

Vitals

Current medications

Which of the following biomarker tests would you perform before conducting an amyloid PET scan?

Name: Hana Age: 62 years old Sex: Female

• Lisinopril 20 mg once daily (QD) • Dapagliflozin 10 mg QD

Question 1

Cummings J, et al. J Prev Alzheimers Dis . 2023;10:362-377. Rabinovici GD, et al. J Prev Alzheimers Dis . 2025;12:100150. Rentz DM, et al. Alzheimers Dement . 2024;20:8162-8171.

Current symptoms

Question

Abigail reports no symptoms but has forgotten to take her blood pressure medication today. She has also missed some recent medical appointments. When reminded, she says “That’s right! Sorry that I forgot. I’ll get those done right away”.

SUBMIT

Family history

Menu WITHIN EACH SECTION, USE THE BUTTONS TO NAVIGATE. Title Baseline question Imaging physician office Hotspot 1 Background Question 1 Expert commentary Clue 1 Hotspot 2 Question 2 Expert commentary Clue 2 Hotspot 3 Background Question 3 Expert commentary Clue 3 Hotspot 4 Background Question 4 Expert commentary Clue 4 Escape door Clue 1 Escape question 1 Clue 2 Escape question 2 Clue 3 Escape question 3 Clue 4 Escape question 4 Key takeaways Conclusion and next steps

Medical history

Clue 2: Mitsuharu’s clinical profile and biomarker test results

• Hypertension and chronic kidney disease (CKD) for the past 10 years: well-controlled with daily medication • Mammogram 2 months ago: missed appointment • Laboratory appointment for wellness examination: not completed • Patient of the practice for 8 years, has previously followed through on all orders

Based on the patient’s clinical profile and imaging biomarker findings in Clue 2, how should his case be interpreted within the amyloid/tau/neurodegeneration (ATN) framework, and what does this suggest regarding the diagnosis? (required)

Name: Layla Age: 69 years old Sex: Female

Escape question 2

Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Ishii K. AJNR Am J Neuroradiol. 2014;35:2030-2038. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

Based on the clinical profile and current imaging findings in Clue 3, which of the following statements would be the least appropriate to make during your consultation? (required)

Escape question 3

What is the most appropriate next step to support shared decision-making based on the information in Clue 4? (required)

CONTINUE TO HOW TO USE

Escape question 4

Key takeaways

CONTINUE TO BIOMARKER TEST RESULTS

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 AD can be ruled out when structural MRI is normal 2 AD can be ruled out when cerebral blood flow and/or glucose metabolism imaging is normal 3 AD can be ruled out when the centiloid value of amyloid PET is below the cutoff value 4 None of the above findings rule out AD 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Baseline question

How many Alzheimer's disease patients do you see on average per week? (required)

TYPE YOUR ANSWER IN THE FIELD PROVIDED

Which of the following findings would lead you to withhold amyloid-targeting therapy due to contraindication? (required)

Hotspot 1

Hotspot 2

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Single, old intracranial hemorrhage (8 mm) on T2-weighted imaging (T2WI)/fluid-attenuated inversion recovery (FLAIR) 2 Two microbleedings (<2 mm) identified by susceptibility weighted imaging (SWI) 3 Superficial hemosiderosis on T2*-weighted imaging (T2*WI) 4 Moderate white matter changes (so-called unidentified bright objects [UBOs] on T2WI/FLAIR) 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Hotspot 3

Hotspot 4

Escape door

Invalid response. Please type in a number value.

Her clinical team wants to initiate imaging investigations, including amyloid positron emission tomography (PET), to support a diagnosis of early-stage Alzheimer’s disease (AD).

Question 3 background

Congratulations on completing the escape room!

BACK TO ESCAPE QUESTION 1

This educational content is intended for a global audience. Local regulations, clinical guidelines, and approval statuses may vary. Learners should always refer to and follow the guidance, policies, and requirements applicable in their own country or institution. This activity is supported by an educational grant from Lilly.

SUBMIT

Room 5: Imaging physician office

PREPARING THE MULTIDISCIPLINARY CARE TEAM

Based on the information in Clue 1, indicating a family history of AD and symptoms raising concern for possible LBD, which of the following imaging tests would you be least likely to choose to distinguish AD from other causes of dementia? (required)

SELECT EACH GLOWING HOTSPOT TO ANSWER THE CORRESPONDING QUESTION. YOU CAN RETURN TO COMPLETED HOTSPOTS AT ANY TIME TO REVIEW YOUR RESPONSES.

Escape question 1

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Q5-only styles Start of question set 1 Amyloid PET 2 Dopamine transporter imaging 3 123I–Metaiodobenzylguanidine (123I–MIBG) myocardial scintigraphy 4 Cerebral blood flow and/or glucose metabolism imaging (e.g., FDG PET, perfusion SPECT) 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

As part of the pretreatment workup, you review the patient’s MRI findings.

Prof Hitoshi Shimada on the utility of biomarkers for AD diagnosis

RETURN TO THE MAIN SITE (OPENS IN A NEW TAB) TO EXPLORE OTHER ESCAPE ROOMS AND LEARN HOW EACH TEAM MEMBER CONTRIBUTES TO COLLABORATIVE PATIENT CARE

6. After each hotspot question, a video will be available with expert commentary and guidance.

7. Use the toolbar to access this help guide, the main menu, glossary, and references.

Prof Hitoshi Shimada on using biomarkers for treatment selection and monitoring

Question 1 background

Prof Hitoshi Shimada on the interpretation of AD imaging biomarkers

Prof Hitoshi Shimada on shared decision-making and imaging biomarkers

Social history Working as a manager at his companyNon-smokerDrinks alcohol almost every day; no history of drug useFamily history Father died from subarachnoid hemorrhageMother diagnosed with hyperlipidemia and dementiaMedical history Taking medications for hypertension and hyperlipidemiaNeurological testing Mini-Mental State Examination (MMSE): 30/30 (normal)Frontal Assessment Battery (FAB): 15/18 (mild impairment)Zung Self-Rating Depression Scale: 36 (within normal limits)Wechsler Memory Scale-Revised, Logical Memory II: 3 (impaired)Current symptoms Over the past 6 months, the patient has become increasingly anxious and has reported difficulty sleepingHe reports making frequent mistakes at workHis family reports no significant changes in his behavior aside from his repeated complaints of anxiety

PLEASE COMPLETE THE FORM (OPENS IN A NEW TAB) TO COLLECT YOUR CME CREDITS, AND TO PROVIDE FEEDBACK

Name: Robert Age: 56 years old Sex: Male

CONTINUE TO ESCAPE QUESTION 3

BACK TO CLUE 3

CONTINUE TO CLUE 4

Collij LE, et al. J Nucl Med. 2025;66:110-116. Ferreira D, et al. Sci Rep. 2017;7:46263. Quispialaya KM, et al. Neurology. 2025;104:e210211.

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CONTINUE TO ESCAPE QUESTION 4

BACK TO CLUE 4

Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

CONTINUE TO KEY TAKEAWAYS

BACK TO ESCAPE QUESTION 4

CONTINUE

BACK TO KEY TAKEAWAYS

Glossary123I‐MIBG, 123I‐Metaiodobenzylguanidine Aβ, beta-amyloid AD, Alzheimer’s disease APOE, apolipoprotein E geneARIA, amyloid-related imaging abnormalities ATN, amyloid/tau/neurodegeneration CSF, cerebrospinal fluid CT, computed tomography FAB, frontal assessment battery FDG, fluorodeoxyglucose FLAIR, fluid-attenuated inversion recovery IWG, International Working Group LBD, Lewy body dementia MMSE, Mini-Mental State Examination MRI, magnetic resonance imaging PET, positron emission tomography SCI, subjective cognitive impairment SPECT, single-photon emission computed tomography SWI, susceptibility weighted imaging T2WI, T2-weighted imaging T2*WI, T2*-weighted imaging UBO, unidentified bright object

Question 4 background

Question 2

Collij LE, et al. Eur J Nucl Med Mol Imaging. 2021;48:2169-2182. Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Ishii K. AJNR Am J Neuroradiol. 2014;35:2030-2038.

Question 3

2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question.

You are evaluating a patient with early-stage AD for eligibility to receive an amyloid-targeting therapy.

SUBMIT

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 Apolipoprotein E (APOE) genotyping 2 Brain structural computed tomography (CT) and/or magnetic resonance imaging (MRI) 3 Cerebral blood flow and/or glucose metabolism imaging (e.g., perfusion single-photon emission computed tomography [SPECT], fluorodeoxyglucose [FDG] PET) 4 Cerebrospinal fluid (CSF) Aβ42 and/or Aβ42:Aβ40 ratio 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

SUBMIT

6. After each hotspot question, a video will be available with expert commentary and guidance.

Which of the following best reflects the correct interpretation of imaging biomarker findings in the diagnosis of AD? (required)

Largent EA, et al. Neurology. 2023;100:1010-1019. O’Brien K, et al. Alzheimers Dement. 2024;21:e14200.

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA

Clue 4: Patient dialogue

CLAIM CREDITS

Imaging physicians play a critical role in supporting diagnosis of AD and patient selection for amyloid-targeting therapies by helping to confirm the presence of AD pathology through imaging biomarkers.It remains essential to exclude surgical or internal causes of cognitive impairment via structural imaging using MRI/CT.Within the ATN framework, imaging physicians contribute to assessing:A (amyloid) pathology via amyloid PETT (tau) pathology via tau PETN (neurodegeneration) via MRI or FDG-PETAs with all biomarkers, imaging physicians must understand the sensitivity, specificity, and limitations of imaging tests.In cases where amyloid-targeted therapy is being considered, imaging physicians should be aware of appropriate use criteria, such as eligibility and exclusion factors, including those visible on MRI (e.g., microhemorrhages and other ARIA risk factors).Shared decision-making around imaging biomarkers requires imaging physicians to use clear, accessible language to help patients and care partners understand the purpose, implications, benefits, and risks of imaging tests, while respecting their values and preferences.

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7. Use the toolbar to access this help guide, the main menu, glossary, and references.

CONTINUE TO THE ESCAPE ROOM

BACK TO TITLE PAGE

How would you frame the findings in your report to support effective shared decision-making? (required)

Question 4

SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Start of question set 1 “Because amyloid PET is positive, initiation of amyloid-targeted therapy is strongly recommended straightaway before further disease progression occurs” 2 “Although the PET scan is positive, we still need CSF testing to confirm the findings before considering treatment” 3 “The scan shows evidence of amyloid pathology and may support treatment eligibility. The patient’s clinical team should determine next steps as part of shared decision-making” 4 “The amyloid PET scan is positive; however, it is recommended that the scan be repeated in six months before making any decisions regarding treatment or care planning” 5 Unsure End of question set Start of rationale Correct! Rationale goes here End of rationale

Title Clue 2: Mitsuharu’s clinical profile and biomarker test results ✅ Centered patient card clipboard top patient image Name: Mitsuharu Age: 70 years old Sex: Male 🔘 Hidden radios that drive the tabs Instruction above tabs SELECT THE TABS TO VIEW MORE Tabs Clinical profile Biomarker test results CLINICAL TAB CONTENT ✅ Unified grey background for patient chart content Social history Social history Retired elementary school teacherEx-smokerNo history of alcohol or drug use Family history Family history Brother with postoperative colon cancerYounger sister with rheumatoid arthritis Medical history Medical history Appendicitis in his 20sCurrently taking medications for hypertension and hyperuricemia Current symptoms Current symptoms This patient developed symptoms approximately 1 year agoInitial symptoms include forgetfulness, frequently asking about the date, and missing commitments with family and friendsHis wife also reports increased irritabilityEvaluation shows mild short-term memory impairment and disorientation to timeNeurological examination shows no deficits, including no aphasia, apraxia, palsy, ataxia, or parkinsonismAs his activities of daily living are still preserved, he was diagnosed with mild cognitive impairment Instruction TAP THE “NEXT” BUTTON TO CONTINUE BIOMARKER TAB CONTENT ✅ Unified grey background for patient chart content Brain MRI Brain MRINo evidently abnormal findings, such as brain atrophy, vascular change, or space-occupying lesion. Image source: QST-ANC original data. FDG PET FDG PETModerately decreased cerebral glucose metabolism around the precuneus and posterior cingulate gyrus. This image was originally published in JNM. Taswell C, et al. J Nucl Med. 2015;56:1547-1553 https://doi.org/10.2967/jnumed. 115.161067. (c) SNMMI. Amyloid PET Amyloid PETFocal but remarkable uptake in the right frontal cortex and precuneus. Centiloid is 17. Image reproduced under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) from Collij LE, et al. Eur J Nucl Med Mol Imaging. 2021;48:2169-2182. Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

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Question 2 Which of the following best reflects the correct interpretation of imaging biomarker findings in the diagnosis of AD? (required) SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON 1AD can be ruled out when structural MRI is normal2AD can be ruled out when cerebral blood flow and/or glucose metabolism imaging is normal3AD can be ruled out when the centiloid value of amyloid PET is below the cutoff value4None of the above findings rule out AD5Unsure Centered Submit Button SUBMIT Feedback box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Question 1 rationale Auto-expanding background box In the diagnosis and management of dementia, including AD, structural CT/MRI should be considered, and the timing should be prior to the administration of amyloid PET. Structural CT/MRI is useful for ruling out non-dementia causes of cognitive impairment (e.g., brain tumors, chronic subdural hematomas, cerebrovascular disorders, normal pressure hydrocephalus) and may also aid in distinguishing dementia-related conditions by evaluating patterns of brain atrophy. If there are no contraindications for MRI, it is recommended over CT. However, it is important to note that structural imaging alone cannot be used to diagnose AD. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 3 background You are evaluating a patient with early-stage AD for eligibility to receive an amyloid-targeting therapy. As part of the pretreatment workup, you review the patient’s MRI findings. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 3

Title Congratulations on completing the escape room! ✅ Completion Box with Confetti Inside You have reached the end of Room 5: imaging physician office ✅ Form Button Box PLEASE COMPLETE THE FORM (OPENS IN A NEW TAB) TO COLLECT YOUR CME CREDITS, AND TO PROVIDE FEEDBACK CLAIM CREDITS ✅ Main Site Box RETURN TO THE MAIN SITE (OPENS IN A NEW TAB) TO EXPLORE OTHER ESCAPE ROOMS AND LEARN HOW EACH TEAM MEMBER CONTRIBUTES TO COLLABORATIVE PATIENT CARE MAIN SITE

Question 4 background You are reporting the results of a positive amyloid PET scan in a patient with early-stage cognitive impairment. The referring clinician is considering an amyloid-targeted therapy. TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 4

Title Question 4 Question text How would you frame the findings in your report to support effective shared decision-making? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1“Because amyloid PET is positive, initiation of amyloid-targeted therapy is strongly recommended straightaway before further disease progression occurs”2“Although the PET scan is positive, we still need CSF testing to confirm the findings before considering treatment”3The scan shows evidence of amyloid pathology and may support treatment eligibility. The patient’s clinical team should determine next steps as part of shared decision-making”4The amyloid PET scan is positive; however, it is recommended that the scan be repeated in six months before making any decisions regarding treatment or care planning”5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Title Clue 3: Robert’s clinical profile and imaging results ✅ Centered patient card clipboard top patient image Name: Robert Age: 56 years old Sex: Male Hidden radios Instruction above tabs SELECT THE TABS TO VIEW MORE Tabs Clinical profile Biomarker test results CLINICAL TAB CONTENT Social history Social history Working as a manager at his companyNon-smokerDrinks alcohol almost every day; no history of drug use Family history Family history Father died from subarachnoid hemorrhageMother diagnosed with hyperlipidemia and dementia Medical history Medical history Taking medications for hypertension and hyperlipidemia Neurological testing Neurological testing Mini-Mental State Examination (MMSE): 30/30 (normal)Frontal Assessment Battery (FAB): 15/18 (mild impairment)Zung Self-Rating Depression Scale: 36 (within normal limits)Wechsler Memory Scale-Revised, Logical Memory II: 3 (impaired) Current symptoms Current symptoms Increasing anxiety over 6 monthsFrequent mistakes at workNo major behavioral changes aside from anxiety Instruction BIOMARKER TAB CONTENT Brain MRI Brain MRINo evidently abnormal finding except for a single microbleeding (<2 mm). Image source: Kim KJ, et al. J Korean Med Sci. 2018;33:e289. FDG PET FDG PETMildly decreased cerebral glucose metabolism in frontoparietal cortices. Image source: QST-ANC original data. Instruction

Clue 1: Hana’s case profile ✅ Centered patient card clipboard top abi image Name: Hana Age: 62 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Reasons for referral Referred to radiology; imaging workup required to help differentiate AD from other causes of dementia, including Lewy body dementia (LBD), in a patient with cognitive decline and atypical featuresSocial history Has worked as an accountant at a company for the past 25 yearsNon-smokerDrinks alcohol socially; no history of drug useFamily history Mother diagnosed with ADMaternal uncle and grandmother diagnosed with dementiaMedical history No significant past illnesses or concurrent conditionsConstipation since her late 40s Right-column bullets Current symptoms About 2 years ago, the patient began forgetting conversations at work; recently this has started to impact her ability to do her jobShe has been unable to remember the password for her home computer, which she has been using for a long timeShe has recently been experiencing mild dizziness when she stands upOccassionally, a blurry shadow appears in her field of visionNo obvious pareidolia or visual hallucinations are reportedNo obvious symptom fluctuations or symptoms of parkinsonism are reported

Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

Title Escape question 2 Question text Based on the patient’s clinical profile and imaging biomarker findings in Clue 2, how should his case be interpreted within the amyloid/tau/neurodegeneration (ATN) framework, and what does this suggest regarding the diagnosis? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1A- N-: findings not consistent with AD pathology2A- N+: neurodegeneration present but not consistent with AD3A+ N-: consistent with early-stage AD pathology without clear evidence of neurodegeneration4A+ N+: consistent with AD pathology with evidence of amyloid deposition and neurodegeneration5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 1

Cummings J, et al. J Prev Alzheimers Dis . 2023;10:362-377. Rabinovici GD, et al. J Prev Alzheimers Dis . 2025;12:100150. Rentz DM, et al. Alzheimers Dement . 2024;20:8162-8171.

ALZHEIMER’S DISEASE IN THE BIOMARKER ERA PREPARING THE MULTIDISCIPLINARY CARE TEAM Welcome to the imaging physician escape room with Professor Hitoshi Shimada. BEGIN footer This educational content is intended for a global audience. Local regulations, clinical guidelines, and approval statuses may vary. Learners should always refer to and follow the guidance, policies, and requirements applicable in their own country or institution. This activity is supported by an educational grant from Lilly.

Title Key takeaways Bullet Box Imaging physicians play a critical role in supporting diagnosis of AD and patient selection for amyloid-targeting therapies by helping to confirm the presence of AD pathology through imaging biomarkers.It remains essential to exclude surgical or internal causes of cognitive impairment via structural imaging using MRI/CT.Within the ATN framework, imaging physicians contribute to assessing:A (amyloid) pathology via amyloid PETT (tau) pathology via tau PETN (neurodegeneration) via MRI or FDG-PETAs with all biomarkers, imaging physicians must understand the sensitivity, specificity, and limitations of imaging tests.In cases where amyloid-targeted therapy is being considered, imaging physicians should be aware of appropriate use criteria, such as eligibility and exclusion factors, including those visible on MRI (e.g., microhemorrhages and other ARIA risk factors).Shared decision-making around imaging biomarkers requires imaging physicians to use clear, accessible language to help patients and care partners understand the purpose, implications, benefits, and risks of imaging tests, while respecting their values and preferences. Next Button Box TAP THE “NEXT” BUTTON TO CONTINUE

Title Clue 2: Mitsuharu’s clinical profile and biomarker test results Centered patient card Name: Mitsuharu Age: 70 years old Sex: Male Hidden radios Instruction SELECT THE TABS TO VIEW MORE Tabs Clinical profile Biomarker test results CLINICAL TAB CONTENT Social history Social history Retired elementary school teacherEx-smokerNo history of alcohol or drug use Family history Family history Brother with postoperative colon cancerYounger sister with rheumatoid arthritis Medical history Medical history Appendicitis in his 20sCurrently taking medications for hypertension and hyperuricemia Current symptoms Current symptoms This patient developed symptoms approximately 1 year agoInitial symptoms include forgetfulness, frequently asking about the date, and missing commitments with family and friendsHis wife also reports increased irritabilityEvaluation shows mild short-term memory impairment and disorientation to timeNeurological examination shows no deficits, including no aphasia, apraxia, palsy, ataxia, or parkinsonismAs his activities of daily living are still preserved, he was diagnosed with mild cognitive impairmentTAP THE “NEXT” BUTTON TO CONTINUE BIOMARKER TAB CONTENT Brain MRI Brain MRINo evidently abnormal findings, such as brain atrophy, vascular change, or space-occupying lesion. Image source: QST-ANC original data. FDG PET FDG PETModerately decreased cerebral glucose metabolism around the precuneus and posterior cingulate gyrus. This image was originally published in JNM. Taswell C, et al. J Nucl Med. 2015;56:1547-1553 https://doi.org/10.2967/jnumed.115.161067. (c) SNMMI. Amyloid PET Amyloid PETFocal but remarkable uptake in the right frontal cortex and precuneus. Centiloid is 17. Image reproduced under a Creative Commons Attribution 4.0 License from Collij LE, et al. Eur J Nucl Med Mol Imaging. 2021;48:2169-2182. TAP THE “NEXT” BUTTON TO CONTINUE TO ESCAPE QUESTION 2

Clue 4: Layla’s clinical profile and biomarker test results Layla and her daughter are visiting the imaging department for an amyloid PET scan. Before the procedure, Layla appears confused and says that she does not recall why she is having the scan. Here is her clinical information: ✅ Centered patient card clipboard top abi image Name: Layla Age: 69 years old Sex: Female ✅ Unified grey background for patient chart content Left-column bullets Presenting reason Referred by her neurologist for an amyloid PET scan to confirm eligibility for an amyloid-targeting therapyMedical history Blood tests show controlled hyperlipidemia and no signs of vitamin deficiencies, thyroid dysfunction, or syphilisNeuropsychological testing Recent memory impairment and disorientationActivities of daily living are still preservedClassified as having mild cognitive impairmentCurrent symptoms Progressive memory loss and severe anxiety have been present for the past 2 yearsNo vivid visual hallucinations or unexplained symptom fluctuations have been reportedNeurological examination shows no signs of aphasia, apraxia, paralysis, ataxia, or parkinsonismImaging results MRI shows mild medial temporal lobe atrophy without other significant findings Right-column bullets Notes from referring physician Shared decision-making conversation was conducted; the purpose of biomarker testing and how amyloid PET imaging works was explainedConsent for biomarker testing was obtained from the patient and care partner

Title Question 3 Question text Which of the following findings would lead you to withhold amyloid-targeting therapy due to contraindication? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Single, old intracranial hemorrhage (8 mm) on T2-weighted imaging (T2WI)/fluid-attenuated inversion recovery (FLAIR)2Two microbleedings (<2 mm) identified by susceptibility weighted imaging (SWI)3Superficial hemosiderosis on T2*-weighted imaging (T2*WI)4Moderate white matter changes (so-called unidentified bright objects [UBOs] on T2WI/FLAIR)5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Hotspot 2

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Title Clue 2: Mitsuharu’s clinical profile and biomarker test results Centered patient card Name: Mitsuharu Age: 70 years old Sex: Male Hidden radios Instruction SELECT THE TABS TO VIEW MORE Tabs Clinical profile Biomarker test results CLINICAL TAB CONTENT Social history Social history Retired elementary school teacherEx-smokerNo history of alcohol or drug use Family history Family history Brother with postoperative colon cancerYounger sister with rheumatoid arthritis Medical history Medical history Appendicitis in his 20sCurrently taking medications for hypertension and hyperuricemia Current symptoms Current symptoms This patient developed symptoms approximately 1 year agoInitial symptoms include forgetfulness, frequently asking about the date, and missing commitments with family and friendsHis wife also reports increased irritabilityEvaluation shows mild short-term memory impairment and disorientation to timeNeurological examination shows no deficitsActivities of daily living preserved → diagnosed with mild cognitive impairment BIOMARKER TAB CONTENT Brain MRI Brain MRINo evidently abnormal findings such as atrophy, vascular change, or mass. Image source: QST-ANC original data. FDG PET FDG PETModerately decreased cerebral glucose metabolism around the precuneus and posterior cingulate gyrus. Originally published in JNM. Taswell C, et al. J Nucl Med. 2015;56:1547-1553. Amyloid PET Amyloid PETFocal uptake in right frontal cortex and precuneus. Centiloid is 17. Reproduced under CC BY 4.0 from Collij LE, et al. Eur J Nucl Med Mol Imaging. 2021.

Hotspot 3: Expert commentary

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Escape Door

Hotspot 4: Expert commentary

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Hotspot 1: Expert commentary

How to use 1 1. This room has multiple hotspots which will be presented one at a time. Select each hotspot to access more information and a question. 2 2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question. 3 3. Hotspots will be a mixture of questions and patient scenarios. Answer each by selecting the best choice and then ‘Submit’. You must answer each question to proceed and obtain a clue. 4 4. Clues you collect will appear in the Clues panel. They will give you the information you need to answer the final questions to escape the clinic. You can also tap on the Clues to review the clue pages. 5 5. After each hotspot question, a video will be available with expert commentary and guidance. 6 6. Use the arrow buttons to navigate. 7 7. Use the header bar to access the glossary and the main menu. 8 8. Use the toolbar to access this help guide, clues, glossary, and references.

Title Clue 3: Robert’s clinical profile and imaging results ✅ Centered patient card clipboard top patient image Name: Robert Age: 56 years old Sex: Male 🔘 Hidden radios that drive the tabs Instruction above tabs SELECT THE TABS TO VIEW MORE Tabs Clinical profile Biomarker test results CLINICAL TAB CONTENT Social history Social history Working as a manager at his companyNon-smokerDrinks alcohol almost every day; no history of drug use Family history Family history Father died from subarachnoid hemorrhageMother diagnosed with hyperlipidemia and dementia Medical history Medical history Taking medications for hypertension and hyperlipidemia Neurological testing Neurological testing Mini-Mental State Examination (MMSE): 30/30 (normal)Frontal Assessment Battery (FAB): 15/18 (mild impairment)Zung Self-Rating Depression Scale: 36 (within normal limits)Wechsler Memory Scale-Revised, Logical Memory II: 3 (impaired) Current symptoms Current symptoms Over the past 6 months, the patient has become increasingly anxious and has reported difficulty sleepingHe reports making frequent mistakes at workHis family reports no significant changes in his behavior aside from his repeated complaints of anxiety Instruction TAP THE “NEXT” BUTTON TO CONTINUE BIOMARKER TAB CONTENT Brain MRI Brain MRINo evidently abnormal finding except for a single microbleeding (<2 mm). Image source: Kim KJ, et al. J Korean Med Sci. 2018;33:e289. FDG PET FDG PETMildly decreased cerebral glucose metabolism in frontoparietal cortices. Image source: QST-ANC original data. Instruction TAP THE “NEXT” BUTTON TO RETURN TO THE ESCAPE ROOM

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Title Question 1 Question text Which of the following biomarker tests would you perform before conducting an amyloid PET scan? Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Apolipoprotein E (APOE) genotyping2Brain structural computed tomography (CT) and/or magnetic resonance imaging (MRI)3Cerebral blood flow and/or glucose metabolism imaging (e.g., perfusion single-photon emission computed tomography [SPECT], fluorodeoxyglucose [FDG] PET)4Cerebrospinal fluid (CSF) Aβ42 and/or Aβ42:Aβ40 ratio5Unsure Submit Button SUBMIT Feedback Box Incorrect. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Chouliaras L, O'Brien JT.Mol Psychiatry. 2023;28:4084-4097. Dickerson BC, et al. Alzheimers Dement. 2025;21:e14337. Rabinovici GD, et al. J Nucl Med. 2025;66(Suppl 2):S5-S31.

Hotspot 2: Expert commentary

Question 1 background A 72-year-old female patient has been referred to the imaging department with a 1-year history of cognitive impairment, including progressive memory loss and confusion. The patient also has symptoms of urinary incontinence. Her clinical team wants to initiate imaging investigations, including amyloid positron emission tomography (PET), to support a diagnosis of early-stage Alzheimer’s disease (AD). TAP THE “NEXT” BUTTON TO CONTINUE TO QUESTION 1

Room 5: Imaging physician office

How many Alzheimer's disease patients do you see on average per week? (required) TYPE YOUR ANSWER IN THE FIELD PROVIDED

Largent EA, et al. Neurology. 2023;100:1010-1019. O’Brien K, et al. Alzheimers Dement. 2024;21:e14200.

Title Escape question 1 Question text Based on the information in Clue 1, indicating a family history of AD and symptoms raising concern for possible LBD, which of the following imaging tests would you be least likely to choose to distinguish AD from other causes of dementia? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Amyloid PET2Dopamine transporter imaging3123I–Metaiodobenzylguanidine (123I–MIBG) myocardial scintigraphy4Cerebral blood flow and/or glucose metabolism imaging (e.g., FDG PET, perfusion SPECT)5Unsure Submit Button SUBMIT Feedback Box Correct! TAP THE "NEXT" BUTTON FOR THE RATIONALE

Question 2 rationale Auto-expanding background box None of the listed imaging findings can definitively rule out AD. Structural MRI may appear normal in some patients with early AD, as medial temporal atrophy (including the hippocampus) can be absent or subtle. Although cerebral blood flow or glucose metabolism imaging (e.g., perfusion SPECT, FDG PET) can support a diagnosis of AD, these methods have limited sensitivity and specificity, especially in early stages. Similarly, a centiloid value below the cutoff on amyloid PET does not reliably exclude AD, particularly if amyloid accumulation is localized. Visual interpretation remains the standard method for evaluating amyloid PET scans, and reliance solely on centiloid quantification may result in false negatives. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 3 rationale Auto-expanding background box To reduce the risk of severe adverse effects, including amyloid-related imaging abnormalities (ARIA), MRI must be conducted at baseline before initiating an amyloid-targeting therapy. According to the appropriate use guidelines of amyloid-targeting drugs, the following MRI findings are regarded as contraindications: amyloid-related imaging abnormalities of edema/effusion, >4 cerebral microhemorrhages (≤10 mm at the greatest diameter), superficial siderosis, and any intracerebral macrohemorrhage (>10 mm at greatest diameter), or severe white matter disease. In this case, superficial hemosiderosis is a clear contraindication, as it indicates prior bleeding near the brain surface and is associated with an increased risk of ARIA-related complications. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Question 4 rationale Auto-expanding background box The imaging physician’s role is to clearly describe the presence or absence of amyloid pathology and explain its clinical significance in the report, but not to recommend or initiate therapy. A positive PET scan supports, but does not in itself determine, eligibility for amyloid-targeted therapy. The ultimate treatment decision should be made through shared decision-making between the patient, their care partners, and the treating clinical team. This should consider risks (e.g., ARIA), benefits, comorbidities, MRI findings, and personal goals. By framing findings this way, imaging physicians can contribute accurate and clinically meaningful information to the shared decision-making process, without creating unrealistic expectations or overstepping into treatment recommendations. Instruction Box TAP THE “NEXT” BUTTON TO CONTINUE TO EXPERT COMMENTARY

Escape question 1 rationale Auto-expanding background box Although a positive amyloid PET indicates the presence of amyloid-β pathology and supports a diagnosis of AD, it does not exclude other dementias. Amyloid deposition is frequently seen in LBD, limiting the test’s specificity for AD. Given the patient’s strong family history of AD alongside features suggestive of LBD, such as possible visual disturbances and autonomic symptoms (e.g., orthostatic dizziness), other imaging modalities are more informative for differential diagnosis. FDG PET or perfusion SPECT can highlight characteristic metabolic patterns and cerebral blood flow, respectively. Dopamine transporter imaging and 123I–MIBG myocardial scintigraphy also provide supportive evidence for LBD. Therefore, amyloid PET is the least helpful in distinguishing AD from other potential causes of dementia in this case. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 2

Title Escape question 4 Question text What is the most appropriate next step to support shared decision-making based on the information in Clue 4? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1Tell the patient the scan is used to confirm AD pathology and that a positive result means she can start an amyloid-targeted therapy2Explain the purpose of the PET scan and clarify how the results may support diagnosis and treatment planning3Proceed with the scan and tell the patient the referring clinician will explain the rationale behind the test again at follow up4Defer all further discussion and refer the family back to the referring physician to re-explain the purpose and implications of the PET scan5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 2 rationale Auto-expanding background box This patient is classified as A+ N+ under the ATN framework. Although the centiloid value is 17 and below the commonly used positivity threshold (typically ~20–25), visual interpretation remains the gold standard for assessing amyloid PET scans. The patient’s scan shows focal but remarkable amyloid uptake in regions typically affected in early AD (e.g., right frontal cortex, precuneus), supporting an A+ classification. The patient also shows moderately reduced glucose metabolism in the precuneus and posterior cingulate gyrus on FDG PET, indicating neurodegeneration (N+), even in the absence of structural MRI abnormalities. The patient’s biomarker profile of A+ N+ is therefore consistent with the AD continuum. It is important to note that semiquantitative values (e.g., centiloid) can underestimate early or localized pathology and should always be interpreted in the context of visual assessment and clinical findings. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 3

Cummings J, et al. J Prev Alzheimers Dis. 2023;10:362-377. Ishii K. AJNR Am J Neuroradiol. 2014;35:2030-2038. Rabinovici GD, et al. J Prev Alzheimers Dis. 2025;12:100150.

Escape question 3 rationale Auto-expanding background box Stating that the patient cannot receive an amyloid-targeting therapy because of his MRI would not be appropriate, because a single small cerebral microbleed does not constitute a contraindication to treatment. In this case, the patient’s FDG PET scan shows mildly decreased glucose metabolism in the frontoparietal cortices, which is consistent with neurodegeneration (N+) under the ATN framework. However, starting amyloid-targeting therapy requires confirmation of amyloid pathology (A+) using amyloid PET or CSF analysis. Additionally, APOE genotyping is recommended to assess the individual’s risk of ARIA, as APOE ε4 carriers are at a higher risk of developing adverse events during treatment. Finally, strict blood pressure control is recommended to reduce the risk of ARIA during treatment and is an appropriate part of patient education and counseling. Instruction Box TAP THE “NEXT” BUTTON FOR CLUE 4

Title Escape question 3 Question text Based on the clinical profile and current imaging findings in Clue 3, which of the following statements would be the least appropriate to make during your consultation? (required) Instruction SELECT THE BEST ANSWER FROM THE 5 OPTIONS, THEN CLICK THE ‘SUBMIT’ BUTTON Question Set 1“Strict control of your blood pressure may reduce the risk of ARIA during treatment with amyloid-targeting therapy”2“You can’t receive amyloid-targeting therapy because your MRI showed a small microbleed. This is a contraindication to treatment”3“Before starting amyloid-targeting therapy, we need to confirm amyloid pathology with a PET scan or spinal fluid test”4“If you undergo genetic testing, the results can help us estimate your individual risk of side effects from the treatment”5Unsure Submit Button SUBMIT Feedback Box Correct. TAP THE "NEXT" BUTTON FOR THE RATIONALE

Escape question 4 rationale Auto-expanding background box When a patient asks why an amyloid PET scan is being done, the imaging physician’s role is to provide a clear, accessible explanation of the purpose of the test and how the results may help clarify diagnosis and guide next steps. This supports shared decision-making by ensuring the patient and family understand what the scan can and cannot show, and by giving space for questions and concerns. It is not appropriate to promise a definitive diagnosis or treatment, or avoid the conversation entirely, as these approaches undermine trust and shared decision-making. If asked about the purpose of biomarker testing, the imaging physician should focus on education, clarification, and listening to the patient’s concerns to help them to understand why the test has been conducted and feel prepared for the next step in their care. Instruction Box TAP THE “NEXT” BUTTON FOR KEY TAKEAWAYS

Collij LE, et al. Eur J Nucl Med Mol Imaging. 2021;48:2169-2182. Jack CR Jr, et al. Alzheimers Dement. 2024;20:5143-5169. Ishii K. AJNR Am J Neuroradiol. 2014;35:2030-2038.

1 1. This room has multiple hotspots which will be presented one at a time. Select each hotspot to access more information and a question. 2 2. A check will appear once you answer a question and obtain a clue. Select the check to go back and review the question. 3 3. Hotspots will be a mixture of questions and patient scenarios. Answer each by selecting the best choice and then ‘Submit’. You must answer each question to proceed and obtain a clue. 4 4. Clues you collect will appear in the Clues panel. They will give you the information you need to answer the final questions to escape the clinic. You can also tap on the Clues to review the clue pages. 5 5. After each hotspot question, a video will be available with expert commentary and guidance. 6 6. Use the arrow buttons to navigate. 7 7. Use the header bar to access the glossary and the main menu. 8 8. Use the toolbar to access this help guide, clues, glossary, and references.

Hotspot 3

Hotspot 4

Bousiges O, Blanc F. Int J Mol Sci. 2022;23:6371. Diaz-Galvan P, et al. Neurology. 2023;101:e178-e188. Shimizu S, et al. Eur J Nucl Med Mol Imaging. 2016;43:184-192.