Study characteristics

Patient sampling

• There were 230 amnestic MCI participants that were evaluable for efficacy.

• The participants were 60 years old or older (US inclusion criteria in clinicaltrials.gov) or over 55 years old (Europe in EUDRACT).

• All participants met the Petersen criteria for amnestic MCI (details of the criteria not provided), had a score of less than or equal to 4 on the Modified Hachinski Ischemic Scale, a MMSE score of 24 to 30, and non‐contrast MRI examination as part of the screening visit that excluded amnestic MCI arising from structural causes, and had not any significant neurologic disease other than suspected amnestic MCI.

• No further details of participant sampling and recruitment were reported.

Patient characteristics and setting

• 232 amnestic MCI participants diagnosed by Petersen criteria (not reported which one of Petersen criteria was used)

• Gender: 114 male, 118 female

• Mean ± SD age:71.1 + 8.62 years, 63 participants were less than 65 years old

• APOE ϵ4 carrier: not reported

• MMSE: not reported

• Years of education: not reported

• Sources of referral: not reported

• Setting: not reported

Index tests

• No data were given regarding the PET/CT scanner used in the different centres. Each participant received one 185 MBq intravenous dose of ¹⁸F‐flutemetamol Injection (≤ 10 mcg total flutemetamol) injected within 40 seconds. A 185 MBq dose exposes the subject to an effective dose of 5.92 mSv of radiation.

• PET imaging started approximately 90 minutes after dosing. Imaging data were collected for 30 minutes in six 5‐minute frames. Images were assessed visually by 5 blinded, independent, and trained readers. Based on the blinded image evaluation, each of 5 independent readers separately categorized each subject as having either 'normal' (negative for Aβ) or 'abnormal' (positive for Aβ uptake) based on the PET image pattern.

• No further details were given regarding the index test.

Target condition and reference standard(s)

• Target condition: Alzheimer’s disease dementia

• Reference standard: NINCDS‐ADRDA criteria for ADD (McKhann 1984), and a CAC (consisted of 4 experts in the diagnosis of memory disorders) determined if the participant progressed or not to probable ADD, blinded to the investigator’s progression assessment, flutemetamol and any other amyloid imaging data.

Flow and timing

• Duration of follow‐up: 3 years

• Number included in analysis: 224 participants: 97 ¹⁸F‐flutemetamol (+) and 127 ¹⁸F‐flutemetamol (‐)

• Progression from MCI to ADD:

• • 97 ¹⁸F‐flutemetamol (+): 52 MCI‐converted to ADD and 45 MCI‐not converted to ADD; 127 ¹⁸F‐flutemetamol (‐): 29 MCI‐converted to ADD and 98 MCI‐not converted to ADD

  • TP = 52; FP = 45; FN = 29; TN = 98

• 8 participants withdrew prior to the first Clinical Adjudication Committee (CAC) evaluation

• Full financial support from the manufacturer of ¹⁸F‐flutemetamol tracer

Comparative

Notes

Methodological quality

Item

Authors' judgement

Risk of bias

Applicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case‐control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Unclear

Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre‐specified?

Unclear

Was the 18F‐flutemetamol PET scan interpretation done by a trained reader physician?

Yes

Did the study provide a clear definition of what was considered to be a 18F‐flutemetamol positive result?

Unclear

Unclear

Unclear

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index tests?

Yes

Low

Low

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?

Yes

Did all patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Was the study with 18F‐flutemetamol free of commercial funding?

No

High

Study characteristics

Patient sampling

• Participants with MCI and Alzheimer’s disease were included from 7 academic memory clinics and healthy volunteers were recruited by advertisement or they were the spouses of Alzheimer’s disease patients or MCI participants.

• We only included data on the performance of the index test to discriminate between people with MCI who converted to dementia and those who remained stable.

• Among those participants, there were 20 MCI participants. No further details of participant sampling and recruitment were reported.

• Inclusion criteria: MMSE 27 to 30 and older than 55 years (Vandenberghe 2010).

Patient characteristics and setting

• 20 MCI participants diagnosed by the Petersen 1999 criteria. Demographic data were reported for 20 MCI participants and they were classified as having amnestic MCI.

• Gender: 11 male, 9 female.

• Mean ± SD age: 72.7 ± 7.09 years (Vandenberghe 2010)

• APOE ϵ4 carrier: not reported

• MMSE: 28.0 ± 0.94 (Vandenberghe 2010)

• Mean ± SD years of education: 14.8 ± 2.97 (Vandenberghe 2010)

• Sources of referral: not reported

• Setting: secondary care (memory clinic)

Index tests

• PET imaging was conducted at 3 different scanning centres using a 16‐slice Biograph PET/CT scanner (Siemens, Er‐ langen, Germany), an ECAT EXACT HR scanner (Siemens), and a GE Advance scanner, respectively.

• All PET time frames were realigned using an automated method and a PET sum image was created. The PET sum image was spatially normalised into Montreal Neurologic Institute space where a volume of interest (VOI) template was used to extract counts in VOIs for frontal, lateral temporal and parietal cortices as well as for the anterior and posterior cingulate. In addition, a reference region corresponding to the cerebellar cortex was defined.

• Standard uptake value ratios (SUVRs) were computed by dividing counts in the target regions with counts in the reference region. The authors computed a composite neocortical SUVR value as an average of the above mentioned cortical VOIs.

• ¹⁸F‐flutemetamol was injected intravenously as a slow bolus (< 40 seconds) in an antecubital vein (target activity set at 185 MBq maximally (max), equivalent to an effective dose of approximately 6 mSv).

• ¹⁸F‐flutemetamol administration mean MBq dose: 173.3 (SD 13.3).

• Time between ¹⁸F‐flutemetamol injection and PET acquisition: from 85 to 115 minutes (6 x 5‐minute frames).

• All PET time frames were realigned using an automated method and a PET sum image was created. The PET sum image was spatially normalized into Montreal Neurologic Institute space where a volume of interest (VOI) template was used to extract counts in VOIs for frontal, lateral temporal and parietal cortices as well as for the anterior and posterior cingulate. In addition, a reference region corresponding to the cerebellar cortex was defined.

• Standard uptake value ratios (SUVRs) were computed by dividing counts in the target regions with counts in the reference region. The authors computed a composite neocortical SUVR value as an average of the above mentioned cortical VOIs.

• Threshold: > 1.5 determined at baseline, based in Vandenberghe study with a threshold > 1.56 (Vandenberghe 2010).

• ROIs included lateral frontal cortex (FRO), lateral temporal cortex (LTC), lateral parietal cortex (PAR), anterior cingulate (ANC), occipital cortex (OCC), and pons (PON).

• A cerebellar ROI served as reference region.

Target condition and reference standard(s)

• Target condition: Alzheimer’s disease dementia.

• Reference standard: not explicitly stated, although NINCDS‐ADRDA criteria for ADD (McKhann 1984) and APA 1994 were baseline diagnostic criteria.

Flow and timing

• Duration of follow‐up: 2 years.

• Number included in analysis: 19 participants: 10 ¹⁸F‐flutemetamol (+) and 9 ¹⁸F‐flutemetamol (‐)

• Progression from MCI to ADD:

• • 10 ¹⁸F‐flutemetamol (+): 8 MCI‐ADD and 2 MCI‐MCI; 9 ¹⁸F‐flutemetamol (‐): 1 MCI‐ADD and 8 MCI‐MCI

  • TP = 8; FP = 2; FN = 1;TN = 8

• Loss to follow‐up: 1 MCI participant

• No further information was given

• Financial support for the baseline study (Vandenberghe 2010) was provided by the manufacturer of ¹⁸F‐flutemetamol tracer and two authors of Thurfjell 2012 were employees

Comparative

Notes

Methodological quality

Item

Authors' judgement

Risk of bias

Applicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case‐control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Unclear

Low

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre‐specified?

Yes

Was the 18F‐flutemetamol PET scan interpretation done by a trained reader physician?

Unclear

Did the study provide a clear definition of what was considered to be a 18F‐flutemetamol positive result?

Yes

Low

Low

DOMAIN 3: Reference Standard

Is the reference standards likely to correctly classify the target condition?

Unclear

Were the reference standard results interpreted without knowledge of the results of the index tests?

Unclear

Unclear

Unclear

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?

Yes

Did all patients receive the same reference standard?

Unclear

Were all patients included in the analysis?

Yes

Was the study with 18F‐flutemetamol free of commercial funding?

No

High