Study characteristics

Patient sampling

• There were 52 MCI at time of performing the test planned as evaluable for efficacy participants.

• The participants were 50 years old or older with memory complaint or cognitive impairment corroborated by an informant, CDR 0.5, and MMSE > 24, no episodic memory cut‐off was required.

• No further details of participant sampling and recruitment were reported

Patient characteristics and setting

• 52 MCI participants diagnosed by CDR 0.5, but the following data related to those reported in the study as the 'efficacy data set'. Therefore we reported data on 47 participants of 52 participants at baseline.

• The mean age was 74.47 (+ 7.72) years for those with Aβ (+) and 70.40 (+ 10.72) years old for those with Aβ (‐).

• 25 of the 47 in the efficacy data set of participants were women.

• APOE ϵ4 carrier: 11 of 17 participants in the Aβ (+) group, and 4 of 30 in the Aβ (‐) were positive to APOE ϵ4.

• MMSE: the mean MMSE for those in the Aβ (+) group was 27.29 (+ 2.14) and 27.53 (+ 1.63) for those in Aβ (‐) group.

• Years of education: the mean for those in Aβ (+) group was 14.47 (+ 2.18) years and 15.27 (+ 2.42) years for those in Aβ (‐) group.

• Sources of referral: not reported.

• Setting: 21 sites in the United States of America, no data regarding the specific setting were reported.

Index tests

• Site PET scanners were qualified with a Hoffman brain phantom.

• Time between the ¹⁸F‐florbetapir injection and PET acquisition: fifty minutes after injection and, a 10‐min emission scan (acquired in 2 × 5 min frames) was obtained.

• ¹⁸F‐florbetapir administration mCi (MBq) dose: 10 mCi (370 MBq).

• PET scanners included Discovery LS PET/CT (GE, Fairfield, CT, USA), Advance PET (GE), ECAT HR+ (Siemens, Washington DC, USA) and Biograph PET/CT (Siemens) models.

• Image reconstruction utilized an iterative algorithm (4 iterations, 16 subsets) and a post‐reconstruction Gaussian filter of 5 mm.

• Semiquantitative visual rating:

After a training session, three nuclear medicine physicians with no access to clinical information, independently rated each PET image for amyloid burden based on successive levels of florbetapir retention from 0 to 4 as follows:

(0) None: predominantly white matter tracer retention with no appreciable cortical gray matter retention above cerebellar grey matter levels;

(1) Low: evidence of increased tracer retention above cerebellar grey levels in 1 or 2 cortical grey regions;

(2) Low‐moderate: either (a) predominantly white matter pattern, but at least 2 cortical regions with increased retention relative to cerebellar grey, or (b) predominantly a cortical gray matter pattern, with most cortical areas mildly positive relative to cerebellum;

(3) Moderate‐high: specific cortical retention generally greater than or equal to white matter retention and at least one cortical area with greatly increased retention relative to cerebellar grey;

(4) High: Specific cortical uptake greater than or equal to white matter background and multiple cortical areas with greatly increased retention relative to cerebellar grey.

• Binary Classification:

The visual reads were used to classify each data set as either visually positive for Aβ or visually negative for Aβ

Visual rating scores of 2 to 4 were considered positive and 0 to 1 were considered negative.

• Cerebellum was used as the 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) were baseline diagnostic criteria, and clinical diagnoses were generated without knowledge of the ¹⁸F‐florbetapir scan results.

Flow and timing

• Duration of follow‐up: 3 years

• Number included in analysis: 47 participants with at least one post baseline measurement; 17 ¹⁸F‐florbetapir (+) and 30 ¹⁸F‐florbetapir (‐)

• Progression from MCI to ADD:

• • ¹⁸F‐florbetapir (+): 6 MCI converted to ADD and 11 MCI not converted to ADD; ¹⁸F‐florbetapir (‐): 3 MCI converted to ADD and 27 MCI not converted to ADD

  • TP = 6; FP = 11; FN = 3; TN = 27

  • Loss to follow‐up including those without any post‐baseline measurement: 15 MCI participants. No further information was given on the MCI group reasons. There were data regarding all groups (ADD, MCI, normal controls) where it was described that the most common reasons for termination were withdrawal of consent (n = 38) and loss of follow‐up (n = 8).

• Financial support from the manufacturer of ¹⁸F‐florbetapir tracer and six authors 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 PET scan interpretation done by a trained reader physician?

Yes

Was there a clear definition of a 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?

Yes

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 free of commercial funding?

No

High

Study characteristics

Patient sampling

• The participants were 90 years old or older. They were participants of a longitudinal, population‐based study (90+ Study) and were invited to participate at this study.

• The participants had normal cognition or with either cognitive or functional impairment resulting from cognition not severe enough to meet DSM‐IV diagnostic criteria and they were classified as cognitively impaired not demented (CIND) and they agreed to postmortem brain donation.

• There were 5 MCI at time of performing the test planned as evaluable for efficacy participants.

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

Patient characteristics and setting

• 5 MCI participants diagnosed as CIND, three were considered as Aβ (+) and two were considered as Aβ (‐).

• The characteristics data of the participants included 13 participants: five of them were MCI participants and eight were normal controls; the mean age was 94.1 (range 90 to 99), for those considered as Aβ (+) the mean age was 94.4 (range 93 to 96) and 94.1 (range 90 to 99) years old for those with Aβ (‐).

Nine of the participants were women, two of them were Aβ (+), and two of four men were Aβ (+) at baseline.

APOE ϵ4 carrier: not reported

MMSE: the mean MMSE was 28 (range 24 to 30); for those considered as in the Aβ (+) group, the mean was 26.5 (range 24 to 29) and 28 (range 25 to 30) for those in the Aβ (‐) group.

Years of education: seven participants were reported having studied after high school: two of them were Aβ (+) and five were Aβ (‐); for those six having studied at high school or with less education, two were Aβ (+) and four were Aβ (‐), respectively.

• Sources of referral: not reported

• Setting: participants lived at home as well as in institutions in the United States of America.

Index tests

• Participants were imaged using clinical PET and PET/computed tomographic scanners.

• Time between the ¹⁸F‐florbetapir injection and PET acquisition: fifty minutes after injection and, a 10‐min emission scan was obtained.

• ¹⁸F‐florbetapir administration mCi (MBq) dose: 10 mCi (370 MBq)

• Images were acquired with a 128 x 128 matrix (zoom x 2) and were reconstructed using iterative or row action maximization likelihood algorithms.

• Semiquantitative visual rating:

After a training session, three nuclear medicine physicians with no access to clinical information, independently rated each PET image for amyloid burden based on successive levels of florbetapir retention from from 0 (no amyloid) to 4 (high levels of cortical amyloid). The median of the three visual scores was used to dichotomize participants into Aβ (‐) (score, 0 to 1 point) and Aβ (+) (score, 2 to 4 points).

Target condition and reference standard(s)

• Target condition: any form of dementia

• Reference standard: DSM‐IV criteria for dementia (APA 1994)

Flow and timing

• Duration of follow‐up (median): 1.5 years (all participants, including those as control normals)

• Number included in analysis: 5 participants; three ¹⁸F‐florbetapir (+) and two ¹⁸F‐florbetapir (‐)

• Progression from MCI to any form of dementia:

• • ¹⁸F‐florbetapir (+): 2 MCI converted to any form of dementia and 1 MCI not converted to any form of dementia; ¹⁸F‐florbetapir (‐): 1 MCI converted to any form of dementia and 1 MCI not converted to any form of dementia; TP = 2; FP = 1; FN = 1; TN = 1

  • Loss to follow‐up: none

• Partial financial support from the manufacturer of ¹⁸F‐florbetapir tracer and three authors 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 PET scan interpretation done by a trained reader physician?

Yes

Was there a clear definition of a positive result?

Unclear

Low

Low

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?

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?

Yes

Were all patients included in the analysis?

Yes

Was the study free of commercial funding?

No

High

Study characteristics

Patient sampling

• 401 amnestic MCI participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The study was performed from September 2010, to August 2014; data analysis was performed from September 2014, to May 2015.

• The participants were between 55 to 90 (inclusive) years old with memory complaints or cognitive impairment corroborated by an informant, CDR 0.5, and MMSE > 24, Hachinski less than or equal to 4, Geriatric Depression Scale less than 6, without any significant neurologic disease other than suspected incipient Alzheimer’s disease, had completed at least 6 years of education, were fluent in Spanish or English.

• No sampling criteria was specified

Patient characteristics and setting

• 401 amnestic MCI participants diagnosed by CDR = 0.5 at time of performing the test, were recruited from ADNI data.

• The mean age was 71.6 (+ 7.5) years for all participants.

• Gender: 182 female in MCI group.

• APOE ϵ4 carrier: 198 participants were positive in the MCI group.

• MMSE: the mean MMSE in the MCI group was 28.1 (+ 1.7).

• Years of education: the mean for those in the MCI group was 16.2 (+ 2.7) years.

• Sources of referral mixed: memory clinics, newspaper ads, radio, and other public media campaigns.

• Setting: multicentre, no other specific data regarding setting was reported.

Index tests

• Florbetapir image data were acquired from a variety of PET scanners (Siemens PET systems, GE, Phillips).

• ¹⁸F‐florbetapir administration mCi (MBq) dose: approximately 10 mCi (370 MBq).

• Time between the ¹⁸F‐florbetapir injection and PET acquisition: between 50 to 70 minutes after injection of approximately 10 mCi, a 20‐min emission scan (acquired in 4 × 5 min frames) was obtained.

• The four frames were coregistered to one another, averaged, interpolated to a uniform image and voxel size (160 × 106 × 96, 1.5mm³), and smoothed to a uniform resolution (8 mm full width half maximum) to account for differences between scanners.

• Visual analysis was performed on axial, sagittal, and coronal slices, in an inverse gray scale, using software that permitted adjustment of image brightness and contrast to each reader’s specifications. Florbetapir positivity was defined as increased tracer uptake in the cerebral cortex that was visually perceived as reduced or absent white matter/gray matter contrast in at least one cortical (frontal, parietal, temporal, occipital) region detectable on more than two adjacent scan slices.

The reader was trained using an online electronic training tool produced by the company who produced the tracer,

and the reader was blinded to all clinical data and any other imaging test of each participant.

• Quantitative analysis: To quantify cortical Aβ, preprocessed florbetapir image data and coregistered structural magnetic resonance images (MRI) were analysed using Freesurfer v4.5.0 MPRAGE scans of one structural 1.5T or 3T MRI scan within 2 months of florbetapir scans were segmented and parcellated into individual cortical regions, used to extract the mean florbetapir uptake from the gray matter of the ROI (lateral and medial frontal, anterior, and posterior cingulate, lateral parietal, and lateral temporal regions) relative to uptake in the whole cerebellum (white and gray matter).

The threshold used was a SUVR > 1.11 determined at baseline.(Landau 2012, Landau 2013).

Target condition and reference standard(s)

• Target condition: Alzheimer’s disease (progression from MCI to ADD)

• Reference standard: NINCDS‐ADRDA criteria

Unclear whether clinicians conducting follow‐up were aware of the ¹⁸F‐florbetapir PET scan results.

Flow and timing

• Participants belonged to the ADNI database, the study was performed from September 2010 to August 2014.

• .All participants received the same reference standard.

• Duration of follow‐up: a median progression‐free follow‐up time of 1.6 years

Number included in analysis:

MCI

• Visual assessment: 401 MCI: 196 MCI with ¹⁸F‐florbetapir positive test: 54 converted to ADD and 142 remained stable; 205 MCI with ¹⁸F‐florbetapir negative test: 7 converted to ADD and 198 remained stable.

• TP = 54; FP = 142; FN = 7; TN = 198

• SUVR > 1.11: 401 MCI: 221 MCI with ¹⁸F‐florbetapir positive test; 53 converted to ADD and 168 remained stable; 180 MCI with ¹⁸F‐florbetapir negative test: 8 converted to ADD and 172 remained stable.

• TP = 53; FP = 168; FN = 8; TN = 172

• Loss to follow‐up: data appeared to have been reported for all 401 participants.

Comparative

Notes

Dr Schreiber kindly sent the ADNI identification code for each MCI participant (mail received 04/07/2017).

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 PET scan interpretation done by a trained reader physician?

Yes

Was there a clear definition of a positive result?

Yes

Low

Low

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?

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?

Yes

Were all patients included in the analysis?

Yes

Was the study free of commercial funding?

Yes

Low