Diagnostic Test Accuracy Review

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11C-PIB-PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)

  1. Shuo Zhang1,*,
  2. Nadja Smailagic2,
  3. Chris Hyde3,
  4. Anna H Noel-Storr4,
  5. Yemisi Takwoingi5,
  6. Rupert McShane4,
  7. Juan Feng6

Editorial Group: Cochrane Dementia and Cognitive Improvement Group

Published Online: 23 JUL 2014

DOI: 10.1002/14651858.CD010386.pub2


How to Cite

Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, Feng J. 11C-PIB-PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews 2014, Issue 7. Art. No.: CD010386. DOI: 10.1002/14651858.CD010386.pub2.

Author Information

  1. 1

    China Medical University, Department of Neurology, Shengjing Hospital, Shenyang, Liaoning, China

  2. 2

    University of Cambridge, Institute of Public Health, Cambridge, UK

  3. 3

    University of Exeter Medical School, University of Exeter, Institute of Health Research, Exeter, UK

  4. 4

    University of Oxford, Radcliffe Department of Medicine, Oxford, UK

  5. 5

    University of Birmingham, Public Health, Epidemiology and Biostatistics, Birmingham, UK

  6. 6

    Shengjing Hospital, China Medical University, Department of Neurology, Shenyang, China

*Shuo Zhang, Department of Neurology, Shengjing Hospital, China Medical University, 36 Shanhao Street, Shenyang, Liaoning, 110004, China. submission@126.com.

Publication History

  1. Publication Status: New
  2. Published Online: 23 JUL 2014

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Characteristics of included studies [ordered by study ID]
Forsberg 2010

Study characteristics

Patient samplingTwenty-one patients with MCI and 37 patients with mild AD were recruited from Department of Geriatric Medicine at University Hostpital. No further details of recruitment were reported. Participants were referred from the primary care centres in the community (Forsberg 2008).

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

No exclusion criteria were reported


Patient characteristics and setting21 MCI participants diagnosed by the modified Petersen criteria (Winblad 2004) at baseline (Forsberg 2008). All subjects lived independently in the community and a majority of the subjects below 65 years of age had still a professional job

Gender: 8 male; 13 female

AGE: mean: 63.3±7.8 years (range 50–78); MCI-AD: 63.4±7.9 years; MCI-MCI: 62.6±8.4 years

APOE ε4 carrier: 14 (67%) (8 MCI-MCI; 6 MCI-AD)

MMSE: mean 28.2±1.4 (range 25–30); MCI-AD 27.0±1.3; MCI-MCI 28.9±0.9

Sources of referral: primary care centres in community

Setting: secondary care - outpatients (Department of Geriatric Medicine clinic)


Index testsThe PET examination with 11C-PIB was performed at Uppsala PET centre/Uppsala Imanet AB in Uppsala, Sweden. Production of 11C-PIB, tracer doses, and scanner protocol for transmissions, emissions and reconstructions have been described in detail previously (Klunke 2004)

Time between PIB injection and PET acquisition: 60 minutes

PIB administration dose: 300MBq

Quantitative data on 11C-PIB retention were generating giving late scan ratio data for 11C-PIB retention (Forsberg 2008). ROIs (regions of interest) included the frontal, parietal and temporal cortices divided right and left, posterior cingulate, striatum, primary visual cortex and thalamus

Threshold: ROI to-cerebellar ratio >1.6 (PIB retention detecting regions: global cortex and thalamus). Threshold determined at follow-up.

Index test was conducted at baseline


Target condition and reference standard(s)Target condition: Alzheimer's disease dementia (conversion from MCI to AD)

Reference standard: NINCDS-ADRDA criteria

Details of follow-up procedures were not specified. Unclear whether clinicians conducting follow-up were aware of PIB-PET analysis results


Flow and timingAll participants received the same reference standard

Duration of follow-up: within 8.1±0.5 months (2-16 months) after their PET scans 7 MCI patients converted to AD; after 45.5±8.5 months of clinical follow-up 14 patients remained MCI stable; mean duration for all participants was not reported; average: 33.3±19.3 months (the data was calculated by ZS)

Number included in analysis: 21 MCI: 11 MCI with positive PIB test: 7 converted to AD and 4 remained stable; 10 MCI with negative PIB test remained stable

TP=7; FP=4; FN=0; TN=10

Loss to follow-up: data appeared to have been reported for all 21 participants


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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
UnclearLow

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?No
HighLow

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
UnclearLow

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
Low

Grimmer 2013

Study characteristics

Patient samplingParticipants had been referred for the diagnostic evaluation by general practitioners, specialists, or other institutions. No further details of recruitment were reported

Exclusion criteria: psychotropic medication, substance misuse, major abnormalities in routine blood testing, or other neurological or psychiatric disorders


Patient characteristics and setting28 MCI participants diagnosed by the modified Petersen criteria (Winblad 2004) and CDR=0.5 (Morris 1993) criteria at baseline

Gender: 14 male; 14 female

AGE: mean: 67.9±7.4 years (range 50–79)

APOE ε4 carrier: not reported

MMSE: mean 26.0±3.19 (range 15–30)

Education: 11.8±2.2 years (range 8-17)

Sources of referral: mixed: primary and secondary care, and other institutions

Setting: secondary care - outpatients (Psychiatry and Psychotherapy Department clinic)


Index testsTime between PIB injection and PET acquisition: 40-60 minutes

PIB administration dose: 628 MBq (range 385 to 723 MBq

Threshold: PIB-PET findings at baseline were dichotomised into amyloid positive or amyloid-negative using a cerebrum to cerebellar vermis ratio threshold of 1.4 as cut-off using proposed methods described above (Jack 2008).

Threshold determined at baseline.

Index test was conducted at baseline.


Target condition and reference standard(s)Target condition: Alzheimer's disease dementia and other forms of dementia

Reference standard: NINCDS-ADRDA criteria for Alzheimer's disease dementia and the Land criteria (Brun 1994) for FTD

Clinicians conducting follow-up were blinded for the baseline PIB-PET findings


Flow and timingAll participants received the same reference standard

Duration of follow-up: mean was 31.2±7.8 months

Number included in analysis: 28 MCI: 17 MCI with PIB positive test: 9 converted to AD and 8 remained stable; 11 MCI with PIB negative test: 3 converted to non-AD (2 FTD; 1 dementia not specified), 7 remained stable and 1 reverted to normal

Conversion from MCI to AD dementia:

TP=9; FP=8 FN=0; TN=11

Conversion from MCI to all dementia:

TP=9; FP=8 FN=3; TN=8

Loss to follow-up: data appeared to have been reported for all 28 participants


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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?Yes
UnclearLow

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
LowLow

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
LowLow

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
Low

Jack 2010

Study characteristics

Patient sampling218 MCI participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (retrospective study). No discussion on when patients were recruited. 53 participants assessed by PIB-PET imaging and 165 by cerebrospinal fluid Aβ42 methods. No sampling criteria specified.

We only included data on performance of the PIB-PET index test to discriminate between patients with MCI who convert to dementia and those who remained stable at follow-up.

No exclusion criteria were reported


Patient characteristics and setting53 MCI participants diagnosed by the Petersen 2001 criteria. Demographic data reported on 218 participants

Gender: 72 (33%) female

AGE: 75 year

APOE ε4 carrier not reported:

MMSE: median (IQR) 27 (25, 29)

Education: median duration (IQR) 16 (14, 18)

Sources of referral: mixed: the local Alzheimer’s Disease Research Center (ADRC), memory clinics, newspaper ads, radio and other public media campaigns

Setting: mixed (ADNI participants at 13 different sites)


Index testsA global cortical PIB PET retention summary was formed by combining the prefrontal, orbitofrontal, parietal, temporal, anterior cingulate and posterior cingulate/precuneus values for each subject, using a weighted average of these regions of interest values

Larger regions of interest were given greater weight. PIB PET ratio values calculated by dividing the median value in each target cortical region of by the median value in the cerebellar grey matter region of interest of the atlas

Time between PIB injection and PET acquisition: 50-70 minutes

PIB administration dose: not reported

Threshold: mean neocortical distribution volume ratio (DVR) >1.5 (PIB retention detecting regions:  global cortex). Threshold determined at baseline.

Index test was conducted at baseline


Target condition and reference standard(s)Target condition: Alzheimer's disease (conversion from MCI to AD)

Reference standard: NINCDS-ADRDA criteria

Unclear whether clinicians conducting follow-up were aware of PIB-PET analysis results


Flow and timingNo discussion on when patients were recruited

All participants received the same reference standard

Duration of follow-up: a median progression-free follow-up time of 1.7 years

Number included in analysis: 53 MCI: 34 MCI with PIB positive test: 15 converted to AD and 19 remained stable; 19 MCI with PIB negative test: 3 converted to AD and 16 remained stable

TP=15; FP=19; FN=3; TN=16

Loss to follow-up: data appeared to have been reported for all 53 participants


Comparative


NotesThe trial investigators contacted; they provided requested data tor the 2X2 table to be completed; email from Dr Weigand on 11/5/12


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?No
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Unclear
HighLow

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
LowLow

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
UnclearLow

DOMAIN 4: Flow and Timing

Was there an appropriate interval between index test and reference standard?Unclear
Did all patients receive the same reference standard?Yes
Were all patients included in the analysis?Yes
Low

Koivunen 2011

Study characteristics

Patient samplingTwenty-nine consecutive MCI patients seen at the memory clinic and who volunteered for PET scanning, and thirteen healthy controls were included in the study. We only included data on performance of the index test to discriminate between patients with MCI who convert to dementia and those who remained stable.

No inclusion or exclusion criteria described


Patient characteristics and setting29 participants diagnosed by Petersen 2004 criteria: all patients had subjective memory impairment that was confirmed in neuropsychological testing, and some patients had mild decline in other cognitive domains. Clinical Dementia Rating (CDR) was 0.5, global cognition was normal, activities of daily living were not impaired, and no subject had dementia at baseline

Gender: 11 women, 18 men

Age: total sample 71.3±6.4 years; MCI converters 73.6±7.2 years; non-MCI converters 70.8±4.9 years

APOE ε4 carrier: total sample 17; MCI converters 14; non-MCI converters 3

MMSE: total sample 26.9±1.6; MCI converters 26.2±1.5; non-MCI converters 27.9±1.3

Sources of referral: not reported

Setting: secondary care - outpatients (memory clinic)


Index testsAn Advance PET scanner was used in the 3D scanning mode.ROIs were drawn on the anterior and posterior cingulate, lateral frontal cortex, caudate nucleus, putamen, thalamus, lateral temporal cortex, parietal cortex, medial temporal lobe, and pons. Average regional ratio values of 11C-PIB uptake were calculated using these ROIs from spatially normalised parametric ratio images

Time between PIB injection and PET acquisition: 90 minutes.

PIB administration dose: not reported

Threshold: region-to-cerebellum ratio≥1.5 (PIB retention detecting regions: global cortex, caudate nucleus, putamen, thalamus, pons). Threshold determined at baseline

Index test was conducted at baseline


Target condition and reference standard(s)Target condition: Alzheimer's disease dementia (conversion from MCI to AD)

Reference standard: NINCDS-ADRDA criteria; DSM-IV criteria

Unclear whether clinicians conducting follow-up were aware of PIB-PET analysis results


Flow and timingIt was not clear whether all participants received the both reference standards

Duration of follow-up: 2 years

Number included in analysis: 29 MCI: 17 MCI converted to AD and 12 remained stable

1) Anterior cingulate: sensitivity=82%; specificity=58%

TP=14; FP=5; FN=3; TN=7

2) Posterior cingulate: sensitivity=94%; specificity=58%

TP=16; FP=5; FN=1; TN=7

3) Lateral frontal cortex: sensitivity=65%; specificity=67%

TP=11; FP=4; FN=6; TN=8

4) Parietal cortex: sensitivity=41%; specificity=67%

TP=7; FP=4; FN=11; TN=8

5) Temporal cortex: 53%; specificity=67%

TP=9; FP=4; FN=8; TN=8

Loss to follow-up: data appear to have been included for all 29 participants


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability concerns

DOMAIN 1: Patient Selection

Was a consecutive or random sample of patients enrolled?Yes
Was a case-control design avoided?Yes
Did the study avoid inappropriate exclusions?Unclear
LowLow

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
LowLow

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
UnclearLow

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
Low

Okello 2009

Study characteristics

Patient samplingThirty-one participants were recruited from UK and Finnish Hospitals. No further details of recruitment were reported

Patients with significant white matter disease in the view of an experienced radiologist were excluded from the study. No further exclusion criteria were reported


Patient characteristics and setting31 MCI participants diagnosed by the Petersen 2001 criteria: subjective memory complaint by the patient, preferably corroborated by an informant; objective memory impairment as assessed by performance below age-matched normals on at least one neuropsychological measure of memory; relatively normal performance in other cognitive domains; intact activities of daily living; no dementia. A strict cut-off score was not applied for the definition of objective memory impairment

Gender: 19 male, 12 female

Age: total sample 69.4±7.9 years; MCI converters 71.6±6.3 years; non-MCI converters 67.9±9.0 years

APOE ε4 carrier: not reported

MMSE: total sample 27.5±1.5; MCI converters 27.1±1.5; non-MCI converters 27.9±1.3

Sources of referral: not reported

Setting: secondary - inpatients (three UK hospitals and one Finland hospital)


Index testsAll UK participants were scanned using a Siemens ECAT EXACT HR+ camera in 3-dimensional acquisition mode. The Finland sample were scanned with a GE advance camera, using previously described protocol (Kemppainen 2006)

Time between PIB injection and PET acquisition: 90 minutes for DVR; 40-60 minutes for SUVR

PIB administration dose: 367±25 MBq in UK; 487±44 MBq in Finland

Threshold: region to cerebellum ratio ≥ 2SD greater than the control mean in all 6 ROIs (regions of interest). PIB retention ratio values for each MCI participant were compared to that of the control mean of their scanning site (visual assessment)

Threshold determined at baseline

Index test was conducted at baseline


Target condition and reference standard(s)Target condition: Alzheimer's dementia (conversion from MCI to Alzheimer's dementia)

Reference standard: NINCDS-ADRDA criteria

Unclear whether clinicians conducting follow-up were aware of PIB-PET analysis results


Flow and timingAll participants received the same reference standard

Duration of follow-up: total sample: mean 2.68±0.6 years (32.2±7.2 months), range 1-3 years; mean 2.9±0.5 years in converters; 2.5±0.7 years in non-converters

At follow-up: 15 MCI-converters and 17 MCI-nonconverters

Number included in analysis=31: 17 with positive PIB tests: 14 MCI-AD, 3 MCI-MCI; 14 with negative PIB tests: 1 MCI-AD, 13 MCI-MCI

TP=14; FP=3; FN=1; TN=13

Loss to follow-up: data appeared to have been reported for all 31 participants


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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
UnclearLow

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
LowLow

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
UnclearLow

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
Low

Ossenkoppele 2012

Study characteristics

Patient samplingAt baseline 15 participants were included in each group: MCI, AD and controls. No further details of patient sampling and recruitment were reported.

We only included data on performance of the index test to discriminate between patients with MCI who convert to dementia and those who remained stable

Exclusion criteria were a history of major psychiatric or neurological illness (other than AD) and the use of nonsteroidal antiinflammatory drugs Patients with severe vascular events during the follow-up period, such as stroke or haemorrhage, were also excluded


Patient characteristics and setting15 participants diagnosed by the Petersen 1999 criteria

Gender: male 9; female 3

Age: 67±7

APOE ε4 carrier: 8

MMSE: 27±3

Education: median (range): 6 (3-7)

Sources of referral: not reported

Setting: not reported


Index testsA dynamic emission scan in three-dimensional acquisition mode was used

Time between PIB injection and PET acquisition: 90 minutes

PIB administration dose: 351± 82 MBq

Threshold: Visual assessment. 11CPIB scans were classified as either positive or negative, based on visual inspection of parametric BPND images by a trained nuclear medicine physician. Not reported when threshold was determined

Index test was conducted at baseline


Target condition and reference standard(s)Target condition: conversion from MCI to AD or other type of dementia

Reference standards: NINCDS-ADRDA criteria for AD (McKhann 1984); Reference standard for the clinical criteria for FTD not reported


Flow and timingDuration of follow-up: 2.5 years (range 2.0–4.0 years)

Number included in analysis: 12 MCI: 5 PIB+: 4 MCI-AD, 1MCI-non-converter: 7 PIB-: 1 MCI-FTD; 6 MCI-non-converters

Conversion from MCI to AD: 5 PIB+: 4 MCI-converters and 1 MCI-non-converter; 7 PIB-: 0 MCI-converters and 7 MCI-non-converters (6 MCI-MCI; 1 MCI-FTD)

TP=4; FP=1; FN=0; TN=7

Conversion from MCI to all dementia: 5 PIB+: 4 MCI-converters and 1 MCI non-converter; 7 PIB-: 1 MCI-converter and 6 MCI- non-converters. Two out of seven MCI-non-converters converted to ‘cognitively improved’ and five remained stable

TP=4; FP=1; FN=1; TN=6

Loss to follow-up: 3 MCI patients refused to participate in the follow-up study due to lack of motivation


Comparative


NotesThe trial investigators contacted; they provided requested data tor the 2X2 table to be completed and confirmed there are no overlapping patients with the Ossencoppele 2012a study; email from Dr Ossenkopele on 5/3/13


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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?Yes
UnclearLow

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
UnclearLow

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
HighLow

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?No
Low

Ossenkoppele 2012a

Study characteristics

Patient sampling154 participants included from the outpatient memory clinic of the VU University Medical centre for assessing the impact of molecular imaging on the diagnostic process. Among those participants there were 30 MCI participants. No further details of patient sampling and recruitment were reported.

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

Exclusion criteria: major clinical and psychiatric disorders, recent vascular events and excessive substance abuse


Patient characteristics and setting30 MCI participants diagnosed by the Petersen 2001 criteria

Gender: male 23; female 7

Age: 64±9

APOE ε4 carrier: not reported

MMSE: 27±2

Sources of referral: not reported

Setting: secondary care - outpatients (memory clinic)


Index testsA dynamic emission scan in three-dimensional acquisition mode was used

Time between PIB injection and PET acquisition: 90 minutes

PIB administration dose: 367± 43 MBq at baseline

Threshold: Visual assessment: [11C]PIB PET scans were rated as either PIB-positive (PIB1; binding in more than one cortical brain region; i.e., frontal, parietal, temporal, or occipital) or PIB-negative (PIB2, predominantly white matter binding), based on visual inspection of parametric BPND images by a trained nuclear medicine physician. Not reported when threshold was determined.

Index test was conducted at baseline and at follow up. It was not reported whether the index test baseline results were interpreted without knowledge of the results of the reference standard.

Outcome measures were changes in clinical diagnosis and confidence in that diagnosis before and after disclosing PET results. The main focus of this study was not ‘conversion from MCI to dementia; however, the author provided us with the relevant information for creating 2X2 table and, therefore, this study has been included.


Target condition and reference standard(s)Target condition: conversion from MCI to AD or other type of dementia

Reference standards: not explicitly stated, although NINCDS-ADRDA criteria for AD (McKhann 1984), Neary 1998 criteria for FTD were baseline diagnostic criteria


Flow and timingDuration of follow-up: 2 years

Number included in analysis: 12 MCI: 7 PIB+: 6 MCI-AD and 1 MCI-MCI; 5 PIB-: 1 MCI-FTD and 2 MCI-MCI and 1 MCI-cognitively improved and 1MCI-psychiatric disorder

Conversion from MCI to AD: 7 PIB+: 6 MCI-converters and 1 MCI-non-converter; 5 PIB-: 0 MCI-converters and 5 MCI-non-converters

TP=6; FP=1; FN=0; TN=5

Conversion from MCI to all dementia: 7 PIB+: 6 MCI-converters and 1 MCI non-converter; 5 PIB-: 1 MCI-converter and 4 MCI- non-converters.

TP=6; FP=1; FN=1; TN=4

Loss to follow-up: 18 MCI patients. No further information


Comparative


NotesThe trial investigators contacted; they provided requested data tor the 2X2 table to be completed and confirmed there are no overlapping patients with the Ossencoppele 2012 study; email from Dr Ossenkopele on 5/3/13


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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?Yes
UnclearLow

DOMAIN 2: Index Test All tests

Were the index test results interpreted without knowledge of the results of the reference standard?Unclear
If a threshold was used, was it pre-specified?Unclear
HighLow

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
HighLow

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?No
High

Villemagne 2011

Study characteristics

Patient samplingMCI and DAT participants were recruited from the Austin Health Memory Disorders Clinic. Controls were recruited by advertisement and from the Melbourne Healthy Aging Study. We only included data on performance of the index test to discriminate between patients with MCI who convert to dementia and those who remained stable..

No further details on recruitment are presented. No inclusion or exclusion criteria are described


Patient characteristics and setting67 MCI participants diagnosed by the Petersen 1999 criteria. Demographic data were reported for 65 MCI participants who were further classified as a amnestic MCI (n=53) or nonamnestic MCI (4 nonamnestic single domain and 8 nonamnestic multiple domain)

Gender: 36 male, 29 female

Age:73.4±8.5 years

APOE ε4 carrier: 41 (63%)

MMSE: 26.5±2.9

Years of education: 12.2±4.3

Sources of referral: mixed: advertisements and the Melbourne Healthy Aging Study

Setting: secondary care - outpatients (memory clinic)


Index testsStandardized uptake values (SUVs) for PiB were calculated for all brain regions examined and SUV ratios (SUVRs) were generated by dividing all regional SUVs by the cerebellar cortex SUV. ROI measurements were averaged across both hemispheres. Neocortical Ab burden was expressed as the average SUVR of the area-weighted mean of frontal, and posterior cingulate regions

Time between PIB injection and PET acquisition: 40 minutes

PIB administration dose: 370MBq

Threshold: neocortical standardised uptake values ratio (SUVR) > 1.5 (PIB retention detecting regions: global cortex). To define a PiB SUVR cut-off, a hierarchical cluster analysis was performed on all healthy controls. Threshold determined at baseline and was consistent with cutoff values used in previous PIB-PET studies (Bourgeat 2010; Jack 2008)

Index test was conducted at baseline


Target condition and reference standard(s)Target condition: Alzheimer's disease dementia and other forms of dementia

Reference standard: NINCDS-ADRDA criteria for Alzheimer's disease dementia. Neurologist and a neuropsychologist conducting follow-up blind to PIB status

Reference standards for VD and FTD not reported


Flow and timingDuration of follow-up: mean was 20±3 months.

All participants received the same reference standard

Number included in analysis: 65 MCI: 45 'amyloid positive': 30 MCI-AD, 15 MCI-MCI; 20 'amyloid negative': 5 converters (1 MCI-AD; 1 MCI-VD; 1 MCI-FTD; 2 LBD); 15 non-converters (13 MCI-MCI; 2 MCI-HC)

Conversion from MCI to AD: 45 PIB+: 30 MCI-converters (MCI-AD) and 15 MCI-non-converter (MCI-MCI); 20 PIB-: 1 MCI-converter (MCI-AD) and 19 MCI-non-converters (1 MCI-VD; 1 MCI-FTD; 2 LBD; 13 MCI-MCI; 2 MCI-HC)

TP=30; FP=15; FN=1; TN=19

Conversion from MCI to all dementia: 45 PIB+: 30 MCI-converters and 15 MCI non-converter; 20 PIB-: 5 MCI-converters (1 MCI-AD; 1 MCI-VD; 1 MCI-FTD; 2 LBD) and 15 MCI- non-converters. Two out of seven MCI-non-converters converted to ‘cognitively improved’ and five remained stable

TP=30; FP=15; FN=5; TN=15

Loss to follow-up: 2 MCI participants: 1 participant was withdrawn by their caregivers and 1 participant was not contactable


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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
UnclearLow

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
LowLow

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
UnclearLow

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?No
Low

Wolk 2009

Study characteristics

Patient samplingTwenty-six patients with MCI, 22 patients with mild Alzheimer's disease and 35 healthy elderly participants. The clinical diagnosis for those who entered the University of Pittsburgh Alzheimer’s Disease Research Center (ADRC) was made through consensus at a conference. The conference was attended by neurologists, psychiatrists, and neuropsychologists experienced in the diagnosis of dementia. Assessment included medical and neurological history and examination, a semi-structured psychiatric evaluation, and psychometric testing.

We only included data on performance of the index test to discriminate between patients with MCI who convert to dementia and those who remained stable. MCI participants were recruited from ADRC. Nine participants already had PiB PET data. No further details of recruitment were reported.

Inclusion criteria: age 40 years or older, proficient English speaker, and a reliable caregiver

Exclusion criteria: lifetime history of schizophrenia, manic-depressive disorder, or schizoaffective disorder; prior electroconvulsive therapy; current substance abuse/dependence or within 2 years of symptom onset; and any medical condition that could affect neuropsychological testing


Patient characteristics and setting26 MCI participants diagnosed by the Petersen 2004 and modified Petersen (Winblad 2004) criteria. MCI-multiple cognitive domain cases were reviewed and subdivided according to the Gauthier et al. scheme (Gauthier 2008). No strict cutoffs on psycho-metric testing were used. Impairment was "generally" less than 1.5 SDs of University of Pittsburgh ADRC age-adjusted norms (13 single-domain amnestic-MCI; 6 multi-domain a-MCI; 7 non-amnestic MCI). The clinicians were aware of the previous year’s diagnosis at follow-up consensus discussions

Gender: total 7 female and 19 male; 3 of 19 amnestic-MCI is female, 4 of 7 nonamnestic-MCI is female

Age: total 70.2±8.8 years; amnestic-MCI is 71.6±8.0,  noamnestic-MCI is 69.6±9.2

APOE ε4 carrier: total 14 APOE4 carrier; 9 out of 11 a-MCI Amyloid-Positive; 4 out of 8 a-MCI Amyloid-Negative; 0 out of 3 na-MCIAmyloid-Positive; 1 out of 3 na-MCIAmyloid-Negative. One a-MCI patient did not have ApoE results available

MMSE: total  27.3±1.9 (calculated by ZS); amnestic-MCI is 27.2±2.1; noamnestic-MCI is 27.7±1.1

Education: mean 16.6± 3.3 years for a-MCI; mean 18.7± 2.6 years for na-MCI

Sources of referral: not reported

Setting: tertiary setting - Pittsburg Alzheimer’s Disease Research Center


Index testsPET imaging was conducted on a Siemens/CTI ECAT HR+(Siemens, Erlangen, Germany). The scanner was equipped with Neuro-insert (CTI PET Systems, Knoxville, TN) to reduce the contribution of scattered photons

Time between PIB injection and PET acquisition: 90 minutes for DVR; 40–60 minutes for SUR

PIB administration dose: 14.3±2.2mCi

Threshold:DVR or SUR of region of interest > upper-inner fence of the control subjects. To avoid a strict cutoff, authors defined an intermediate range 2.5% greater than and less than this cutoff (Aizenstein 2008). Subjects who had a PiB DVR value exceeding the intermediate range in any ROI was defined as amyloid-positive, and those under the intermediate range were defined as amyloid-negative. For the two MCI patients who did not have DVR values SUV ratios were used to determine cutoffs (these are not described). Threshold determined at baseline.

ROIs were defined on a co-registered magnetic resonance image, as described previously (Price 2005); these included frontal, anterior cingulate, precuneus, lateral temporal, parietal, medial temporal, occipital, and sensorimotor cortices, anterior ventral striatum, subcortical white matter, and pons. A cerebellar ROI served as reference region, and the pons and subcortical white matter ROIs were measures of nonspecific ligand retention. Scanning was performed within approximately 6 months of ADRC evaluation (mean SD, 14.9 ± 7.3 weeks)

Index test was conducted at baseline and the results were available for all participants


Target condition and reference standard(s)Target condition: conversion from MCI to Alzheimer’s disease dementia

Reference standard: the clinical diagnosis was made through consensus at a conference, attended by neurologists, psychiatrists and neuropsychologists experienced in the diagnosis of dementia

It was not reported whether the reference standard results were interpreted without knowledge of the results of the index test


Flow and timingDuration of follow-up: mean 21.2 ± 16.0 months subsequent to their PiB scan

All participants received the same reference standard

Number included in analysis: 23 MCI: 13 'amyloid positive': 5 MCI-AD, 8 MCI-MCI; 10 'amyloid negative': 0 MCI-AD; 10 non-converters (7 MCI-MCI; 3 MCI-normal)

TP=5; FP=8; FN=0; TN=10

Loss to follow-up: 3 MCI participants; they did not have follow-up assessment; two of those patients did not complete the entire protocol


Comparative


Notes


Methodological quality

ItemAuthors' judgementRisk of biasApplicability 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?Yes
UnclearLow

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
LowLow

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
HighLow

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?No
Low

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Choo 2011Target condition: not looking at conversion from MCI to dementia. The focus of the study is the annual change in PIB retention

Driscoll 2011Target condition: not looking at conversion from MCI to dementia

Ellis 2010Target condition: not looking at conversion from MCI to dementia

Fagan 2007Index test: PIB-PET test performed at follow-up

Target condition: not looking at conversion from MCI to dementia

Kadir 2012Target condition: not looking at conversion from MCI to dementia

Kadir 2012aTarget condition: not looking at conversion from MCI to dementia

Resnick 2010Target condition: not looking at conversion from MCI to dementia. The focus of the study is the association abeta deposition and cognitive decline

Rowe 2010Target condition: not looking at conversion from MCI to dementia

Shinotoh 2011Index test: threshold not used

Target condition: not looking at conversion from MCI to dementia. The focus of the study is the change in PIB retention over time

Sojkova 2008Participants: 28 non-demented subjects; only 6 participants with mild cognitive impairment (CDR=0.5) at baseline

Target condition: not looking at conversion to dementia. The focus of the study is the annual change in PIB retention in high and low PIB retention groups

Sojkova 2011Target condition: not looking at conversion from MCI to dementia. The focus of the study is the annual change in PIB retention over time

 
Characteristics of ongoing studies [ordered by study ID]

Trial name or titleHuman amyloid-imaging studies with Pittsburgh Compound-B in Mild Cognitive Impairment (MCI): Is MCI the critical period of amyloid plaque deposition?

Target condition and reference standard(s)Target condition: conversion from MCI to Alzheimer's disease dementia

Reference standard: not reported

Index and comparator tests11C-PIB-PET

Starting datenot reported

Contact informationsd3zc@hscmail.mcc.virginia.edu

Notes

 
Tests. Data tables by test

TestNo. of studiesNo. of participants

 1 11C-PIB-PET AD dementia9274

 2 11C-PIB-PET All dementia4117

 
Table 1. Demographic and patient characteristics

StudyN/n Age Gender

M (%)
MMSE scoreAPOE Ɛ4 carrier (%)Years of education/

Verhage's classification*
MCI diagnostic criteriaSamplingSources of referralSetting

Forsberg 2010 (Sweden)21/2163.3 ± 7.88 (38.1)28.2±1.414 (66.7)12.7 ±3.1Winblad 2004Not reportedPrimary care centers in communitySecondary care: outpatients

Grimmer 2013 (Germany)28/2867.9±7.414 (50)26.0±3.2Not reported11.8 ±2.2 (range 8-17)CDR=0.5 and Winbald 2004Not reportedGP surgeries or specialists or other institutionsSecondary care: outpatients

Jack 2010 (USA)53/5375Not reported27Not reported16Petersen 2010ADNI participantsMixedMixed: 13 different sites

Koivunen 2011 (Finland)29/2971.3 ± 6.418 (62.1)26.9±1.617 (58.6)Not reportedPetersen 2004Consecutive sampleNot reportedSecondary care: outpatients: memory clinic:

Okello 2009 (UK/Finland)31/3169.4 ± 7.919 (61.3)27.5±1.5Not reportedNot reportedPetersen 2010Not reportedNot reportedSecondary care: inpatients

*Ossenkoppele 2012 (Netherland)15/1267±7Not reported27±3Not reportedmedian 6

(range 3-7)*
Petersen 2001Not reportedNot reportedNot reported

Ossenkoppele 2012a (Netherland)30/1264±9Not reported27±2Not reportedNot reportedPetersen 1999Not reportedNot reportedSecondary care: outpatients: memory clinic:

Villemagne 2011 (Australia)67/6573.4±8.536 (55.4)26.5±2.941 (63)12.2 ±4.3Petersen 1999Not reportedMixed (advertisements and the Melbourne Healthy Aging StudySecondary care: outpatients: memory clinic:

Wolk 2009 (USA)26/2370.2±8.8Not reported27.3±1.9Not reported17.2 ±3.2Petersen 2004; Winbald 2004Not reportedNot reportedTertiary setting: Pittsburg ADRC

 N=number of MCI participants at baseline; n=number of participants included in analysis at follow-up; M=number of males
*Study used Verhage's classification on a scale of 1-7 (means 6; range 3-7), not years, for the unit of education
 
Table 2. Index test and number of converters to Alzheimer's disease dementia

StudyThreshold

(pre-specified

Yes/No)
Measure of PIB amyloid retentionImage analysisTime between PIB injection and PET acquisition (min)PIB dosePIB retention detecting regionsNumber of PIB positive

(%)
Number of converters (%)Duration of follow-up

Mean (months) / Maximum (years)

Forsberg 2010 (Sweden)Not specified analytical approach of ROI to-cerebellar ratio >1.6 (No)ROI to-cerebellar ratioSPM2 and MATLAB 7.160300 MBqGlobal cortex and thalamus11 (52.4)7 (33.3)33.3 ±19.3 / Not reported

Grimmer 2013 (Germany)Not specified analytical approach of ROI to-cerebellar vermis ratio of 1.4 (Yes)ROI to-cerebellar ratioNot reported40-60628 MBq (range 385 to 723 MBq)Global cortex17 (60.7)9 (32.2)31.2 ±7.8 / Not reported

Jack 2010 (USA)DVR of ROI to-cerebellar ratio >1.5 (Yes)Average neocortical to-cerebellar ratioAutomated image

processing pipeline
Range 50-70Not reportedGlobal cortex34 (64.2)18 (34.0)Not reported / 1.7 (median)

Koivunen 2011 (Finland)Not specified analytical approach of ROI to-cerebellar ratio > 1.5 (Yes)Posterior cingulate

to-cerebellar ratio
SPM290Not reportedGlobal cortex, caudate nucleus, putamen, thalamus, pons21 (72.4)17 (58.6)Not reported /

2

Okello 2009 (UK/Finland)RATIO > 2 SD greater

than the

control mean in

all 6 ROI (visual interpretation) (Yes)
RATIOSPMRange 60–90367 ± 25 MBqGlobal cortex17 (54.8)15 (48.4)27.5±1.5 /

3 (range 1-3)

Ossenkoppele 2012 (Netherland)Not reported

(visual interpretation)
Visual inspection of parametric BPND images by a trained nuclear medicine physicianBPND90351 ± 82 MBqGlobal cortex, frontal, parietal and lateral temporal and medial temporal lobe and posterior cingulate5 (41)4 (33.3)30.0±6.0 /

4 (range 2-4)

Ossenkoppele 2012a (Netherland)Not reported

(visual interpretation)
Visual inspection of parametric BPND and SUVr images by a trained nuclear medicine physicianBPNDRange 60-90367 ± 43 MBqFrontal, parietal, temporal and occipital lobe7 (58.3)6 (50.0)Not reported /

2

Villemagne 2011 (Australia)SUV of ROI

>1.5 (Yes)
Average neocortical to-cerebellar ratioMilxView40370 MBqGlobal cortex45 (69.2)31 (68.9)20.0±3.0 /

Not reported

Wolk 2009 (USA)DVR or SUV of ROI

> upper-inner

fence of the controls; an intermediate range 2.5% greater than and less than this cut-off

subjects

(visual interpretation) (Yes)
ROI to-cerebellar ratioSPM590 for DVR; range

40–60 for SUVR
14.3 ± 2.2 mCiGlobal cortex, anterior ventral

striatum, subcortical white matter, pons
13 (56.5)5 (21.7)21.2±16.0 /

Not reported

 
Table 3. Index test: Criteria for quantitative or visual interpretation and PIB retention in brain ROI areas

Threshold for a positive PIB-PET test

Quantitative interpretation:

1. DVR (Distribution Volume Ratio) of ROI: >1.5 (n=1)

2. SUVR (Standardised Uptake Volume ratio) of ROI: > 1.5 (n=1)

3. Not specified analytical approach of ROI: 1.4; >1.5; >1.6 (n=3)


Visual interpretation:

1. RATIO > 2SD than control mean in 6 ROI (n=1)

2. DVR or SVR of ROI > upper-inner fence of the control (n=1)

3. Threshold not reported in 2 studies


Measure of PIB amyloid retentionPIB retention in brain areas (ROI)

1. ROI to cerebellar ratio (n=3)Global cortex

Global cortex and thalamus

Global cortex, anterior ventral striatum, subcortical white matter, pons

2. Average neocortical to cerebellar ratio (n=2)Global cortex

3. Posterior cingulate to cerebellar ratio (n=1)Global cortex, caudate nucleus, putamen, thalamus, pons

4. RATIO (n=1)Global cortex

5. Visual inspection of parametric BPND images (n=1)Global cortex, frontal, parietal and lateral temporal and medial temporal lobe and posterior cingulate

6. Visual inspection of parametric BPND and SUVR images (n=1)Frontal, parietal, temporal and occipital

 
Table 4. Sensitivity and likelihood ratios for 11C-PIB-PET at fixed values of specificity for Alzhemer's dementia

StatisticFixed value of specificity %Estimated sensitivity % (95% confidence interval)Positive likelihood ratio (95% confidence interval)Negative likelihood ratio (95% confidence interval)

All studies (n = 9; cases = 112 ; non-cases = 162)

Lower quartile5696 (88, 99)2.19 (2.09, 2.29)0.07 (0.02, 0.23)

Median5896 (87, 99)2.29 (2.17, 2.41)0.07 (0.02, 0.24)

Upper quartile8189 (68, 97)4.66 (4.03, 5.39)0.14 (0.05, 0.44)

Sensitivity analyses



Reference standard NINCDS-ADRDA only (n = 7; cases = 89; non-cases = 144)

Lower quartile5696 (84, 99)2.18 (2.06, 2.32)0.07 (0.02, 0.30)

Median5896 (83, 99)2.28 (2.14, 2.43)0.07 (0.02, 0.31)

Upper quartile8188 (62, 97)4.62 (3.86, 5.55)0.15 (0.04, 0.56)

Threshold pre-specified (n = 7; cases = 101; non-cases = 140)

Lower quartile5695 (84, 99)2.16 (2.02, 2.30)0.09 (0.03, 0.30)

Median5894 (83, 98)2.25 (2.10, 2.41)0.10 (0.03, 0.32)

Upper quartile8185 (61, 95)4.46 (3.67, 5.42)0.19 (0.06, 0.55)

 The middle 50% of specificities from the studies are between the lower and upper quartile, i.e. the interquartile range