appendix 1 the search strategies -...

Table S1: The search strategies of electronic databases and hits retrieved

Source

Search strategy Hits retrieved

1. MEDLINE In-process and other non-indexed citations and MEDLINE 1950-2014 (OvidSP)

1. Positron-Emission Tomography/ 2. (PiB or PIB).ti,ab. 3. "Pittsburgh compound B".ti,ab. 4. "C Pittsburgh".ti,ab. 5. (PIB-PET or PET-PIB).ti,ab. 6. "amyloid deposition".ti,ab. 7. "[11C]PIB".ti,ab. 8. "amyloid ligand*".ti,ab. 9. ((PET and (scan* or imag*)) or "positron emission tomography").ti,ab. 10. or/1-9 11. (alzheimer* or dement* or AD).ti,ab. 12. exp dementia/ 13. ((cognit* or memory or cerebr* or mental*) adj3 (declin* or impair* or los* or deteriorat* or degenerat* or complain* or disturb* or disorder*)).ti,ab. 14. MCI.ti,ab. 15. (nMCI or aMCI or mMCI).ti,ab. 16. ("N-MCI" or "A-MCI" or "M-MCI").ti,ab. 17. ("CDR 0.5" or "clinical dementia rating scale 0.5" or "0.5 CDR").ti,ab. 18. ("GDS 3" or "3 GDS").ti,ab. 19. ("global deterioration scale" and "stage 3").ti,ab. 20. or/11-19 21. (1999* or 2000* or 2001* or 2002* or 2001* 2002* or 2003* or 2004* or 2005* or 2006* or 2007* or 2008* or 2009* or 2010* or 2011* or 2012* or 2013* or 2014*).ed. 22. 10 and 19 and 21 23. (animals not (humans and animals)).sh. 24. 22 not 23

645

2. EMBASE 1980-2014 (OvidSP)

1. Positron-Emission Tomography/ 2. (PiB or PIB).ti,ab. or pittsburgh compound B/ 3. "Pittsburgh compound B".ti,ab. 4. "C Pittsburgh".ti,ab. 5. (PIB-PET or PET-PIB).ti,ab. 6. "amyloid deposition".ti,ab. 7. "[11C]PIB".ti,ab. 8. "amyloid ligand*".ti,ab. 9. ((PET and (scan* or imag*)) or "positron emission tomography").ti,ab.

439

10. or/1-9 11. (alzheimer* or dement* or AD).ti,ab. 12. exp dementia/ 13. ((cognit* or memory or cerebr* or mental*) adj3 (declin* or impair* or los* or deteriorat* or degenerat* or complain* or disturb* or disorder*)).ti,ab. 14. MCI.ti,ab. 15. (nMCI or aMCI or mMCI).ti,ab. 16. ("N-MCI" or "A-MCI" or "M-MCI").ti,ab. 17. ("CDR 0.5" or "clinical dementia rating scale 0.5" or "0.5 CDR").ti,ab. 18. ("GDS 3" or "3 GDS").ti,ab. 19. ("global deterioration scale" and "stage 3").ti,ab. 20. or/11-19 21. 10 and 20 22. (1999* or 2000* or 2001* or 2002* or 2001* 2002* or 2003* or 2004* or 2005* or 2006* or 2007* or 2008* or 2009* or 2010* or 2011* or 2012* or 2013* or 2014*).em. 23. 21 and 22 24. limit 23 to human

3. PsycINFO 1806-2014 (OvidSP)

1. Positron-Emission Tomography/ 2. (PiB or PIB).ti,ab. or pittsburgh compound B/ 3. "Pittsburgh compound B".ti,ab. 4. "C Pittsburgh".ti,ab. 5. (PIB-PET or PET-PIB).ti,ab. 6. "amyloid deposition".ti,ab. 7. "[11C]PIB".ti,ab. 8. "amyloid ligand*".ti,ab. 9. ((PET and (scan* or imag*)) or "positron emission tomography").ti,ab. 10. or/1-9 11. (alzheimer* or dement* or AD).ti,ab. 12. exp dementia/ 13. ((cognit* or memory or cerebr* or mental*) adj3 (declin* or impair* or los* or deteriorat* or degenerat* or complain* or disturb* or disorder*)).ti,ab. 14. MCI.ti,ab. 15. (nMCI or aMCI or mMCI).ti,ab. 16. ("N-MCI" or "A-MCI" or "M-MCI").ti,ab. 17. ("CDR 0.5" or "clinical dementia rating scale 0.5" or "0.5 CDR").ti,ab. 18. ("GDS 3" or "3 GDS").ti,ab. 19. ("global deterioration scale" and "stage 3").ti,ab. 20. or/11-19 21. 10 and 20

245

Note: MCI= mild cognitive impairment, AD=Alzheimer’s disease, N-MCI= non-amnestic mild cognitive impairment, A-MCI= amnestic mild cognitive impairment, M-MCI= multiple mild cognitive impairment, CDR=clinical dementia rating, GDS= global deterioration scale

22. (1999* or 2000* or 2001* or 2002* or 2001* 2002* or 2003* or 2004* or 2005* or 2006* or 2007* or 2008* or 2009* or 2010* or 2011* or 2012* or 2013* or 2014*).up. 23. 21 and 22

4. ISI Web of Knowledge: BIOSIS Previews (1926-2014) Topic=(PiB OR PIB OR "Pittsburgh compound B" OR "C Pittsburgh" OR "PiB-PET" OR "PET-PiB" OR "amyloid ligand*" OR "[11C]PiB" OR "amyloid deposition") AND Topic=(alzheimer* OR AD OR dement* OR cognit* OR MCI OR memory) AND Year Published=(1999-2014) Timespan=2003-2011. Databases=BIOSIS Previews. Lemmatization=On

628

5. ISI Web of Knowledge: Citation Databases : Science Citation Index Expanded (SCI-EXPANDED); Social Sciences Citation Index (SSCI); Arts & Humanities Citation Index (A&HCI); Conference Proceedings Citation Index- Science (CPCI-S); Conference Proceedings Citation Index- Social Science & Humanities (CPCI-SSH)

Topic=(PiB OR PIB OR "Pittsburgh compound B" OR "C Pittsburgh" OR "PiB-PET" OR "PET-PiB" OR "amyloid ligand*" OR "[11C]PiB" OR "amyloid deposition") AND Topic=(alzheimer* OR AD OR dement* OR cognit* OR MCI OR memory) AND Year Published=(1999-2014) Timespan=1999-2014. Databases=BIOSIS Previews. Lemmatization=On

587

6. LILACs (BIREME) PiB OR PIB OR "Pittsburgh compound B" OR "C Pittsburgh" OR PiB-PET OR PET-PiB OR "amyloid ligand*" OR "amyloid deposition" [Words]

77

Total before de-duplication 2621

Total after de-duplication 784

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-‐statement.org.

PRISMA 2009 Flow Diagram 2621 records identified through databases searching

645 from MEDLINE 439 from EMBASE 245 from PsycINFO 628 from BIOSIS Previews 587 from Science Citation Index 77 from LILACs

Screen

ing

Includ

ed

Eligibility

Iden

tification

784 records after duplicates removed

89 records screened

695 records excluded after reviewing abstracts 366 Not studies either PIB or cognitive impairment 124 laboratory Not human 149 target condition not looking at conversion to AD 56 other imaging biomarkers rather than PIB

55 full-‐text articles assessed for eligibility

34 records excluded based on first full-‐text assessment 30 not perspective studies 4 review, case report or editorial

11 Studies included in qualitative synthesis

11 Studies included in meta-‐analysis

(6 studies in short-‐term follow-‐up subgroup, 5 studies in long-‐term follow-‐up subgroup)

44 records excluded based on detailed full-‐text assessment 4 insufficient data to complete 2x2 table 7 not MCI patients at baseline 4 reference standards were mixed wth other types of dementias 8 not a delayed verification study 4 index test data for combined PIB biomarkers 3 PIB were mixed with other tracers of PET 10 not threshold used 4 multiple publications

Table 3: 11C-PIB-PET parameters, method of image interpretation, protocols and reference standard in short-term follow-up subgroup

MCI=mild cognitive impairment; ROC=receiver operating characteristic; SUVR=standardised uptake value ratio; DVR=distribution volume ratio; SPM=Statistical Parametric Mapping; ROI=regions of interest; BPND =parametric nondisplaceable binding potential images; PIB=Pittsburgh compound B; PET=positron emission tomography; 11C-PIB-PET= 11C-Pittsburgh compound B positron emission tomography; MBq=megabecquerel; mCi=millicuries; NA=not available. 1 mCi = 37 MBq. Unless otherwise indicated, continuous data are means ± standard deviations or means. Data in parentheses are the percentage of the parameters. a：An intermediate range 2.5% greater than and less than cut-off subjects.

Study and Year(region)

Threshold/ prespecified (Yes/No /NA)

PIB amyloid positive (%)

Measure of PIB amyloid retention

Method of image analysis

Time between PIB injection and PET acquisition (minutes)

PIB dose PIB retention detecting regions

Jack 2010(USA) Mean neocortical (ROI)DVR ＞1.5/ (Yes)

34(64.2) Mean neocortical-to-cerebellar ratio

automated image; processing pipeline

Range 50–70 NA Global cortex, not be specified

Wolk 2009 (USA) DVR or SUVR of ROI＞ upper-inner fence of the control; a(visual interpretation) / (Yes)

13(56.5) ROI to-cerebellar ratio

SPM5 90 for DVR; range 40-60 for SUR

14.3±2.2mCi

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

Villemagne 2011(Australia)

Neocortical SUVR > 1.5/ (Yes)

45(69.2) Average neocortical-to-cerebellar ratio

MilxView 40 370MBq Global cortex

Koivunen 2011 (Finland)

Not specified analytical approach of ROI to-cerebellar ratio > 1.5/ (Yes)

21(72.4) Posterior cingulate to-cerebellar ratio

SPM2 90 NA Global cortex, caudate nucleus, putamen, thalamus and pons.

Ossenkoppele 2013 (Netherland)

Not reported(visual interpretation) / (NA)

7(58.3) Visual inspection of parametric BPND images by a nuclear medicine physician

BPND Range 60-90 367±43 MBq

Global cortex, frontal, parietal, temporal and occipital lobe

Hatashita 2013 (Japan)

Mean neocortical (ROI)DVR�1.49(visual interpretation) / (Yes)

51(75) ROI to-cerebellar ratio

PMOD 60 561.5±11.2 MBq

Global cortex, cingulate gyrus, precuneus cortex and cerebellar cortex.

Table 4: 11C-PIB-PET parameters, method of image interpretation, protocols and reference standard in long-term follow-up subgroup

Study and Year(region)

Threshold/ prespecified (Yes/No/NA)

PIB amyloid positive (%)

Measure of PIB amyloid retention

Method of image analysis

Time between PIB injection and PET acquisition (minutes)

PIB dose PIB retention detecting regions

Okello 2009(UK/Finland) [20]

RATIO≧2 SD greater than the control mean in all 6 ROI(visual interpretation) / (Yes)

17(54.8) RATIO SPM range 60-90 432.8±70.6MBq Global cortex

Forsberg 2010(Sweden) [22]

Not specified analytical approach of ROI to-cerebellar ratio >1.6 / (No)


SPM2 and MATLAB 7.1

60 300MBq Global cortex and thalamus

Ossenkoppele 2012 (Netherland) [25]

Not reported (visual interpretation) /(NA)

5(41.0) Visual inspection of parametric BPND images by a nuclear medicine physician

BPND 90 351±82MBq Global cortex and posterior cingulate

Grimmer 2013 (Germany) [26]

Not specified analytical approach of ROI to-cerebellar vermis ratio of 1.4 / (Yes)


NA Range 40-60 628MBq(range 385 to723 MBq)

Global cortex

Kemppainen 2014 (Finland) [12]

Not specified analytical approach of ROI to-cerebellar ratio and SUVR of 1.5/ (Yes)


SPM8 Range 60-90 443MBq±89MBq Global cortex, posterior cingulate and cerebellar cortex.

ROC: receiver operating characteristic; RATIO, target region-to cerebellum ratios; SUVR, standardised uptake value ratio; SPM, Statistical Parametric Mapping; ROI, regions of interest; BPND parametric nondisplaceable binding potential images; MBq, megabecquerel. Unless otherwise indicated, continuous data are means ± standard deviations or means. Data in parentheses are the percentage of the parameters.

Table 5: Risk of bias and applicability judgments in QUADAS-2 items

QUADAS =Quality Assessment of Diagnostic Accuracy Studies; MCI= mild cognitive impairment; AD=Alzheimer’s disease; PIB=Pittsburgh compound B; 11C-PIB-PET= 11C-Pittsburgh compound B positron emission tomography;

Domain Patient Selection Index Test Reference Standard Flow and Timing Questions (yes, no, or unclear)

Was a consecutive or random sample of MCI patients enrolled?

Were the results of 11C-PIB-PET imaging test interpreted without knowledge of the results of the reference standard?

Is the progression to AD likely to correctly classify the target condition?

Was there an appropriate interval between 11C-PIB-PET imaging test and progression to AD?

Was a case-control design avoided?

If a threshold of 11C-PIB amyloid positivity was used, was it pre-specified?

Were the converting AD results interpreted without knowledge of the results of the PIB-PET imaging test?

Did all MCI patients receive the same standard of progression to AD?

Did the study avoid inappropriate exclusions?

Were all MCI patients included in the analysis?

Risk of bias (high, low, or unclear)

Could the selection of MCI patients have introduced bias?

Could the conduct or interpretation of the 11C-PIB-PET imaging test have introduced bias?

Could the progression to AD, its conduct, or its interpretation have introduced bias?

Could the MCI patient flow have introduced bias?

Concerns about applicability (high, low, or unclear)

Are there concerns that the included patients do not match the review question?

Are there concerns that the 11C-PIB-PET imaging, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by progression to AD does not match the question?

Table 6: Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study according to the suggestion of QUADAS-2

Study Risk of bias Applicability concerns Patient

Selection Index Test

Reference Standard

Flow and Timing

Patient Selection

Index Test

Reference Standard

Forsberg 2010 NA H NA L L L L Grimmer 2013 NA L L L L L L Jack 2010 H L NA L L L L Koivunen 2011 L L NA L L L L Okello 2009 NA L NA L L L L Ossenkoppele 2012 NA NA H L L L L Ossenkoppele 2013 NA H H H L L L Villemagne 2011 NA L NA L L L L Wolk 2011 NA L H L L L L Hatashita 2013 NA L NA L L L L Kemppainen 2014 NA L NA L L L L

QUADAS =Quality Assessment of Diagnostic Accuracy Studies; L=low risk or concern; H=high risk or concern; NA= not available/ unclear risk or concern

Table 7: Results of sensitivity analysis: the influence of each study for the outcome of meta-analysis

DOR= diagnostic odds ratio; 95%CI=95% confidence interval Note: Sensitivity analysis in each subgroup was performed by excluding studies one at a time starting from the minimum to maximum follow-up peroid to assess the influence of individual study on DOR. There was no obvious impact on our findings in each subgroup, it provides stronger evidence of an effect and of generalizability in this meta-analysis.

Author Short-term follow-up subgroup

Author Long-term follow-up subgroup

DOR 95%CI DOR 95%CI

Jack 2010 25.765 8.621-77.000 Forsberg 2010 37.333 8.407-165.78 Koivunen 2011 12.428 4.676-33.032 Grimmer 2013 40.417 9.003-181.43 Ossenkoppele 2013 11.892 4.867-29.057

Kemppainen 2014 41.639 9.843-176.15

Villemagne 2011 10.469 4.059-27.003

Ossenkoppele 2012 35.554 8.269-152.88

Wolk 2011 13.838 5.221-36.678 Okello 2009 29.302 5.792-148.24 Hatashita 2013 12.278 4.553-33.111 Combined 13.01 5.48- 30.87 Combined 36.88 9.65-140.96

appendix 1 the search strategies -...

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