Peripheral brain-derived neurotrophic factor levels in Alzheimer’s disease and mild cognitive impairment:
a comprehensive systematic review and meta-analysis
Supplementary Material - Tables
Bo Yi Kim1, Seon Heui Lee2, Petra L. Graham3, FrancescoAngelucci4, Alejandro Lucia5, Helios Pareja-Galeano5, Thomas Leyhe6, Yuda Turana7,
I Re Lee8, Ji Hye Yoon1, and Jae Il Shin8
1. Ewha Womans University College of Medicine, Seoul, Korea
2. Department of Nursing Science, College of Nursing, Gachon University, Incheon, Korea
3. Department of Statistics, Macquarie University, Sydney, NSW 2109, Australia
4. Department of Clinical and Behavioural Neurology, IRCCS Santa Lucia Foundation, Via Ardeatina 354, 00142 Rome, Italy.
5. European University of Madrid and Research Institute of Hospital 12 de Octubre ('i+12'), Spain
6. Center of Old Age Psychiatry, Psychiatric University Hospital, Basel, Switzerland
7. Department of Neurology, Atma Jaya Catholic University of Indonesia, Indonesia
8. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
Note: All reference numbers refer to the reference list in the main manuscript text.
Table e-1. Checklist summarizing compliance with PRISMA guidelines
sdfsdfsdSection/topic / # / Checklist item / Reported on page #TITLE
Title / 1 / Identify the report as a systematic review, meta-analysis, or both. / 1
ABSTRACT
Structured summary / 2 / Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. / 2
INTRODUCTION
Rationale / 3 / Describe the rationale for the review in the context of what is already known. / 3-4
Objectives / 4 / Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). / 4
METHODS
Protocol and registration / 5 / Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. / N/A
Eligibility criteria / 6 / Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. / 5-7
Information sources / 7 / Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. / 5-7
Search / 8 / Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. / 5-7
Study selection / 9 / State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). / 5-7 (Figure1)
Data collection process / 10 / Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. / 5-7
Data items / 11 / List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. / Supplementary tables
Risk of bias in individual studies / 12 / Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. / 7
Summary measures / 13 / State the principal summary measures (e.g., risk ratio, difference in means). / 7
Synthesis of results / 14 / Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I2) for each meta-analysis. / 7-8
Section/topic / # / Checklist item / Reported on page #
Risk of bias across studies / 15 / Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). / 7-8
Additional analyses / 16 / Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. / 7-8
RESULTS
Study selection / 17 / Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. / 9-10
Study characteristics / 18 / For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. / Supplementary tables
Risk of bias within studies / 19 / Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). / 14
Results of individual studies / 20 / For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. / 9-12, Table1, Supplementary figures
Synthesis of results / 21 / Present results of each meta-analysis done, including confidence intervals and measures of consistency. / 9-12, Table1, Supplementary figures
Risk of bias across studies / 22 / Present results of any assessment of risk of bias across studies (see Item 15). / 12
Additional analysis / 23 / Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). / 13-14
DISCUSSION
Summary of evidence / 24 / Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). / 15-17
Limitations / 25 / Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). / 17-18
Conclusions / 26 / Provide a general interpretation of the results in the context of other evidence, and implications for future research. / 18
FUNDING
Funding / 27 / Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. / 18
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
Table e-2. The Newcastle-Ottawa Scale (NOS) for the quality assessment of case-control studies
Author, year(reference) / Selection / Comparability / Exposure / Total
S1 / S2 / S3 / S4 / C1 / C2 / E1a / E1b / E2 / E3 / E4
Forlenza et al.,
2015 (23) / * / * / - / * / * / * / - / - / * / - / - / 6
Passaro et al,
2015 (24) / * / * / - / * / - / * / - / * / * / - / - / 6
Alvarez et al.,
2014 (25) / * / * / - / - / * / * / - / - / - / - / - / 4
Coelho et al.,
2014 (26) / * / * / - / * / * / * / - / - / * / - / - / 6
Curto et al.,
2014 (27) / * / * / - / - / - / - / - / - / - / - / - / 2
Diniz et al.,
2014 (28) / * / * / - / - / * / * / - / - / * / - / - / 5
Liu et al.,
2014 (29) / * / * / - / * / * / * / - / - / - / - / - / 5
Faria et al.,
2014 (44) / * / * / - / * / * / - / - / - / * / - / - / 5
Nagata et al.,
2014 (30) / * / * / - / - / * / - / - / - / * / - / - / 4
Nascimento et al.,
2014 (31) / * / * / * / - / * / * / - / - / * / - / - / 6
Turana et al.,
2014 (32) / * / * / - / * / * / * / - / - / * / - / - / 6
Sonali et al.,
2013 (33) / * / * / - / * / * / * / - / - / * / - / - / 6
Ventriglia et al.,
2013 (34) / * / * / - / - / - / - / - / - / * / - / - / 3
Konukoglu et al.,
2012 (35) / * / * / - / * / * / * / - / - / * / - / - / 6
O'Bryant et al.,
2011 (36) / * / * / - / - / - / * / - / - / * / - / - / 4
Angelucci et al.,
2010 (17) / * / * / - / - / * / * / - / - / * / - / - / 5
Forlenza et al.,
2010 (38) / * / * / - / * / - / * / - / - / * / - / - / 5
Leyhe et al.,
2009 (39) / * / * / - / * / * / * / - / - / * / - / - / 6
O'Bryant et al.,
2009 (40) / * / * / - / - / - / * / - / - / * / - / - / 4
Yu et al.,
2008 (45) / * / * / - / * / * / * / - / - / * / - / - / 6
Leyhe et al.,
2008 (41) / * / * / - / - / * / - / - / - / * / - / - / 4
Laske et al.,
2007 (46) / * / * / - / - / * / - / - / - / * / - / - / 4
Laske et al.,
2006 (42) / * / * / - / - / - / - / - / - / * / - / - / 3
Laske et al.,
2006 (2) (47) / * / * / - / - / - / - / - / - / * / - / - / 3
Yasutake et al.,
2006 (43) / * / * / - / * / - / * / - / * / * / - / - / 6
Laske et al.,
2005 (48) / * / * / - / - / - / - / - / - / * / - / - / 3
Table e-3. Sensitivity analyses
(1) Sensitivity analysis in in Alzheimer’s disease patients compared with healthy controls.2
Study omitted / SMD / 95% CI / p-value / Tau2 / I2Forlenza et al., 2015 / -0.157 / (-0.406,0.091) / 0.214 / 0.239 / 0.865
Passaro et al., 2015 / -0.136 / (-0.381,0.11) / 0.278 / 0.232 / 0.860
Alvarez et al., 2014 / -0.164 / (-0.417,0.089) / 0.203 / 0.248 / 0.865
Coelho et al., 2014 / -0.141 / (-0.385,0.103) / 0.258 / 0.231 / 0.863
Curto et al., 2014 / -0.232 / (-0.457,-0.006) / 0.044 / 0.192 / 0.840
Faria et al., 2014 / -0.214 / (-0.446,0.017) / 0.070 / 0.200 / 0.841
Liu et al., 2014 / -0.144 / (-0.397,0.109) / 0.265 / 0.248 / 0.860
Sonali et al., 2013 / -0.200 / (-0.441,0.041) / 0.103 / 0.220 / 0.851
Ventriglia et al., 2013 / -0.136 / (-0.383,0.111) / 0.281 / 0.233 / 0.842
Konukoglu et al., 2012 / -0.214 / (-0.449,0.022) / 0.075 / 0.211 / 0.852
O'Bryant et al., 2011 / -0.178 / (-0.438,0.082) / 0.180 / 0.265 / 0.858
Angelucci et al., 2010 / -0.209 / (-0.446,0.028) / 0.083 / 0.211 / 0.849
Forlenza et al., 2010 / -0.148 / (-0.397,0.1) / 0.241 / 0.238 / 0.864
Leyhe et al., 2009 / -0.133 / (-0.375,0.108) / 0.279 / 0.227 / 0.862
O'Bryant et al., 2009 / -0.171 / (-0.427,0.084) / 0.189 / 0.255 / 0.864
Leyhe et al., 2008 / -0.136 / (-0.379,0.107) / 0.273 / 0.229 / 0.862
Laske et al., 2007 / -0.144 / (-0.39,0.102) / 0.251 / 0.234 / 0.863
Yasutake et al., 2006 / -0.131 / (-0.374,0.113) / 0.293 / 0.227 / 0.858
Laske et al., 2006 (2) / -0.140 / (-0.383,0.103) / 0.258 / 0.230 / 0.863
Laske et al., 2005 / -0.143 / (-0.386,0.1) / 0.248 / 0.231 / 0.864
The heterogeneity results are not drastically changed by removal of any given study, study effects are also quite stable although the removal of Curto et al results in a significant overall effect. Removal of this study cannot be recommended.
(2) Sensitivity analysis in patients with mild cognitive impairment compared with healthy controls
Study omitted / SMD / 95% CI / p-value / Tau2 / I2Forlenza et al., 2015 / 0.002 / (-0.326,0.33) / 0.992 / 0.199 / 0.814
Alvarez et al., 2014 / -0.050 / (-0.408,0.308) / 0.784 / 0.247 / 0.848
Diniz et al., 2014 / -0.069 / (-0.428,0.29) / 0.708 / 0.249 / 0.849
Faria et al., 2014 / -0.133 / (-0.466,0.199) / 0.432 / 0.207 / 0.823
Nascimento et al., 2014 / -0.050 / (-0.394,0.294) / 0.776 / 0.231 / 0.848
Turana et al., 2014 / -0.028 / (-0.381,0.325) / 0.878 / 0.238 / 0.839
Sonali et al., 2013 / -0.100 / (-0.446,0.246) / 0.571 / 0.231 / 0.845
Angelucci et al., 2010 / -0.155 / (-0.469,0.159) / 0.334 / 0.180 / 0.806
Forlenza et al., 2010 / 0.014 / (-0.294,0.322) / 0.927 / 0.169 / 0.784
Yu et al., 2008 / -0.116 / (-0.463,0.23) / 0.511 / 0.225 / 0.817
As before the removal of any given study does not alter the heterogeneity within this study and the resulting estimates remain stable and similar to the original analysis.