CAT (Critical Appraised Topic)

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1

CAT (Critical Appraised Topic) Part I

Title

Can a mass spectrum analysis of a blood sample be used for an earlier diagnosis of Alzheimer’s disease?

Author Ida Dreier,

Lector/MSc in Pharmaceutical Chemistry, Ph.D.

iddr@ucl.dk

UCL University College

Biomedical Laboratory Science – Niels Bohrs Alle 1, 5230 Odense M Date of publication

June 28, 2019 Revised

September 30, 2019

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2 Background for the clinical question

Alzheimer’s disease(AD) is the most common form of dementia among elderly individuals worldwide and patients with AD are estimated to increase about 50% until 2025 (1, 2). The mechanism of AD is still not fully understood but the hallmarks for AD are the formation of amyloid plaques and neurofibrillary tangles caused by abnormally phosphorylated tau(P-tau) and total tau(T-tau) in the brain (1, 3, 4). The pathology of AD is synaptic dysfunction and degeneration, which correlate with the clinical characterization such as cognitive decline/deterioration and behavioral disorders (5). The current National clinical guideline for diagnosis of mild cognitive impairment(MCI) and dementia (6) recommend cognitive test as part of the basic clinical assessment supported by CT and MRI scans which provides structural imaging of the brain (6).

An early diagnosis of AD is important for the patient because it can lead to a better and a more target- oriented treatment and enhance the therapeutic success (7, 8). Biomarkers may occur in the early stages of AD before the appearance of the more conventional symptoms and could therefore lead to an early diagnosis. Amyloid-β(Aβ), P-tau and T-tau are cerebrospinal fluid(CSF) biomarkers for AD (known as the

“Alzheimer’s CSF profile), but the concentration of the CSF biomarkers depends on some confounding factors associated to pre-analytical factors (2). Therefore, the search for plasma AD-specific biomarkers is important, because the blood sample procedure is a less invasive procedure than a lumbar puncture, and it may also lead to an earlier diagnosis of AD. The challenges however lie in, that the CSF biomarkers for AD are in high abundance and low sample complexity, compared to AD-specific biomarkers in plasma samples (9, 10). But a way to overcome this could be to use Mass spectroscopy(MS) as a method for identification of plasma AD-specific biomarkers. Since MS can provide a quick and excellent method to identify and quantify biomarkers presented in very low concentration, because of the method’s exquisite selectivity and sensitivity as a detector (11).

The clinical question

The focused clinical question is based on a clinical subject, and the PICO Model (12, p. 34–7) has been used to define and focus the clinical question – see table 1.

 What is the evidence for using mass spectrometry to analyse a blood sample for specific biomarker(s) which could lead to an earlier diagnosis of Alzheimer’s disease compared to an analysis of the cerebrospinal fluid

Table 1 - Overview of the PICO model

P Population

I Intervention

C Comparison

O Outcome Alzheimer’s disease MS analysis of blood

samples

Analysis of

cerebrospinal fluid (any technique)

Earlier diagnosis of Alzheimer’s disease

Inclusion criteria

In this CAT two sets of inclusion criteria have been applied. The first set of inclusion criteria when searching the different databases was a Block search methods, and the second set of criteria was first applied for the articles chosen for full-text-reading.

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3 First set of inclusion criteria:

 Language: English, Danish, Norwegian, Swedish, and German The first set of inclusion criteria is based on my own language skills.

Second set of inclusion criteria:

 10 years’ time boundary (2009-2019)

 Specific biomarkers either amyloid-β, phosphorylated tau(P-tau) or total tau(T-tau) or neurofilament light proteins

 Reviews must be systematic reviews

A 10 years’ time boundary was chosen because mass spectrometry is a relatively new technic especially when analysing biological macromolecules (13, 14). The already known CSF biomarkers for AD (amyloid- β, P-tau, and T-tau) are chosen as specific biomarkers for this search (3). The time boundary and the specific biomarkers were not applied in the first set of criteria because a broad search was preferred in the block search since it is a research field in rapid development.

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4

Part II

Search strategy

A basic literature matrix has been constructed and a selection of the relevant databases have been made before the relevant literature search for the clinical question has been conducted. In the following sections descriptions of the basic literature matrix, which databases have been chosen, and an example of the block search and final search string for one database can be seen.

The Basic literature matrix

The purpose with the basic literature matrix is to identify important keywords and phrases relevant for the clinical question. The keywords and phrases are of course inspired by the clinical question and are expanded by using MeSH terms from PubMed and Thesaurus terms from the EBSCO databases. This will insure that relevant synonyms are included in the basic literature matrix - see table 2. The keywords in blocks 1, 2, 3, and 5 are very narrow and specific keywords, which will insure a precise search for the intervention, population and comparison. Whereas block 4 is a more open keyword search for the intervention to insure a novel biomarker is not missed in this CAT. Furthermore, the five blocks have been priority base on the clinical question with mass spectrometry having the highest rank.

Table 2 - The basic literature matrix

Block 1 Mass spectrometry

(Intervention)

Block 2 Alzheimer (Population)

Block 3 Blood sample (Intervention)

Block 4 Biomarker (Intervention)

Block 5 Cerebrospinal-

fluid (Comparaison)

 Mass spectrometry

 Mass spectroscopy

 Mass spectroscopic technique

 Mass spectrometry analysis

 Mass spectrometer

 Mass spectrum

 Mass spectrum analysis

 Mass spectrum analyses

 Alzheimer

 Alzheimer’s disease

 Alzheimer Syndrome

 Alzheimer Dementia

 Amyloid beta- protein

 Blood sample

 Serum

 Blood serum

 Plasma

 Biomarker

 Biological marker

 Serum marker

 Biochemical marker

 Cerebrospinal fluid

 Cerebro spinal fluid

The following databases are included in the block search: PubMed, Academic Search Premier, CINAHL, and PsycINFO. In appendix 1 a description and argumentation for including the four databases can be seen.

Furthermore, the search strategy used for all four database can be seen in figure 1 but is also elaborated in appendix 1.

In table 3 the final search string can be seen for the four chosen databases, and in appendix 2 the single word search and the final search string can be seen for all four databases.

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5 The same search strategy was used for all four databases using a systematic literature search based on a technic called block searching. The following protocol was applied for all four databases:

 Individual search on all keywords and phrases in each block of the basic literature matrix (According to the specific databases relevant truncation and quotation search was used)

 Combining all the individual keywords and phrases in each block with OR

 Combing all the block with AND

Figure 1 – Search strategy for the systematic block search

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6 The final block searching for the four databases

Table 3 - The final search string for the four chosen databases

Final search string Hits: May 1^th

2019

Limits Hits with limits:

May 1^th 2019

PubMed

(((((((((((((((((Mass spectroscopy) OR Mass spectrometry) OR Mass spectroscopic techniques) OR Mass spectroscopic technique) OR Mass spectrometry analysis) OR Mass spectrometer) OR Mass spectrometers) OR Mass spectrum) OR Mass spectrums) OR Mass spectrum analysis) OR Mass spectrum analyses)) AND

((((((((Alzheimer) OR Alzheimers) OR Alzheimer’s disease) OR Alzheimers disease) OR Alzheimer’s) OR Alzheimer Syndrome) OR Alzheimer Dementia) OR Amyloid beta-protein)) AND (((((blood sample) OR blood samples) OR Serum) OR blood serum) OR plasma))) AND ((((((((Biomarker) OR Biomarkers) OR Biological marker) OR Biological markers) OR Serum marker) OR Serum markers) OR Biochemical marker) OR Biochemical markers))) AND ((Cerebrospinal fluid) OR Cerebro spinal fluid)

83

Languages:

Danish English German Norwegian

Swedish

83

Academic Search Premier

( Mass spectrum analys#s OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrosc* technique* OR Mass spectrom* OR Mass spectrosc* ) AND ( Alzheimer* OR Alzheimer* disease OR Alzheimer* Syndrome OR Alzheimer* Dementia OR Amyloid beta-protein* ) AND ( Blood sample* OR Serum OR "Blood serum" OR Plasma ) AND ( Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker* ) AND cerebrospinal fluid

49

CINAHL

( Mass spectrosc* OR Mass spectrom* OR Mass spectrosc* technique* OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrum analys#s ) AND ( Alzheimer* OR Alzheimer* disease OR Alzheimer* Syndrome OR Alzheimer* Dementia OR Amyloid beta-protein* ) AND ( Blood sample* OR Serum OR “Blood serum” OR Plasma ) AND ( Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker* ) AND cerebrospinal fluid

11 11

PsycINFO

( Mass spectrosc* OR Mass spectrom* OR Mass spectrosc* technique* OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrum analys#s ) AND ( Alzheimer* OR Alzheimer* disease OR Alzheimer* Syndrome OR Alzheimer* Dementia OR Amyloid beta-protein* ) AND ( Blood sample* OR Serum OR “Blood serum” OR Plasma ) AND ( Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker* ) AND Cerebrospinal fluid

32 32

Total number 175

Total number after removal of duplications*

106

* The removal of the duplications are described in more details in section – Search results including flow diagram

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7 Search results including flow-diagram

Using block search as a search method a total number of 175 articles were found in the four databases mentioned previously. After duplications were removed (Duplicates = 27, Triplets = 12, and Quartets = 6 leading to a total number of 45 articles and a total of 69 hits) a total of 106 articles were left for screening.

The 106 articles were first screened based on title and abstract leading to an exclusion of 78 articles, which left 28 articles for full-text reading (Four of the 28 articles were published before 2009 but were already excluded due to other reasons – see the flow diagram in figure 3). Three of the 28 articles could not be provided in full-text, nine articles were excluded because the articles were reviews but not systematic reviews, and 14 were excluded because of wrong biomarkers and/or methods. This leads to the inclusion of two articles - see figure 2 for the two articles.

In figure 3 the flow diagram over the article-selection-process can be seen and in table 4 a matrix with the basic informations for the two selected articles are provided.

 Jun Seok Kim, Hee-Sung Ahn, Soo Min Cho, Ji Eun Lee, YoungSoo Kim, Cheolju Lee. Detection and quantification of plasma amyloid-β by selected reaction monitoring mass spectrometry. Anal Chim Acta. 2014; 840:1–9 (16)

 Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, Fowler C, Li QX, Martins R, Rowe C, Tomita T, Matsuzaki K, Ishii K, Ishii K, Arahata Y, Iwamoto S, Ito K, Tanaka K, Masters CL, Yanagisawa K.

High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018;

554(7691):249–54 (17)

Figure 2 – Articles included in the CAT

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8 Flow diagram of articles

Identification of records through database search:

PubMed = 83

Academic Search Premier = 49 CINAHL = 11

PsycINFO = 32

n = 175

Removal of duplicates:

Duplicates = 27 (1 · 27 = 27) Triplets = 12 (2 · 12 = 24) Quartets = 6 (3 · 6 = 18)

n = 106

Identification of records through other sources:

n = 0

Records screen:

Title and abstract n = 106

Records excluded:

Title and abstract n = 78

Identification

Records assessed for eligibility:

Full-text

n = 28

Records excluded Full-text

Wrong biomarkers and/or methods:

(n = 14)

Reviews (not systematic):

(n = 9) Not available:

(n = 3)

n = 26 Records included:

n = 2 Screening EligibilityIncluded

Articles = 45 Hits = 69

Figure 3 – Flow diagram of articles

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9 Matrix of article

Table 4 – Matrix of the two selected articles

Nb Authors Title Year

Country Purpose Included individuals

Patients AD

Standard

of truth Methods Sensitivity Specificity ROC

analyses CV%

1

Nkamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, Fowler C, Li QX, Martins R, Rowe C, Tomita T, Matsuzaki K, Ishii K, Ishii K, Arahata Y, Iwamoto S, Ito K, Tanaka K, Masters CL, Yanagisawa K

Detection and quantification of plasma amyloid-β by selected reaction monitoring mass

spectrometry

2014 Republic of Korea

Accurately and precisely quantify of total Aβ level in human plasma

Not relevant

Selected reaction

monitoring mass spectrometry (SRM-MS), (high pH reversed- phase liquis chromatographu (RPLC))

Not relevant Not relevant

Not relevant

25,3

2

Jun Seok Kim, Hee-Sung Ahn, Soo Min Cho, Ji Eun Lee, YoungSoo Kim, Cheolju Lee

High

performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature

2018 Japan and

Australia

To assess the performance of three plasma-Aβ biomarkers for

determining an

individual’s Aβ status

373 59 PIB-PET IP-MS 86.1% 82.3% 0.914 Not

relevant

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10

Part III

Critical assessment

The Critical Appraisal Skills Programme (CASP) (15) is used for the critical assessment of the two articles included in this study – see table 5.

Jun Seok Kim et al. 2014 (16). The aim in the study by Jun Seok Kim et al. is to accurately and precisely quantify the total of Aβ level in human plasma using first high pH reversed-phase liquid chromatography(RPLC) followed by a liquid chromatography selected reaction monitoring mass spectrometry(LC-SRM/MS). Aβ17-28 is chosen as the best candidate for a surrogate petide of Aβ, and the method is optimized using synthetic Aβ (SRM) and transgenic mice plasma (high pH RPLC). Furthermore a calibration curve for Aβ17-28 using a stable isotope standard(SIS) peptide as internal standard was conducted providing a LOQ at 132 ρmol/L, before LC-SRM/MS quantitation of total Aβ in human plasma (Human sample from Sigma-Aldrich) was preformed using the optimized procedure. The results are presented reasonably in tables and figures. The triplicate SRM/MS measurements (retention time) showing a highly reproducibility with CV% values of 3.65%, 4.65%, and 2.59%, but the reproducibility of the sample preparation (high pH RPLC) was less impressive resulting in an overall CV% of 25.3%.

The study is considered reasonable valid, and the design and laboratory methods used in the study are well described. The CV% for SRM/MS measurements for each trail is consisting of only three measurements which must be considered a fairly few number to calculate a CV% from. The CV% for the reproducibility of the sample preparation are not listed and thus gives doubts about the total CV%.

Nakamura A et al. 2018 (17). The aim in this study is to assess the performance of three plasma-Aβ biomarkers (ratio of plasma Aβa-42 to the APP669-711 fragment (APP669-711/Aβa-42), the ratio of plasma Aβa-40/Aβ1- 42, and a composite biomarker score that incorporate both) for determining an individual’s Aβ status, and thereby separating individuals with high levels of Aβ(Aβ⁺) from individuals with low levels of Aβ(Aβ^-). The study also try to improve the general application and reproducibility of the immunoprecipitation-mass spectrometry(IP-MS) which can be used to measure the three plasma-Aβ biomarkers. The level of plasma Aβ was measured using IP-MS including 62 cognitively normal individuals, 30 with MCI and 29 with AD giving a total of 121 samples from the Japanese National Center for Geriatrics and Gerontology(NCGG), and 156 cognitively normal individuals, 68 with MCI and 30 with AD giving a total of 253 samples from Australian Imaging Biomarkers and Lifestyle Study of Ageing(AIBL) (Cohort study). As golden standard C-labelled Pittsburgh compound-B positron-emission tomography(PIB-PET) or other ligands were used for all individuals. The results are well presented in tables and figures and Receiver Operating Characteristic(ROC) analyses were used to assess the biomarkers performance in predicting Aβ⁺/Aβ^- status. The area under curve(AUC), sensitivity, specificity, and accuracy at an optimal cut-off point were used for the performance measures. The study showed that Aβ-related plasma biomarkers are correlated with CSF Aβ and PET imaging, and that the composite biomarker showed the highest and most stable performance for the three plasma biomarkers through all the analyses with a sensitivity 86.1%, specificity 82.3%, accuracy 84.2%, AUC of 0.914 for the NCGG+AIBL overall (n = 373) and cut-off 0.376 (common cut-off value).

The study is considered valid. Both the design of the study, methods used in the laboratory, and the results are well described. The sample size is considered reasonable and representative in age, sex and disease status. The data analyses were conducted in a blind and independent way and the study includes two

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11 independent data sets (Japan and Australia). The study also address several issues that has to be taken into account before clinical application can be considered. This also increases the study’s validity.

Table of ratings

In table 5 a rating of the two articles are seen – the rating a based on Critical Appraisal Skills Programme – CASP Checklist for Diagnostic Test study (15). The study of Jun Seok Kim et al. 2014 (16) is not a diagnostic study but it has been chosen to still use the CASP checklist for diagnostic test study, as there are no other checklist that fits the study better.

Table 5 – CASP checklist for diagnostic test study for the two selected articles

Are the results of the study valid What are the

results? Will the results help locally?

1. Was there a clear question for the study to address? 2. Was there a comparison with an appropriate reference standard? 3. Did all patients get the diagnostic test and reference standard? 4. Could the results of the test have been influenced by the results of the reference standard? 5. Is the disease status of the tested population clearly described? 6. Were the methods for performing the test described in sufficient detail? 7. What are the results? Jun Seok Kim et al. = CV%, Nakamur et al. = ROC analyses (AUC) 8. How sure are we about the results? Consequences and cost of alternatives performed? 9. Can the results be applied to your patients/the population of interest? 10. Can the test be applied to your patient or population of interest? 11. Were all outcomes important to the individual or population considered? 12. What would be the impact of using this test on your patients/population?

Jun Seok Kim et al.

2014

Yes yes Not relevant No Not relevant Yes 25,3 Sure Not relevant Not relevant Not relevant Not relevant

Nakam ura A et al.

2018

Yes Yes Yes No yes Yes 0.914 Very sure Yes Yes Yes A less invasive methods for the patients

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12 The overall assessment and conclusion

The two studies included in this CAT show that this is a research field in development. The challenge for this novel research field is that, while still looking for specific plasma biomarkers reflecting the patient cognitive status, the research also has to take into account how to accurately and precisely quantify the specific plasma biomarkers that are only presented in very low concentration and in high sample complexity. Therefor the evidence cannot support a recommendation to use a MS analysis of a blood sample to diagnosis of AD.

Declaration on the authors' independence No political or economic conflicts of interest.

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13 Reference

1. Galozzi S, Marcus K, Barkovits K. Amyloid-β as a biomarker for Alzheimer’s disease: quantification methods in body fluids. Expert Rev Proteomics. 2015; 12(4):343–54.

2. Fania C, Arosio B, Capitanio D, Torretta E, Gussago C, Ferri E, et al. Protein signature in cerebrospinal fluid and serum of Alzheimer’s disease patients: The case of apolipoprotein A-1 proteoforms. PloS One.

2017; 12(6):e0179280.

3. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J Intern Med. 2018; 284(6):643–63.

4. Veitinger M, Oehler R, Umlauf E, Baumgartner R, Schmidt G, Gerner C, et al. A platelet protein biochip rapidly detects an Alzheimer’s disease-specific phenotype. Acta Neuropathol (Berl). 2014; 128(5):665–

77.

5. Bah JMC, Jensen SS, Larsen MR, Heegaard NHH. Characterization of the Human Cerebrospinal Fluid Phosphoproteome by Titanium Dioxide Affinity Chromatography and Mass Spectrometry. Anal Chem.

2008; 80(16):6308–16.

6. NKR: Diagnostik af mild cognitive impairment og demens [Internet]. [cited 2019 Jun 18]. Available from: https://www.sst.dk/da/udgivelser/2018/nkr-diagnostik-af-mild-cognitive-impairment-og- demens.

7. Inoue K, Tsuchiya H, Takayama T, Akatsu H, Hashizume Y, Yamamoto T, et al. Blood-based diagnosis of Alzheimer’s disease using fingerprinting metabolomics based on hydrophilic interaction liquid

chromatography with mass spectrometry and multivariate statistical analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2015; 974:24–34.

8. Richens JL, Vere K-A, Light RA, Soria D, Garibaldi J, Smith AD, et al. Practical detection of a definitive biomarker panel for Alzheimer’s disease; comparisons between matched plasma and cerebrospinal fluid. Int J Mol Epidemiol Genet. 2014; 5(2):53–70.

9. Sarasa L, Allué JA, Pesini P, González-Martínez Á, Sarasa M. Identification of β-amyloid species in canine cerebrospinal fluid by mass spectrometry. Neurobiol Aging. 2013; 34(9):2125–32.

10. Lame ME, Chambers EE, Blatnik M. Quantitation of amyloid beta peptides Aβ1–38, Aβ1–40, and Aβ1–

42 in human cerebrospinal fluid by ultra-performance liquid chromatography–tandem mass spectrometry. Anal Biochem. 2011; 419(2):133–9.

11. Gleave M. The strengths of mass spectrometry are not just sensitivity and selectivity. Bioanalysis. 2011;

3(3):245–7.

12. Lund H, Juhl C, Andreasen J, Møller A. Håndbog i litteratursøgning og kritisk læsning: redskaber til evidensbaseret praksis. Kbh.: Munksgaard; 2014.

13. Tanaka K, Waki H, Ido Y, Akita S, Yoshida Y, Yoshida T, et al. Protein and polymer analyses up to m/z 100 000 by laser ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom RCM.

1988; 2(8):151–3.

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14 14. The Nobel Prize. The Nobel Prize in Chemistry 2002. NobelPrize.org [Internet]. [cited 2019 Mar 5].

Available from: https://www.nobelprize.org/prizes/chemistry/2002/tanaka/facts/.

15. CASP UK. CASP Checklists. Critical Appraisal Skills Programme [Internet]. 2018 [cited 2019 Jun 26].

Available from: https://casp-uk.net/casp-tools-checklists/.

16. Jun Seok Kim, Hee-Sung Ahn, Soo Min Cho, Ji Eun Lee, YoungSoo Kim, Cheolju Lee. Detection and quantification of plasma amyloid-β by selected reaction monitoring mass spectrometry. Anal Chim Acta. 2014; 840:1–9.

17. Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018; 554(7691):249–54.

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Appendix – 1

Selection of the relevant databases

Since no two databases included precisely the same material, it is important to choose and include more than one database for the search. The inclusion of more than one database should help you prevent missing a key publication for the relevant topic.

PubMed is a database that includes more the 29 million citations within the fields of biomedical and life science (a), which makes it a well-suited database for finding relevant material for the clinical question. Academic Search Premier is an interdisciplinary database, which include relevant subjects such as biology, chemistry, and science and technology that is relevant for the clinical question (b). Therefore, PubMed and Academic Search Premier are well-suited databases for fining relevant literature for answering the clinical question, and therefore both databases are included in the study.

A search in EBSCO (all databases selected) was conducted January 30th 2019 to investigate if other databases could also be of interest. The search in EBSCO was first conducted with the first keyword from block 1 from the basic literature matrix (Keyword = Mass spectrometry). This search was made as a Boolean/Phrase search with and without quotes. The keyword from block 1 was then combined with the first keyword from block 2 (Keyword = Alzheimer) and then from block 3 (Keyword = blood sample). The databases were listed according to hits. The result from the EBSCO search can be seen in table A.

Table A - EBSCO database search including all databases in EBSCO (January 30th 2019)

Keywords and phases The top three databases according to hits Mass spectrometry

Medline (317,791)

Academic Search Premier (196,980) CINAHL (14,262)

”Mass spectrometry”

Medline (292,262)

Academic Search Premier (196,673) CINAHL (14,258)

”Mass spectrometry” and Alzheimer

Medline (2291)

Academic Search Premier (1576) PsycINFO (434)

”Mass spectrometry” and Alzheimer and blood sample

Medline (30)

Academic Search Premier (21) PsycINFO (9)

”Mass spectrometry” and Alzheimer and ”blood sample”

Medline (4) CINAHL (1)

Academic Search Premier (1)

From the search in EBSCO two other databases was suggested hence CINAHL and PsycINFO. Based on that search more information for the two databases (CINAHL and PsycINFO) was conducted. CINAHL is a database related to nursing and associated health professionals and can therefore be a relevant database to include for the clinical question (c). PsycINFO is a database with citations of behavioural and social science research (d),

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16 and is therefore relevant compared to the keyword Alzheimer. Hence CINAHL and PsycINFO were also included in the group of relevant databases. The following databases are therefor included: PubMed, Academic Search Premier, CINAHL, and PsycINFO.

Documentation for the search strategy used in the different databases

The same search strategy was used for all four databases using a systematic literature search based on a technic called block searching. The following protocol was used for all four databases:

 Individual search on all keywords and phrases in each block of the basic literature matrix (According to the specific databases relevant truncation and quotation search was used)

 Combining all the individual keywords and phrases in each block with OR

 Combing all the block with AND

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17

Appendix – 2

PubMed

The search in PubMed was conducted January 31^th 2019 and the results for the block search including single word searching can be seen in table B. In table C the final search string can be seen for each block and for all the five blocks combined, and it was conducted January 31^th 2019 and the search on the combined block was conducted again May the 1^th 2019.

Table B - Block search including single keyword search in Academic Search Premier

# Database: PubMed Date: January 31^th 2019

Hits: Block: Comment

1 Mass spectroscopy 335,392

1

All fields

2 Mass spectrometry 320,778 All fields

3 Mass spectroscopic technique 450 All fields

4 Mass spectroscopic techniques 4801 All fields

5 Mass spectrometry analysis 229,438 All fields

6 Mass spectrometer 17,984 All fields

7 Mass spectrometers 2058 All fields

8 Mass spectrum 330,998 All fields

9 Mass spectrums 64 All fields

10 Mass spectrum analysis 324,921 All fields

11 Mass spectrum analyses 321,291 All fields

#1#2#3#4#5#6#7#8#9#10#11 349,393

12 Alzheimer 102,870

2

All fields

13 Alzheimers 105,019 All fields

14 Alzheimer’s 146,133 All fields

15 Alzheimer’s disease 142,237 All fields

16 Alzheimers disease 103,412 All fields

17 Alzheimer Syndrome 99,889 All fields

18 Alzheimer Dementia 101,128 All fields

19 Amyloid beta-protein 45,905 All fields

#12#13#14#15#16#17#18#19 162,057

20 Blood sample 106,980

3

All fields

21 Blood samples 301,527 All fields

22 Serum 1,056,784 All fields

23 Blood serum 1,056,784 All fields

24 Plasma 875,189 All fields

#20#21#22#23#24 2,024,198

25 Biomarker 808,079

4

All fields

26 Biomarkers 764,794 All fields

27 Biological marker 784,711 All fields

28 Biological markers 791,314 All fields

29 Serum marker 788,805 All fields

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18

30 Serum markers 795,789 All fields

31 Biochemical marker 772,378 All fields

32 Biochemical markers 779,213 All fields

#25#26#27#28#29#30#31#32 910,996

33 Cerebrospinal fluid 111,020

5 All fields

34 Cerebro spinal fluid 111,529 All fields

#33#34 111,529

Block 1-5 combined #1-#34 82

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19

Table C - The final search string for each block and the combination of the blocks for PubMed

Database Final search string Hits:

January 31^th 2019

Hits:

May 1^th 2019

January 31^th 2019

Hits with limits:

May 1^th 2019

PubMed

Block 1

Search string:

((((((((((Mass spectroscopy) OR Mass spectrometry) OR Mass spectroscopic techniques) OR Mass spectroscopic technique) OR Mass spectrometry analysis) OR Mass spectrometer) OR Mass spectrometers) OR Mass spectrum) OR Mass spectrums) OR Mass spectrum analysis) OR Mass spectrum analyses

349,393

Block 2

Search sting:

(((((((Alzheimer) OR Alzheimers) OR Alzheimer’s disease) OR Alzheimers disease) OR Alzheimer’s) OR Alzheimer Syndrome) OR Alzheimer Dementia) OR Amyloid beta-protein

162,057

Block 3 Search string:

((((blood sample) OR blood samples) OR Serum) OR blood serum) OR plasma 2,024,198

Block 4

Search string:

(((((((Biomarker) OR Biomarkers) OR Biological marker) OR Biological markers) OR Serum marker) OR Serum markers) OR Biochemical marker) OR

Biochemical markers

910,996

(Cerebrospinal fluid) OR Cerebro spinal fluid 111,529

Block 1-5 combined

Search:

(((((((((((((((((Mass spectroscopy) OR Mass spectrometry) OR Mass spectroscopic techniques) OR Mass spectroscopic technique) OR Mass spectrometry analysis) OR Mass spectrometer) OR Mass spectrometers) OR Mass spectrum) OR Mass spectrums) OR Mass spectrum analysis) OR Mass spectrum analyses)) AND ((((((((Alzheimer) OR Alzheimers) OR Alzheimer’s disease) OR Alzheimers disease) OR Alzheimer’s) OR Alzheimer Syndrome) OR Alzheimer Dementia) OR Amyloid beta-protein)) AND (((((blood sample) OR blood samples) OR Serum) OR blood serum) OR plasma))) AND

((((((((Biomarker) OR Biomarkers) OR Biological marker) OR Biological markers) OR Serum marker) OR Serum markers) OR Biochemical marker) OR Biochemical markers))) AND ((Cerebrospinal fluid) OR Cerebro spinal fluid)

82 83

Languages:

Swedish 82 83

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20 Academic Search Premier

The search in Academic Search Premier was conducted February 8^th 2019 and the results for the block search including single word searching can be seen in table D. In table E the final search string can be seen for each block and for all the five blocks combined, and it was conducted February 20^th 2019 and the search on the combined block was conducted again May the 1^th 2019.

Table D - Block search including single keyword search in Academic Search Premier

# Database: Academic Search Premier Date: February 8^th 2019

1 Mass spectrosc* 72,933

1

Boolean/Phrase

2 Mass spectrom* 209,097 Boolean/Phrase

3 Mass spectrosc* technique* 1,127 Boolean/Phrase

5 Mass spectrom* analys#s 27,699 Boolean/Phrase

6 Mass spectrum* 59,278 Boolean/Phrase

7 Mass spectrum analys#s 55,882 Boolean/Phrase

#1#2#3#4#5#6#7 220,498

8 Alzheimer* 89,788

2

Boolean/Phrase

9 Alzheimer* disease 82,264 Boolean/Phrase

10 Alzheimer* Syndrome 871 Boolean/Phrase

11 Alzheimer* Dementia 41,662 Boolean/Phrase

12 Amyloid beta-protein* 11,199 Boolean/Phrase

#8#9#10#11#12 90,377

13 Blood sample* 71,845

3

Boolean/Phrase

14 Serum 418,886 Boolean/Phrase

15 “Blood serum” 55,794 Boolean/Phrase

16 Plasma 514,917 Boolean/Phrase

#13#14#15#16 905,429

17 Biomarker* 127,506

4

Boolean/Phrase

18 Biological marker* 16,445 Boolean/Phrase

19 Serum marker* 10,173 Boolean/Phrase

20 Biochemical marker* 85,685 Boolean/Phrase

#17#18#19#20 177,085

21 Cerebrospinal fluid 37,075 5 Boolean/Phrase

#21 37,075

(21)

21

Table E - The final search string for the blocks and for the combination of all the blocks Academic Search Premier

Database Final search string Hits February 20th

2019

Hits: May 1th 2019

February 20th 2019

Hits with limits:

May 1th 2019

Academic Search Premier

Block 1

Search string:

Mass spectrum analys#s OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrosc* technique* OR Mass spectrom*

OR Mass spectrosc*

221,158

10 years Languages:

Swedish Block 2

Search string:

Alzheimer* OR Alzheimer* disease OR Alzheimer* Syndrome OR

Alzheimer* Dementia OR Amyloid beta-protein* 90,612 Block 3 Search string:

Blood sample* OR Serum OR "Blood serum" OR Plasma 908,893 Block 4

Search string:

Biomarker* OR Biological marker* OR Serum marker* OR

Biochemical marker* 178,651

Cerebrospinal fluid 37,075

Block 1-5 combined

Search string:

( Mass spectrum analys#s OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrosc* technique* OR Mass spectrom*

OR Mass spectrosc* ) AND ( Alzheimer* OR Alzheimer* disease OR Alzheimer* Syndrome OR Alzheimer* Dementia OR Amyloid beta-protein* ) AND ( Blood sample* OR Serum OR "Blood serum"

OR Plasma ) AND ( Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker* ) AND cerebrospinal fluid

48 49 48 49

(22)

22 CINAHL

The search in CINAHL was completed February 21^th 2019 and the results for the block search including single key word searching can be seen in table F. In table G the final search string can be seen for each block and for all the five blocks combined. The search on the combined block was conducted again May the 1^th 2019.

Table F - Block search including single keyword search in Academic Search Premier

# Database: CINAHL Date: February 21th 2019

1 Mass spectrosc* 575

1

Boolean/Phrase

3 Mass spectrosc* technique* 36 Boolean/Phrase

5 Mass spectrom* analys#s 1,036 Boolean/Phrase

6 Mass spectrum* 93 Boolean/Phrase

7 Mass spectrum analys#s 9 Boolean/Phrase

#1#2#3#4#5#6#7 15,079

8 Alzheimer* 35,838

2

Boolean/Phrase

12 Amyloid beta-protein* 166 Boolean/Phrase

#8#9#10#11#12 35,875

3

Boolean/Phrase

15 “Blood serum” 439 Boolean/Phrase

#13#14#15#16 150,021

4

Boolean/Phrase

19 Serum marker* 3,657 Boolean/Phrase

20 Biochemical marker* 2,299 Boolean/Phrase

#17#18#19#20 85,528

#21 11,676

(23)

23

Table G - The final search string for the blocks and for the combination of all the blocks CINAHL

Database Final search string Hits February

21^th 2019

Hits: May 1th 2019

February 21^th 2019

Hits with limits:

May 1th 2019

CINAHL

Block 1

Search string:

Mass spectrosc* OR Mass spectrom* OR Mass spectrosc* technique* OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrum analys#s

15,079

10 years Languages

Swedish Block 2

Search string:

Alzheimer* OR Alzheimer* disease OR Alzheimer*

Syndrome OR Alzheimer* Dementia OR Amyloid beta- protein*

35,875

Blood sample* OR Serum OR “Blood serum” OR Plasma 150,021 Block 4

Search string:

Biomarker* OR Biological marker* OR Serum marker*

OR Biochemical marker*

85,528 Block 5 Search string:

Block 1-5 combined

Search string:

( Mass spectrosc* OR Mass spectrom* OR Mass spectrosc* technique* OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrum analys#s ) AND ( Alzheimer* OR Alzheimer* disease OR Alzheimer*

Syndrome OR Alzheimer* Dementia OR Amyloid beta- protein* ) AND ( Blood sample* OR Serum OR “Blood serum” OR Plasma ) AND ( Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker* ) AND cerebrospinal fluid

11 11 11 11

(24)

24 PsycINFO

The search in PsycINFO was completed February 21^th 2019 and the results for the block search including single keyword searching can be seen in table H. In table I the final search string can be seen for each block and for all the five blocks combined. The search on the combined block was conducted again May the 1^th 2019.

Table H - Block search including single keyword search in PsycINFO

# Database: PsycINFO Date: February 21th 2019

1 Mass spectrosc* 149

1

Boolean/Phrase

3 Mass spectrosc* technique* 5 Boolean/Phrase

5 Mass spectrom* analys#s 379 Boolean/Phrase

6 Mass spectrum* 29 Boolean/Phrase

7 Mass spectrum analys#s 2 Boolean/Phrase

#1#2#3#4#5#6#7 3,345

8 Alzheimer* 64,833

2

Boolean/Phrase

12 Amyloid beta-protein* 2,724 Boolean/Phrase

#8#9#10#11#12 65,071

3

Boolean/Phrase

15 “Blood serum” 4,343 Boolean/Phrase

#13#14#15#16 58,189

4

Boolean/Phrase

19 Serum marker* 537 Boolean/Phrase

20 Biochemical marker* 729 Boolean/Phrase

#17#18#19#20 27,840

#21 10,949

(25)

25

Table I - The final search string for the blocks and for the combination of all the blocks PsycINFO

Database Final search string Hits February

21^th 2019

Hits: May 1th 2019

February 21^th 2019

Hits with limits:

May 1th 2019

PsycINFO

Block 1

Search string:

Mass spectrosc* OR Mass spectrom* OR Mass spectrosc*

technique* OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrum analys#s

3,345

Languages Danish English German Norwegian

Swedish Block 2

Search string:

Alzheimer* OR Alzheimer* disease OR Alzheimer* Syndrome OR Alzheimer* Dementia OR Amyloid beta-protein*

Blood sample* OR Serum OR “Blood serum” OR Plasma 58,189 Block 4

Search string:

Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker*

Block 1-5 combined

Search string:

( Mass spectrosc* OR Mass spectrom* OR Mass spectrosc*

technique* OR Mass spectrom* analys#s OR Mass spectrum* OR Mass spectrum analys#s ) AND ( Alzheimer* OR Alzheimer*

disease OR Alzheimer* Syndrome OR Alzheimer* Dementia OR Amyloid beta-protein* ) AND ( Blood sample* OR Serum OR

“Blood serum” OR Plasma ) AND ( Biomarker* OR Biological marker* OR Serum marker* OR Biochemical marker* ) AND Cerebrospinal fluid

32 32 32 32

(26)

26 Reference - Appendix

a. NCBI - PubMED. Home - PubMed - NCBI [Internet]. n.d. [cited 2019 Mar 5]. Available from:

https://www.ncbi.nlm.nih.gov/pubmed/.

b. Academic Search Premier | EBSCO. EBSCO Information Services, Inc. [Internet]. n.d. [cited 2019 Mar 5]. Available from: https://www.ebsco.com/products/research-databases/academic- search-premier.

c. EBSCO. CINAHL Complete | Full-Text Nursing Journals | EBSCO [Internet]. n.d. [cited 2019 Mar 5]. Available from: https://www.ebscohost.com/nursing/products/cinahl-databases/cinahl- complete.

d. American Psychological Association. PsycINFO. https://www.apa.org [Internet]. n.d. [cited 2019 Mar 5]. Available from: https://www.apa.org/pubs/databases/psycinfo.