11/7/2018 PROSPERO

102557 Animal 51162

Effect of statins on Alzheime

Animal review
To edit the record click Start an update below. This will create a new version of the record - the existing
version will remain unchanged.

1. * Review title.
Give the working title of the review. This must be in English. The title should have the interventions or exposures being
reviewed and the associated health or social problems.
Effect of statins on Alzheimer’s disease models: A systematic review and meta-analysis.

2. Original language title.

For reviews in languages other than English, this field should be used to enter the title in the language of the review. This will
be displayed together with the English language title.

3. * Anticipated or actual start date.

Give the date when the systematic review commenced, or is expected to commence.

10/06/2018

4. * Anticipated completion date.

Give the date by which the review is expected to be completed.

10/06/2019

5. * Stage of review at time of this submission.

Indicate the stage of progress of the review by ticking the relevant Started and Completed boxes. Additional information may
be added in the free text box provided.

Please note: Reviews that have progressed beyond the point of completing data extraction at the time of initial registration are
not eligible for inclusion in PROSPERO. Should evidence of incorrect status and/or completion date being supplied at the time
of submission come to light, the content of the PROSPERO record will be removed leaving only the title and named contact
details and a statement that inaccuracies in the stage of the review date had been identified.

This field should be updated when any amendments are made to a published record and on completion and publication of the
review.
The review has not yet started: No

Review stage Started Completed

Preliminary searches No Yes

Piloting of the study selection process No Yes

Formal screening of search results against eligibility criteria No Yes

Data extraction No No

Risk of bias (quality) assessment No No

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Review stage Started Completed

Data analysis No No

Provide any other relevant information about the stage of the review here (e.g. Funded proposal, protocol not yet finalised).

6. * Named contact.
The named contact acts as the guarantor for the accuracy of the information presented in the register record.

SYED OBAIDUR RAHMAN

Email salutation (e.g. "Dr Smith" or "Joanne") for correspondence:

Mr RAHMAN

7. * Named contact email.

Enter the electronic mail address of the named contact.

syedobaid2995@gmail.com

8. * Named contact address.

PLEASE NOTE this information will be published in the PROSPERO record so please do not enter private information

Enter the full postal address for the named contact.

Pharmacology Research Laboratory, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi-
110062, India

9. Named contact phone number

Enter the telephone number for the named contact, including international dialling code.

7503564208

10. * Organisational affiliation of the review.

Full title of the organisational affiliations for this review and website address if available. This field may be completed as ‘none’ if
the review is not affiliated to any organisation.

None

Organisation web address:

11. * Review team members and their organisational affiliations.

Give the title, first name and last name of all members of the team working directly on the review. Give the organisational
affiliations of each member of the review team.

Mr SYED OBAIDUR RAHMAN. Jamia Hamdard

Mr SALMAN HUSSAIN. Jamia Hamdard
Dr Abul Kalam Najmi. Jamia Hamdard

12. * Funding sources/sponsors.

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Give details of the individuals, organisations, groups or other legal entities who take responsibility for initiating, managing,
sponsoring and/or financing the review. Any unique identification numbers assigned to the review by the individuals or bodies
listed should be included.

None

13. * Conflicts of interest.

List any conditions that could lead to actual or perceived undue influence on judgements concerning the main topic investigated
in the review.
None

14. Collaborators.
Give the name, affiliation and role of any individuals or organisations who are working on the review but who are not listed as
review team members.

15. * Review question.

Give details of the question to be addressed by the review, clearly and precisely.

Is Statin a promising drug candidate for the treatment of AD?

Does statins have any impact on brain level of Amyloid-β?
Assessment of neuroprotective potential of statins?
What is the effect of statin on behavioural outcomes?

Context and rationale

Statins are HMG-CoA reductase inhibitors and a powerful cholesterol lowering agents. Statins have proved to be a huge
success in preventing coronary heart diseases and thus reducing the risk of stroke and heart failure. Since studies have
demonstrated strong correlation of vascular and cholesterol related pathways with the prevalence of AD, it was hypothesized
that statin may play a significant role in preventing or treating AD. And as hypothesized both preclinical and clinical studies
have exhibited beneficial effect of statins against AD indicating neuroprotective actions of cholesterol synthesis reduction.
On the contrary several large clinical trials have reported no significant difference in cognitive functions of statin treated vs
placebo group. Even a Cochrane systematic review and meta-analysis on 26,340 participants concluded that administration of
statins in late life have no effect in preventing AD or dementia in patients at high risk of vascular disease. These contradictory
studies have kept the importance of statin against AD still under debate. The present requirement is to fully clarify the potential
mechanism by which statin had shown neuroprotective actions during AD. Whether the protection due to reduction in
cholesterol synthesis or some other pleiotropic action of statins?
In some in-vivo model of AD, statins have demonstrated significant improvement in neuron density, long term potentiation and
behavioral dysfunction via reducing Aβ load, inflammatory cytokines and oxidative stress. A systematic review will be
performed on these in-vivo studies to assess the cumulative effect of statin on Aβ accumulation, neuroinflammation, neuron
density and cognitive impairment. If studies found to be homogenous then meta-analysis will be performed for quantitative
evaluations. Subgroup analysis will be done to identify any significant difference in the statin effects that can be due to
variations in experimental factors like type of statin selected, dosage of statin, species and duration of treatment. These
analyses might help in proper understanding of factors that lead to the discrepancy among different studies and thus in future
can help in proper translation of these results into the clinical trials.

16. * Searches.
Give details of the sources to be searched, and any restrictions (e.g. language or publication period). The full search strategy is
not required, but may be supplied as a link or attachment.
1. MEDLINE via PubMed
2. Scopus
3. EMBASE
4. Reference lists of included studies
5. Reference lists of relevant reviews

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6. Conference proceedings

17. URL to search strategy.

Give a link to the search strategy or an example of a search strategy for a specific database if available (including the keywords
that will be used in the search strategies).
https://www.crd.york.ac.uk/PROSPEROFILES/102557_STRATEGY_20180626.pdf

Yes I give permission for this file to be made publicly available

18. * Human disease modelled.

Give a short description of the disease, condition or healthcare domain being modelled.

Alzheimer’s disease

19. * Animals/population.
Give summary criteria for the animals being studied by the review, e.g. species, sex, details of disease model. Please include
details of both inclusion and exclusion criteria.

Inclusion criteria:
All rodents’ population.

Exclusion criteria:
Non-rodents animals, human studies, invitro studies and in silico studies

20. * Intervention(s), exposure(s).

Give full and clear descriptions of the nature of the interventions or the exposures to be reviewed (e.g. dosage, timing,
frequency). Please include details of both inclusion and exclusion criteria.

Inclusion criteria:
Statins (Simavastatin, Atorvastatin, Lovastatin, Fluvastatin, Pitavastatin and Pravastatin). In any dose and dosage form.

Exclusion criteria:
All Interventions other than statin, Combination of statins with ohter intervention

21. * Comparator(s)/control.
Where relevant, give details of the type(s) of control interventions against which the experimental condition(s) will be compared
(e.g. another intervention or a non-exposed control group). Please include details of both inclusion and exclusion criteria.

Inclusion criteria:
A non-statin exposed rodent's model of Alzheimer's disease (i.e. an Alzheimer's disease rodent's model not exposed to any
kind of intervention)

Exclusion criteria:
Rodent's models without Alzheimer's disease (i.e. a normal control or sham control groups), Rodent's model of Alzheimer's
disease exposed to statin or any other kind of intervention.

22. * Types of study to be included.

Give details of the types of study (study designs) eligible for inclusion in the review. If there are no restrictions on the types of
study design eligible for inclusion, or certain study types are excluded, this should be stated. Please include details of both
inclusion and exclusion criteria.

Inclusion criteria:
We will include only in vivo pre-clinical studies

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Exclusion criteria:
We will exclude all study design other than in vivo pre-clinical studies like in vitro pre-clinical studies; clinical studies (humans)
and others

23. Other selection criteria or limitations applied.

Give details of any other inclusion and exclusion criteria (e.g. publication date or language restrictions).

24. * Outcome measure(s).

Give detail of the outcome measures to be considered for inclusion in the review. Please include details of both inclusion and
exclusion criteria.

Inclusion criteria:
studies assessing effect of statin on Aβ level, behavioural outcomes and Neuroprotective potential

Exclusion criteria:
Studies not assessing effect of statin on Aβ level

25. N/A.
This question does not apply to systematic reviews of animal studies for human health submissions.

26. * Study selection and data extraction.

Procedure for study selection

All the retrieved articles were examined against the inclusion and exclusion criteria. In the first pass, articles were screened on
the basis of title and abstract. Full text articles were retrieved in the first pass were further screened in the second pass. To
independent reviewers were participated in the screening phase and any discrepancy in the article inclusion were first tried to
resolved by consensus. If consensus not achieved then resolved by discussion with third reviewer.

Prioritise the exclusion criteria

1. Studies involving human participants (Clinical studies)
2. Review articles, Letter to Editor and short communications
3. Studies not related to statins
4. Not an animal model of Alzheimer’s disease
5. Studies involving animals other than rodents
6. Not assessing Aβ level as the outcomes of interest

Methods for data extraction

Two independent reviewers will extract data from selected studies. If data isn't found then the author of that study will be
requested through e-mail. If author is unable to reply the data will be extracted using digital ruler/ Image processing software
(e.g. Image J). Studies will be excluded if data isn't retrievable through above mentioned procedures.

Data to be extracted: study design

Total sample size, Sample size of intervention group, Sample size of control group

Data to be extracted: animal model

Species, gender, disease induction, age at start of intervention, age at the termination of the intervention

Data to be extracted: intervention of interest

Intervention, Route of administration, Dose, Vehicle, Duration of intervention, pre-treatment/post-treatment

Data to be extracted: primary outcome(s)

Aβ level. Mean and SD values of the outcomes will be recorded, continuous data type, Unit of measurement may vary in
different studies depending upon the method of evaluation.

Data to be extracted: secondary outcome(s)

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Behavioural outcomes, Neuronal count/survival rate, Brain cholesterol level. Mean and SD values of the outcomes will be
recorded, continuous data type, Unit of measurement may vary in different studies depending upon the method of evaluation.

Data to be extracted: other

First author and publication year

27. * Risk of bias and/or quality assessment.

State whether and how risk of bias and/or study quality will be assessed. Assessment tools specific for pre-clinical animal
studies include SYRCLE’s risk of bias tool and the CAMARADES checklist for study quality

No risk of bias and/or quality assessment planned

No

By use of SYRCLE’s risk of bias tool

No

By use of SYRCLE’s risk of bias tool adapted as follows:

No

By use of the CAMARADES checklist for study quality

No

By use of the CAMARADES checklist for study quality, adapted as follows:

Yes

by Peng et al, 2014 in '' Impact of Statins on Cognitive Deficits in Adult Male Rodents
after Traumatic Brain Injury: A Systematic Review''.

Other criteria, namely

No

Method for risk of bias and/or quality assessment

Two independent reviewers will be assessing the risk of bias/study quality in each study and any discrepancy will be resolved
by the third reviewer.

28. * Strategy for data synthesis.

Planned approach
Data will be extracted in a predesign data tabular form. Two reviewers will abstract the data independently. Any discrepancy will
be resolved by discussion with the third reviewer. If the studies used the same type of intervention and comparator with the
same result then we will pool the data using the random effect model.

Effect measure
For each outcome measure, standardized Mean Difference (SMD) will be used. We will calculate 95% confidence interval and
two-sided p values for each result.

Effect models
Random effect model will be used.

Heterogeneity
Cochrane χ² test.

Other
If required meta-regression will be done.

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29. * Analysis of subgroups or subsets.

Subgroup analyses
Subgroup analysis will be performed on the basis of type of statins, Gender, Treatment schedule and others

Sensitivity
Sensitivity analysis will be performed by excluding each study at a time

Publication bias
Visual inspection of funnel plot

30. * Review type.

Type of review
Animal model review No

Experimental animal exposure review No

Pre-clinical animal intervention review Yes

31. Language.
Select each country individually to add it to the list below, use the bin icon to remove any added in error.

English

There is an English language summary.

32. Country.
Select the country in which the review is being carried out from the drop down list. For multi-national collaborations select all
the countries involved.

India

33. Other registration details.

List other places where the systematic review protocol is registered. The name of the organisation and any unique identification
number assigned to the review by that organisation should be included.
None

34. Reference and/or URL for published protocol.

Give the citation and link for the published protocol, if there is one.
None

No I do not make this file publicly available until the review is complete

35. Dissemination plans.

Give brief details of plans for communicating essential messages from the review to the appropriate audiences.

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Do you intend to publish the review on completion?

Yes

36. * Keywords.
Give words or phrases that best describe the review. Separate keywords with a semicolon or new line.
Statins; Amyloid-β level; Alzheimer’s disease; Rodents; Neuronal survival rate; Behavioural outcomes;

37. Details of any existing review of the same topic by the same authors.
Give details of earlier versions of the systematic review if an update of an existing review is being registered, including full
bibliographic reference if possible.
None

38. * Current review status.

Review status should be updated when the review is completed and when it is published.

Review_Ongoing

39. Any additional information.

Provide any further information the review team consider relevant to the registration of the review.

40. Details of final report/publication(s).

This field should be left empty until details of the completed review are available. Give the full citation for the final report or
publication of the systematic review.

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