Title: Translational Models for Vascular Cognitive Impairment. A Review Including Larger Species

Transcription

1 Author s response to reviews Title: Translational Models for Vascular Cognitive Impairment. A Review Including Larger Species Authors: Atticus Hainsworth (ahainsworth@sgul.ac.uk) Stuart Allan (stuart.allan@manchester.ac.uk) Johannes Boltze (johannes.boltze@emb.fraunhofer.de) Catriona Cunningham (catriona.cunningham@postgrad.manchester.ac.uk) Chad Farris (cfarris@bu.edu) Elizabeth Head (Elizabeth.Head@uky.edu;) Masafumi Ihara (ihara@ncvc.go.jp) Jeremy Isaacs (jeremy.isaacs@nhs.net) Raj Kalaria (raj.kalaria@newcastle.ac.uk) Saskia Lesnik-Oberstein (Lesnik@lumc.nl) Mark Moss (markmoss@bu.edu) Björn Nitzsche (bjoern.nitzsche@izi.fraunhofer.de) Gary Rosenberg (GRosenberg@salud.unm.edu) Julie Rutten (j.w.rutten@lumc.nl) Melita Salkovic-Petrisic (melita.salkovic.petrisic@mef.hr) Aron Troen (aron.troen@mail.huji.ac.il) Version: 1 Date: 26 Sep 2016 Author s response to reviews: Dear Editor

2 RE: BMED-D Translational Models for Vascular Cognitive Impairment. A Position Statement Including Larger Species. BMC Medicine Thank you for giving us the opportunity to revise our manuscript. Please find below our pointby-point responses to the comments, marked *****. All changes to the manuscript are indicated in the text by highlighting and comments. With best regards, Atticus Hainsworth On behalf of: Atticus H Hainsworth; Stuart Allan; Johannes Boltze; Catriona Cunningham; Chad Farris; Elizabeth Head; Masafumi Ihara; Jeremy D. Isaacs; Raj N. Kalaria; Saskia AJ Lesnik- Oberstein; Mark Moss; Björn Nitzsche; Gary A. Rosenberg; Julie W. Rutten; Melita Salkovic- Petrisic; Aron M. Troen Reviewer reports Reviewer #1: I think the authors have aimed to provide a review of the various animal models which exist for VCI and draw the reader's attention to the fact that they have also included large animal models. I think a review in this field, especially including larger animals, is warranted and I think the expertise of this particular group of authors is well suited to providing a comprehensive and authoritative review which will be well received and well cited by the scientific community. ****** We thank the reviewer for these positive remarks I think multi-author review papers are challenging as everyone has a slightly different style and at times I didn't find the writing style of this paper particularly clear but this can easily be remedied. ***** We have attempted to smooth the writing style, as indicated. The authors seem to have performed a review of existing literature and used this, along with, of course, their own knowledge to produce this literature review - yet I'm a little confused as to whether the review is claiming to be a narrative review (which it is) or a systematic review (which it isn't). ****** We thank the reviewer for pointing this out. We have attempted to remove this confusion. This is not a systematic review. At the end of the Introduction section we have inserted the statement:..this is a narrative review, derived from consensus between experts

3 from 12 laboratories across seven countries. Relevant systematic reviews are available [Jiwa et al 2010, Madigan et al ]. Thus, it's not clear why there a section entitled 'methods' ****** We included a Methods section (now also containing Ethics statements) to indicate how we approached the review. This appears to be quite common practice now. in addition, the overall clarity of the paper could be improved by using more informative subtitles. The title of the article states this is a 'position statement' yet the authors don't define what they mean by a position statement - why is a position statement necessary? ******* The term position statement has been universally unpopular and we have removed it. The title of this review is now: Translational Models for Vascular Cognitive Impairment. A Consensus Review Including Larger Species In addition, many of the sub-titles have been modified. Some of the recommendations to the community aren't particularly insightful especially for a manuscript which calls itself a position statement - for example, adherence to ARRIVE guidelines is stated yet it would be useful to know what particular aspects of experimental design are weak in these type of studies? ****** This sentence has been inserted: ARRIVE guidelines. Specifically, random allocation of animals to experimental groups and blinded assessment of outcomes were quite rare in earlier studies (pre-2010) [Jiwa et al ]. 1st sentence of abstract doesn't quite make sense grammatically. ***** this opening sentence now reads: Disease models are useful for prospective studies of pathology, for identification of molecular and cellular mechanisms, for pre-clinical testing of interventions and validation of clinical biomarkers. Introduction, line 28 - word missing after 'molecular' and before 'underpinning'? ****** This sentence has been modified for clarity and now reads: While characterization of the neuropathological and radiological features of human VCI has improved over the last two decades (see adjoining articles) the molecular changes that underpin these characteristics remain elusive. The first section of the introduction gives an overview of VCI and some suggestions for what purpose a model of VCI might fit (e.g. pre-clinical testing of compounds etc.) but I didn't feel the title of this section was quite appropriate. ******* The title of this section has been modified accordingly, now simply Introduction.

4 Also, this section doesn't adequately explain why such a review as this is warranted. ******** An explanation for the motivation to write this review has been added to the Introduction: It is appropriate and timely to seek international accord on such models. Following a recent NIH-sponsored Alzheimer's Disease-Related Dementias 2016 Summit ( recommendation #1 for VCI was to Establish new animal models that: (i) reproduce small vessel disease and other key pathogenic processes thought to result in cognitive impairment; (ii) are easily applicable to both VCID and AD research for advances in mixed etiology dementias; (iii) address vascular contributions to dementia via both white matter and grey matter or (iv) include genetic and acquired conditions that are associated with VCID. This statement reflects the growing recognition that despite the important role vascular changes play in dementia (whether independently or through interaction with neurodegenerative processes) their specific contributions to cognitive impairment are poorly understood Hence, as argued here, better animal models will be critical to achieve therapy and prevention. The authors refer to MCAO as a gold standard of pre-clinical stroke research - do they mean for ischemic stroke and/or VCI - I assume they mean for ischemic stroke - how do they defend the statement this is the gold standard? *********** The term gold standard has been omitted. This sentence now reads: We have included models of focal ischemia (middle cerebral artery occlusion, MCAo) as this is a validated, translational model of cerebrovascular injury. Line 18 - subtitle 'overview' is not informative to reader. ************** This subtitle now reads: Overview of Experimental Species Lines what risk factors do primates share with humans? ********* This claim has been removed. Methods - it isn't clear what is meant by the authors presenting a synopsis based on literature searches and their own expertise - didn't the authors simply do a literature review and together with their own knowledge write a section of the paper? ***** This sentence has been modified for clarity and now reads: For each model, expert practitioners used web-based searches and their own expertise to write a section of the review. Line 50 - 'Intraluminal filament is the most adopted approach'...for what? ***** This sentence has been modified for clarity and now reads: Intraluminal filament is the most adopted approach for induction of MCAo..

5 It isn't clear from the review whether the authors are assessing models for their ability to replicate only the cognitive effects of VCI or also want to assess their suitability for assessing the pathological aspects of VCI - I assume it is a combination of the two and of course some models may more accurately model the pathological aspects but not the cognitive aspects but still be a useful model to use for examining potential molecular targets whereas the opposite scenario (i.e. model more accurately mimics the cognitive aspects) may be better suited for examining candidate treatment efficacy. A table (or two!) at least is warranted whereby the authors list all the cognitive (and/or pathological)symptoms/effects associated with VCI and indicate which models do or don't model those particular aspects of the cognitive or pathological deficits of VCI. ****** We are grateful for this excellent suggestion. A Table has been added, as recommended, before the Discussion section. This table compares salient features of clinical VCI with the animal models considered. Reviewer #2: The article provides an overview of animal models of stroke and VCI. This is a topic that has been extensively reviewed, in a more comprehensive manner and at more depth. the current review provides a cursory summary of some models, and lacks the depth and critical evaluation this topics requires. Therefore, it's not clear what new information this articles adds to existing literature. Of note, the first author has just published a review article in Stroke on the same topic "Madigan JB, Wilcock DM, Hainsworth AH. Vascular Contributions to Cognitive Impairment and Dementia: Topical Review of Animal Models. Stroke Jul;47(7):1953-9". He has also published a similar review in 2010 "Jiwa NS, Garrard P, Hainsworth AH. Experimental models of vascular dementia and vascular cognitive impairment: a systematic review. J Neurochem Nov;115(4):814-28". ****** This is an understandable concern. In fact, the recent review in Stroke (Madigan et al. 2016) is a systematic review, presented as an update to a previous systematic review (Jiwa et al 2010). Both those previous reviews had just three authors, and were essentially outputs from Dr Hainsworth s own laboratory. By contrast, the current manuscript represents an international consensus between multiple authors. As stated in the Introduction: This is a narrative review, derived from consensus between experts from 12 laboratories across seven countries. Relevant systematic reviews are available [Jiwa et al 2010, Madigan et al ]. In addition, the emphasis on larger experimental species, including unpublished original data, is a novel feature of the present review. Although the article is presented as a "A Position Statement", it's not clear which views the statement refers to and how widely representative they are. ****** As noted above, the term Position Statement has been removed.

6 A more scholarly, comprehensive and widely representative of both clinical an scientific (including animal models) was earlier published in Stroke "Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzman DM, Rosenberg GA, Wallin A, Dichgans M, Marler JR, Leblanc GG. National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke Sep;37(9): " ****** We find this claim puzzling. Hachinski et al 2006 is an excellent document (cited in our original text) covering many aspects of VCI. However, it has just two pages (1990 words) on experimental models. Most of the animal models presented in our present review were not mentioned in the Hachinski 2006 document. Indeed some of them had not been published or did not exist at that time (e.g. CADASIL mice, hypoperfused baboons). The Hachinski 2006 document makes very little mention of larger species Editorial Requests Ethics: If your study involves humans, human data or animals, then your article should contain an ethics statement which includes the name of the committee that approved your study. ***** A section has been added: Ethical statements on animal data presented here Consent: If your article is a prospective study involving human participants then your article should include a statement detailing consent for participation. **** Not applicable no human data If individual clinical data is presented in your article, then you must clarify whether consent for publication of these data was obtained. **** Not applicable no human data Availability of supporting data: **** Not applicable this is a narrative review Authors Contributions: ***** done. See Author Contributions section