Variability of functional outcome measures used in animal models of stroke and vascular cognitive impairment - a review of contemporary studies

Abstract

Despite promising preclinical data, few novel stroke therapies have shown efficacy in man. Efforts to improve standards in conduct and reporting of preclinical research are ongoing. In clinical trials, inconsistency in outcome measures led to regulatory agencies and funders mandating use of a core set of functional outcomes. Our aim was to describe functional outcome measures in preclinical stroke and vascular cognitive impairment (VCI) studies. From 14 high impact journals (January 2005-December 2015 inclusive), 91,956 papers were screened with 1302 full texts analyzed for stroke (ischemic and hemorrhagic) and 56 for VCI studies. In total, 636 (49%) stroke and 37 (66%) VCI papers reported functional outcome measures. There were 74 different functional assessments reported in stroke and 20 in VCI studies. Neurological deficit scores (74%) and Morris water maze (60%) were most commonly used in stroke and VCI, respectively. However, inconsistencies in methods used to assess and score recovery were noted. Neurological and behavioural functional outcome measures are increasingly used in preclinical stroke or VCI studies; however, there is substantial variation in methods. A strict standardized outcome set may not be suitable for translational work, but greater consistency in choice, application and reporting of outcomes may improve the science.

Keywords: Rodent; functional outcome measure; hemorrhagic stroke; middle cerebral artery occlusion; vascular cognitive impairment.

Figure 1.

Strategy implemented in the focused literature search. Papers were selected on the basis of set inclusion/exclusion criteria and after further comprehensive review, papers that had no reported functional outcome measures as their primary or secondary endpoint were excluded from the final analysis. This yielded 636 papers for stroke and 37 for vascular cognitive impairment (VCI).

Figure 2.

Number of papers published each year with functional assessments. The number of preclinical stroke (a) or VCI (b) papers reporting functional assessments over the 11 years of the review period. The number of papers per year in stroke and VCI, respectively were: 2005: 29,1; 2006: 30, 1; 2007: 32, 2; 2008: 37, 1; 2009: 38, 5; 2010: 33, 2; 2011: 97, 3; 2012: 75, 3; 2013: 101, 5; 2014: 82, 2; 2015: 82, 12. A significant increase in stroke papers describing functional outcome assessments was observed after 2010 (unpaired t-test; ***p < 0.0001 comparing articles from 2000 to 2010 vs. articles 2011–2015, inclusive). Data generated from 14 specified peer-reviewed journals (Supplementary Table I).

Figure 3.

The prevalence of species and sex of animals used in stroke and VCI papers. (a) The percentage of papers using each species in stroke and VCI studies. (b) The percentage of papers using each sex across stroke and VCI studies. Percentage was calculated as portion of total amount of papers included in the final analysis (n = 636 and n = 37, respectively).

Figure 4.

Top 10 functional assessments used in preclinical stroke or VCI papers. Top 10 functional assessments in (a) stroke outcome measures (n = 967) and (b) VCI outcome measures (n = 65) included in the final analysis. Percentage was calculated as a portion of the number of functional assessments made.

Figure 5.

Prevalence of outcome measures used in papers according to stroke model. The preferred functional outcome measure used in papers using (a) endothelin-1 or (b) the thrombotic model to induce experimental stroke was determined. Percentage was calculated as a portion of all outcome measures used (a: n = 48; b: n = 101).

Figure 6.

Prevalence of the number of different outcome measures reported in preclinical stroke or VCI papers. The number of preclinical stroke papers using one or more functional outcome measures was determined for (a) stroke and (b) VCI papers. These represented for increasing number of outcome measures employed: (a) 1 = 344 papers (54%), 2 = 159 (25%), 3 = 81 (13%), 4 = 34 (5%), 5 = 7 (1%), 6 = 6 (1%), 7 = 1 (0.2%), 8 = 0 (0%), 9 = 1 (0.2%), 10 = 4 (1%) and (b) 1 = 20 papers (54%), 2 = 10 (27%), 3 = 4 (13 = 11%), 4 = 1 (3%), 5 = 0 (0%), 6 = 0 (0%), 7 = 0 (0%), 8 = 1 (3%), 9 = 0 (0%), 10 = 0 (0) 11 = 1 (3%). Percentage was calculated as a portion of all papers included.