Translational models for vascular cognitive impairment: a review including larger species

As noted previously [9‐11, 14], no experimental model replicates all pathologic and cognitive aspects of human VCI (Table 1). Animal models are useful to reflect a pathological process (e.g., white matter hypoxia, arterial fibrosis, amyloid accumulation) rather than a human disease. Old dogs with canine cognitive dysfunction syndrome and aged primates (> 20 years of age) being possible exceptions, none of the models discussed here results in a ‘demented’ animal. That said, all the animal models considered above reproduce at least one of the pathological processes in human VCI. Because the sequence of events leading from experimental challenge to brain pathology, and thus to VCI, can be characterised in animal models (and interventions imposed), the models may help to identify pathways that lead to VCI. As the pathogenesis of SVD, the most common cause of VCI, remains unknown, a valid model of SVD-dependent VCI remains a challenge. Making these conceptual and biological limitations explicit will expedite the development and appropriate use of translational models for VCI.

There are several general limitations in the extant literature. Most animal studies involve short-term follow-up (typically, less than 4 weeks). Male animals are generally used and females usually avoided due to influences of the reproductive cycle. Few studies have correlated cognitive changes with anatomical changes, as seen by pathology or MRI. Most of the available cognitive paradigms are derived from AD models. Many experimental studies are under-powered (i.e., use a small number of animals) and few are replicated.

We have a number of recommendations for the VCI research community. First, it would be advantageous to increase our knowledge and experience in larger species with more abundant white matter and gyrencephalic brain anatomy. This is especially important given the central role of white matter lesions in human VCI. Second, robust neuropsychological methods for assessing VCI in experimental animals (particularly larger species) would be beneficial. Cognitive impairment (and recovery) are the most complex aspects of human VCI, and will likely differ between animals and humans (for example, experimental species lack spoken language). Thus, aspiring to a precise behavioural replication in an animal may not be possible. Nevertheless, a core toolkit of validated, reproducible, species-appropriate tests of a cognitive phenotype is required. With respect to SVD, simple behavioural indicators analogous to the key cognitive features of the syndrome in humans (impaired processing speed, apathy and executive dysfunction) should be welcome. Third, progress on translational VCI models will be more rapid if high standards of ‘Methodological quality’ [15] outlined in ARRIVE guidelines [138] and in previous translational consensus documents [139, 140] are followed. Specifically, random allocation of animals to experimental groups and blinded assessment of outcomes was quite rare in earlier studies (prior to 2010) [10]. Future experimental studies should adhere to available guidelines on experimental design, regarding a priori statistical power calculation, randomisation, blinding of observers, and confirmation by at least two independent laboratories [15, 138‐140]. It appears likely that negative outcomes of animal studies are rarely published. Fourth, as neuroimaging (particularly MRI) has a central role in human VCI, future pre-clinical studies will be enhanced by brain imaging data. Radiological features (diffuse white matter lesions, lacunar infarcts) are the main clinical biomarkers of SVD. Hence, correlative studies relating MRI to brain pathology in animals will continue to be informative.

Experiments using gyrencephalic species may be costly and long in duration to afford sufficient statistical power. A possible solution is a step-wise approach that employs rodents to study fundamental aspects of cerebrovascular disease common to all species, and large animals to study aspects of VCI that require a large gyrencephalic brain. Extending studies across species will clarify molecular, cellular and physiological events that lead from vascular disease to neuronal injury and cognitive dysfunction in humans, and improve the likelihood of achieving new preventive and therapeutic interventions in VCI.