FHU VasCog researches are translational, promoting back-and-forths between basic studies (search for new pathological pathways and new therapeutical targets, development of drug candidates), preclinical studies (development of new models, drug candidate testing) and the clincial studies (pharmacological tests, cohorts, epidemiology…)
Three themes are investigated:
Stroke-associated cognitive disorders (CDs)
In one patient out of three, stroke is associated with occurrence of CI or dementia, leading to a high morbidity. Given the aging population, stroke is one of the major contributors to the future increase of dementia incidence. Despite the growing health, social and economic burden of post-stroke CDs, it remains necessary to develop biomarkers for (i) early detection of CDs enabling early initiation of treatment and (ii) patient stratification and recruitment in clinical trials assessing new therapeutic strategies, potentially disease-modifying ones since there is a unique therapeutic window opportunity following stroke to preserve cognition. Treatment of post-stroke CDs to prevent dementia is the second critical priority for clinical care and research. Secondary prevention of vascular or metabolic risk factors may contribute to delayed occurrence of post-stroke CDs but is insufficient due to lack of patient adherence and lack of global disease-modifying strategies, targeting more specific pathways.
In this context, we can highlight several results:
- Development of a murine model with long-term occurrence of memory impairment (novel object recognition, Morris water maze) six months after the induction of cerebral ischaemia through transient occlusion of middle cerebral artery. These cognitive disorders are associated with changes in surface hippocampal neurons (Delattre et al, 2017);
- Generation of novel data on clinical modelling of stroke-associated CDs. Firstly, pre-stroke CDs were observed to be associated with either vascular or degenerative markers (Aβ1-40 and Aβ1-42) suggesting a vascular and degenerative origin (Moulin et al, 2017). Secondly, the profile of stroke patients mostly likely to develop CI has been identify locally and in collaboration with the Munich teams (Moulin et al, 2016 ; Zietemann et al, submitted)
- The analysis of animal model and the STROKEDEM cohort have demonstrated by multimodal use of imaging, the role of hippocampal deformations and brain disconnectivity in occurrence of cognitive impairments, with identification of a brain network dysfunction in all patients with post-stroke CDs (Delattre et al, 2017 ; Bournonville et al, in press). VasCog funded Project
Diabetes-associated cognitive disorders
Relationship between metabolic (glucose or lipid related) and cognitive disorders is recognized but not well understood. The FHU VasCog has supported several projects to investigate glucose-related disorders’ impact on cognition:
- Investigation of the Insulin resistance observed in patient with Alzheimer disease (AD) has deciphered a new pathophysiologic pathway of AD involving a new role for the TAU protein (Marciniak et al., 2017). Indeed, Tau deletion was found to induce hippocampal resistance to insulin with loss of neuronal plasticity and memory impairments due to impaired inhibition of the insulin-pathway inhibitor PTEN. Interestingly, the hypothalamic anorexigenic effect of insulin was also observed inducing possible effects on the peripheral metabolic disorders. Tau loss of functions in AD could initiate and amplify a detrimental vicious circle linking peripheral metabolic deregulation and AD lesion developments. VasCog funded Project
- A new model of metabolic related cognitive syndrome in mice fed with High Fat Diet (HFD) regimen (12 months) was also developed and characterized at 3, 6, 9 and 12 months. This HFD regimen induced metabolic changes (fat accumulation in different body region, hypercholesterolemia, glucose intolerance…). At 6, 9 and 12 months, these mice developed progressively a cognitive impairment that was related to a dysfunction in the neurovascular unit (Petrault et al, in preparation). VasCog funded Project
Four clinically oriented research projects exploring the clinical impact and possible management of diabetes and cognitive disorders have also been explored. These projects are described in the healthcare part of the project.
Silent brain lesion-associated cognitive disorders
Cerebral microbleeds (CMBs) contributions to cognitive impairments in the general population and in patients with dementia are at the moment unknown. To further investigate this impact of silent CMBs on cognitive functions, we have developed two robust models of micro haemorrhages:
- A first unique cortical micro-haemorrhage (CMH) mouse model was obtained consistently by stereotactical administration of collagenase in C57B6/J mice, inducing brain cortical lesions observed at 24h by MRI. 6 weeks post-lesion assessment of CMH mice showed impaired brain regional metabolism and cognitive declines that could be significantly modulated by pharmaceutical drugs (Bergeron et al, 2018).
- The second model of CMBs consists in disseminated brain micro-haemorrhages induced by systemic administration of microparticles (cyclodextrines). The brain microbleeds obtained seemed innocuous on brain cells and on cognitive functions at 7 days but will be investigated for 12 months to assess their long-term cognitive impacts. VasCog funded Projects
Clinical investigations are related to those more basic projects and will be further developed later in the report (re-start and 3ICH trials, Pr Cordonnier meta-analyses: Charidimou A et al. Neurology, 2017 and Stroke, 2017).