Towards the concept of disease-modifier in post-stroke or vascular cognitive impairment: a consensus report

Abstract

Background: Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier.

Consensus and suggestions: Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied.

Conclusion: A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.

Keywords: Clinical trial; Disease-modifying therapy; Multimodal approach; Post-stroke cognitive impairment; Vascular cognitive impairment; Vascular dementia.

Fig. 1

The crossroad of cognitive disorders. Cognitive disorders may be related to vascular or degenerative processes, or both in the mixed form. Vascular risk factors influence both vascular- and degenerative-related cognitive impairment, but also have a direct impact on cognitive functions

Fig. 2

Interactions between pre- and post-stroke cognitive disorders and dementia. Pre-stroke dementia may be related to vascular or degenerative processes, indicating that cognitive impairment after a stroke can be associated with a pure vascular mechanism or a mixed process. Stroke induces regional atrophy through neuronal death directly related to the vascular lesion, or indirectly to the Alzheimer’s disease (AD)-related pathway

Fig. 3

Pathophysiological mechanisms of interactions between vascular and degenerative processes in both vascular and mixed dementia (Adapted from [40]). MTL medial temporal lobe. The figure integrates an image of western blot (tau expression after middle cerebral artery occlusion in mice) and immunohistochemistry (amyloid peptide expression after middle cerebral artery occlusion in rat)

Fig. 4

Cellular and molecular mechanisms of vascular dementia and post-stroke cognitive disorders: presentation of all pathways involved in the neurovascular unit and their contribution to vascular impairment and neuronal injury responsible for occurrence and progression of cognitive decline. Aβ beta-amyloid

Fig. 5

Early phases of strategy development through a matrix approach using a biomarker battery. The aim of this process is to reinforce the rationale of Go/No Go decision before the translation to phase 3. For each animal or clinical study, the effect level should be determined and integrated into a matrix model in order to properly assess the relevance of the tested strategy

Fig. 6

Multiple biomarkers for patient clustering within the spectrum of vascular dementia. Clinical, biological, functional, and lesion biomarkers should be integrated in an algorithm to identify relevant and homogenous patient clusters, with a view to a more accurate predictive diagnosis and stratification for inclusion in clinical trials. fMRI functional magnetic resonance imaging, DTI diffusion tensor imaging, EEG electroencephalography