Despite recent advances in basic and clinical science, dementia remains an area of high unmet medical need. The role of cerebrovascular mechanisms in the pathogenesis and progression of cognitive and functional impairment in dementia is being revived. In order to facilitate the development of therapeutic approaches, it is critical that a number of fundamental elements are integrated into research strategies investigating cerebrovascular pathologies as these will maximize the opportunity of bringing medicines to patients in a timely manner.
The goal of the pharmaceutical industry is to provide medicines with direct clinical utility to patients and wider value to caregivers and healthcare systems. To do this, there are two fundamental elements that require an integrated approach to facilitate the development of medicines: a deep understanding of the disease phenotype and trajectories coupled with a deep understanding of causative biological mechanisms. Together, knowledge of these areas will enable the generation of high confidence targets with robust human rationale. Gaps in these areas can introduce significant risks into drug development programs that can lead to delays, potential safety concerns, lack of efficacy and ultimately loss of confidence in prosecuting the science.
Although cerebrovascular disease (CVD) is a fundamental component of vascular dementia (VaD), vascular/post-stroke cognitive impairment (VCI/PSCI), it is also believed to be a significant contributor to onset and progression of the dementias inclusive of Alzheimer's disease (AD) [1,2]. The clinicopathological presentation of CVD is complex and heterogeneous affecting both large and small cerebral vessels with consequent impact on the presentation of cognitive impairment, its progression and overall quality of life (e.g. disability, depression, apathy and behavioural changes) . Given the high global prevalence of CVD-associated cognitive impairment and the lack of treatment options, there is a clear unmet need for therapies targeting vascular mechanisms that precipitate such neurodegenerative diseases.
It is important that further clinical trials in this area take learnings not only from the previously unsuccessful efforts to demonstrate efficacy in VaD or mixed AD-VaD populations (reviewed in [3,4]) but also from the revised clinical trial designs for AD . These include using the proposed mechanism to guide patient enrichment strategies, obtaining early evidence of target engagement (TE), improved dose selection criteria and the use of appropriate cognitive tests. Where these have been recently applied in AD + CVD  and AD  trials, there is encouraging evidence with respect to both mechanism and clinical outcomes.
Key areas of focus
There are a number of critical areas of basic, translational and clinical research that will be critical in the evolution of this area and these are summarized in Figure 1. Fundamental to progress is the need for prospective natural history studies that are inclusive of CVD, whether accompanying a clinical diagnosis of VaD/VCI/PSCI or AD. These will permit the large-scale application of neuroimaging techniques (e.g. MRI, amyloid/tau/FDG–PET) and CSF biomarkers, and help drive standardization of these techniques together with identifying appropriate clinical outcome measures (i.e. cognitive and functional endpoints) for efficacy trials and in the longer term with the identification of surrogate endpoints to enable earlier decision making. Mapping out the longitudinal trajectories of disease will also be important in identifying the potential opportunities for therapeutic intervention, particularly if stages can be identified where there are significant changes in functional target expression and/or a neuroimaging/biomarker feature. Robust quantitative knowledge will also enable more efficient clinical trial designs that can power studies appropriately and may also lead to application of small, experimental medicine (EM) studies early in development programs to probe mechanism and exploratory outcome measures. Coordination of these activities is an area of strategic importance as it will facilitate innovation, replication (through multi-centre approaches) and validation, as well as harmonization of methods. This will require investment in both people and infrastructure but will ultimately increase overall confidence in the mechanisms and clinical science associated with CVD.
Schematic representation of industry needs to facilitate drug development in VaD/VCI
It is likely that the CVD-enriched patient groups studied with this type of approach will be closer to the community-based dementia populations in which the clinical effectiveness of anti-dementia drugs, once launched, will eventually be assessed [8,9]. Therefore, its study will also permit the collection and assessment of ‘real-world’ evidence and digital outcome measures (e.g. electronic diaries, remote cognitive assessments and biosensors), which will be of wider benefit to pharma, patients and payors. Finally, well-defined cohorts of homogeneous CVD patients will enable ‘at scale’ genetics studies and the identification of novel targets/pathways and, together with extensively curated biobanksamples (e.g. CSF, plasma and post-mortem tissues), the identification of candidate biomarkers of disease state and progression. Thus, a fully inclusive approach embracing mechanisms of CVD in dementia as well as opportunities for personalized medicine will ultimately permit a change in the landscape of current treatment options.
Translational science, including the appropriate use of relevant animal models, is also an essential component providing connectivity between target-mechanisms/pharmacological response/patient populations . Given the elementary and relevant differences between rodent and human brains (e.g. relative white matter abundance and arterial dimensions), it is perhaps inevitable that there is the potential for translational gaps . It is important that the field continues to refine and develop models that reflect an increased understanding of the neurovascular unit and the clinicopathology of CVD. Exchange of models and/or tissue samples to validate models together with the development of robust translation pharmacology packages to support interventional studies will improve confidence in this area. In particular for the latter point, demonstration of drug exposure/TE at the site of action and a downstream pharmacological response should become a gold standard for these types of studies. Translation, therefore, needs to be driven by findings from human biology as the starting point that further underpins the need to understand the patient, their genotypic–phenotypic attributes and apparent sensitivities of mechanisms and markers that contribute to patient presentation and their cognitive and functional decline. Investment of resource in this area will enable the longer term viability of the strategy by increasing the probability of success at each development stage and therefore provide increased confidence of investing in the development of novel therapeutics.
Working across boundaries
In order to maximize the probability of success, a multi-disciplinary approach is therefore encouraged that cuts across both the private and public sectors connecting industry not only with basic research and neurology but also with wider scientific disciplines such as neuropathology, radiology, cardiology and imaging science. The approach taken by the MRC Dementia Platform UK (DPUK) Vascular Disease Mechanisms Experimental Theme serves as a pragmatic example that brings together in a pre-competitive environment a wide range of disciplines, including basic and translational researchers, stem cell specialists, clinicians, imaging specialists and industry representatives (DPUK Vascular Disease Mechanisms, http://www.dementiasplatform.uk/research/experimental-medicine/; accessed November 2016). The aim of this group is to “harmonize basic science, translational and clinical approaches that includes the integration of a deeper understanding of the contribution of peripheral and central vascular disease mechanisms in diverse dementia populations” and contribute to the advancement of disease understanding. It is also recognized that there are multiple complementary efforts initiating in this area (SVDs@target: A new Horizon 2020 project, http://www.svds-at-target.eu/; accessed November 2016)  and together with the introduction of integrated funding mechanisms (e.g. Stroke Association, British Heart Foundation and Alzheimer's Society) these will serve to bring together basic and clinical science with industrial partners, to further catalyse and accelerate this area of high unmet medical need. Future research opportunities with the recently established MRC Dementia Research Institute may also provide an important focus for multi-disciplinary collaboration.
In conclusion, a reappreciation of the importance of CVD in dementia together with the emergence of tools to finely map vascular pathologies and increasingly integrated nodes of pre-competitive research presents a significant opportunity to identify druggable targets and pathways. Given the potential for multiple pathways to be involved in CVD, consideration should also be given early in clinical programs to the development of combination therapies. A refined understanding of the different CVD populations will also enable an efficient pharmacological examination of these pathways leading to a sustainable investigational pipeline of treatment options for this important disease area.
The authors declare that there are no competing interests associated with the manuscript.
- CSF, cerebrospinal fluid; CVD
Mechanism of Action
Medical Research Council
magnetic resonance imaging
positron emission tomography
post-stroke cognitive impairment
vascular cognitive impairment