Introduction, Background, Objectives and Expected results
1. The burden of cognitive impairment is important and will increase in the future
The prevalence of cognitive impairment will double over the next 25 years, because of the increased life expectancy. This is mainly explained by an increased prevalence of both Alzheimer and vascular pathologies in ageing brains. This “tsunami” will have consequences on all medical specialties, because many frequent and apparently unrelated disorders, such as hip fractures, cardiac failure, renal failure, have a time-course that is highly influenced by the presence of cognitive impairment. Beyond medical aspects, the consequences will be major for families, society and health care expenditures due to dependency.
2. Stroke lesions lead to an anticipation of the clinical onset of degenerative cognitive impairment
The association of stroke and dementia is frequent and can be seen either in the diagnostic work-up of patients attending a memory clinic, or during the follow-up of stroke patients. Both ischemic and hemorrhagic strokes lead to a high risk of cognitive impairment and dementia. About one in ten patients have dementia before their first stroke, one in ten develops new dementia after their first stroke and more than one in three develops dementia after a recurrent stroke.
The clinical onset of cognitive impairment of degenerative origin, may be anticipated by stroke lesions or postponed by an effective stroke prevention. The hypothesis that a brain infarct or a brain haemorrhage that cannot induce dementiaby its own, may lead to an anticipation of the clinical onset of Alzheimer’s disease (AD) when it occurs in a patient who is at a preclinical stage of AD, has never been challenged during the last 18 years. It has even been reinforced by neuro-pathological studies, showing that, for the same burden of Alzheimer lesions of the brain, patients with infarcts or haemorrhages have a more severe cognitive impairment, and by a trial showing that the treatment of systolic hypertension in the elderly decreases the incidence of dementia in general, including risk of AD.
As vascular causes of cognitive impairment are common, and often preventable, patients could benefit from early detection of risk factors and therapy, and an accurate diagnosis of vascular cognitive impairment and VaD is therefore a challenge. We should also bear in mind that post stroke dementia is just the tip of the iceberg, and accounts for a small part of the cognitive consequences of stroke, as most of these consequences are represented by cognitive-impairment without dementia.
3. Vascular risk factors may also influence the time-course of degenerative cognitive impairment in the absence of stroke
Even in the absence of stroke, vascular risk factors and cognitive disorders are related. These factors can be of endothelial origin (e.g. arterial hypertension, sleep apnoea syndrome, cardiac surgery), metabolic (e.g. diabetes, dyslipidaemia, metabolic syndrome, hyperhomocysteinaemia), environmental (e.g. tobacco smoking, other toxic agents) or of other origin such as inflammation (e.g. infection, sepsis) or hyperphosphorylation of Tau proteins induced by anaesthetic agents. All these factors can lead to the anticipation of the clinical onset of a so-called “silent” degenerative process leading to cognitive impairment and, at the latest stage, dementia.
4. Vascular risk factors potential targets for the prevention of cognitive impairment
Vascular risk factors are therefore potential targets for the prevention of cognitive impairment, irrespective of its mechanism, vascular, degenerative or mixed. Their optimal management should theoretically prevent cognitive impairment in patients with silent Alzheimer of vascular lesions of the brain. This hypothesis is strongly supported by two independent population-based studies in the United Kingdom and in Denmark, showing that – after adjustment on confounders – cognitive decline was more severe in cohorts collected years ago than in more recent ones. The most likely explanation is that vascular risk factors are better treated nowadays.
Several randomised controlled trials indicate that antihypertensive treatment can prevent the occurrence of dementia, especially of AD type, in hypertensive patients aged 60 years or more and a recent metaanalysis supports the beneficial impact of statins to prevent dementia occurrence and memory loss. An observational study from our group, including 233 patients with AD, followed-up on average for 4 years, showed that the annual decline in MMS was smaller in patients in whom all vascular risk factors were treated, compared with the other (1.5 points + 2.5 points, versus 2.5 points + 2 points, p< 0.04). In addition, vascular and metabolic risk factors have also been reported to have a negative influence on the response to symptomatic and disease-modifier treatments in AD, explaining that they should be integrated in the design of clinical trial to optimize the efficacy of treatment.
5. How can vascular risk factors interfere with cognitive impairment?
The interactions between vascular or metabolic factors and cognitive disorders represent an opportunity to better understand the pathophysiological processes beyond the amyloid and tau cascades, because vascular, metabolic, inflammatory and oxidative mechanisms are involved in Alzheimer’s disease (AD). Vascular and metabolic risk factors may induce cognitive impairment via several mechanisms:
(i) symptomatic brain lesions (brain infarcts and haemorrhages).
(ii) silent lesions of vascular origin of the brain (leucoaraiosis, microbleeds, silent infarcts, silent haemorrhages, secondary atrophy); these brain lesions of vascular origin may be severe enough to induce cognitive impairment in the absence of any other additional pathology, but they may also be less severe and just contribute to the lesion burden in patients at a preclinical stage of Alzheimer’s disease.
(iii) direct effect of vascular risk factors on cognitive functions, as demonstrated for hyperglycaemia, associated with disturbances of long-term potentiation, the neurobiological basis of learning and memory processes.
(iv) interaction with the specific pathophysiology of neurodegenerative pathways (amyloid or tau cascades), as vascular or metabolic factors modulate the amyloid or tau cascades associated with AD.
(v) a direct effect on neurodegenerative process, in particular hippocampal atrophy. Cognitive decline is related to hippocampal atrophy that is underlain by toxic effect of amyloid peptide. Nevertheless, other factors could have a deleterious effect on hippocampus, with an acceleration of atrophy: our group has shown that a vascular injury in cortex and striatum leads to a long-term hippocampal atrophy, in relation with a decrease in BDNF expression (unpublished data). Arterial hypertension, and hyperglycaemia are also associated with hippocampal atrophy. The evolution of hippocampal atrophy related to vascular, inflammation or metabolic factors could be an interesting way to better understand the influence of these co-morbidities on the evolution of AD-related cognitive decline.
A better knowledge of the role of vascular and metabolic risk factors in the pathogenesis of cognitive disorders, the identification of predictors of outcome and the development of new therapeutic strategies (including drugs, nutrition and physical activity) can lead to a true prevention of diseases known to prominently of degenerative origin.
To explore the preclinical and clinical aspects of this scientific question, we focus on: (i) the characterization of the role of these vascular factors, and their mechanisms of action, by clinical, imaging, and biological means, in cohorts of patients with either mild cognitive impairment (MCI) or acute stroke; (ii) the assessment of animal models that reproduce relevant clinical situation of co-morbidities; and (iii) phase2/phase3 clinical trials that integrate these co-morbities in the protocol design.
Over a 5-year project, we will study aged people with vascular, metabolic and inflammatory disorders as well as patients with cognitive impairment. The Vascog project therefore challenges the need for a transdisciplinary and multi-modal approach. The objectives of the Vascog project are to identify:
- The interaction of vascular factors with genetics, lifestyle and sex differences, sustaining different aging pathologies and their relationship.
- How vascular and metabolic determinants will trigger cognitive disorders with or without interaction with degenerative process.
- Biomarkers that can parallel the evaluation in animal and human models of vascular and metabolic factors on cognitive functioning. These novel biomarkers of brain and cognitive dysfunction as well as cellular and molecular alterations will consist in biological, electrophysiological and psychophysiological tools, morphological imaging as well as functional neuroimaging and quantitative post-mortem analysis.
- The positive and if possible the negative predictive value of the co-morbidity “MATRIX” using linear and non-linear (artificial neural networks) biomathematics and modelling.
- New pharmacological and therapeutic paradigms to treat vascular and metabolic-related cognitive disorders in both symptomatic and disease-modifying strategies as well to test influence of cognitive disorder on the effect of drugs used to treat vascular and metabolic risk factors.
A key asset of Vascog is to understand pathological brain and altered cognition in aging. Through the multidisciplinary and translation approach of the project and the share of the specific expertise research units and hospital departments that have already an international positioning, Vascog project should contribute to place Lille as the reference centre in the field.
We will determine whether the early management of vascular and metabolic risk factors (arterial hypertension, diabetes mellitus, smoking etc), or cardiac disorders (atrial fibrillation, cardiac failure), or vascular lesions of the brain (potentially “silent”) decreases the burden for the society of cognitive impairments.
The constitutive teams have already experiences
- in clinical, biological, imaging and genetic cohorts to determine the phenotype of patients, and to identify clinical features that will be tested in animals in a translational research,
- in the multimodal evaluation of cognitive functions (clinical scales, automatic paradigms, neuro-physiological explorations, morphologic and functional MRI, spectro MRI, metabolic imaging),
- the understanding of the basic components of neurodevelopment and neurodegeneration, tobetter identify potential therapeutic targets.
Health care organisation
The early identification of cognitive disorders that may negatively interfere with the management of chronic disorders (arterial hypertension, diabetes mellitus, Parkinson’s disease, cardiac failure, atrial fibrillation etc) will stress the need for a better organisation of health care. The management of these patients will target both minimising the symptoms and modifying the time-course of the degenerative process.
The education program will inform health providers on the links between vascular and metabolic factors and cognitive impairment, increase the knowledge on this relationship and attract future researchers in this field. The most important expected result is to disseminate this knowledge in the medical community, to favour the emergence of abilities in social sciences, and initiate new training programs useful for the need of the industry.
Valorisation and industry partners
This project will reinforce the links with the industry partners via:
- the investigation networks, with an emphasis on the design and involvement in trials testing the impact of lifestyle changes or drugs to prevent cognitive disorders in the context of vascular and metabolic risk factors,
- the development of new tools and software to identify patients presenting cognitive disorders associated with vascular and metabolic disorders to adapt public health policy in this field (ANR grant, Alicante and INRIA),
- the development of new therapeutic approaches, and prevention with nutrition, physical activity, and drugs, in collaboration of the “Compétitivité Nutrition Santé Longévité” pole and local enterprises of biotechnology.