2016 call for projects

2016 call for projects

RESISTAU project- What is role of the Tau protein role on the Insulin resistance of the central nervous centre?

Dr David BLUM (JPARC UMR-S-1172)

Results summary

Brain of patients with Alzheimer disease (AD) present a brain resistance to insulin which participates, by hippocampal alterations, to the synaptic/cognitive disorders and brain lesion developments. In addition, it also creates by hypothalamic effects, to peripheral metabolic disorders for the AD patients. The underlying molecular mechanisms are mostly unknown.

Thanks to the RESISTAU project, we have demonstrated that the Tau protein is a key element of the brain response to insulin. We have highlighted by electrophysiological and biochemical analyses, that the Tau deletion in a mouse model, induced a hippocampal resistance to insulin’s effects. The underlying mechanism goes through the inhibition of the IRS-1 protein, which impacts the upstream insulin fixation to it receptor. This inhibition is controlled by the lipid phosphatase PTEN enzyme which function is to down-regulated the insulin signaling pathway and is normally controlled negatively by the Tau protein. In case of Tau deletion, the mice can’t suppress PTEN and therefore, exhibits a brain insulin resistance.

Interestingly, Tau loss is also responsible for an inhibition of the insulin anorexigenic effects by hypothalamic regulation, inducing some peripheral metabolic disorders, such as alteration of the glucose tolerance.

In relation with our experimental data from the animal models, our genetic analyses indicate in Human, an association between the Tau haplotypes and the glucose homeostasis. Our results demonstrate for the first time that the Tau protein is a major actor in the nervous centre response to insulin. This suggests that a function loss of Tau observed in the Alzheimer disease or in Tauopathies can be an instrument of the insulin resistance development in the Central nervous system observed in neurodegenerative diseases.

Publications and communications

This work has been published in the Journal of Experimental Medicine (Impact factor: 12) and two review papers are currently prepared. Several communications have been made in scientific congress (Vienna, Austria; Washington, USA; Bonn, Switzerland) as well as in communications towards the general audience (Press release by the CHRU Lille, Inserm, Eurasanté, La Voix du Nord, France Alzheimer, Sciences et Vie…)

Prevalency of cognitive disorders in diabetes patients treated into tertiary centres

Pr Anne Vambergue (endocrinology department, CHRU Lille)

Introduction

Diabetes is associated with diverse cognitive alterations: subtle cognitive decline with slow risk of evolution, light cognitive disorder with a risk of progression toward dementia, and dementia related to cerebro-vascular physiopathologies or Alzheimer type neurodegenerative pathologies. Some factors can worsen the cognitive functions of diabetes patients and cognitive disorders are themselves factors of a worse diagnosis for diabetes. Therefore, detection of cognitive disorders (CD) in patients with diabetes is of great importance in clinical practice however, CD frequency associated to diabetes is not known.

Objective

Based on a systematic screening, to determine the frequency, the severity and the etiology of cognitive disorders for patients with diabetes treated in the diabetology department of the CHRU Lille.

Patients and methodes

Patients :

All patients with diabetes over 50 years-old hospitalized in the diabetology department.

Methodes :

It has been systematically performed a global evaluation of the patients’ cognitive function using the MOCA test (Montréal Cognitive Assessment) performed by a trained neuropsychologist. An under 25 point MOCA score is pointing cognitive dysfunctions and the patient is therefore refereed to the Memory Clinic for definition of the CD etiology and treatment. This study has been performed by three multidisciplinary teams working in complementarity. The study has been authorized by the ethic committee in October 2015 and conducted in 2016.

Results

Thirty five percent of the 191 tested patients had cognitive impairment with a MOCA score < 26 points. Those patients were significantly older, had retinopathy and neuropathy, had more history of stroke, and amputation for diabetic foot wounds (article under submission). Hence, with this clinical study, we demonstrate (i) a high prevalence of cognitive disorder in diabetes patients, and (ii) we targeted a population at high risk of cognitive impairment. These results had immediate repercussions in the care and management of these diabetes patients since they help clinicians to early detect cognitive disorder proposing a systematic testing of cognition, and to correctly adapt the anti-diabetic therapies in this population at high risk of poor glycemic control, increased hospitalizations and severe hypoglycaemic episodes. Moreover, this collaboration will lead to a second cohort of diabetic patients, in order to characterize the pathophysiological pathway of cognitive disorders in this population, using a multimodal approach based on cognitive evaluation, biological sampling, imaging, high resolution EEG and biomarkers for neurodegenerative diseases.

Following actions

Consecutively to the highlighted MOCA score < 26, diabetic patients included in this study with a cognitive disorder were referred to the memory clinic. More than one third of them did not come to the memory consultation. The possible reasons are the severity of cognitive disorders, the old age, the numerous medical visits of these patients with many co-morbidities, and insufficient information on the objectives of a cognitive evaluation at the memory clinic. We are therefore considering (i) an advanced memory consultation (with a neurologist and a neuropsychologist) in the Diabetes Department, (ii) to provide more information to patients using leaflets, therapeutic education program, web site and animations for the general public….

The year following this study (2017), diabetic patients referred by diabetologists to the memory clinic decreased. This finding leads to the urgent need to consider cognitive disorders as a diabetes complication, as micro and macro-angiopathy. This implies that cognitive decline has to be screen in diabetes consultation, and therefore that diabetologists and general practitioner have to be educated on this complication and the tools to detect it. A training course program was organized (AUEC VasCog) that will begin at Lille University in 2018.

Validation in French of the Montreal Cognitive Assessment (MoCA) phone test

Pr Kathy Dujardin (Neuropsychologist, University Lille Hospital, Inserm UMR1171, Lille University) assessment by phone test (MOCATEL)

Context

Prevalence of cognitive impairments and dementia is very high in elderly people as nowadays 47.5 million persons suffer from dementia, according to the world Health organization. This amount is estimated to increase to 75.6 million by year 2030. Moreover, around 16% of non-dement person still have some mild cognitive impairments (which increase the risk of dementia) with an increased incidence with ageing.

Cognitive impairments are the most frequent symptoms of neurodegenerative diseases and a frequent after-effect of neurovascular pathologies. After a neurovascular stroke, one over ten patients show signs of dementia and the ratio rise to one over three patients after a stroke relapse. The impact on society is very high due to the loss of autonomy for the patient. It is the major cause of admission within specialized institutions.

Objectives

One of the objectives of the FHU Project is to prevent the establishment and/or the worsening of the cognitive decline by acting on the metabolic and vascular risk factors using innovative therapeutic strategies. Those factors (diabetes, hypertension, dyslipidaemia, obesity…) are known to influence negatively the cognitive trajectory of a patient. In patients exhibiting such factors, those cognitive impairments are present many years before the diagnosis of cognitive disorder but are not detected due to lack of tools to allow a quick and efficient screening on a large scale. Such early detection would allow the set-up of preventive and therapeutic measures avoiding or slowing down the evolution toward dementia.

The objective of the MOCATEL project is to validate in French, a screening scale of cognitive impairments with satisfactory psychometric quality and administrable by Phone in 5 minutes. Once validated, this scale would eventually be used for diabetic patient follow-up (using for example, the SOPHIA system, French health insurance service for follow up of patient with chronic disease).

Methods

120 subjects, without any neurologic, psychiatric, metabolic or heart diseases have been recruited from 5 age class and 4 socio-cultural background to participate to the test. Three groups of 40 patients suffering from motor and cognitive diseases, Alzheimer disease and diabetes were also recruited. The complete MoCa test and the 5minutes Moca test are administrated to all subjects in a counterbalanced way. Data analyses will determine the internal and external validity, inter-examiner fidelity, test-rest fidelity, sensibility and specificity of the 5min-MoCa test.

Project progresses

The trial protocol has been validated by the patient protection committee in April 2017 and the trial was started in July 2017. The “pathologic group” patients have been recruited and tested. The recruitment of healthy subjects is on-going.

Neurovascular exploration of the cognitive decline induced by metabolic syndrome in the murine model

Project of Dr Michèle Bastide (lecturer, UMR-S-1171)

Context and Objectives

Metabolic syndrome is a cluster of physiologic conditions that will foster cardiovascular diseases and could also induce a cognitive decline according some recent epidemiologic investigations. This relationship could be particularly significant and deleterious when the vascular risk factors are present during midlife (around 45-55 years).

How the vascular risk factors can impact the brain and increase the risk of developing a cognitive decline?

What are the possible mechanisms, knowing that metabolic alterations are progressive and insidious?

To answer those questions, we have developed a preclinical mouse model of metabolic syndrome induced by a fat enriched diet. The mice are followed up for 12 months allowing the slow set-up of metabolic disorders. The establishment of a metabolic syndrome has been validated and the consequences on the cognitive function have been characterized showing a significant impairment of the mice episodic memory. Those initial results validated the preclinical model and allow us to explore further the anatomic and functional impact of the metabolic syndrome at different age from 0 to 12 months.

Three parameters will be investigated to analyze brain modifications induce by the metabolic syndrome:

  • Impact on the cerebral blood vessel is not yet well understood: ex-vivo analyzes on isolated pial arteries (Halpern arteriograph) and on microvessels are planned using a novel analysis technic on brain slice;
  • Impact on brain structures will also be investigated in vivo using MRI: analyze the anatomic modification of brain zone involved in memory functions (T2), the neuroglia tissue light modifications (ADC) and integrity of the blood barrier (D*);
  • Identification of biomarkers of metabolic induced brain damage: After culling, mice brains will be harvested and used 1) for immunohistochemical analyses on slices to check the neuron integrity, synaptic plasticity, neuronal and/or vascular inflammation, 2) for proteomic analyses on slides to identify protein or lipid modifications in region of interest.

By cross-analyzing those results, we should be able to highlight the long-term cerebral-vascular damage induced by the metabolic syndrome and their role in the onset of the cognitive decline while identifying novel biomarkers that will be used when testing drug modulations. Those results will also consist on a useful database to correlate with the clinical investigations initiated in the Lille hospital on a cohort of patients with diabetes which seems to present a large portion of subjects with cognitive impairments. They will also help to set up new clinical cohorts to test mechanistic hypotheses

Results

A preclinical model has been successfully developed to investigate the impact of several metabolism impairments on the onset of cognitive decline. Mice fed with high fat diet have been monitored for 12 months with evaluation points at 3, 6, 9, 12 months and compared with mice fed with normal diet. Metabolic profile (hypercholesterolemia, visceral adipose tissue, steatosis, glucose intolerance) and cognitive profile (visual recognition memory loss) have been characterized.