The Alcohol Use Disorder (AUD) research topic focuses on the effects of chronic and heavy alcohol consumption on brain and cognition. We are one of the few laboratories to investigate Korsakoff syndrome (KS), especially with neuroimaging techniques.

Our goal is twofold :

1 – To deepen our fundamental understanding of the pathophysiological mechanisms leading to alcohol-related cognitive deficits and brain abnormalities :

• Role of alcohol withdrawal, nutritional alterations, sleep disorders and liver dysfunction
• Temporal cascade of the different brain pathophysiological mechanisms leading to specific cognitive deficits
• Interaction between ageing and alcohol consumption
• Similarities and differences between AUD patients with and without KS

2 – To improve the clinical treatment of AUD patients with and without KS :

• Modifications of healthcare pathway or development of innovative treatment options for AUD patients with neuropsychological deficits
• Detection of AUD patients at risk to develop KS

We mainly use psychological, neuropsychological, biological, sleep and neuroimaging (structural MRI, DTI, resting-state fMRI, FDG-PET) examinations.

We are also engaged in the development of new methods to better evaluate the effects of AUD and we recently set-up a biobank (COBIOM) to prospectively collect blood of AUD patients at treatment entry.

Behavioral and Psychological Symptoms of Dementia (BPSD), also called neuropsychiatric symptoms (NPS) are highly common in the course of neurodegenerative diseases. They include a wide range of symptoms, such as agitation, aggression, impulsivity, delusions, hallucinations, depression, anxiety, apathy, deshinibition, loss of empathy, perseverations, compulsions, sleep and appetite disorders.

BPSD affect various neurodegenerative disease, such as Alzheimer’s disease, Lewy body demantia, fronto-temporal dementia, and vascular dementia. They are  associated with worst cognitive and functional prognosis, and with higher patient and caregiver distress.

The Behavioral and Psychological Symptoms of Dementia research topic aims at understanding the brain mechanisms underlying Behavioral and Psychological Symptoms of neurodegenerative diseases.

To this aim, we use multimodal neuroimaging, blood and cerebrospinal fluid biomarkers in combinaison with clinical, cognitive, sleep and behavioral assessments, to investigate the pathophysiological mechanisms underlying BPSD.

There is an increasing emphasis on development and use of blood-based biomarkers :

• for diagnosis and prediction of dementia
• to identify underlying pathophysiological mechanisms
• to serve as intermediate outcome measures to monitor response to interventions

IMAP+ and Age-Well offers a unique set of complementary assessments including blood-based markers (general health, emotions, stress, ageing and Alzheimer’s disease) but also detailed cognitive, lifestyle, and neuroimaging measures. The combination of these databases and multimodal analyses give us the opportunity to better understand the role and relevance of blood-based biomarkers in the context of ageing and dementia and to calculate specific composite measures that appear as particularly promising. This is the case for the allostatic load (AL) aims to capture the overall physiological wear-and-tear of the body triggered by the repeated activation of compensatory physiological mechanisms as a response to life-long stress.

We are particularly interested in :

• understanding the role of blood-based biomarkers as risk factors for dementia and in particular in Alzheimer’s disease as illustrated by the figure below

Voxel-wise association between glycemia and neuroimaging (A) and overlap of the glycemia-related changes and Alzheimer’s disease-related alterations (B) for structural MRI, FDG-PET, and amyloid-PET in cognitively unimpaired adults (Palix et al., Neurobiology of Aging, 2022)

• understanding the biological mechanisms by which lifestyle and psychoaffective factors impact brain health from normal ageing to dementia
• evaluating the impact of mental training on the blood-based markers and the specific links highlighted

There is growing evidence in the literature that we could modify the course of neurodegenerative diseases, and brain and mental health in general, by modifying our lifestyle. A recent review suggests that ~40% of Alzheimer’s disease cases could be prevented by acting on modifiable risk factors, including lifestyle factors (Livingston et al., Lancet, 2020). The Lifestyle factors in ageing and Alzheimer’s disease research topic aims at understanding the brain mechanisms underlying the effects of lifestyle factors from normal ageing to Alzheimer’s disease dementia.

To this aim we use multimodal neuroimaging – structural MRI, functional MRI, FDG and amyloid-PET – in combination with lifestyle assessments – cognitive, physical, social engagement and diet.

We are especially interested in (i) understanding the brain mechanisms of reserve across disease stages, (ii) assessing the combined/relative effects of lifestyle factors on neuroimaging measurements (iii) identifying critical windows of time where exposure to positive lifestyle factors may have a greater impact and (iv) assessing the interaction between lifestyle factors and other nonmodifiable risk factors, including sex and genetics.

We aim at better identifying the factors that could promote healthy ageing and prevent or delay Alzheimer’s disease and dementia in general. Notably, we are coordinating a large European project (www.medit-ageing.eu) assessing the effects of meditation training both in a population of expert meditators and in cognitively unimpaired elderly who were proposed an original 18-month meditation program. Multiple complementary neuroimaging techniques are used to assess the impact on brain health but also the underlying mechanisms.

Mood, anxiety, and stress-related disorders are the most prevalent psychiatric conditions, affecting millions worldwide. They cause significant distress and impairment, and are a leading cause of suicide attempts and completed suicides.

Our program of research specifically focuses on discovering the fundamental causes of mood, anxiety, and stress-related disorders in humans in order to develop and implement new, more effective treatment strategies, including using pharmacotherapy, neurostimulation, and psychotherapeutic approaches.

The medial temporal lobe (MTL) is one of the most studied brain regions because of its involvement in a myriad of cognitive processes and its sensitivity to ageing, neurological and psychiatric diseases. Importantly, MTL subregions – including hippocampal subfields – are differentially i) affected in different conditions (eg normal ageing vs Alzheimer’s disease) and ii) involved in cognitive functions. Thus, we aim at providing a granular description of the alterations and functioning of the MTL and its subregions using advanced multimodal imaging techniques. More precisely, we investigate two specific topics:

Structural imaging : In 2010, we developed an ultra-high resolution MRI sequence together with a manual segmentation protocol to precisely estimate hippocampal subfields volumes. We then improved our sequence and now use Automatic Segmentation of Hippocampal Subfields (ASHS). In addition, we use a surface-based approach based on voxelwise analyses coupled with 3D hippocampal surface mapping. These techniques were applied to evaluate the pattern of atrophy in diverse populations, including in patients across the Alzheimer’s disease continuum. Our group is also contributing to the Hippocampal Subfields Group (www.hippocampalsubfields.com), an international collaborative project aiming at standardizing hippocampal subfields delineation.

Functional connectivity : Since the MTL is highly connected to the rest of the brain through specific networks, we use resting-state fMRI data with a seed-based correlation approach to study i) hippocampal subfield networks and ii) the anterior temporal and posterior medial systems.

We use multimodal neuroimaging techniques and computational modelling to investigate the pathophysiological mechanisms of Alzheimer’s disease and identify early biomarkers of cognitive decline. The populations we are interested in range from cognitively normal individuals (young to elderly adults to investigate normal ageing processes) to patients with subjective cognitive decline, mild cognitive impairment and dementia. We are also especially interested in the psycho-affective risk-factors (depression, stress, anxiety), their links with brain integrity and how they could be prevented.

As the field is moving toward a biological definition of Alzheimer’s disease, the role of biomarkers in diagnosis is becoming predominant, e.g. with the A/T/N scheme standing for amyloid, tau, and neurodegeneration. Providing such biomarkers however requires specific and rare equipment, and demands significant financial and human resources. Moreover, other brain damages such as vascular lesions are an additional burden in Alzheimer’s disease, and may contributes to the substantial worsening of cognitive functions as the disease progresses. Based on machine learning and multimodal imaging, my research at the Chetelat’s lab is therefore twofold.

My first aim is to provide proxies for the classical A/T/N biomarkers which will be more easily available and affordable. Early phase AV45 PET is indeed a suitable tool to provide proxies of hypoperfusion resulting from neurodegeneration (N) and amyloid (A), providing 2 biomarkers in a single acquisition.

My second aim is to complement the A/T/N scheme with a V index for vascular damage. White matter hyperintensities (WMH) being the most relevant white matter lesion in dementia in relation to vascular disease, I am investigating the association between WMH and Alzheimer’s disease pathology, as well as with other markers of whole brain changes (structural and functional connectivity), with the ambition of providing a new biomarker of WMH burden.

The team focused on schizophrenic disorders investigates neural networks in patients with schizophrenia in using multimodal neuroimaging (anatomical and functional MRIs, Diffusion Tensor Imaging, Magnetic Resonance Spectroscopy).

Our researches showed that patients presented (i) a reduction in leftward hemispheric lateralization for language that might be underlain by both (ii) grey matter abnormalities through a volume reduction in the regions involved in language and (iii) white matter (WM) abnormalities characterized by a decreased integrity of the regions and fasciculi that underlie the language network.

We also observed that (iv) abnormalities of the intra-hemispheric anatomical connectivity (left fronto-temporal fasciculi) were found in the patients with schizophrenia whereas a decreased inter-hemispheric connectivity (callosal fibers) was only observed in patients with auditory verbal hallucinations.
Finally, we demonstrated that (v) patients treated with typical antipsychotics (as haloperidol) presented a decreased WM integrity than those treated with clozapine.

The team also uses multimodal imaging to study the impact of various therapeutic strategies (magnetic stimulation guided by neuronavigation, adapted physical activity) on the human brain, in healthy subjects and patients with schizophrenia; white matter changes (Diffusion Tensor Imaging), glutamate and N‐Acetyl aspartate (Magnetic Resonance Spectroscopy), default networks (functional Magnetic Resonance Imaging) are particularly investigated (see clinical trials).

The Sleep disorders research topic focuses on the impact of sleep quality and disturbances on brain integrity and cognition, with a particular interest for memory consolidation. We are one of the few teams in the world to have sleep data (questionnaires, actigraphy, polysomnography) combined with detailed cognitive assessment and multimodal neuroimaging (structural MRI, DTI, resting-state fMRI, FDG-PET, amyloid-PET, high-resolution hippocampal sequence).

Our goal is twofold :

1- To better characterize the impact of sleep disturbances on brain integrity and cognition in ageing and Alzheimer’s disease and unravel the underlying mechanisms :

• Fine-grained analysis of sleep oscillations
• Particular interest for sleep apnea
• Detailed investigation of sleep-dependent memory consolidation
• Determine the period during which sleep disturbances have the greatest impact on brain and cognition to develop effective interventions.

2 – To improve the management of sleep disorders in ageing and Alzheimer’s disease :

• Influence on some lifestyle factors (physical activity, cognitive reserve) on the association between sleep, cognition and brain integrity
• Effects of non-pharmacological interventions (meditation)

Of note, we are also interested by these questions in patients with Alcohol Use Disorder and Korsakoff syndrome.

This research topic focuses on an holistic approach of neurocognitive disorders, aiming at disentangle multiple factors leading to cognitive, behavioral and functional changes in patient with neurocognitive disorders. Indeed, brain diseases (such as Alzheimer’s pathology) lead to neurodegeneration and cognitive symptoms, but several other factors “beyond the brain” also contribute to symptoms and can influence the clinical phenotype as well as the complications of the disease. We specifically focus on frailty, chronic disease and polypharmacy in addition to brain lesions (measured in vivo with biomarkers) to better explain at the individual levels the predictors of clinical changes.

For example, we study in older adults with neurocognitive disorders the respective impact of brain lesions (notably white matter hyperintensities measured with structural MRI, Alzheimer’s biomarkers measured with PET-scan, CSF or plasma), frailty (measured with Fried phenotype or frailty index), intrinsic capacities (measured with WHO-based tools) and medication (notably anticholinergic burden measured with the Drug Burden Index) and their relationships, to better understand and predict cognitive decline, behavioral symptoms and loss of autonomy.

At the era of disease-modifying therapies in Alzheimer’s disease, a better understanding of the origin of each symptom, at each stage, for each patient is critical.