L’hypothèse du double syndrome cognitif dans la maladie de Parkinson : études en IRM des corrélats structuraux et fonctionnels

La maladie de Parkinson (MP) est une pathologie neurodégénérative caractérisée par des troubles moteurs. Cependant, des symptômes non-moteurs tels que les troubles cognitifs font partie intégrante du tableau clinique de la maladie. Trois grandes présentations cliniques des troubles cognitifs dans la MP peuvent être distinguées : (a) l’absence de troubles significatifs malgré d’éventuels symptômes, (b) les troubles cognitifs légers et (c) la démence de la maladie de Parkinson. Les troubles cognitifs légers renvoient à des déficits cognitifs significatifs en l’absence de déclin cognitif global et d’impact sur les principales activités de la vie quotidienne. Ces troubles, communs dans la maladie de Parkinson, peuvent affecter diverses fonctions cognitives. L’hypothèse du double syndrome suggère l’existence de deux sous-types cognitifs : frontostriatal, caractérisé par des déficits attentionnels et/ou exécutifs, et cortical postérieur, caractérisé par des déficits visuospatiaux, mnésiques et/ou langagiers. Ce dernier a été associé avec un risque accru d’évolution précoce vers la démence. À ce jour, peu d’études ont pris en compte l’hétérogénéité des troubles cognitifs légers observés dans la MP et aucune étude n’a déterminé des sous-types sur la base de l’hypothèse du double syndrome. Par ailleurs, nous manquons de biomarqueurs in-vivo associés à ces sous-types cognitifs.Les objectifs principaux de cette thèse étaient (a) de proposer un état de l’art concernant les résultats en neuroimagerie associés à des sous-types cognitifs distincts de troubles cognitifs légers dans la maladie de Parkinson et (b) d’identifier en IRM des changements structuraux et fonctionnels du cerveau associés aux sous-types frontostriatal et cortical postérieur.Par conséquent, nous avons réalisé une revue systématique qui a montré un manque dans la littérature scientifique étant donné que seules dix études de neuroimagerie considérant des sous-types de troubles cognitifs légers dans la maladie de Parkinson ont été identifiées. Par la suite, nous avons conduit deux études en IRM pour identifier des modifications structurales et fonctionnelles de repos dans des sous-types cognitifs de troubles cognitifs légers. Nous avons utilisé les données issues d’un groupe de patients non-déments présentant une maladie de Parkinson (n=114) dont le sous-type cognitif a été déterminé sur la base de leurs performances à une batterie de tests neuropsychologiques : (a) avec une cognition normale (PD-NC) (n=41), (b) avec un sous-type frontostriatal (PD-FS) (n=16), (c) avec un sous-type cortical postérieur (PD-PC) (n=25) et (d) avec un sous-type mixte (PD-MS), c’est-à-dire une combinaison de déficits frontostriataux et corticaux postérieurs (n=32). Pour les analyses fonctionnelles, des données issues de 24 sujets sains appariés en âge ont également été utilisées.Nos résultats ont montré (a) des altérations structurales plus abondantes et plus étendues chez les patients avec des déficits corticaux postérieurs (PD-PC et PD-MS), (b) une augmentation de la connectivité fonctionnelle au sein des ganglions de la base chez les patients PD-PC et (c) une diminution de la connectivité fonctionnelle dans divers réseaux de repos chez les patients avec des déficits frontostriataux (PD-FS et PD-MS). De futures études longitudinales seront nécessaires pour évaluer la progression de ces modifications structurales et fonctionnelles et pour déterminer le potentiel prédictif de ces marqueurs au regard du risque d’évoluer vers la démence.Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor disorders. However, non-motor symptoms, including cognitive impairment, are also part of the clinical presentation. According to the severity of cognitive impairment, three presentations are usually distinguished in PD: (a) the absence of significant cognitive impairment despite possible symptoms, (b) mild cognitive impairment (MCI) and (c) PD dementia. MCI refers to significant cognitive deficits without global cognitive decline nor impact on activities of daily living. This condition is common in Parkinson’s disease (PD-MCI), can affect one or several cognitive functions and is heterogenous. According to the dual syndrome hypothesis, PD-MCI can be subdivided into two cognitive subtypes: a frontostriatal one, characterized by attentional and/or executive deficits, and a posterior cortical one, characterized by visuospatial, memory and/or language deficits. The latter has been associated with a higher risk of developing dementia earlier. To date, only few studies have considered the cognitive heterogeneity in PD-MCI and no study defined PD-MCI subtypes based on the dual syndrome hypothesis. Besides, in-vivo biomarkers of these cognitive subtypes are lacking.The main objectives of this thesis were (a) to propose a state-of-the-art on neuroimaging outcomes associated with distinct PD-MCI cognitive subtypes, and (b) to identify structural and functional MRI brain changes associated with the frontostriatal and posterior cortical subtypes.Therefore, we performed a systematic review which showed a gap in the scientific literature given that only ten neuroimaging studies considering PD-MCI subtypes were identified. Thereafter, we conducted two studies to identify structural and resting-state functional MRI modifications in PD-MCI subtypes. We used data from non-demented PD patients (n=114) whose cognitive subtype was determined by their cognitive performance at a comprehensive neuropsychological test battery: (a) patients with normal cognition (PD-NC) (n=41), (b) patients with a frontostriatal subtype (PD-FS) (n=16), (c) patients with a posterior cortical subtype (PD-PC) (n=25) and (d) patients with a mixed subtype (PD-MS) (i.e. combination of frontostriatal and posterior cortical deficits) (n=32). For functional analyses, data from 24 age-matched healthy controls were also used.Our results showed (a) more abundant and more extensive structural alterations in patients with posterior cortical deficits (PD-PC and PD-MS), (b) increased functional connectivity within the basal ganglia in PD-PC patients and (c) decreased functional connectivity in various resting-state networks in patients with frontostriatal deficits (PD-FS and PD-MS). Further longitudinal studies are needed to assess the progression of these structural and functional modifications and to determine the predictive potential of these markers regarding the risk of developing dementia

The frontostriatal subtype of mild cognitive impairment in Parkinson's disease, but not the posterior cortical one, is associated with specific EEG alterations

BACKGROUND: The 'dual syndrome' hypothesis states that two cognitive subtypes can be distinguished in mild cognitive impairment in Parkinson's disease (PD-MCI): a frontostriatal one, characterized by attentional and/or executive deficits, and a posterior cortical one, characterized by visuospatial, memory and/or language deficits. The latter type has been associated with a higher risk of earlier development of PD dementia. The functional bases of these subtypes remain partly unknown. OBJECTIVE: To identify EEG modifications associated with PD-MCI subtypes. METHODS: 75 non-demented PD patients underwent a comprehensive neuropsychological assessment and a high-density EEG. They were classified as having normal cognition (PD-NC; n = 37), PD-MCI with a frontostriatal subtype (PD-FS; n = 11) or PD-MCI with a posterior cortical subtype (PD-PC; n = 27). Two EEG analyses were performed: (a) spectral powers quantification and (b) functional connectivity analysis. RESULTS: PD-FS patients displayed spectral and functional EEG alterations, namely (a) higher powers in the theta and delta bands, (b) lower powers in the beta2 band and (c) lower functional connectivity in the beta2 band compared to PD-NC and PD-PC patients. These alterations were mainly located in the frontal, limbic and parietal regions. There were no significant differences between PD-NC and PD-PC. CONCLUSION: EEG alterations previously reported in PD-MCI may only concern the frontostriatal subtype, and not the posterior-cortical subtype. This provides evidence for the dual syndrome hypothesis and emphasizes the importance of identifying PD-MCI subtypes. It also shows the promising potential of EEG to discriminate between PD-MCI subtypes

Posterior Cortical Cognitive Deficits Are Associated With Structural Brain Alterations in Mild Cognitive Impairment in Parkinson’s Disease

International audienceContext : Cognitive impairments are common in patients with Parkinson’s disease (PD) and are heterogeneous in their presentation. The “dual syndrome hypothesis” suggests the existence of two distinct subtypes of mild cognitive impairment (MCI) in PD: a frontostriatal subtype with predominant attentional and/or executive deficits and a posterior cortical subtype with predominant visuospatial, memory, and/or language deficits. The latter subtype has been associated with a higher risk of developing dementia. Objective : The objective of this study was to identify structural modifications in cortical and subcortical regions associated with each PD-MCI subtype. Methods : One-hundred and fourteen non-demented PD patients underwent a comprehensive neuropsychological assessment as well as a 3T magnetic resonance imaging scan. Patients were categorized as having no cognitive impairment ( n = 41) or as having a frontostriatal ( n = 16), posterior cortical ( n = 25), or a mixed ( n = 32) MCI subtype. Cortical regions were analyzed using a surface-based Cortical thickness (CTh) method. In addition, the volumes, shapes, and textures of the caudate nuclei, hippocampi, and thalami were studied. Tractometric analyses were performed on associative and commissural white matter (WM) tracts. Results : There were no between-group differences in volumetric measurements and cortical thickness. Shape analyses revealed more abundant and more extensive deformations fields in the caudate nuclei, hippocampi, and thalami in patients with posterior cortical deficits compared to patients with no cognitive impairment. Decreased fractional anisotropy (FA) and increased mean diffusivity (MD) were also observed in the superior longitudinal fascicle, the inferior fronto-occipital fascicle, the striato-parietal tract, and the anterior and posterior commissural tracts. Texture analyses showed a significant difference in the right hippocampus of patients with a mixed MCI subtype. Conclusion : PD-MCI patients with posterior cortical deficits have more abundant and more extensive structural alterations independently of age, disease duration, and severity, which may explain why they have an increased risk of dementia

Anxiety in Parkinson's disease is associated with changes in the brain fear circuit

Background: Anxiety is frequent in Parkinson's disease (PD) and has a negative impact on disease symptoms and quality of life. The underlying mechanisms remain largely unknown. The aim of this study was to identify anatomical and functional changes associated to PD-related anxiety by comparing the volume, shape and texture of the amygdala, the cortical thickness as well as the functional connectivity (FC) of the fear circuit in patients with and without clinically relevant anxiety.Methods: Non-demented PD patients were recruited, and anxiety was quantified using the Parkinson Anxiety Scale. Structural MRI was used to compare cortical thickness and amygdala structure and resting-state functional MRI to compare FC patterns of the amygdala and resting-state functional networks in both groups.Results: We included 118 patients: 34 with (A+) and 84 without (A-) clinically relevant anxiety. Clusters of cortical thinning were identified in the bilateral fronto-cingulate and left parietal cortices of the A+ group. The texture and the shape of the left amygdala was different in the A+ group but the overall volume did not differ between groups. FC between the amygdala and the whole brain regions did not differ between groups. The internetwork resting-state FC was higher between the "fear circuit" and salience network in the A+ group.Conclusion: Anxiety in PD induces structural modifications of the left amygdala, atrophy of the bilateral fronto-cingulate and the left parietal cortices, and a higher internetwork resting-state FC between the fear circuit and the salience network

Trauma-related intrusive memories and anterior hippocampus structural covariance: an ecological momentary assessment study in posttraumatic stress disorder

Abstract Trauma-related intrusive memories (TR-IMs) are hallmark symptoms of posttraumatic stress disorder (PTSD), but their neural correlates remain partly unknown. Given its role in autobiographical memory, the hippocampus may play a critical role in TR-IM neurophysiology. The anterior and posterior hippocampi are known to have partially distinct functions, including during retrieval of autobiographical memories. This study aimed to investigate the relationship between TR-IM frequency and the anterior and posterior hippocampi morphology in PTSD. Ninety-three trauma-exposed adults completed daily ecological momentary assessments for fourteen days to capture their TR-IM frequency. Participants then underwent anatomical magnetic resonance imaging to obtain measures of anterior and posterior hippocampal volumes. Partial least squares analysis was applied to identify a structural covariance network that differentiated the anterior and posterior hippocampi. Poisson regression models examined the relationship of TR-IM frequency with anterior and posterior hippocampal volumes and the resulting structural covariance network. Results revealed no significant relationship of TR-IM frequency with hippocampal volumes. However, TR-IM frequency was significantly negatively correlated with the expression of a structural covariance pattern specifically associated with the anterior hippocampus volume. This association remained significant after accounting for the severity of PTSD symptoms other than intrusion symptoms. The network included the bilateral inferior temporal gyri, superior frontal gyri, precuneus, and fusiform gyri. These novel findings indicate that higher TR-IM frequency in individuals with PTSD is associated with lower structural covariance between the anterior hippocampus and other brain regions involved in autobiographical memory, shedding light on the neural correlates underlying this core symptom of PTSD

Heterogeneity of PD-MCI in candidates to subthalamic deep brain stimulation: associated cortical and subcortical modifications

International audienceBackground: Parkinson’s disease mild cognitive impairment (PD-MCI) is frequent and heterogenous. There is no consensus about its influence on subthalamic deep brain stimulation (STN-DBS) outcomes. Objective: To determine the prevalence of PD-MCI and its subtypes in candidates to STN-DBS. Secondarily, we sought to identify MRI structural markers associated with cognitive impairment in these subgroups. Methods: Baseline data from the French multicentric PREDISTIM cohort were used. Candidates to STN-DBS were classified according to their cognitive performance in normal cognition (PD-NC) or PD-MCI. The latter included frontostriatal (PD-FS) and posterior cortical (PD-PC) subtypes. Between-group comparisons were performed on demographical and clinical variables as well as on T1-weighted MRI sequences at the cortical and subcortical levels. Results: 320 patients were included: 167 (52%) PD-NC and 153 (48%) PD-MCI patients. The latter group included 123 (80%) PD-FS and 30 (20%) PD-PC patients. There was no between-group difference regarding demographic and clinical variables. PD-PC patients had significantly lower global efficiency than PD-FS patients and significantly worse performance on visuospatial functions, episodic memory, and language. Compared to PD-NC, PD-MCI patients had cortical thinning and radiomic-based changes in the left caudate nucleus and hippocampus. There were no significant differences between the PD-MCI subtypes. Conclusion: Among the candidates to STN-DBS, a significant proportion has PD-MCI which is associated with cortical and subcortical alterations. Some PD-MCI patients have posterior cortical deficits, a subtype known to be at higher risk of dementia