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We aimed to investigate cortical and subcortical brain alterations in people with Parkinson's disease with polysomnography-confirmed rapid eye movement (REM) sleep behavior disorder (RBD). Thirty people with Parkinson's disease, including 15 people with RBD, were recruited and compared with 41 healthy controls. Surface-based cortical and subcortical analyses were performed on T1-weighted images to investigate thickness and shape abnormalities between groups, and voxel-based and deformation-based morphometry were performed to investigate local volume. Correlations were performed in patients to investigate the structural correlates of motor activity during REM sleep. People with RBD showed cortical thinning in the right perisylvian and inferior temporal cortices and shape contraction in the putamen compared with people without RBD. Compared with controls, people with RBD had extensive cortical thinning and volume loss, brainstem volume was reduced, and shape contraction was found in the basal ganglia and hippocampus. In comparison to controls, people without RBD showed more restricted thinning in the sensorimotor, parietal, and occipital cortices, reduced volume in the brainstem, temporal and more posterior areas, and shape contraction in the pallidum and hippocampus. In Parkinson's disease, higher tonic and phasic REM sleep motor activity was associated with contraction of the thalamic surface, extensive cortical thinning, and subtle volume reduction in the middle temporal gyrus. In Parkinson's disease, the presence of RBD is associated with extensive cortical and subcortical abnormalities, suggesting more severe neurodegeneration in people with RBD. This provides potential neuroanatomical correlates for the more severe clinical phenotype reported in people with Parkinson's disease with RBD., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Introduction: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Depressive and anxiety symptoms are frequent features of PD, DLB and iRBD, and some studies suggest that depressive symptoms are a marker for neurodegeneration in iRBD. However, the pathophysiology of depressive and anxiety symptoms in iRBD is still unclear. This study aimed to investigate cortical and subcortical gray matter (GM) volume substrates of depressive and anxiety symptoms in iRBD patients., Methods: Forty-six polysomnography-confirmed iRBD patients and 31 healthy controls (HC) without cognitive or mood impairment were recruited. All participants underwent 3-T magnetic resonance imaging and completed the Beck Depression Inventory Second Edition (BDI-II) and Beck Anxiety Inventory (BAI) questionnaires. Voxel-based morphometry analysis was performed to assess GM volume in cortical and subcortical structures. Between-group comparisons and regressions were performed., Results: iRBD patients with depressive symptoms (BDI-II score > 13 or the use of antidepressants to treat depression) showed reduced GM volume in the caudate nucleus compared to HC and iRBD patients without depressive symptoms. Moreover, iRBD patients with anxiety symptoms (BAI score > 9 or the use of anxiolytics to treat anxiety) showed reduced GM volume in the left amygdala extending to the hippocampus compared to HC and iRBD patients without anxiety symptoms. In iRBD patients, higher BDI-II and BAI total scores were associated with lower GM volumes in these regions respectively., Conclusion: Depressive and anxiety symptoms in iRBD patients are related to patterns of cortical and subcortical GM volume loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To investigate cortical and subcortical gray matter abnormalities underlying cognitive impairment in patients with REM sleep behavior disorder (RBD) with or without mild cognitive impairment (MCI)., Methods: Fifty-two patients with RBD, including 17 patients with MCI, were recruited and compared to 41 controls. All participants underwent extensive clinical assessments, neuropsychological examination, and 3-tesla MRI acquisition of T1 anatomical images. Vertex-based cortical analyses of volume, thickness, and surface area were performed to investigate cortical abnormalities between groups, whereas vertex-based shape analysis was performed to investigate subcortical structure surfaces. Correlations were performed to investigate associations between cortical and subcortical metrics, cognitive domains, and other markers of neurodegeneration (color discrimination, olfaction, and autonomic measures)., Results: Patients with MCI had cortical thinning in the frontal, cingulate, temporal, and occipital cortices, and abnormal surface contraction in the lenticular nucleus and thalamus. Patients without MCI had cortical thinning restricted to the frontal cortex. Lower patient performance in cognitive domains was associated with cortical and subcortical abnormalities. Moreover, impaired performance on olfaction, color discrimination, and autonomic measures was associated with thinning in the occipital lobe., Conclusions: Cortical and subcortical gray matter abnormalities are associated with cognitive status in patients with RBD, with more extensive patterns in patients with MCI. Our results highlight the importance of distinguishing between subgroups of patients with RBD according to cognitive status in order to better understand the neurodegenerative process in this population., (© 2018 American Academy of Neurology.)

Prospective memory (PM) refers to the ability to remember to execute an intention at the appropriate moment in the future, which can be performed either at the appearance of an event (event-based, EBPM) or after a certain amount of time (time-based, TBPM). PM is generally impaired during aging but the cerebral substrates of this decline have been little investigated. Using functional Magnetic Resonance Imaging (fMRI), we investigated the neural bases of PM in 20 young and 20 healthy older adults. They were proposed a task of semantic categorisation of pictures (ongoing task). For some blocks, participants only had to perform this ongoing task while, for others, a PM instruction was added. In this case, a supplementary answer in response to a specific colour of border for EBPM or at specific time intervals for TBPM was expected. PM, and more particularly TBPM, declined in older adults. For both PM conditions, older adults recruited additional brain areas, but also showed reduced deactivations of other regions. These results are discussed in light of models of the aging brain.

The brain mechanisms underlying the effect of intellectual enrichment may evolve along the normal aging Alzheimer's disease (AD) cognitive spectrum and may include both protective and compensatory mechanisms. We assessed the association between early intellectual enrichment (education, years) and average cortical florbetapir standardized uptake value ratio as well as performed voxel-wise analyses in a total of 140 participants, including cognitively normal older adults, mild cognitive impairment (MCI), and AD patients. Higher education was associated with lower cortical florbetapir positron emission tomography (florbetapir-PET) uptake, notably in the frontal lobe in normal older adults, but with higher uptake in frontal, temporal, and parietal regions in MCI after controlling for global cognitive status. No association was found in AD. In MCI, we observed an increased fluorodeoxyglucose positron emission tomography (FDG-PET) uptake with education within the regions of higher florbetapir-PET uptake, suggesting a compensatory increase. Early intellectual enrichment may be associated with protection and compensation for amyloid beta (Aβ) deposition later in life, before the onset of dementia. Previous investigations have been controversial as regard to the effects of intellectual enrichment variables on Aβ deposition; the present findings call for approaches aiming to evaluate mechanisms of resilience across disease stages., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We proposed to explore the functional brain changes during a self-reference processing (SRP) task in adolescents with sexual abuse-related post-traumatic stress disorder (N = 10), compared with healthy adolescents (N = 10). While patients showed no behavioral disturbances in (SRP), they exhibited changes in activity and connectivity in regions involved in emotional regulation (amygdala and dorsal prefrontal cortex) and semantic memory (temporal and ventrolateral prefrontal regions). These preliminary results suggest that these alterations may have an effect on self-esteem which may contribute to a possible retention and impairment of symptoms in adulthood.

Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer's disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity (other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment.

Neuroimaging biomarkers, namely hippocampal volume loss, temporoparietal hypometabolism, and neocortical β-amyloid (Aβ) deposition, are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our aim was to characterize the cognitive and brain profiles of elders classified as positive or negative for each biomarker to further our understanding of their use in the preclinical diagnosis of AD. Fifty-four cognitively normal individuals (age = 65.8 ± 8.3 years) underwent neuropsychological tests (structural MRI, FDG-PET, and Florbetapir-PET) and were dichotomized into positive or negative independently for each neuroimaging biomarker. Demographic, neuropsychological, and neuroimaging data were compared between positive and negative subgroups. The MRI-positive subgroup had lower executive performances and mixed patterns of lower volume and metabolism in AD-characteristic regions and in the prefrontal cortex. The FDG-positive subgroup showed only hypometabolism, predominantly in AD-sensitive areas extending to the whole neocortex, compared with the FDG-negative subgroup. The amyloid-positive subgroup was older and included more APOE ε4 carriers compared with the amyloid-negative subgroup. When considering MRI and/or FDG biomarkers together (i.e., the neurodegeneration-positive), there was a trend for an inverse relationship with Aβ deposition such that those with neurodegeneration tended to show less Aβ deposition and the reverse was true as well. Our findings suggest that: (1) MRI and FDG biomarkers provide complementary rather than redundant information and (2) relatively young cognitively normal elders tend to have either neurodegeneration or Aβ deposition, but not both, suggesting additive rather than sequential/causative links between AD neuroimaging biomarkers at this age. Significance statement: Neuroimaging biomarkers are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our findings suggest that MRI and FDG-PET biomarkers should be used in combination, offering an additive contribution instead of reflecting the same process of neurodegeneration. Moreover, the present study also challenges the hierarchical use of the neuroimaging biomarkers in preclinical AD because it suggests that the neurodegeneration observed in this population is not due to β-amyloid deposition. Rather, our results suggest that β-amyloid- and tau-related pathological processes may interact but not necessarily appear in a systematic sequence., (Copyright © 2015 the authors 0270-6474/15/3510403-10$15.00/0.)

Information that is processed with reference to oneself, i.e. Self-Referential Processing (SRP), is generally associated with better remembering compared to information processed in a condition not related to oneself. This positive effect of the self on subsequent memory performance is called as Self-Reference Effect (SRE). The neural basis of SRE is still poorly understood. The main goal of the present work was thus to highlight brain changes associated with SRE in terms of activity and functional coupling and during both encoding and retrieval so as to assess the relative contribution of both processes to SRE. For this purpose, we used an fMRI event-related self-referential paradigm in 30 healthy young subjects and measured brain activity during both encoding and retrieval of self-relevant information compared to a semantic control condition. We found that SRE was associated with brain changes during the encoding phase only, including both greater activity in the medial prefrontal cortex and hippocampus, and greater functional coupling between these brain regions and the posterior cingulate cortex. These findings highlight the contribution of brain regions involved in both SRP and episodic memory and the relevance of the communication between these regions during the encoding process as the neural substrates of SRE. This is consistent with the idea that SRE reflects a positive effect of the reactivation of self-related memories on the encoding of new information in episodic memory.

The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D₁ receptor agonism and D₁/D₂ agonist selectivity. A 3D structure model of the D₁ receptor in its agonist-bound state was constructed with a full D₁ agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D₁ agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D₁ and D₂ receptors revealed differences in shape and ligand-interacting features that determine selectivity of D₁ and D₂ receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D₁/D₂ receptor agonist selectivity were also identified; those were Ser/Cys³·³⁶, Tyr/Phe⁵·³⁸, Ser/Tyr⁵·⁴¹, and Asn/His⁶·⁵⁵ in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D₁ and D₂ agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand-protein interactions for which experimental information is limited., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A combined modeling approach was used to identify structural factors that underlie the structure-activity relationships (SARs) of full dopamine D₂ receptor agonists and structurally similar inactive compounds. A 3D structural model of the dopamine D₂ receptor was constructed, with the agonist (-)-(R)-2-OH-NPA present in the binding site during the modeling procedure. The 3D model was evaluated and compared with our previously published D₂ agonist pharmacophore model. The comparison revealed an inconsistency between the projected hydrogen bonding feature (Ser-TM5) in the pharmacophore model and the TM5 region in the structure model. A new refined pharmacophore model was developed, guided by the shape of the binding site in the receptor model and with less emphasis on TM5 interactions. The combination of receptor and pharmacophore modeling also identified the importance of His393⁶·⁵⁵ for agonist binding. This convergent 3D pharmacophore and protein structure modeling strategy is considered to be general and can be highly useful in less well-characterized systems to explore ligand-receptor interactions. The strategy has the potential to identify weaknesses in the individual models and thereby provides an opportunity to improve the discriminating predictivity of both pharmacophore searches and structure-based virtual screens., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)