Dynamics of pH-dependent self-association and membrane binding of a dicarboxylic porphyrin: a study with small unilamellar vesicles

AbstractSteady-state and stopped-flow measurements of the absorbance and fluorescence of aqueous solutions were performed to characterize the pH-dependent ionization and aggregation states of deuteroporphyrin. Porphyrin self-association promoted by neutralization of the carboxylic groups takes place within a few milliseconds impeding characterization of the monomer ionization states. Extrapolation at infinite dilution of the values obtained from steady-state measurements yielded the pKs of the carboxylic groups (6.6, 5.3) and inner nitrogens (4.1, 2.3). The kinetics of interactions of the porphyrin with unilamellar fluid state dioleoylphosphatidylcholine vesicles was examined in a large pH range, with focus on the entry step. From alkaline pH to a value of 6.5, the entrance rate is maximal (1.69×106 M−1 s−1 versus phospholipid concentration). It decreases to 2.07×105 M−1 s−1 at lower pH with an apparent pK of 5.39. This effect appears to be related to the formation of porphyrin dimer rather than to the protonation of inner nitrogen. In keeping with previous data, these results support the concept of a pH-mediated selectivity of carboxylic porphyrins for tumor. They also indicate that the propensity of these molecules to self-associate at low pH could yield to some retention in acidic intracellular vesicles of the endosome/lysosome compartment

Exposure to negative socio-emotional events induces sustained alteration of resting-state brain networks in older adults

Basic emotional functions seem well preserved in older adults. However, their reactivity to and recovery from socially negative events remain poorly characterized. To address this, we designed a ‘task–rest’ paradigm in which 182 participants from two independent experiments underwent functional magnetic resonance imaging while exposed to socio-emotional videos. Experiment 1 (N = 55) validated the task in young and older participants and unveiled age-dependent effects on brain activity and connectivity that predominated in resting periods after (rather than during) negative social scenes. Crucially, emotional elicitation potentiated subsequent resting-state connectivity between default mode network and amygdala exclusively in older adults. Experiment 2 replicated these results in a large older adult cohort (N = 127) and additionally showed that emotion-driven changes in posterior default mode network–amygdala connectivity were associated with anxiety, rumination and negative thoughts. These findings uncover the neural dynamics of empathy-related functions in older adults and help understand its relationship to poor social stress recovery

Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia.

International audienceBACKGROUND: Hippocampal atrophy is a well-known feature of Alzheimer's disease (AD), but sensitivity and specificity of hippocampal volumetry are limited. Neuropathological studies have shown that hippocampal subfields are differentially vulnerable to AD; hippocampal subfield volumetry may thus prove to be more accurate than global hippocampal volumetry to detect AD. METHODS: CA1, subiculum and other subfields were manually delineated from 40 healthy controls, 18 AD, 17 amnestic Mild Cognitive Impairment (aMCI), and 8 semantic dementia (SD) patients using a previously developed high resolution MRI procedure. Non-parametric group comparisons and receiver operating characteristic (ROC) analyses were conducted. Complementary analyses were conducted to evaluate differences of hemispheric asymmetry and anterior-predominance between AD and SD patients and to distinguish aMCI patients with or without β-amyloid deposition as assessed by Florbetapir-TEP. RESULTS: Global hippocampi were atrophied in all three patient groups and volume decreases were maximal in the CA1 subfield (22% loss in aMCI, 27% in both AD and SD; all p < 0.001). In aMCI, CA1 volumetry was more accurate than global hippocampal measurement to distinguish patients from controls (areas under the ROC curve = 0.88 and 0.76, respectively; p = 0.05) and preliminary analyses suggest that it was independent from the presence of β-amyloid deposition. In patients with SD, whereas the degree of CA1 and subiculum atrophy was similar to that found in AD patients, hemispheric and anterior-posterior asymmetry were significantly more marked than in AD with greater involvement of the left and anterior hippocampal subfields. CONCLUSIONS: The findings suggest that CA1 measurement is more sensitive than global hippocampal volumetry to detect structural changes at the pre-dementia stage, although the predominance of CA1 atrophy does not appear to be specific to AD pathophysiological processes

Self-reference effect on memory in healthy aging, mild cognitive impairment and Alzheimer’s disease: Influence of identity valence

International audienceThe self-reference effect (SRE) has been shown to benefit episodic memory in healthy individuals. In healthy aging, its preservation is acknowledged, but in Alzheimer’s disease (AD), the jury is still out. Furthermore, there has yet to be a study of the SRE in amnestic mild cognitive impairment (aMCI). As self-reference implies subjective self-representations, and positive information enhance memory performance, we set out to examine the effects of 1) material and 2) identity valence on the SRE across the early stages of AD. Twenty healthy older individuals and 40 patients (20 diagnosed with aMCI and 20 diagnosed with mild AD) performed a memory task. Participants had to judge positive and negative personality trait adjectives with reference to themselves or to another person, or else process these adjectives semantically. We then administered a recognition task. Participants also completed a questionnaire on identity valence. Among healthy older individuals, the SRE benefited episodic memory independently of material and identity valence. By contrast, among aMCI patients, we only observed the SRE when the material was positive. When self-referential material was negative, patients’ performance depended on the valence of their self-representations: negative self-representations correlated with poor recognition of negative self-referential adjectives. Finally, performance of patients with mild AD by condition and material valence were too low and inappropriate to be subjected to relevant analyses. The persistence of an SRE for positive adjectives in aMCI suggests the existence of a positivity effect for self-related information, which contributes to wellbeing. The absence of an SRE for negative adjectives, which led aMCI patients to dismiss negative self-related information, could be due to low self-esteem. These results corroborate the mnenic neglect model and point out the importance of the psychoaffective dimension in patients with aMCI, which could constitute a major factor for the preservation of their self-esteem and self-related memory.Keywords: self-reference effect; positivity effect; episodic memory; amnestic mild cognitive impairment; Alzheimer’s diseas

Quali-quantitative assessment of self-reported cognitive difficulties in non-demented elders: association with medical help seeking, cognitive deficits and beta-amyloid imaging

International audienceINTRODUCTION:Subjective cognitive decline (SCD) could help identify early stages of Alzheimer's disease. However, SCD is multidetermined and protean, and the type of cognitive complaint associated with preclinical Alzheimer's disease needs refinement.METHODS:A total of 185 nondemented elders recruited from either the community or from a memory clinic filled a questionnaire. We searched for item responses associated with medical help seeking, cognitive deficits, and β-amyloidosis.RESULTS:Compared with community-recruited control subjects (n = 74), help-seeking patients reported a stronger multidomain SCD that was mostly unrelated to the presence of detectable cognitive deficits. Only a few items, notably assessing temporal disorientation, distinguished help-seeking patients with (n = 78) or without (n = 33) memory deficits. Associations between SCD and β-amyloidosis were not restricted to the memory domain and varied across clinical stages.DISCUSSION:Detailed evaluation of SCD could provide accessible indication of the presence of β-amyloid or cognitive deficits, which might prove useful for early diagnosis and clinical trial enrichment strategies

Interaction between years of education and APOE 4 status on frontal and temporal metabolism

International audienceABSTRACT: Objective: To examine interactions between years of education and APOE ε4 status on gray matter volume and metabolism in cognitively healthy subjects.Methods: Seventy-two healthy subjects (28 APOE ε4 carriers and 44 non-carriers; from 23 to 84 years of age) with FDG-PET and structural MRI were included. A subgroup also underwent florbetapir-PET. We tested the interaction effect between years of education and APOE ε4 status (carrier vs. non-carrier) on FDG-PET and structural MRI within the whole brain (voxel-wise) adjusting for age and sex. Computed florbetapir SUVr values were used for complementary analyses.Results: We found an interaction between years of education and APOE ε4 status on fronto-temporal FDG-PET metabolism, such that higher education was positively related to fronto-temporal metabolism only in APOE ε4 carriers. Complementary analyses revealed that: i) this interaction was independent from amyloid load; ii) increased metabolism in APOE ε4 carriers in this region correlated with episodic memory performances; iii) lower educated APOE ε4 carriers showed decreased metabolism relative to non-carriers in medial temporal and prefrontal areas, while higher educated carriers were comparable to non-carriers in these areas and showed increased metabolism in the middle temporal lobe.Conclusions: Our results showed that an environmental factor such as education may counteract the effects of APOE ε4 on metabolism independently of amyloid deposition. Higher metabolism in higher (compared to lower) educated APOE ε4 carriers was found in regions that sustain episodic memory. Overall, our results point to education as a protective factor that may help to postpone cognitive changes in APOE ε4 carriers

Subjective cognitive decline in cognitively normal elders from the community or from a memory clinic: Differential affective and imaging correlates

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Is there a specific memory signature associated with Aβ-PET positivity in patients with amnestic mild cognitive impairment?

International audienceAmnestic mild cognitive impairment (aMCI) is a clinical entity with various potential etiologies including but not limited to Alzheimer's disease. We examined whether a positive ([18F]Florbetapir) beta amyloid positron emission tomography scan, supporting underlying Alzheimer's disease pathophysiology, was associated with specific memory deficits in 48 patients with aMCI (33 beta amyloid positive, 15 beta amyloid negative). Memory was evaluated using an autobiographical fluency task and a word-list learning task with 2 different encoding types (shallow/incidental versus deep/intentional). Compared with 40 beta amyloidenegative controls, both aMCI subgroups demonstrated severe deficits in the global memory score and in most subscores of both tasks. Finer-grained analyses of memory tests showed subtle association with beta amyloid status, revealing a stronger impairment of the primacy effect in beta amyloidepositive patients. Structural magnetic resonance imaging showed that both aMCI subgroups exhibited comparable atrophy patterns, with similar degrees of medial temporal volume loss compared with controls. Specifically assessing the primacy effect might complement global memory scores in identifying beta amyloidepositive patients with aMCI

Brain alterations in pediatric PTSD Functional brain alterations during self-reference processing in adolescents with sexual abuse related posttraumatic stress disorder: A preliminary report

International audienceInterpersonal childhood traumas are associated with more severe post-traumatic stress disorder at adulthood and have a critical impact on the development of the self. We proposed to explore the functional brain changes during a self-reference processing task in adolescents with sexual abuse related post-traumatic stress disorder (N = 10), compared to healthy adolescents (N = 10). While patients showed no behavioral disturbances in self-reference processing, 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

Neural correlates of Self-Reference Effect in early Alzheimer’s disease

International audienceInformation 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