Locus coeruleus features are linked to vagus nerve stimulation response in drug-resistant epilepsy.

The locus coeruleus-norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.

Impact of light on task-evoked pupil responses during cognitive tasks.

Light has many non-image-forming functions including modulation of pupil size and stimulation of alertness and cognition. Part of these non-image-forming effects may be mediated by the brainstem locus coeruleus. The processing of sensory inputs can be associated with a transient pupil dilation that is likely driven in part by the phasic activity of the locus coeruleus. In the present study, we aimed to characterise the task-evoked pupil response associated with auditory inputs under different light levels and across two cognitive tasks. We continuously monitored the pupil of 20 young healthy participants (mean [SD] 24.05 [4.0] years; 14 women) whilst they completed an attentional and an emotional auditory task whilst exposed to repeated 30-40-s blocks of light interleaved with darkness periods. Blocks could either consist of monochromatic orange light (0.16 melanopic equivalent daylight illuminance (EDI) lux) or blue-enriched white light of three different levels [37, 92, 190 melanopic EDI lux; 6500 K]. For the analysis, 15 and then 14 participants were included in the attentional and emotional tasks, respectively. Generalised linear mixed models showed a significant main effect of light level on the task-evoked pupil responses triggered by the attentional and emotional tasks (p ≤ 0.0001). The impact of light was different for the target versus non-target stimulus of the attentional task but was not different for the emotional and neutral stimulus of the emotional task. There is a smaller sustained pupil size during brighter light blocks but, a higher light level triggers a stronger task-evoked pupil response to auditory stimulation, presumably through the recruitment of the locus coeruleus.

In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men.

The regional integrity of brain subcortical structures has been implicated in sleep-wake regulation, however, their associations with sleep parameters remain largely unexplored. Here, we assessed association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem and the variability in the sleep electrophysiology in a large sample of 18-to-31 years healthy young men (N = 321; ~ 22 years). Separate Generalized Additive Model for Location, Scale and Shape (GAMLSS) revealed that sleep onset latency and slow wave energy were significantly associated with MTsat estimates in the brainstem (pcorrected ≤ 0.03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction-pcorrected ≤ 0.03), with higher MTsat value linked to better values in the two sleep metrics in the younger individuals of our sample aged ~ 18 to 20 years. Similar associations were detected across different parts of the brainstem (pcorrected ≤ 0.03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the brainstem nuclei essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

Impact of repeated short light exposures on sustained pupil responses in an fMRI environment.

Light triggers numerous non-image-forming, or non-visual, biological effects. The brain correlates of these non-image-forming effects have been investigated, notably using magnetic resonance imaging and short light exposures varying in irradiance and spectral quality. However, it is not clear whether non-image-forming responses estimation may be biased by having light in sequential blocks, for example, through a potential carryover effect of one light onto the next. We reasoned that pupil light reflex was an easy readout of one of the non-image-forming effects of light that could be used to address this issue. We characterised the sustained pupil light reflex in 13-16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light (0.16 melanopic equivalent daylight illuminance lux) and polychromatic blue-enriched white light of three different levels (37, 92, 190 melanopic equivalent daylight illuminance lux). As expected, higher melanopic irradiance was associated with larger sustained pupil light reflex in each cognitive domain. This result was stable over the light sequence under higher melanopic irradiance levels compared with lower ones. Exploratory frequency-domain analyses further revealed that sustained pupil light reflex was more variable under lower melanopic irradiance levels. Importantly, sustained pupil light reflex varied across tasks independently of the light condition, pointing to a potential impact of light history and/or cognitive context on sustained pupil light reflex. Together, our results emphasise that the distinct contribution and adaptation of the different retinal photoreceptors influence the non-image-forming effects of light and therefore potentially their brain correlates.

Light modulates task-dependent thalamo-cortical connectivity during an auditory attentional task.

Exposure to blue wavelength light stimulates alertness and performance by modulating a widespread set of task-dependent cortical and subcortical areas. How light affects the crosstalk between brain areas to trigger this stimulating effect is not established. Here we record the brain activity of 19 healthy young participants (24.05±2.63; 12 women) while they complete an auditory attentional task in darkness or under an active (blue-enriched) or a control (orange) light, in an ultra-high-field 7 Tesla MRI scanner. We test if light modulates the effective connectivity between an area of the posterior associative thalamus, encompassing the pulvinar, and the intraparietal sulcus (IPS), key areas in the regulation of attention. We find that only the blue-enriched light strengthens the connection from the posterior thalamus to the IPS. To the best of our knowledge, our results provide the first empirical data supporting that blue wavelength light affects ongoing non-visual cognitive activity by modulating task-dependent information flow from subcortical to cortical areas.

Locus coeruleus activity while awake is associated with REM sleep quality in older individuals.

BACKGROUNDThe locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans.METHODSWe used 7-Tesla functional MRI, sleep electroencephalography (EEG), and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22 years old; 28 women, 5 men) and 19 older (~61 years old; 14 women, 5 men) individuals.RESULTSWe found that, in older but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC.CONCLUSIONThese findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and we found that the LC may be an important target in the treatment of sleep- and age-related diseases.FUNDINGThis work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20), Action de Recherche Concertée - Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), ULiège, and European Regional Development Fund (Radiomed & Biomed-Hub).

Structural and functional characterization of the locus coeruleus in young and late middle-aged individuals.

Introduction: The brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine the potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast. Methods: We used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals. Results: Whole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Importantly, while the LC contrast was higher in older individuals, the functional response of the LC was not significantly associated with its contrast. Discussion: These findings may suggest that the age-related alterations of the LC structural integrity may not be related to changes in its functional response. The results further suggest that LC responses may remain stable in healthy individuals aged 20 to 70.

In vivo Locus Coeruleus activity while awake is associated with REM sleep quality in healthy older individuals.

The locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.

Depressive symptoms in cognitively unimpaired older adults are associated with lower structural and functional integrity in a frontolimbic network.

Subclinical depressive symptoms are associated with increased risk of Alzheimer's disease (AD), but the brain mechanisms underlying this relationship are still unclear. We aimed to provide a comprehensive overview of the brain substrates of subclinical depressive symptoms in cognitively unimpaired older adults using complementary multimodal neuroimaging data. We included cognitively unimpaired older adults from the baseline data of the primary cohort Age-Well (n = 135), and from the replication cohort ADNI (n = 252). In both cohorts, subclinical depressive symptoms were assessed using the 15-item version of the Geriatric Depression Scale; based on this scale, participants were classified as having depressive symptoms (>0) or not (0). Voxel-wise between-group comparisons were performed to highlight differences in gray matter volume, glucose metabolism and amyloid deposition; as well as white matter integrity (only available in Age-Well). Age-Well participants with subclinical depressive symptoms had lower gray matter volume in the hippocampus and lower white matter integrity in the fornix and the posterior parts of the cingulum and corpus callosum, compared to participants without symptoms. Hippocampal atrophy was recovered in ADNI, where participants with subclinical depressive symptoms also showed glucose hypometabolism in the hippocampus, amygdala, precuneus/posterior cingulate cortex, medial and dorsolateral prefrontal cortex, insula, and temporoparietal cortex. Subclinical depressive symptoms were not associated with brain amyloid deposition in either cohort. Subclinical depressive symptoms in ageing are linked with neurodegeneration biomarkers in the frontolimbic network including brain areas particularly sensitive to AD. The relationship between depressive symptoms and AD may be partly underpinned by neurodegeneration in common brain regions.

White matter hyperintensity topography in Alzheimer's disease and links to cognition.

INTRODUCTION: White matter hyperintensities (WMH) are often described in Alzheimer's disease (AD), but their topography and specific relationships with cognition remain unclear. METHODS: Regional WMH were estimated in 54 cognitively impaired amyloid beta-positive AD (Aßpos-AD), compared to 40 cognitively unimpaired amyloid beta-negative older controls (Aßneg-controls) matched for vascular risk factors. The cross-sectional association between regional WMH volume and cognition was assessed within each group, controlling for cerebral amyloid burden, global cortical atrophy, and hippocampal atrophy. RESULTS: WMH volume was larger in Aßpos-AD compared to Aßneg-controls in all regions, with the greatest changes in the splenium of the corpus callosum (S-CC). In Aßpos-AD patients, larger total and regional WMH volume, especially in the S-CC, was strongly associated with decreased cognition. DISCUSSION: WMH specifically contribute to lower cognition in AD, independently from amyloid deposition and atrophy. This study emphasizes the clinical relevance of WMH in AD, especially posterior WMH, and most notably S-CC WMH.

Subjective cognitive decline: opposite links to neurodegeneration across the Alzheimer's continuum.

Subjective memory decline is associated with neurodegeneration and increased risk of cognitive decline in participants with no or subjective cognitive impairment, while in patients with mild cognitive impairment or Alzheimer's-type dementia, findings are inconsistent. Our aim was to provide a comprehensive overview of subjective memory decline changes, relative to objective memory performances, and of their relationships with neurodegeneration, across the clinical continuum of Alzheimer's disease. Two hundred participants from the Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce (IMAP+) primary cohort and 731 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) replication cohort were included. They were divided into four clinical groups (Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce/Alzheimer's Disease Neuroimaging Initiative): controls (n = 67/147, age: 60-84/60-90, female: 54/55%), patients with subjective cognitive decline (n = 30/84, age: 54-84/65-80, female: 44/63%), mild cognitive impairment (n = 50/369, age: 58-86/55-88, female: 45/44%) or Alzheimer's-type dementia (n = 36/121, age: 51-86/61-90, female: 41/41%). Subjective and objective memory scores, and their difference (i.e. delta score reflecting memory awareness), were compared between groups. Then, voxelwise relationships between subjective memory decline and neuroimaging measures of neurodegeneration [atrophy (T1-MRI) and hypometabolism (18F-fluorodeoxyglucose-PET)] were assessed across clinical groups and the interactive effect of the level of cognitive impairment within the entire sample was assessed. Analyses were adjusted for age, sex and education, and repeated including only the amyloid-positive participants. In Imagerie Multimodale de la maladie d'Alzheimer à un stade Précoce, the level of subjective memory decline was higher in all patient groups (all P < 0.001) relative to controls, but similar between patient groups. In contrast, objective memory deficits progressively worsened from the subjective cognitive decline to the dementia group (all P < 0.001). Accordingly, the delta score showed a progressive decline in memory awareness across clinical groups (all P < 0.001). Voxelwise analyses revealed opposite relationships between the subjective memory decline score and neurodegeneration across the clinical continuum. In the earliest stages (i.e. patients with subjective cognitive decline or Mini Mental State Examination > 28), greater subjective memory decline was associated with increased neurodegeneration, while in later stages (i.e. patients with mild cognitive impairment, dementia or Mini Mental State Examination < 27) a lower score was related to more neurodegeneration. Similar findings were recovered in the Alzheimer's Disease Neuroimaging Initiative replication cohort, with slight differences according to the clinical group, and in the amyloid-positive subsamples. Altogether, our findings suggest that the subjective memory decline score should be interpreted differently from normal cognition to dementia. Higher scores might reflect greater neurodegeneration in earliest stages, while in more advanced stages lower scores might reflect decreased memory awareness, i.e. more anosognosia associated with advanced neurodegeneration.

Evaluation of the early-phase [18F]AV45 PET as an optimal surrogate of [18F]FDG PET in ageing and Alzheimer's clinical syndrome.

Dual-phase [18F]AV45 positron emission tomography (PET) is highly promising in the assessment of neurodegenerative diseases, allowing to obtain information on both neurodegeneration (early-phase; eAV45) and amyloid deposition (late-phase; lAV45) which are highly complementary; yet eAV45 needs further evaluation. This study aims at validating eAV45 as an optimal proxy of [18F]FDG PET in a large mixed-population of healthy ageing and Alzheimer's clinical syndrome participants (n = 191) who had [18F]FDG PET, eAV45 and lAV45 scans. We found early time frame 0-4 min to give maximal correlation with [18F]FDG PET and minimal correlation with lAV45. Moreover, maximal overlap of [18F]FDG PET versus eAV45 associations with clinical diagnosis and cognition was obtained with pons scaling. Across reference regions, classification performance between clinical subgroups was similar for both eAV45 and [18F]FDG PET. These findings highlight the optimal use of eAV45 to assess neurodegeneration as a validated proxy of [18F]FDG PET. On top of this purpose, this study showed that combined [18F]AV45 PET dual-biomarker even outperformed [18F]FDG PET or lAV45 alone.

Association of quality of life with structural, functional and molecular brain imaging in community-dwelling older adults.

BACKGROUND: As the population ages, maintaining mental health and well-being of older adults is a public health priority. Beyond objective measures of health, self-perceived quality of life (QoL) is a good indicator of successful aging. In older adults, it has been shown that QoL is related to structural brain changes. However, QoL is a multi-faceted concept and little is known about the specific relationship of each QoL domain to brain structure, nor about the links with other aspects of brain integrity, including white matter microstructure, brain perfusion and amyloid deposition, which are particularly relevant in aging. Therefore, we aimed to better characterize the brain biomarkers associated with each QoL domain using a comprehensive multimodal neuroimaging approach in older adults. METHODS: One hundred and thirty-five cognitively unimpaired older adults (mean age ± SD: 69.4 ± 3.8 y) underwent structural and diffusion magnetic resonance imaging, together with early and late florbetapir positron emission tomography scans. QoL was assessed using the brief version of the World Health Organization's QoL instrument, which allows measuring four distinct domains of QoL: self-perceived physical health, psychological health, social relationships and environment. Multiple regression analyses were carried out to identify the independent global neuroimaging predictor(s) of each QoL domain, and voxel-wise analyses were then conducted with the significant predictor(s) to highlight the brain regions involved. Age, sex, education and the other QoL domains were entered as covariates in these analyses. Finally, forward stepwise multiple regressions were conducted to determine the specific items of the relevant QoL domain(s) that contributed the most to these brain associations. RESULTS: Only physical health QoL was associated with global neuroimaging values, specifically gray matter volume and white matter mean kurtosis, with higher physical health QoL being associated with greater brain integrity. These relationships were still significant after correction for objective physical health and physical activity measures. No association was found with global brain perfusion or global amyloid deposition. Voxel-wise analyses revealed that the relationships with physical health QoL concerned the anterior insula and ventrolateral prefrontal cortex, and the corpus callosum, corona radiata, inferior frontal white matter and cingulum. Self-perceived daily living activities and self-perceived pain and discomfort were the items that contributed the most to these associations with gray matter volume and white matter mean kurtosis, respectively. CONCLUSIONS: Better self-perceived physical health, encompassing daily living activities and pain and discomfort, was the only QoL domain related to brain structural integrity including higher global gray matter volume and global white matter microstructural integrity in cognitively unimpaired older adults. The relationships involved brain structures belonging to the salience network, the pain pathway and the empathy network. While previous studies showed a link between objective measures of physical health, our findings specifically highlight the relevance of monitoring and promoting self-perceived physical health in the older population. Longitudinal studies are needed to assess the direction and causality of the relationships between QoL and brain integrity.

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear. Objective: To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism. Design, Setting, and Participants: This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses. Main Outcomes and Measures: Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes. Results: Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms. Conclusions and Relevance: The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

Cross-sectional and longitudinal characterization of SCD patients recruited from the community versus from a memory clinic: subjective cognitive decline, psychoaffective factors, cognitive performances, and atrophy progression over time.

BACKGROUND: Subjective cognitive decline (SCD) defines a heterogeneous population, part of which having Alzheimer's disease (AD). We aimed at characterizing SCD populations according to whether or not they referred to a memory clinic, by assessing the factors associated with increased AD risk. METHODS: Seventy-eight cognitively unimpaired older adults from the IMAP+ study (Caen) were included, amongst which 28 healthy controls (HC) and 50 SCD recruited from the community (SCD-community; n = 23) or from a memory clinic (SCD-clinic; n = 27). Participants underwent cognitive, psychoaffective, structural MRI, FDG-PET, and amyloid-PET assessments. They were followed up over a mean period of 2.4 ± 0.8 years. The groups were compared in terms of baseline and follow-up levels of SCD (self- and informant-reported), cognition, subclinical anxiety and depression, and atrophy progression over time. We also investigated SCD substrates within each SCD group through the correlations between self-reported SCD and other psychometric and brain measures. RESULTS: Compared to HC, both SCD groups showed similar cognitive performances but higher informant-reported SCD and anxiety. Compared to SCD-community, SCD-clinic showed higher informant-reported SCD, depression score, and atrophy progression over time but similar brain amyloid load. A significant increase over time was found for depression in the SCD-community and for self-reported praxis-domestic activities SCD factor in the SCD-clinic. Higher self-reported SCD correlated with (i) lower grey matter volume and higher anxiety in SCD-community, (ii) greater informant-reported SCD in SCD-clinic, and (iii) lower glucose metabolism in both SCD groups. CONCLUSIONS: Higher subclinical depression and informant-reported SCD specifically characterize the SCD group that refers to a memory clinic. The same group appears as a frailer population than SCD-community as they show greater atrophy progression over time. Yet, both the SCD groups were quite similar otherwise including for brain amyloid load and the SCD-community showed increased depression score over time. Altogether, our findings highlight the relevance of assessing psychoaffective factors and informant-reported SCD in SCD populations and point to both differences and similarities in SCD populations referring or not to a memory clinic.

Current rectification in a single molecule diode: the role of electrode coupling.

We demonstrate large rectification ratios (> 100) in single-molecule junctions based on a metal-oxide cluster (polyoxometalate), using a scanning tunneling microscope (STM) both at ambient conditions and at low temperature. These rectification ratios are the largest ever observed in a single-molecule junction, and in addition these junctions sustain current densities larger than 10(5) A cm(-2). By following the variation of the I-V characteristics with tip-molecule separation we demonstrate unambiguously that rectification is due to asymmetric coupling to the electrodes of a molecule with an asymmetric level structure. This mechanism can be implemented in other type of molecular junctions using both organic and inorganic molecules and provides a simple strategy for the rational design of molecular diodes.