Brain age as a biomarker for pathological versus healthy ageing - a REMEMBER study.

OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.

An extension of the novelty-seeking model: Considering the plurality of novelty types and their differential interactions with memory.

The novelty-seeking model suggests that curiosity and creativity originate from novelty processes. However, different types of novelty exist, each with distinctive relationships with memory, which potentially influence curiosity and creativity in distinct ways. We thus propose expanding the NSM model to consider these different novelty types and their specific involvement in creativity.

Awareness and cognitive rehabilitation in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: Awareness influences the evolution of neurodegenerative dementias. We gathered participants' and caregivers assessments of dependence in daily activities and we studied how each score would be related to next year participant autonomy, independently of other explicative variables. METHOD: We retrospectively analyzed data from mildly demented participants with a clinical diagnosis of Alzheimer's disease (AD, n = 186) and frontotemporal dementia (FTD, n = 29) and their relatives. A research tool was used to assess participant dependence in 98 daily activities and associated caregiver burden. A discrepancy score between the patient's and relative's judgment was calculated to evaluate awareness of dependence in activities at baseline. This dependence scores, as well as sex, age, education, and 1 year difference in Mini-Mental State Examination were taken as possible explicative variables for dependence in activities adapted by therapists during a 1-year cognitive rehabilitation program. RESULTS: Patients with FTD showed less awareness for daily dependence (discrepancy 20.9% vs. 11.8% in AD). Both groups benefited from cognitive rehabilitation (25% decrease in dependence) and subjective burden of relatives was decreased in both groups. In the AD group, there was a significant positive relationship between both caregiver (P < 0.001) and participant's (P < 0.02) evaluation of dependence in daily activities at inclusion and dependence of participants in adapted activities after 1 year. DISCUSSION: Awareness of impairment in daily activities is a clinical symptom that is more important at inclusion in FTD than in AD. However, in participants with AD who, as a group, significantly benefit from a cognitive rehabilitation program, not only caregiver's but also participant's assessment of dependence at baseline is correlated to subsequent, next year greater dependence in daily activities adapted by the therapists. Although discrepant, both caregiver and participant evaluations appear to be important variables to understand the evolution and the benefit of care in participants at early stages of dementia.

Contextual novelty detection and novelty-related memory enhancement in amnestic mild cognitive impairment.

INTRODUCTION: Though novelty processing plays a critical role in memory function, little is known about how it influences learning in memory-impaired populations, such as amnestic Mild Cognitive Impairment (aMCI). METHODS: 21 aMCI patients and 22 age- and education-matched healthy older participants performed two tasks-(i) an oddball paradigm where fractals that were often repeated (60 % of the stimuli), less frequently repeated (20 %), or novel (presented once each) were shown to assess novelty preference (longer viewing time for novel than familiar stimuli), and (ii) a Von Restorff paradigm assessing novelty-related effects on memory. Participants studied 22 lists of 10 words. Among these lists, 18 contained an isolated word different from the others by its distinctive aspect, here the font size (90-point, 120-point or 150-point against 60-point for non-isolated words). The remaining four were control lists without isolated words. After studying each list, participants freely recalled the maximum words possible. RESULTS: For the oddball task, a group-by-stimulus type ANOVA on median viewing times revealed a significant effect of stimulus type, but not of group. Both groups spent more time on novel stimuli. For the Von Restorff task, both aMCI and healthy controls recalled the isolated words (presented in 120-point or 150-point, but not 90-point) better than others (excluding primacy and recency effects). Novelty-related memory benefit-gain factor-was computed as the difference between the recall scores for isolated and other words. A group-by-font size ANOVA on gain factors revealed no group effect, nor interaction, suggesting that aMCI patients benefited from novelty, alike controls. CONCLUSION: Novelty preference and the boosting effect of isolation-related novelty on subsequent recall seem preserved despite impaired episodic memory in aMCI patients. This is discussed in the light of contemporary divergent theories regarding the relationship between novelty and memory, as either being independent or parts of a continuum.

Neural correlates of impaired cognitive processes underlying self-unawareness in Alzheimer's disease.

Self-unawareness concerning current symptoms remains a clinical challenge in Alzheimer's disease. Reduced self-awareness likely depends on complex biopsychosocial mechanisms that comprise multiple cognitive processes, regulated by personal goals and values. We specifically reviewed the cognitive processes impaired in unaware participants with AD by emphasizing the related impaired brain activity observed during task-based fMRI. Unawareness can be explained by a failure in functioning of or in connection between brain regions that intervene in access, retrieval and updating of (present or extended) self-information (posterior midline, medial temporal, inferior parietal cortices), or in its monitoring, evaluation, or control (medial and lateral prefrontal cortices). Although one must be cautious when relating function to brain regions, impaired processes were tentatively related to the Cognitive Awareness Model. Although brain function depends on neural networks, impaired brain activity during cognitive processes was discussed according to previous studies reporting correlations between brain regions and scores of anosognosia. The review provides a framework to help clinicians considering processes that can explain unawareness in dementia. In patients at early stages of AD, different levels of awareness of cognitive or social clinical changes might be described as impairment in the interaction between specific cognitive processes and contents.

Prediction of cognitive decline in healthy aging based on neuropsychiatric symptoms and PET-biomarkers of Alzheimer's disease.

Neuropsychiatric symptoms (NPS) have been associated with a risk of accelerated cognitive decline or conversion to dementia of the Alzheimer's Disease (AD) type. Moreover, the NPS were also associated with higher AD biomarkers (brain tau and amyloid burden) even in non-demented patients. But the effect of the relationship between NPS and biomarkers on cognitive decline has not yet been studied. This work aims to assess the relationship between longitudinal cognitive changes and NPS, specifically depression and anxiety, in association with AD biomarkers in healthy middle-aged to older participants. The cohort consisted of 101 healthy participants aged 50-70 years, 66 of whom had neuropsychological assessments of memory, executive functions, and global cognition at a 2-year follow-up. At baseline, NPS were assessed using the Beck Depression and Anxiety Inventories while brain tau and amyloid loads were measured using positron emission topography. For tau burden, THK5351 uptake is used as a proxy of tau and neuroinflammation. Participants, declining or remaining stable at follow-up, were categorized into groups for each cognitive domain. Group classification was investigated using binary logistic regressions based on combined AD biomarkers and the two NPS. The results showed that an association between anxiety and prefrontal amyloid burden significantly classified episodic memory decline, while the classification of global cognitive decline involved temporal and occipital amyloid burden but not NPS. Moreover, depression together with prefrontal and hippocampal tau burden were associated with a decline in memory. The classification of participants based on executive decline was related to depression and mainly prefrontal tau burden. These findings suggest that the combination of NPS and brain biomarkers of AD predicts the occurrence of cognitive decline in aging.

Neuropsychological predictions on involuntary autobiographical memory and déjà vu.

I strongly support Barzykowski and Moulin in their proposal that common retrieval mechanisms can lead to distinct phenomenological memory experiences. I emphasize the importance of one of these mechanisms, namely the attribution system. Neuropsychological studies should help clarifying the role of these retrieval mechanisms, notably in cases of medial temporal-lobe lesions and cases of dementia.

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).

Multimodal imaging of microstructural cerebral alterations and loss of synaptic density in Alzheimer's disease.

Multiple neuropathological events are involved in Alzheimer's disease (AD). The current study investigated the concurrence of neurodegeneration, increased iron content, atrophy, and demyelination in AD. Quantitative multiparameter magnetic resonance imaging (MRI) maps providing neuroimaging biomarkers for myelination and iron content along with synaptic density measurements using [18F] UCB-H PET were acquired in 24 AD and 19 Healthy controls (19 males). The whole brain voxel-wise group comparison revealed demyelination in the right hippocampus, while no significant iron content difference was detected. Bilateral atrophy and synaptic density loss were observed in the hippocampus and amygdala. The multivariate GLM (mGLM) analysis shows a bilateral difference in the hippocampus and amygdala, right pallidum, left fusiform and temporal lobe suggesting that these regions are the most affected despite the diverse differences in brain tissue properties in AD. Demyelination was identified as the most affecting factor in the observed differences. Here, the mGLM is introduced as an alternative for multiple comparisons between different modalities, reducing the risk of false positives while informing about the co-occurrence of neuropathological processes in AD.

Targeting the function of the transentorhinal cortex to identify early cognitive markers of Alzheimer's disease.

Initial neuropathology of early Alzheimer's disease accumulates in the transentorhinal cortex. We review empirical data suggesting that tasks assessing cognitive functions supported by the transenthorinal cortex are impaired as early as the preclinical stages of Alzheimer's disease. These tasks span across various domains, including episodic memory, semantic memory, language, and perception. We propose that all tasks sensitive to Alzheimer-related transentorhinal neuropathology commonly rely on representations of entities supporting the processing and discrimination of items having perceptually and conceptually overlapping features. In the future, we suggest a screening tool that is sensitive and specific to very early Alzheimer's disease to probe memory and perceptual discrimination of highly similar entities.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

INTRODUCTION: Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). METHODS: We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. RESULTS: The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. DISCUSSION: Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

A day that America will remember: flashbulb memory, collective memory, and future thinking for the capitol riots.

ABSTRACTThis study explores the topics of flashbulb memory, collective identity, future thinking, and shared representations for a public event. We assessed the memories of the Capitol Riots, which happened in Washington DC, on 6 January 2021. Seventy Belgian and seventy-nine American citizens participated in an online study, in which they freely recalled the unfolding of Capitol Riots and answered questions regarding their memory. Inter-subjects similarity of recalled details was analysed using a schematic narrative template (i.e., the event, the causes and the consequences). Results revealed that representations of the event, and its causes were more similar among Belgians compared to Americans, whereas Americans' representations of the consequences showed more similarity than Belgians'. Also, as expected, Americans reported more flashbulb memories (FBMs) than Belgians. The analysis underlined the importance of rehearsal through media and communication in FBM formation. This research revealed a novel relation between FBM and future representations. Regardless of national identity, participants who formed an FBM were more likely to think that the event would be remembered in the future, that the government should memorialise the event, and that a similar attack on the Capitol could happen in the future compared to participants who did not form FBM.

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.

Effort during prolonged wakefulness is associated with performance to attentional and executive tasks but not with cortical excitability in late-middle-aged healthy individuals.

OBJECTIVE: Sleep loss negatively affects brain function with repercussion not only on objective measures of performance but also on many subjective dimensions, including effort perceived for the completion of cognitive processes. This may be particularly important in aging, which is accompanied by important changes in sleep and wakefulness regulation. We aimed to determine whether subjectively perceived effort covaried with cognitive performance in healthy late-middle-aged individuals. METHOD: We assessed effort and performance to cognitive tasks in 99 healthy adults (66 women; 50-70 years) during a 20-hr wake extension protocol, following 7 days of regular sleep and wake times and a baseline night of sleep in the laboratory. We further explored links with cortical excitability using transcranial magnetic stimulation coupled to electroencephalography. RESULTS: Perceived effort increased during wake extension and was highly correlated to subjective metrics of sleepiness, fatigue, and motivation, but not to variations in cortical excitability. Moreover, effort increase was associated with decreased performance to some cognitive tasks (psychomotor vigilance and two-back working memory task). Importantly, effort variations during wakefulness extension decreased from age 50 to 70 years, while more effort is associated with worse performance in older individuals. CONCLUSION: In healthy late-middle-aged individuals, more effort is perceived to perform cognitive tasks, but it is not sufficient to overcome the performance decline brought by lack of sleep. Entry in the seventh decade may stand as a turning point in the daily variations of perceived effort and its link with cognition. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The use of distraction to improve episodic memory in ageing: A review of methods and theoretical implications.

Healthy ageing is characterized by changes in several cognitive functions, including episodic memory and inhibition. While the age-related decrease in the ability to inhibit irrelevant stimuli is often associated with lower performance, especially in episodic memory, some studies have highlighted the boosting effect of distraction in several tasks in older adults, including episodic memory tasks related to recollection. The aim of this article is to review and compare previous studies according to specific study features and to consider the results in light of the dual-process model of recollection and familiarity that were used by the authors of the reviewed articles. This work led to the identification of two major points of comparison between the studies: the timeline of the distraction intervention and the implicit nature of the processes at play, which both allowed for different implications to the relationship with recollection. The use of distraction in memory tasks can enhance episodic memory, and especially recollective processes, due to specific actions at encoding and retrieval. These findings open the door to further investigations but also raise several questions concerning the role of implicit processes and the negative impact of distraction, for example. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Frontal grey matter microstructure is associated with sleep slow waves characteristics in late midlife.

STUDY OBJECTIVES: The ability to generate slow waves (SW) during non-rapid eye movement (NREM) sleep decreases as early as the 5th decade of life, predominantly over frontal regions. This decrease may concern prominently SW characterized by a fast switch from hyperpolarized to depolarized, or down-to-up, state. Yet, the relationship between these fast and slow switcher SW and cerebral microstructure in ageing is not established. METHODS: We recorded habitual sleep under EEG in 99 healthy late midlife individuals (mean age = 59.3 ± 5.3 years; 68 women) and extracted SW parameters (density, amplitude, frequency) for all SW as well as according to their switcher type (slow vs. fast). We further used neurite orientation dispersion and density imaging (NODDI) to assess microstructural integrity over a frontal grey matter region of interest (ROI). RESULTS: In statistical models adjusted for age, sex, and sleep duration, we found that a lower SW density, particularly for fast switcher SW, was associated with a reduced orientation dispersion of neurites in the frontal ROI (p = 0.018, R2ß* = 0.06). In addition, overall SW frequency was positively associated with neurite density (p = 0.03, R2ß* = 0.05). By contrast, we found no significant relationships between SW amplitude and NODDI metrics. CONCLUSIONS: Our findings suggest that the complexity of neurite organization contributes specifically to the rate of fast switcher SW occurrence in healthy middle-aged individuals, corroborating slow and fast switcher SW as distinct types of SW. They further suggest that the density of frontal neurites plays a key role for neural synchronization during sleep. TRIAL REGISTRATION NUMBER: EudraCT 2016-001436-35.

Timely coupling of sleep spindles and slow waves linked to early amyloid-ß burden and predicts memory decline.

Sleep alteration is a hallmark of ageing and emerges as a risk factor for Alzheimer's disease (AD). While the fine-tuned coalescence of sleep microstructure elements may influence age-related cognitive trajectories, its association with AD processes is not fully established. Here, we investigated whether the coupling of spindles and slow waves (SW) is associated with early amyloid-ß (Aß) brain burden, a hallmark of AD neuropathology, and cognitive change over 2 years in 100 healthy individuals in late-midlife (50-70 years; 68 women). We found that, in contrast to other sleep metrics, earlier occurrence of spindles on slow-depolarisation SW is associated with higher medial prefrontal cortex Aß burden (p=0.014, r²ß*=0.06) and is predictive of greater longitudinal memory decline in a large subsample (p=0.032, r²ß*=0.07, N=66). These findings unravel early links between sleep, AD-related processes, and cognition and suggest that altered coupling of sleep microstructure elements, key to its mnesic function, contributes to poorer brain and cognitive trajectories in ageing.

Shared vivid remembering: age-related differences in across-participants similarity of neural representations during encoding and retrieval.

Recent advances in multivariate neuroimaging analyses have made possible the examination of the similarity of the neural patterns of activations measured across participants, but it has not been investigated yet whether such measure is age-sensitive. Here, in the scanner, young and older participants viewed scene pictures associated with labels. At test, participants were presented with the labels and were asked to recollect the associated picture. We used Pattern Similarity Analyses by which we compared patterns of neural activation during the encoding or the remembering of each picture of one participant with the averaged pattern of activation across the remaining participants. Results revealed that across-participants neural similarity was higher in young than in older adults in distributed occipital, temporal and parietal areas during encoding and retrieval. These findings demonstrate that an age-related reduction in specificity of neural activation is also evident when the similarity of neural representations is examined across participants.

Feeling the ease: How the use of oral motor fluency changes in amnesia.

The present study examined the evolution observed in amnesic patients' use of motor fluency when making recognition memory decisions. In this experiment, 9 patients with amnesia and 18 matched controls were presented with two recognition memory tasks composed of 3 types of items: (1) natural words, (2) nonwords difficult to pronounce, and (3) nonwords easy to pronounce, the latter having been shown to be processed in a surprisingly fluent manner as long as participants can articulate them at a subvocal level (i.e., oral motor fluency). Our results provide evidence that the motor-movement manipulation was successful to induce a fluency effect. More specifically, data revealed that both amnesic patients and control participants showed a pattern of response consistent with the use of fluency as a cue to memory for studied items. However, only control participants relied on fluency to increase their rate of "yes" responses for unstudied items. These results suggest that patients with amnesia set a more conservative response criterion before relying on oral motor fluency, showing a pattern consistent with the idea that fluency is only used as a cue to memory when it exceeds a certain threshold. These findings are discussed in terms of adaptative metacognition strategies implemented by amnesic patients to reduce fluency-based memory errors as well as in terms of the variations that seem to occur in these strategies depending on the type of fluency that is experienced.