Differential functions of the dorsal and intermediate regions of the hippocampus for optimal goal-directed navigation in VR space.

Goal-directed navigation requires the hippocampus to process spatial information in a value-dependent manner, but its underlying mechanism needs to be better understood. Here, we investigated whether the dorsal (dHP) and intermediate (iHP) regions of the hippocampus differentially function in processing place and its associated value information. Rats were trained in a place-preference task involving reward zones with different values in a visually rich virtual reality environment where two-dimensional navigation was possible. Rats learned to use distal visual scenes effectively to navigate to the reward zone associated with a higher reward. Inactivation of both dHP and iHP with muscimol altered the efficiency and precision of wayfinding behavior, but iHP inactivation induced more severe damage, including impaired place preference. Our findings suggest that the iHP is more critical for value-dependent navigation toward higher-value goal locations.

Predictors of long-term memory and network connectivity 10 years after anterior temporal lobe resection.

OBJECTIVE: Anterior temporal lobe resection (ATLR) effectively controls seizures in medically refractory temporal lobe epilepsy but risks significant episodic memory decline. Beyond 1 year postoperatively, the influence of preoperative clinical factors on episodic memory and long-term network plasticity remain underexplored. Ten years post-ATLR, we aimed to determine biomarkers of successful memory network reorganization and establish presurgical features' lasting impact on memory function. METHODS: Twenty-five ATLR patients (12 left-sided) and 10 healthy controls underwent a memory-encoding functional magnetic resonance imaging paradigm alongside neuropsychometry 10 years postsurgery. Generalized psychophysiological interaction analyses modeled network functional connectivity of words/faces remembered, seeding from the medial temporal lobes (MTLs). Differences in successful memory connectivity were assessed between controls and left/right ATLR. Multivariate regressions and mixed-effect models probed preoperative phenotypes' effects on long-term memory outcomes. RESULTS: Ten years post-ATLR, lower baseline functioning (verbal and performance intelligence quotient) and a focal memory impairment preoperatively predicted worse long-term memory outcomes. Poorer verbal memory was significantly associated with longer epilepsy duration and earlier onset age. Relative to controls, successful word and face encoding involved increased functional connectivity from both or remnant MTL seeds and contralesional parahippocampus/hippocampus after left/right ATLR. Irrespective of surgical laterality, successful memory encoding correlated with increased MTL-seeded connectivity to frontal (bilateral insula, right anterior cingulate), right parahippocampal, and bilateral fusiform gyri. Ten years postsurgery, better memory performance was correlated with contralateral frontal plasticity, which was disrupted with longer epilepsy duration. SIGNIFICANCE: Our findings underscore the enduring nature of functional network reorganizations to provide long-term cognitive support. Ten years post-ATLR, successful memory formation featured stronger connections near resected areas and contralateral regions. Preoperative network disruption possibly influenced effectiveness of postoperative plasticity. These findings are crucial for enhancing long-term memory prediction and strategies for lasting memory rehabilitation.

Exploring Memory Systems After Pediatric Posterior Fossa Tumor: From Memory Profile Comparisons in Nonirradiated Versus Irradiated Patients to Episodic Memory Tests Capable of Detecting Radiation-induced Hippocampal Damage.

AIMS: Pediatric posterior fossa tumor (PFT) survivors experience long-term cognitive sequelae, including memory disorders, for which irradiation is one of the main risk factors. The aims of the present study were to (1) explore the profile of impairment in episodic, semantic, working and procedural memory systems in irradiated versus nonirradiated PFT survivors, and (2) test whether an autobiographical questionnaire and a two-phase ecological test (Epireal) assessing episodic memory are more sensitive to radiation-induced hippocampal damage than commonly used tests. MATERIALS AND METHODS: A total of 60 participants (22 irradiated PFT survivors, 17 nonirradiated PFT survivors, and 21 controls) were included in the prospective IMPALA study. They all underwent a broad battery of tests assessing the different memory systems in two 2-day sessions 3 weeks apart. We performed between-groups comparisons and analyzed impairment profiles, using -1.65 SDs as a cut-off. For irradiated patients, correlations were calculated between mean radiation doses to key brain structures involved in memory (hippocampus, cerebellum, and striatum) and corresponding memory scores. RESULTS: PBT survivors performed significantly more poorly than controls (p < 0.001) on conventional tests of episodic, semantic and working memory: 64% of irradiated patients and 35% of nonirradiated patients had a deficit in at least two memory systems, with episodic memory impairment being more specific to the irradiated group. Epireal had a larger effect size than the other episodic memory tests, allowing us to detect deficits in a further 18% of irradiated patients. These deficits were correlated with the mean radiation dose to the left hippocampus. CONCLUSION: Memory impairment is a frequent long-term cognitive sequela in PFT survivors, especially after radiation therapy. New ecological tests of episodic memory that are more sensitive to radiation-induced deficits than conventional tests could yield specific markers of the toxicity of medial temporal lobe irradiation.

Menopause status- and sex-related differences in age associations with spatial context memory and white matter microstructure at midlife.

Decline in spatial context memory emerges in midlife, the time when most females transition from pre- to post-menopause. Recent evidence suggests that, among post-menopausal females, advanced age is associated with functional brain alterations and lower spatial context memory. However, it is unknown whether similar effects are evident for white matter (WM) and, moreover, whether such effects contribute to sex differences at midlife. To address this, we conducted a study on 96 cognitively unimpaired middle-aged adults (30 males, 32 pre-menopausal females, 34 post-menopausal females). Spatial context memory was assessed using a face-location memory paradigm, while WM microstructure was assessed using diffusion tensor imaging. Behaviorally, advanced age was associated with lower spatial context memory in post-menopausal females but not pre-menopausal females or males. Additionally, advanced age was associated with microstructural variability in predominantly frontal WM (e.g., anterior corona radiata, genu of corpus callosum), which was related to lower spatial context memory among post-menopausal females. Our findings suggest that post-menopausal status enhances vulnerability to age effects on the brain's WM and episodic memory.

Lifespan differences in hippocampal subregion connectivity patterns during movie watching.

Age-related episodic memory decline is attributed to functional alternations in the hippocampus. Less clear is how aging affects the functional connections of the hippocampus to the rest of the brain during episodic memory processing. We examined fMRI data from the CamCAN dataset, in which a large cohort of participants watched a movie (N = 643; 18-88 years), a proxy for naturalistic episodic memory encoding. We examined connectivity profiles across the lifespan both within the hippocampus (anterior, posterior), and between the hippocampal subregions and cortical networks. Aging was associated with reductions in contralateral (left, right) but not ipsilateral (anterior, posterior) hippocampal subregion connectivity. Aging was primarily associated with increased coupling between the anterior hippocampus and regions affiliated with Control, Dorsal Attention and Default Mode networks, yet decreased coupling between the posterior hippocampus and a selection of these regions. Differences in age-related hippocampal-cortical, but not within-hippocampus circuitry selectively predicted worse memory performance. Our findings comprehensively characterize hippocampal functional topography in relation to cognition in older age, suggesting that shifts in cortico-hippocampal connectivity may be sensitive markers of age-related episodic memory decline.

Modeling the contribution of theta-gamma coupling to sequential memory, imagination, and dreaming.

Gamma oscillations nested in a theta rhythm are observed in the hippocampus, where are assumed to play a role in sequential episodic memory, i.e., memorization and retrieval of events that unfold in time. In this work, we present an original neurocomputational model based on neural masses, which simulates the encoding of sequences of events in the hippocampus and subsequent retrieval by exploiting the theta-gamma code. The model is based on a three-layer structure in which individual Units oscillate with a gamma rhythm and code for individual features of an episode. The first layer (working memory in the prefrontal cortex) maintains a cue in memory until a new signal is presented. The second layer (CA3 cells) implements an auto-associative memory, exploiting excitatory and inhibitory plastic synapses to recover an entire episode from a single feature. Units in this layer are disinhibited by a theta rhythm from an external source (septum or Papez circuit). The third layer (CA1 cells) implements a hetero-associative net with the previous layer, able to recover a sequence of episodes from the first one. During an encoding phase, simulating high-acetylcholine levels, the network is trained with Hebbian (synchronizing) and anti-Hebbian (desynchronizing) rules. During retrieval (low-acetylcholine), the network can correctly recover sequences from an initial cue using gamma oscillations nested inside the theta rhythm. Moreover, in high noise, the network isolated from the environment simulates a mind-wandering condition, randomly replicating previous sequences. Interestingly, in a state simulating sleep, with increased noise and reduced synapses, the network can "dream" by creatively combining sequences, exploiting features shared by different episodes. Finally, an irrational behavior (erroneous superimposition of features in various episodes, like "delusion") occurs after pathological-like reduction in fast inhibitory synapses. The model can represent a straightforward and innovative tool to help mechanistically understand the theta-gamma code in different mental states.

Identifying the nature of episodic memory deficits in Major Depressive Disorder using a Real-World What-Where-When task.

ABSTRACTDeficits in episodic memory have been reported in various psychiatric conditions, including Major Depressive Disorder (MDD). Many widely used episodic memory tests do not have the ability to distinguish between impaired memory of separate components of a real-life event (e.g., what happened, where it happened and when), and impaired binding of such real-life features. To address this issue, a naturalistic, real-world What-Where-When memory task was employed to assess the nature of episodic memory impairments in MDD. A validation study established that the task is sensitive to age-related episodic memory changes, and that intentional encoding does not invalidate the task. The main study then compared the performance of patients with depression and control participants on the intentionally encoded WWW task. Patients with MDD presented an overall episodic memory impairment arising from deficits in object memory and the ability to bind objects to temporal context. Taken together, our study confirms the episodic memory impairment in MDD, by providing evidence of deficient object memory and reduced ability to bind temporal context to objects in patients. Our naturalistic WWW task presents a promising approach for thorough identification of the nature of episodic memory impairments, under a real-world environment, in various conditions, including MDD.

The influence of emotion on temporal context models.

Temporal context models (TCMs) have been influential in understanding episodic memory and its neural underpinnings. Recently, TCMs have been extended to explain emotional memory effects, one of the most clinically important findings in the field of memory research. This review covers recent advances in hypotheses for the neural representation of spatiotemporal context through the lens of TCMs, including their ability to explain the influence of emotion on episodic and temporal memory. In recent years, simplifying assumptions of "classical" TCMs - with exponential trace decay and the mechanism by which temporal context is recovered - have become increasingly clear. The review also outlines how recent advances could be incorporated into a future TCM, beyond classical assumptions, to integrate emotional modulation.

WeChat usage and preservation of cognitive functions in middle-aged and older Chinese adults: indications from a nationally representative survey, 2018-2020.

PURPOSE: To investigate the associations between the most popular social media platform WeChat usage and cognitive performance among the middle-aged and older Chinese population using data from a nationally representative survey. METHODS: In total, 17,472 participants (≥ 45 years old) from the China Health and Retirement Longitudinal Study (CHARLS, Wave 4, 2018) were analyzed. Cognitive performance including episodic memory and executive function was assessed using Mini-Mental Status Examination (MMSE). Other confounding variables included socio-economic characteristics, medical status, and lifestyle-related information. Multiple linear regression models were used to test the association between cognitive performance and WeChat usage by introducing covariates hierarchically. Subgroup analyses of age and gender were conducted to estimate the robustness of the primary findings. RESULTS: After adjusting for multiple confounders across all linear models, WeChat usage is significantly associated with executive function, episodic memory, and global cognitive performance (all p values<0.05). Such results remained robust in subgroup analyses, stratified by age and gender, and also verified according to longitudinal analyses. Compared to 'Chat-only' users who only used WeChat for online interpersonal communication, further usage of WeChat functions such as using 'Moments' appeared to be significantly associated with better cognitive performance, especially for episodic memory. CONCLUSION: Social media usage is significantly and positively associated with better cognitive performance among the middle-aged and older Chinese population. Along with point-to-point messaging, using 'Moments' and extended social media platform functions may correlate to better cognitive performance.

'Citicoline' and support of the memory function: Evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006.

Following an application from Egde Pharma Sp. z o.o, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Poland, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to citicoline and memory. The Panel considers that the food, citicoline (cytidine 5-diphosphocholine, CDP-Choline) inner salt, is sufficiently characterised. Improvement, maintenance or reduced loss of memory is a beneficial physiological effect for middle-aged or elderly adults encountering age-associated subjective memory impairment. The applicant identified three pertinent human intervention studies in healthy individuals that investigated the effect of citicoline on memory. In weighing the evidence, the Panel took into account that only one randomised controlled trial in healthy participants showed a beneficial effect of citicoline on episodic memory when consumed at doses of 500 mg/day for 12 weeks, whereas this effect has not been observed in another study using citicoline at doses of 1 g/day for 3 months or supported by data obtained in patients with dementia using doses of 1 g/day for 12 weeks and 12 months. No convincing evidence of a plausible mechanism by which citicoline or any of its components (in addition to their endogenous synthesis) could exert an effect on memory in humans has been provided. The Panel concludes that a cause-and-effect relationship has not been established between the consumption of citicoline (CDP-Choline) inner salt and improvement, maintenance or reduced loss of memory in middle-aged or elderly adults encountering age-associated subjective memory impairment.

Episodic-like memory in wild free-living blue tits and great tits.

Episodic-like memory in non-human animals represents the behavioral characteristics of human episodic memory-the ability to mentally travel backward in time to "re-live" past experiences. A focus on traditional model species of episodic-like memory may overlook taxa possessing this cognitive ability and consequently its evolution across species. Experiments conducted in the wild have the potential to broaden the scope of episodic-like memory research under the natural conditions in which they evolved. We combine two distinct yet complementary episodic-like memory tasks (the what-where-when memory and incidental encoding paradigms), each targeting a different aspect of human episodic memory, namely the content (what-where-when) and process (incidental encoding), to comprehensively test the memory abilities of wild, free-living, non-caching blue tits (Cyanistes caeruleus) and great tits (Parus major). Automated feeders with custom-built programs allowed for experimental manipulation of spatiotemporal experiences on an individual-level basis. In the what-where-when memory experiment, after learning individualized temporal feeder rules, the birds demonstrated their ability to recall the "what" (food type), "where" (feeder location), and "when" (time since their initial visit of the day) of previous foraging experiences. In the incidental encoding experiment, the birds showed that they were able to encode and recall incidental spatial information regarding previous foraging experiences ("where" test), and juveniles, but not adults, were also able to recall incidentally encoded visual information ("which" test). Consequently, this study presents multiple lines of converging evidence for episodic-like memory in a wild population of generalist foragers, suggesting that episodic-like memory may be more taxonomically widespread than previously assumed.

Algorithmic Spaced Retrieval Enhances Long-Term Memory in Alzheimer Disease: Case-Control Pilot Study.

BACKGROUND: Spaced retrieval is a learning technique that involves engaging in repeated memory testing after increasingly lengthy intervals of time. Spaced retrieval has been shown to improve long-term memory in Alzheimer disease (AD), but it has historically been difficult to implement in the everyday lives of individuals with AD. OBJECTIVE: This research aims to determine, in people with mild cognitive impairment (MCI) due to AD, the efficacy and feasibility of a mobile app that combines spaced retrieval with a machine learning algorithm to enhance memory retention. Specifically, the app prompts users to answer questions during brief daily sessions, and a machine learning algorithm tracks each user's rate of forgetting to determine the optimal spacing schedule to prevent anticipated forgetting. METHODS: In this pilot study, 61 participants (young adults: n=21, 34%; healthy older adults: n=20, 33%; people with MCI due to AD: n=20, 33%) used the app for 4 weeks to learn new facts and relearn forgotten name-face associations. Participation during the 4-week period was characterized by using the app once per day to answer 15 questions about the facts and names. After the 4-week learning phase, participants completed 2 recognition memory tests approximately 1 week apart, which tested memory for information they had studied using the app as well as information they had not studied. RESULTS: After using the mobile app for 1 month, every person with MCI due to AD demonstrated improvements in memory for new facts that they had studied via the app compared to baseline (P<.001). All but one person with MCI due to AD (19/20, 95%) showed improvements of more than 10 percentage points, comparable to the improvements shown by young adults and healthy older adults. Memory for name-face associations was similarly improved for all participant groups after using the app but to a lesser degree. Furthermore, for both new facts and name-face associations, we found no memory decay for any participant group after they took a break of approximately 1 week from using the app at the end of the study. Regarding usability, of the 20 people with MCI due to AD, 16 (80%) self-adhered to the app's automated practice schedule, and half of them (n=10, 50%) expressed an interest in continuing to use it. CONCLUSIONS: These results demonstrate early evidence that spaced retrieval mobile apps are both feasible for people with early-stage AD to use in their everyday lives and effective for supporting memory retention of recently learned facts and name-face associations.

Affective music during episodic memory recollection modulates subsequent false emotional memory traces: an fMRI study.

Music is a powerful medium that influences our emotions and memories. Neuroscience research has demonstrated music's ability to engage brain regions associated with emotion, reward, motivation, and autobiographical memory. While music's role in modulating emotions has been explored extensively, our study investigates whether music can alter the emotional content of memories. Building on the theory that memories can be updated upon retrieval, we tested whether introducing emotional music during memory recollection might introduce false emotional elements into the original memory trace. We developed a 3-day episodic memory task with separate encoding, recollection, and retrieval phases. Our primary hypothesis was that emotional music played during memory recollection would increase the likelihood of introducing novel emotional components into the original memory. Behavioral findings revealed two key outcomes: 1) participants exposed to music during memory recollection were more likely to incorporate novel emotional components congruent with the paired music valence, and 2) memories retrieved 1 day later exhibited a stronger emotional tone than the original memory, congruent with the valence of the music paired during the previous day's recollection. Furthermore, fMRI results revealed altered neural engagement during story recollection with music, including the amygdala, anterior hippocampus, and inferior parietal lobule. Enhanced connectivity between the amygdala and other brain regions, including the frontal and visual cortex, was observed during recollection with music, potentially contributing to more emotionally charged story reconstructions. These findings illuminate the interplay between music, emotion, and memory, offering insights into the consequences of infusing emotional music into memory recollection processes.

Variation in encoding context benefits item recognition.

The current study assesses whether varying the encoding context of a repeated event is a potential strategy to improve recognition memory across retrieval contexts. Context variability, also known as encoding variability, has historically been investigated primarily using recall and cued recall tasks, with the consensus being that encoding variability is not necessarily beneficial for episodic retrieval. However, recent studies (see text) suggest that test type may determine the strategy's effectiveness. Aligned with these recent findings, we found consistent benefits to simple item recognition when a word was studied in more variable contexts compared to less variable contexts across four experiments. This main effect of context variability occurred when crossed with a manipulation of repetition spacing and when crossed with a manipulation of encoding-retrieval context match. Variation in encoding contexts beyond the future retrieval context led to better item recognition than repeated study exposures within the future retrieval context. We argue that the current study and other recent findings indicate a need to re-evaluate the historical consensus on encoding variability as a beneficial strategy for learning.

Effect of levels-of-processing on rates of forgetting.

The levels-of-processing (LOP) framework, proposing that deep processing yields superior retention, has provided an important paradigm for memory research and a practical means of improving learning. However, the available levels-of-processing literature focuses on immediate memory performance. It is assumed within the LOP framework that deep processing will lead to slower forgetting than will shallow processing. However, it is unclear whether, or how, the initial level of processing affects the forgetting slopes over longer retention intervals. The present three experiments were designed to explore whether items encoded at qualitatively different LOP are forgotten at different rates. In the first two experiments, depth of processing was manipulated within-participants at encoding under deep and shallow conditions (semantic vs. rhyme judgement in Experiment 1; semantic vs. consonant-vowel pattern decision in Experiment 2). Recognition accuracy (d prime) was measured between-participants immediately after learning and at 30-min, 2-h, and 24-h delays. The third experiment employed a between-participants design, contrasting the rates of forgetting following semantic and phonological (rhyme) processing at immediate, 30-min, 2-h, and 6-h delays. Results from the three experiments consistently demonstrated a large effect size of levels of processing on immediate performance and a medium-to-large level effect size on delayed recognition, but crucially no LOP × delay group interaction. Analysis of the retention curves revealed no significant differences between the slopes of forgetting for deep and shallow processing. These results suggest that the rates of forgetting are independent of the qualitatively distinct encoding operations manipulated by levels of processing.

Active maintenance in working memory reinforces bindings for future retrieval from episodic long-term memory.

Many theories assume that actively maintaining information in working memory (WM) predicts its retention in episodic long-term memory (LTM), as revealed by the beneficial effects of more WM time. In four experiments, we examined whether affording more time for intentional WM maintenance does indeed drive LTM. Sequences of four words were presented during trials of simple span (short time), slow span (long time), and complex span (long time with distraction; Experiments 1-2). Long time intervals entailed a pause of equivalent duration between the words that presented a blank screen (slow span) or an arithmetic problem to read aloud and solve (complex span). In Experiments 1-3, participants either serially recalled the words (intentional encoding) or completed a no-recall task (incidental encoding). In Experiment 4, all participants were instructed to intentionally encode the words, with the trials randomly ending in the serial-recall or no-recall task. To ensure similar processing of the words between encoding groups, participants silently decided whether each word was a living or nonliving thing via key press (i.e., an animacy judgment; Experiments 1 and 3-4) or read the words aloud and then pressed the space bar (Experiment 2). A surprise delayed memory test at the end of the experiment assessed LTM. Applying Bayesian cognitive models to disambiguate binding and item memory revealed consistent benefits of free time to binding memory that were specific to intentional encoding in WM. This suggests that time spent intentionally keeping information in WM is special for LTM because WM is a system that maintains bindings.

Validation of a rodent model of episodic memory replay.

Vivid episodic memories in humans have been described as the replay of the flow of past events in sequential order. Recently, Panoz-Brown et al. Current Biology, 28, 1628-1634, (2018) developed an olfactory memory task in which rats were presented with a list of trial-unique odors in an encoding context; next, in a distinctive memory assessment context, the rats were rewarded for choosing the second to last item from the list while avoiding other items from the list. In a different memory assessment context, the fourth to last item was rewarded. According to the episodic memory replay hypothesis, the rat remembers the list items and searches these items to find the item at the targeted locations in the list. However, events presented sequentially differ in memory trace strength, allowing a rat to use the relative familiarity of the memory traces, instead of episodic memory replay, to solve the task. Here, we directly manipulated memory trace strength by manipulating the odor intensity of target odors in both the list presentation and memory assessment. The rats relied on episodic memory replay to solve the memory assessment in conditions in which reliance on memory trace strength is ruled out. We conclude that rats are able to replay episodic memories.

The memory systems of the human brain and generative artificial intelligence.

Generative Artificial Intelligence foundation models (for example Generative Pre-trained Transformer - GPT - models) can generate the next token given a sequence of tokens. How can this 'generative AI' be compared with the 'real' intelligence of the human brain, when for example a human generates a whole memory in response to an incomplete retrieval cue, and then generates further prospective thoughts? Here these two types of generative intelligence, artificial in machines and real in the human brain are compared, and it is shown how when whole memories are generated by hippocampal recall in response to an incomplete retrieval cue, what the human brain computes, and how it computes it, are very different from generative AI. Key differences are the use of local associative learning rules in the hippocampal memory system, and of non-local backpropagation of error learning in AI. Indeed, it is argued that the whole operation of the human brain is performed computationally very differently to what is implemented in generative AI. Moreover, it is emphasized that the primate including human hippocampal system includes computations about spatial view and where objects and people are in scenes, whereas in rodents the emphasis is on place cells and path integration by movements between places. This comparison with generative memory and processing in the human brain has interesting implications for the further development of generative AI and for neuroscience research.

Are autistic traits associated with a social-emotional memory bias?

Autistic traits are associated with differential processing of emotional and social cues. By contrast little is known about the relationship of autistic traits to socio-emotional memory, though research suggests an integral relationship between episodic memory processes and psychosocial well-being. Using an experimental paradigm, we tested if autistic traits moderate the effects of negative emotion and social cues on episodic memory (i.e. memory for past events). Young adults (N = 706) with varied levels of self-reported autistic traits (24% in clinical range) encoded images stratified by emotion (negative, neutral) and social cues (social, non-social) alongside a neutral object. After 24 h, item memory for images and associative memory for objects was tested. For item memory, after controlling for anxiety, a small effect emerged whereby a memory-enhancing effect of social cues was reduced as autistic traits increased. For associative memory, memory for pairings between neutral, but not negative, images reduced as autistic traits increased. Results suggest autistic traits are associated with reduced ability to bind neutral items together in memory, potentially impeding nuanced appraisals of past experience. This bias toward more negative, less nuanced memories of past experience may represent a cognitive vulnerability to social and mental health challenges commonly associated with autistic traits and a potential intervention target.

Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer's continuum.

Introduction: The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum. Methods: We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aß42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis. Results: CSF Aß42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aß-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aß42/40 and meta-memory persisted. In the SCD subset, higher Aß-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance. Discussion: These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.