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.

Perirhinal cortex is associated with fine-grained discrimination of conceptually confusable objects in Alzheimer's disease.

The perirhinal cortex (PrC) stands among the first brain areas to deteriorate in Alzheimer's disease (AD). This study tests to what extent the PrC is involved in representing and discriminating confusable objects based on the conjunction of their perceptual and conceptual features. To this aim, AD patients and control counterparts performed 3 tasks: a naming, a recognition memory, and a conceptual matching task, where we manipulated conceptual and perceptual confusability. A structural MRI of the antero-lateral parahippocampal subregions was obtained for each participant. We found that the sensitivity to conceptual confusability was associated with the left PrC volume in both AD patients and control participants for the recognition memory task, while it was specifically associated with the volume of the left PrC in AD patients for the conceptual matching task. This suggests that a decreased volume of the PrC is related to the ability to disambiguate conceptually confusable items. Therefore, testing recognition memory or conceptual matching of easily conceptually confusable items can provide a potential cognitive marker of PrC atrophy.

Associations Between Cognitive Complaints, Memory Performance, Mood, and Amyloid-ß Accumulation in Healthy Amyloid Negative Late-Midlife Individuals.

BACKGROUND: Cognitive complaints are gaining more attention as they may represent an early marker of increased risk for AD in individuals without objective decline at standard neuropsychological examination. OBJECTIVE: Our aim was to assess whether cognitive complaints in late middle-aged individuals not seeking medical help are related to objective cognitive outcomes known as early markers for AD risk, concomitant affective state, and amyloid-ß (Aß) burden. METHODS: Eighty-seven community-based cognitively normal individuals aged 50-69 years underwent neuropsychological assessment for global cognition, using Preclinical Alzheimer's Cognitive Composite 5 (PACC5) score, and a more specific episodic memory measure. Affective state was based on self-assessment questionnaires for depression and anxiety. Aß PET burden was assessed via [18F]Flutemetamol (N = 84) and [18F]Florbetapir (N = 3) uptake. Cognitive complaints were evaluated using Cognitive Difficulties Scale. RESULTS: Higher cognitive complaints were significantly associated with lower episodic memory performance and worse affective state. Moreover, higher level of cognitive complaints was related to higher (but still sub-clinical) global Aß accumulation (at uncorrected significance level). Importantly, all three aspects remained significant when taken together in the same statistical model, indicating that they explained distinct parts of variance. CONCLUSION: In healthy Aß negative late middle-aged individuals, a higher degree of cognitive complaints is associated with lower episodic memory efficiency, more anxiety and depression, as well as, potentially, with higher Aß burden, suggesting that complaints might signal subtle decline. Future studies should untangle how cognitive complaints in healthy aging populations are related to longitudinal changes in objective cognition and AD biomarker correlates.

Positive Effect of Cognitive Reserve on Episodic Memory, Executive and Attentional Functions Taking Into Account Amyloid-Beta, Tau, and Apolipoprotein E Status.

Studies exploring the simultaneous influence of several physiological and environmental factors on domain-specific cognition in late middle-age remain scarce. Therefore, our objective was to determine the respective contribution of modifiable risk/protective factors (cognitive reserve and allostatic load) on specific cognitive domains (episodic memory, executive functions, and attention), taking into account non-modifiable factors [sex, age, and genetic risk for Alzheimer's disease (AD)] and AD-related biomarker amount (amyloid-beta and tau/neuroinflammation) in a healthy late-middle-aged population. One hundred and one healthy participants (59.4 ± 5 years; 68 women) were evaluated for episodic memory, executive and attentional functioning via neuropsychological test battery. Cognitive reserve was determined by the National Adult Reading Test. The allostatic load consisted of measures of lipid metabolism and sympathetic nervous system functioning. The amyloid-beta level was assessed using positron emission tomography in all participants, whereas tau/neuroinflammation positron emission tomography scans and apolipoprotein E genotype were available for 58 participants. Higher cognitive reserve was the main correlate of better cognitive performance across all domains. Moreover, age was negatively associated with attentional functioning, whereas sex was a significant predictor for episodic memory, with women having better performance than men. Finally, our results did not show clear significant associations between performance over any cognitive domain and apolipoprotein E genotype and AD biomarkers. This suggests that domain-specific cognition in late healthy midlife is mainly determined by a combination of modifiable (cognitive reserve) and non-modifiable factors (sex and age) rather than by AD biomarkers and genetic risk for AD.

Aging and binding in short-term memory: processes involved in conjunctive and relational binding.

In visual short-term binding memory tasks, some studies suggested that aging disrupts relational binding more than conjunctive binding, whereas others report equivalent age-related differences in both types of binding. Yet, demands in controlled resources are potentially the greatest for relational short-term binding. In order to test the hypothesis that aging would affect preferentially tasks demanding in controlled processes, we assessed the contribution of controlled and automatic memory processes to relational and conjunctive short-term binding. Groups of young and older adults studied shape-colour (Exp.1 and 3) or object-colour (Exp.2) pairs in a relational condition in which items were linked to colour patches and a conjunctive condition where colour was integrated into the items. Memory for bindings was tested with a reconstruction task (Exp. 1 and 2) or with a recognition memory task (Exp. 3) under inclusion and exclusion instructions (Process Dissociation Procedure). The three experiments showed that the retrieval of both relational and conjunctive bindings relied primarily on controlled memory processes, the use of which was diminished in older participants. This study brings additional evidence that age-related differences in top-down control processes explain at least partly decreased short-term binding capacities.

Relationship between brain AD biomarkers and episodic memory performance in healthy aging.

The presence of brain biomarkers can be observed decades before the first clinical symptoms of Alzheimer's disease (AD). We aimed to determine whether associations between biomarkers and episodic memory performance already exist in a healthy late middle-aged population or only in participants over 60 years old. Performance at the Free and Cued Selective Reminding Test [FCSRT], the Logical Memory test and the Mnemonic Similarity Task [MST] was determined in sixty healthy participants (50-70 y.) with a negative status for amyloid-beta (Aß) biomarker. We assessed Aß cortical level and tau/neuroinflammation burden using PET scanner, and hippocampal atrophy with MRI scanner. Generalized linear mixed models showed that MST scores (recognition and pattern separation) were positively associated with hippocampal volume in participants over 60 years. No association between memory performance and Aß and tau/neuroinflammation burden was found in the older or in the younger age group. This suggests that visual recognition memory and discrimination of lures may constitute early cognitive markers of memory decline in an older population.

Early brainstem [18F]THK5351 uptake is linked to cortical hyperexcitability in healthy aging.

BACKGROUNDNeuronal hyperexcitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-ß (Aß) protein accumulation - both central to AD neuropathology - promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aß aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau - and its associated neuroinflammation - and cortical Aß aggregations remains unknown.METHODSWe probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late-middle-aged individuals (50-69 years; 45 women and 19 men). We assessed whole-brain [18F]THK5351 PET uptake as a proxy measure of tau/neuroinflammation, and we assessed whole-brain Aß burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers.RESULTSWe found that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment was associated with increased cortical excitability (r = 0.29, P = 0.02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (P value corrected for family-wise error [PFWE-corrected] < 0.001), was not significantly associated with cortical excitability (r = 0.14, P = 0.25). Importantly, no significant association was found between early Aß cortical deposits and cortical excitability (r = -0.20, P = 0.11).CONCLUSIONThese findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGF.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.

Familiarity for entities as a sensitive marker of antero-lateral entorhinal atrophy in amnestic mild cognitive impairment.

Alzheimer's disease (AD) symptomatology typically starts with memory deficits. Neurofibrillary tangles - one of the neuropathological hallmarks of AD - first affect the transentorhinal cortex (i.e., Brodmann's area 35 - BA35 and antero-lateral entorhinal cortex), a subregion of the antero-lateral parahippocampal region (also comprising BA36) currently hypothesized to serve as a functional hub representing entities. Here, we tested this hypothesis by investigating whether atrophy of antero-lateral parahippocampal subregions affects memory for entities. Patients with amnestic mild cognitive impairment (aMCI; known to be at high-risk of AD and to present with variable antero-lateral parahippocampal atrophy; N = 17) and healthy older control participants (N = 17) underwent a high-resolution MRI scan of the antero-lateral parahippocampal subregions and a visual object familiarity task, critically including three conditions with increasing need for entity-level representation: (1) letting all fluency cues contribute to familiarity, (2) precluding conceptual fluency, and (3) also precluding perceptual fluency, thereby directly tapping familiarity for entities. In aMCI, right antero-lateral entorhinal cortex specifically contributed to familiarity for entities, an association that was stronger than with familiarity in the 'discriminative' condition (2) (also precluding conceptual fluency, but tested in a viewpoint-dependent fashion as traditionally). In contrast, right BA36 specifically contributed to familiarity in the discriminative condition, an association that appeared marginally stronger than with familiarity for entities. These results shed new light on the functional hierarchy that may exist within the antero-lateral parahippocampal hub. Importantly, familiarity requiring an entity-level representation may specifically target transentorhinal integrity, opening a promising avenue to develop the still-lacking clinical marker of AD-related initial decline.

Interactions with the integrative memory model.

The integrative memory model formalizes a new conceptualization of memory in which interactions between representations and cognitive operations within large-scale cerebral networks generate subjective memory feelings. Such interactions allow to explain the complexity of memory expressions, such as the existence of multiples sources for familiarity and recollection feelings and the fact that expectations determine how one recognizes previously encountered information.

Preserved wake-dependent cortical excitability dynamics predict cognitive fitness beyond age-related brain alterations.

Age-related cognitive decline arises from alterations in brain structure as well as in sleep-wake regulation. Here, we investigated whether preserved wake-dependent regulation of cortical function could represent a positive factor for cognitive fitness in aging. We quantified cortical excitability dynamics during prolonged wakefulness as a sensitive marker of age-related alteration in sleep-wake regulation in 60 healthy older individuals (50-69 y; 42 women). Brain structural integrity was assessed with amyloid-beta- and tau-PET, and with MRI. Participants' cognition was investigated using an extensive neuropsychological task battery. We show that individuals with preserved wake-dependent cortical excitability dynamics exhibit better cognitive performance, particularly in the executive domain which is essential to successful cognitive aging. Critically, this association remained significant after accounting for brain structural integrity measures. Preserved dynamics of basic brain function during wakefulness could therefore be essential to cognitive fitness in aging, independently from age-related brain structural modifications that can ultimately lead to dementia.

Cognitive efficiency in late midlife is linked to lifestyle characteristics and allostatic load.

We investigated whether cognitive fitness in late midlife is associated with physiological and psychological factors linked to increased risk of age-related cognitive decline. Eighty-one healthy late middle-aged participants (mean age: 59.4 y; range: 50-69 y) were included. Cognitive fitness consisted of a composite score known to be sensitive to early subtle cognitive change. Lifestyle factors (referenced below as cognitive reserve factors; CRF) and affective state were determined through questionnaires, and sleep-wake quality was also assessed through actimetry. Allostatic load (AL) was determined through a large range of objective health measures. Generalized linear mixed models, controlling for sex and age, revealed that higher cognitive reserve and lower allostatic load are related to better cognitive efficiency. Crystallized intelligence, sympathetic nervous system functioning and lipid metabolism were the only sub-fields of CRF and AL to be significantly associated with cognition. These results show that previous lifestyle characteristics and current physiological status are simultaneously explaining variability in cognitive abilities in late midlife. Results further encourage early multimodal prevention programs acting on both of these modifiable factors to preserve cognition during the aging process.

An integrative memory model of recollection and familiarity to understand memory deficits.

Humans can recollect past events in details (recollection) and/or know that an object, person, or place has been encountered before (familiarity). During the last two decades, there has been intense debate about how recollection and familiarity are organized in the brain. Here, we propose an integrative memory model which describes the distributed and interactive neurocognitive architecture of representations and operations underlying recollection and familiarity. In this architecture, the subjective experience of recollection and familiarity arises from the interaction between core systems (storing particular kinds of representations shaped by specific computational mechanisms) and an attribution system. By integrating principles from current theoretical views about memory functioning, we provide a testable framework to refine the prediction of deficient versus preserved mechanisms in memory-impaired populations. The case of Alzheimer's disease (AD) is considered as an example because it entails progressive lesions starting with limited damage to core systems before invading step-by-step most parts of the model-related network. We suggest a chronological scheme of cognitive impairments along the course of AD, where the inaugurating deficit would relate early neurodegeneration of the perirhinal/anterolateral entorhinal cortex to impaired familiarity for items that need to be discriminated as viewpoint-invariant conjunctive entities. The integrative memory model can guide future neuropsychological and neuroimaging studies aiming to understand how such a network allows humans to remember past events, to project into the future, and possibly also to share experiences.

Superior explicit memory despite severe developmental amnesia: In-depth case study and neural correlates.

The acquisition of new semantic memories is sometimes preserved in patients with hippocampal amnesia. Robust evidence for this comes from case reports of developmental amnesia suggesting that low-to-normal levels of semantic knowledge can be achieved despite compromised episodic learning. However, it is unclear whether this relative preservation of semantic memory results from normal acquisition and retrieval or from residual episodic memory, combined with effortful repetition. Furthermore, lesion studies have mainly focused on the hippocampus itself, and have seldom reported the state of structures in the extended hippocampal system. Preserved components of this system may therefore mediate residual episodic abilities, contributing to the apparent semantic preservation. We report an in-depth study of Patient KA, a 27-year-old man who had severe hypoxia at birth, in which we carefully explored his residual episodic learning abilities. We used novel speeded recognition paradigms to assess whether KA could explicitly acquire and retrieve new context-free memories. Despite a pattern of very severe amnesia, with a 44-point discrepancy between his intelligence and memory quotients, KA exhibited normal-to-superior levels of knowledge, even under strict time constraints. He also exhibited normal-to-superior recognition memory for new material, again under strict time constraints. Multimodal neuroimaging revealed an unusual pattern of selective atrophy within each component of the extended hippocampal system, contrasting with the preservation of anterior subhippocampal cortices. A cortical thickness analysis yielded a pattern of thinner but also thicker regional cortices, pointing toward specific temporal lobe reorganization following early injury. We thus report the first case of superior explicit learning and memory in a severe case of amnesia, raising important questions about how such knowledge can be acquired.

Fast, but not slow, familiarity is preserved in patients with amnestic mild cognitive impairment.

Recognition memory--affected early in the course of Alzheimer Disease (AD)--is supposed to rely on two processes: recollection (i.e., retrieval of details from the encoding episode) and familiarity (i.e., acontextual sense of prior exposure). Recollection has repeatedly been shown to be impaired in patients with amnestic Mild Cognitive Impairment (aMCI)--known to be at high risk for AD. However, studies that evaluated familiarity in these patients have reported conflicting results. Here, we assessed familiarity in single-domain aMCI patients (n = 19) and healthy matched controls (n = 22). All participants underwent a classic yes/no recognition memory paradigm with confidence judgements, allowing an estimation of familiarity and recollection similar to the approach used in previous studies. In addition, they underwent a novel speeded recognition memory task, the Speed and Accuracy Boosting procedure, based on the idea that familiarity is fast and hence that fast answers rely on familiarity. On the classic yes/no task, aMCI patients were found to have impaired performance, reaction times, recollection and familiarity. However, performance and reaction times of aMCI patients did not differ from that of controls in the speeded task. This is noteworthy since this task was comparatively difficult for control subjects. This dissociation within familiarity suggests that a very basic component of declarative memory, probably at the interface between implicit and explicit memory, may be preserved, or possibly released, in patients with aMCI. It is suggested that early subprocesses (e.g., fluency based familiarity) could be preserved in aMCI patients, while delayed ones (e.g., conceptual fluency, post-retrieval monitoring, confidence assessment, or even access to awareness) may be impaired. These findings may provide support for recent suggestions that familiarity may result from the combination of a set of subprocesses, each with its specific temporal signature.

Fast and Famous: Looking for the Fastest Speed at Which a Face Can be Recognized.

Face recognition is supposed to be fast. However, the actual speed at which faces can be recognized remains unknown. To address this issue, we report two experiments run with speed constraints. In both experiments, famous faces had to be recognized among unknown ones using a large set of stimuli to prevent pre-activation of features which would speed up recognition. In the first experiment (31 participants), recognition of famous faces was investigated using a rapid go/no-go task. In the second experiment, 101 participants performed a highly time constrained recognition task using the Speed and Accuracy Boosting procedure. Results indicate that the fastest speed at which a face can be recognized is around 360-390 ms. Such latencies are about 100 ms longer than the latencies recorded in similar tasks in which subjects have to detect faces among other stimuli. We discuss which model of activation of the visual ventral stream could account for such latencies. These latencies are not consistent with a purely feed-forward pass of activity throughout the visual ventral stream. An alternative is that face recognition relies on the core network underlying face processing identified in fMRI studies (OFA, FFA, and pSTS) and reentrant loops to refine face representation. However, the model of activation favored is that of an activation of the whole visual ventral stream up to anterior areas, such as the perirhinal cortex, combined with parallel and feed-back processes. Further studies are needed to assess which of these three models of activation can best account for face recognition.