Perceptual integration and episodic memory in Alzheimer's disease

Binding (i.e., to link different components together) is a key mechanism for episodic memory formation. Normal aging is characterized by a decrease in episodic memory for associations. However, associative memory performance can be improved and age-related differences can even be suppressed when associations are unitized, that is when they are encoded as an integrated whole. A previous study in Alzheimer's disease (AD) showed that patients do not benefit from this particular type of encoding in episodic memory, so that their performance for unitized representations remains very poor. The aim of the current study was to assess whether the unitization mechanism itself (i.e., to integrate components into a whole) is impaired in AD or whether a global memory impairment affects all kinds of representations (unitized and non-unitized). We evaluated this hypothesis in fifteen mild Alzheimer patients and twenty healthy control participants. To systematically increase the demands on unitization, pictures of objects and animals were either left intact, separated into two fragments, or separated into four fragments. Participants viewed the pictures and had to unitize them first in order to recognize it and judge whether it would fit into a shoebox. In a subsequent recognition test where all pictures were intact, they had to retrieve pictures they saw earlier. An analysis of correct recognition of studied pictures showed a significant interaction between group and fragmentation level, indicating a decrease in Alzheimer patients’ performance compared to control participants for pictures that were fragmented at study but not for pictures that were intact at encoding. These findings suggest that the perceptual mechanism of unitization of fragmented stimuli is impaired in Alzheimer's disease

The influence of semantic prior knowledge on associative memory in healthy aging

peer reviewedLa création d’un souvenir épisodique requiert un encodage des différents éléments composant l’événement cible, ainsi que des associations entre ces éléments individuels afin de former un souvenir global et complexe. Cette capacité à lier les éléments entre eux diminue dans le vieillissement normal engendrant un déclin en mémoire épisodique qualifié « d’associatif ». Des études suggèrent que ce déclin peut être atténué lorsque les associations à mémoriser préexistent en mémoire sémantique. Cette revue a pour but de synthétiser les travaux ayant examiné l’influence des connaissances préexistantes en mémoire associative dans le vieillissement normal. À travers une analyse des procédures utilisées dans les études passées, nous suggérons que le paradigme expérimental employé est le principal facteur qui détermine si les participants âgés peuvent utiliser efficacement leurs connaissances préexistantes pour reconnaître des associations. Plus précisément, la manière dont les paires de stimuli sont recombinées entre l’encodage et la récupération semble avoir une forte influence sur les résultats obtenus. Par ailleurs, nous suggérons un rôle du type de relation sémantique impliquée dans la tâche. La nature de la relation sémantique influencerait en effet la mise en place des processus de reconnaissance épisodiques qui évoluent différemment avec l’avancée en âge.The formation of a global and complex episodic memory requires memory for single units of information of the target event but also binding these elements together. This binding capacity diminishes in healthy aging leading to a so-called associative memory deficit. Interestingly, when support is provided during encoding thanks to semantic prior-knowledge (e.g., semantically related word pairs), this associative deficit can be alleviated. The aim of the present review is to summarize the current literature about the influence of prior-knowledge on associative memory performance in healthy aging. Through an analysis of the procedures that have been used in associative memory studies, we suggest two factors that appear to modulate the impact of prior knowledge on older adults’ associative memory. First, the way word pairs are recombined from the encoding to the retrieval phase is the main factor that has to be taken into account. Conditions that promote recall-to-reject discrimination processes lead to similar performance in older compared to younger adults, whereas conditions that require recollection discrimination lead to an age-related decline. Second, the nature of the semantic relations involved in the prior-knowledge support may influence older adults’ performance by modulating the contribution of recollection and familiarity to recognition. Indeed, categorical semantic relations engage both recollection and familiarity-based discrimination, whereas thematic relations allow participants to rely on familiarity-based discrimination only. This latest observation is crucial when one considers recollection as a declining process, in contrast to familiarity, which remains spared in healthy aging. Therefore, future studies should explore the propensity of other semantic relations to alleviate the age-related associative memory decline

Misrecollection prevents older adults from benefitting from semantic relatedness of the memoranda in associative memory.

Memory for episodic associations declines in aging, ostensibly due to decreased recollection abilities. Accordingly, associative unitization - the encoding of associated items as one integrated entity - may potentially attenuate age-related associative deficits by enabling familiarity-based retrieval, which is relatively preserved in aging. To test this hypothesis, we induced bottom-up unitization by manipulating semantic relatedness between memoranda. Twenty-four young and 24 older adults studied pairs of object pictures that were either semantically related or unrelated. Participants subsequently discriminated between intact, recombined and new pairs. We found that semantic relatedness increased the contributions of both familiarity and recollection in young adults, but did not improve older adults' performance. Instead, they showed associative deficits, driven by increased recollection-based false recognition. This may reflect a "misrecollection" phenomenon, in which older adults make more false alarms to recombined pairs with particularly high confidence, due to poorer retrieval monitoring regarding semantically-related associative probes

Computational models can distinguish the contribution from different mechanisms to familiarity recognition

Familiarity is the strange feeling of knowing that something has already been seen in our past. Over the past decades, several attempts have been made to model familiarity using artificial neural networks. Recently, two learning algorithms successfully reproduced the functioning of the perirhinal cortex, a key structure involved during familiarity: Hebbian and anti-Hebbian learning. However, performance of these learning rules is very different from one to another thus raising the question of their complementarity. In this work, we designed two distinct computational models that combined Deep Learning and a Hebbian learning rule to reproduce familiarity on natural images, the Hebbian model and the anti-Hebbian model respectively. We compared the performance of both models during different simulations to highlight the inner functioning of both learning rules. We showed that the anti-Hebbian model fits human behavioral data whereas the Hebbian model fails to fit the data under large training set sizes. Besides, we observed that only our Hebbian model is highly sensitive to homogeneity between images. Taken together, we interpreted these results considering the distinction between absolute and relative familiarity. With our framework, we proposed a novel way to distinguish the contribution of these familiarity mechanisms to the overall feeling of familiarity. By viewing them as complementary, our two models allow us to make new testable predictions that could be of interest to shed light on the familiarity phenomenon

Typicality in the brain during semantic and episodic memory decisions

Typicality is a key semantic dimension supporting the categorical organization of items based on their features. Typical items share more features with other members of their category than atypical items, which are more distinctive. Typicality influences episodic recollection. Yet, the neural substrates of this effect have never been studied. This fMRI study investigated the neural correlates of typicality during semantic and episodic memory decisions . 26 subjects performed a categorization task on typical and atypical word concept and completed a recognition memory task. During the correct recognition of old items, regions from the core recollection network were activated, and typical items were reinstated more than atypical ones in several regions including the anterior temporal lobe. Results suggest that the centrality of this region in the processing of typicality extends to memory retrieval, and that the correct retrieval of typical items requires finer-grained, item-specific, processing, possibly to resolve their greater confusability with other category members.</p

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

Multiple neuropathological changes are involved in Alzheimer's disease (AD). AD hallmark biomarkers are amyloid-beta, tau pathology, and neuronal and synaptic loss. Other possible brain tissue-related biomarkers, such as iron and myelin content in the brain, are less frequently studied. Thanks to quantitative MRI (qMRI), tissue parameters such as magnetization transfer (MT), effective transverse relaxation (R2*), and proton density (PD) can be determined quantitatively, enabling the detection of microstructural tissue-related alterations in aging and neurodegenerative diseases. The current study investigated the co-occurrence of neurodegeneration (as measured with synaptic density), increased iron content, and decreased myelin content in Alzheimer's disease. The study involved 24 amyloid-positive patients (AD, 11 males) and 19 healthy controls (HC, 9 males). All participants underwent a multi-parameter mapping MRI protocol, from which quantitative maps for MTsat and R2* were estimated. Synaptic density was indexed by the total volume distribution map (Vt) derived from [18F] UCB-H PET imaging. First, groups were compared with univariate statistical analyses applied to R2*, MTsat, and Vt maps. Then multivariate General Linear Model (mGLM) was used to detect the co-occurrence of changes in R2*, MTsat, and Vt at the voxel level. Univariate GLM analysis of R2* showed no significant difference between the two groups. In contrast, the same analysis for MTsat resulted in a significant between-group difference in the right hippocampus at the cluster level with a corrected threshold (P-value < .05). The mGLM analysis revealed a significant difference in both right and left hippocampus between the AD and HC groups, as well as in the left precuneus, right middle frontal, and left superior orbitofrontal gyrus when all three modalities were present, suggesting these regions as the most affected despite the diverse changes of myelin, iron, and synapse degeneration in AD. Here, the mGLM is introduced as an alternative for multiple comparisons between different modalities, as it reduces the risk of false positives due to the multiplicity of the tests while informing about the co-occurrence of neuropathological processes in dementia.V

Multimodal imaging of microstructural cerebral changes and loss of synaptic density in Alzheimer’s disease

Background: Multiple neuropathological changes are involved in Alzheimer’s disease (AD) progression. The hallmark biomarkers are amyloid-beta, tau pathology, neuronal and synaptic loss. Other potential biomarkers, such as the level of iron and myelin content in the brain, have not been thoroughly studied. Nevertheless, these can be estimated in vivo thanks to tissue magnetic resonance (MR) properties measured through quantitative MR imaging (qMRI) techniques. Aim: We aimed to assess the co-occurrence of neurodegeneration (as measured with synaptic density), increased iron content and decreased myelin content in Alzheimer’s disease. Method: Data include 24 amyloid-positive Alzheimers patients (AD-11/13 males/females) and 19 healthy controls (HC-9/11 males/females). They underwent a multiparameter qMRI protocol used to generate quantitative maps sensitive to microstructural changes in myelin, iron deposits, and water content in grey matter (GM). Synaptic density was indexed by [18F]UCB-H-PET imaging using the distribution volume density (VT) maps. First, we applied univariate statistical analyses to investigate variation between AD and HC groups for each modality individually. Then, a multivariate GLM approach was used to compare the two groups pooling all modalities. Results/Conclusions: In GM univariate analyses, there was no significant difference between the AD and HC groups in any map at corrected statistical threshold. Conversely, the multivariate analysis on GM, combining MT, R2s, and synaptic density, provided significant group differences (FWEcorr P-value < 0.05) see figure 1. These variations are observed in the right amygdala (at voxel level) and in 5 distinct clusters covering the bilateral anterior hippocampal structures. These show that patients with AD present convergence of neuropathological changes in the hippocampal area, suggesting that different pathological mechanisms co-exist in areas known to harbor early-stage neuronal death

In vivo exploration of synaptic projections in frontotemporal dementia.

The purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer’s disease (AD). Loss of synaptic projections was assessed with ­[18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, ­[18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in ­[18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes

In vivo imaging of synaptic loss in Alzheimer’s disease with [18F]UCB-H Positron Emission Tomography

IUAP - Interuniversity Attraction Poles Programme (IUAP 7/11); ARC - Actions de recherche concertées (ARC 12/17-01); Special Research Funds classical grant 2016 (Faculty of Medicine, University of Liege, Belgium), FRS-FNR