Christine Bastin

18F-flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial.

The most widely studied positron emission tomography ligand for in vivo β‐amyloid imaging is 11C‐Pittsburgh compound B (11C‐PIB). Its availability, however, is limited by the need for an on‐site cyclotron. Validation of the 18F‐labeled PIB derivative 18F‐flutemetamol could significantly enhance access to this novel technology.

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage.

Three sets of research criteria are available for diagnosis of Alzheimers disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimers disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimers disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimers disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimers disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimers disease at the mild cognitive impairment stage and progression to Alzheimers disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimers disease. Their 3-year progression rate to Alzheimers disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimers disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimers disease. Their 3-year progression rate to Alzheimers disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimers disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimers disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimers disease likelihood group. The 3-year progression rate to Alzheimers disease-type dementia was 59% in the high Alzheimers disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimers disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimers disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimers disease likelihood group or the International Working Group-2 prodromal Alzheimers disease group could be considered.

Sleep Contributes to the Strengthening of Some Memories Over Others, Depending on Hippocampal Activity at Learning

Memory consolidation benefits from sleep. In addition to strengthening some memory traces, another crucial, albeit overlooked, function of memory is to erase irrelevant information. Directed forgetting is an experimental approach consisting in presenting “to be remembered” and “to be forgotten” information that allows selectively decreasing or increasing the strength of individual memory traces according to the instruction provided at learning. This paradigm was used in combination with functional MRI to determine, in humans, what specifically triggers at encoding sleep-dependent compared with time-dependent consolidation. Our data indicate that relevant items that subjects strived to memorize are consolidated during sleep to a greater extent than items that participants did not intend to learn. This process appears to depend on a differential activation of the hippocampus at encoding, which acts as a signal for the offline reprocessing of relevant memories during postlearning sleep episodes.

Short-term memory and the left intraparietal sulcus: Focus of attention? Further evidence from a face short-term memory paradigm

This study explored the validity of an attentional account for the involvement of the left intraparietal sulcus (IPS) in visual STM tasks. This account considers that during STM tasks, the IPS acts as an attentional modulator, maintaining activation in long-term memory networks that underlie the initial perception and processing of the specific information to be retained. In a recognition STM paradigm, we presented sequences of unfamiliar faces and instructed the participants to remember different types of information: either the identity of the faces or their order of presentation. We hypothesized that, if the left IPS acts as an attentional modulator, it should be active in both conditions, but connected to different neural networks specialized in serial order or face identity processing. Our results showed that the left IPS was activated during both order and identity encoding conditions, but for different reasons. During order encoding, the left IPS showed functional connectivity with order processing areas in the right IPS, bilateral premotor and cerebellar cortices, reproducing earlier results obtained in a verbal STM experiment. During identity encoding, the left IPS showed preferential functional connectivity with right temporal, inferior parietal and medial frontal areas involved in detailed face processing. These results not only support an attentional account of left IPS involvement in visual STM, but given their similarity with previous results obtained for a verbal STM task, they further highlight the importance of the left IPS as an attentional modulator in a variety of STM tasks.

The Effects of Aging on the Recognition of Different Types of Associations

ABSTRACT The present study examined how aging influences item and associative recognition memory, and compared memory for two types of associations: associations between the same kinds of information and associations between different kinds of information. A group of young adults and a group of older adults performed a forced-choice face recognition task and two multitrial forced-choice associative recognition tasks, assessing memory for face-face and face-spatial location associations. The results showed disproportionate age-related decline of associative recognition compared to intact item recognition. Moreover, aging affected both types of associative tasks in the same way. The findings support an associative deficit hypothesis (Naveh-Benjamin, Journal of Experimental Psychology: Learning, Memory and Cognition, 26, 1170–1187, 2000), which attributes a substantial part of the age effect on episodic memory tasks to difficulty with binding individual components into a cohesive memory trace. This associative deficit seems to affect same-information associations, as well as different-information associations.

Associative memory in aging: The effect of unitization on source memory

In normal aging, memory for associations declines more than memory for individual items. Unitization is an encoding process defined by creation of a new single entity to represent a new arbitrary association. The current study tested the hypothesis that age-related differences in associative memory can be reduced by encoding instructions that promote unitization. In two experiments, groups of 20 young and 20 older participants learned new associations between a word and a background color under two conditions. In the item detail condition, they had to imagine that the item is the same color as the background-an instruction promoting unitization of the associations. In the context detail condition, which did not promote unitization, they had to imagine that the item interacted with another colored object. At test, they had to retrieve the color that was associated with each word (source memory). In both experiments, the results showed an age-related decrement in source memory performance in the context detail but not in the item detail condition. Moreover, Experiment 2 examined receiver operating characteristics in older participants and indicated that familiarity contributed more to source memory performance in the item detail than in the context detail condition. These findings suggest that unitization of new associations can overcome the associative memory deficit observed in aging, at least for item-color associations.

Cognitive reserve impacts on inter-individual variability in resting-state cerebral metabolism in normal aging

There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elderly is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this exploratory multi-center study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention.

Relationships between brain metabolism decrease in normal aging and changes in structural and functional connectivity.

Normal aging is characterized by brain glucose metabolism decline predominantly in the prefrontal cortex. The goal of the present study was to assess whether this change was associated with age-related alteration of white matter (WM) structural integrity and/or functional connectivity. FDG-PET data from 40 young and 57 elderly healthy participants from two research centers (n=49/48 in Center 1/2) were analyzed. WM volume from T1-weighted MRI (Center 1), fractional anisotropy from diffusion-tensor imaging (Center 2), and resting-state fMRI data (Center 1) were also obtained. Group comparisons were performed within each imaging modality. Then, positive correlations were assessed, within the elderly, between metabolism in the most affected region and the other neuroimaging modalities. Metabolism decline in the elderly predominated in the left inferior frontal junction (LIFJ). LIFJ hypometabolism was significantly associated with macrostructural and microstructural WM disturbances in long association fronto-temporo-occipital fibers, while no relationship was found with functional connectivity. The findings offer new perspectives to understand normal aging processes and open avenues for future studies to explore causality between age-related metabolism and connectivity changes.

Metabolic and structural connectivity within the default mode network relates to working memory performance in young healthy adults.

Studies of functional connectivity suggest that the default mode network (DMN) might be relevant for cognitive functions. Here, we examined metabolic and structural connectivity between major DMN nodes, the posterior cingulate (PCC) and medial prefrontal cortex (MPFC), in relation to normal working memory (WM). DMN was captured using independent component analysis of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) data from 35 young healthy adults (27.1 ± 5.1 years). Metabolic connectivity, a correlation between FDG uptake in PCC and MPFC, was examined in groups of subjects with (relative to median) low (n=18) and high (n=17) performance on digit span backward test as an index of verbal WM. In addition, fiber tractography based on PCC and MPFC nodes as way points was performed in a subset of subjects. FDG uptake in the DMN nodes did not differ between high and low performers. However, significantly (p=0.01) lower metabolic connectivity was found in the group of low performers. Furthermore, as compared to high performers, low performers showed lower density of the left superior cingulate bundle. Verbal WM performance is related to metabolic and structural connectivity within the DMN in young healthy adults. Metabolic connectivity as quantified with FDG-PET might be a sensitive marker of the normal variability in some cognitive functions.

The neural substrates of memory suppression: a FMRI exploration of directed forgetting.

The directed forgetting paradigm is frequently used to determine the ability to voluntarily suppress information. However, little is known about brain areas associated with information to forget. The present study used functional magnetic resonance imaging to determine brain activity during the encoding and retrieval phases of an item-method directed forgetting recognition task with neutral verbal material in order to apprehend all processing stages that information to forget and to remember undergoes. We hypothesized that regions supporting few selective processes, namely recollection and familiarity memory processes, working memory, inhibitory and selection processes should be differentially activated during the processing of to-be-remembered and to-be-forgotten items. Successful encoding and retrieval of items to remember engaged the entorhinal cortex, the hippocampus, the anterior medial prefrontal cortex, the left inferior parietal cortex, the posterior cingulate cortex and the precuneus; this set of regions is well known to support deep and associative encoding and retrieval processes in episodic memory. For items to forget, encoding was associated with higher activation in the right middle frontal and posterior parietal cortex, regions known to intervene in attentional control. Items to forget but nevertheless correctly recognized at retrieval yielded activation in the dorsomedial thalamus, associated with familiarity-based memory processes and in the posterior intraparietal sulcus and the anterior cingulate cortex, involved in attentional processes.